Prebiehajúce klinické skúšania na Slovensku

Inclusion Criteria:

newly diagnosed acute lymphoblastic leukemia or
newly diagnosed mixed phenotype acute leukemia (MPAL) meeting one of the following criteria:
biphenotypic with a dominant T or B lineage assignment
bilineal either with a dominant lymphoblastic population or if another reasonable rationale exists to treat the patient with an ALL-based therapy regimen
newly diagnosed acute undifferentiated leukemia
age < 18 years (up to 17 years and 365 days) at the day of diagnosis
patient enrolled in a participating center
written informed consent to trial participation and transfer and processing of data A subsequent removal from the study is only allowed if the inclusion criteria turn out not to be fulfilled or in the case of pregnancy of the patient.
Exclusion Criteria:

Ph+ (BCR-ABL1 or t(9;22)-positive) ALL
bilineal leukemia with a lymphoblastic and a separate non-lymphoblastic (≥ 10% of total cells) blast subset
pre-treatment with cytostatic drugs
glucocorticoid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis
treatment started according to another protocol
underlying disease that does not allow treatment according to the protocol (e.g. severe congenital heart disease, Charcot-Marie Syndrome, Ataxia-teleangiectasia…)
ALL diagnosed as second malignancy and preceding chemotherapy and/or radiotherapy
evidence of pregnancy or lactation period
Sexually active adolescents not willing to use highly effective contraceptive method (pearl index <1) until 12 months after end of anti-leukemic therapy
participation in another clinical trial except for add-on trials within the scope of supportive care approved by the sponsor
live vaccine immunization within 2 weeks before start of protocol treatment

Principal inclusion criteria
• Oropharyngeal squamous cell carcinoma
• Positivity of p16 by imunohistochemistry
• Clinical stage T1-T2, N1-N2c or T3, N2-N2c, UICC 8th edition without distant metastases
• The lifetime cumulative history of smoking cannot exceed 20 packages / years
• WHO status 0-1
• Age ≥ 18 years
• Both genders
• Hemoglobin ≥ 10 g/l
• Platelets ≥1 00x 10x9/l
• Neutrophils ≥ 1,5 x 10x9/l
• Adequate renal functions enable one-week therapy of cisplatina
• Bilirubin, AST or ALT 3x upper limit of norm
• Negative pregnancy test
• Signed informed consent
• Slovak language
• Diagnóza skvamocelulárneho karcinómu (SCC) orofaryngu
• Pozitivita odobratého tkaniva p16 imunohistochemickým vyšetrením
• Klinické štádium T1-T2, N1-N2c alebo T3, N2-N2c, UICC 8. vydanie bez vzdialených metastáz
• Celková celoživotná história fajčenia nesmie prekročiť 20 balení / rokov
• WHO výkonnostný stav 0-1
• Vek ≥ 18 rokov
• Obe pohlavia
• Hemoglobín ≥ 10 g/l
• Trombocyty ≥1 00x 10x9/l
• Neutrofily ≥ 1,5 x 10x9/l
• Adekvátne renálne funkcie umožňujúce podanie týždennej cisplatiny
• Bilirubín, AST alebo ALT ˂ 3x vyšší limit normy
• Negatívny test tehotenstva u fertilných žien
• Podpísaný informovaný súhlas

Principal exclusion criteria
• Tumor in the oral cavity or in nasopharynx or in the hypopharynx or larynx if the p16 is also positive
• Tumor of unknown origin (p16 positivity too)
• Simultaneous tumors
• Patients with invasive malignancy (except non-melanoma skin cancer) and a history of tumor diagnosis less than 3 years
• Previous radiotherapy in the head and neck area to overlap the irradiated volume
• Unstable angina or congestive heart failure requiring hospitalization for the last 6 months
• Transmural myocardial infarction last 6 months
• Active infection requiring i.v. antibiotics at the time of registration
• Chronic obstructive bronchoplumonal disease with exacerbation or other respiratory disease requiring hospitalization or postponement of study treatment within 30 days of enrollment
• Hepatic insufficiency with clinical jaundice and impaired coagulation
• Active AIDS disease, but the protocol does not require HIV testing
• Pregnancy
• Previous allergic reaction to cisplatin
• Nádor nachádzajúci sa v ústnej dutine alebo v nosohltane alebo v hypofaryngu alebo laryngu ak je aj p16 pozitívny
• Karcinóm neznámeho pôvodu na krku (aj ak je p16 pozitívny)
• Simultánne nádory
• Pacienti s invazívnou malignitou (okrem nemelanómového karcinómu kože) a anamnézou diagnózy nádoru kratšou ako 3 roky
• Predchádzajúca rádioterapia v oblasti hlavy a krku, ktorá by znamenala prekrývanie ožarovaného objemu
• Nestabilná angína alebo kongestívne zlyhanie srdca vyžadujúce si hospitalizáciu posledných 6 mesiacov
• Transmurálny infarkt myokardu posledných 6 mesiacov
• Aktívna infekcia vyžadujúca si i.v. antibiotiká v čase registrácie
• Chronická obštrukčná bronchoplumonálna choroba s exacerbáciou alebo iné respiračné ochorenie vyžadujúce si hospitalizáciu alebo odloženie štúdiovej liečby v rámci 30 dní pri registrácii
• Hepatálna insufiencia s klinickou žltačkou a porušenou koaguláciou
• Aktívne ochorenie AIDS, avšak protokol si HIV testovanie nevyžaduje
• Tehotenstvo
• Predchádzajúca alergická reakcia na cisplatinu

Inclusion Criteria:

Previously untreated, histologically proven classical Hodgkin lymphoma;
Staged by PET with diagnostic-quality CT (i.v. contrast).
Clinical stages according to Lugano 2014 and based on FDG/PET CT:
Stage IIB with large mediastinal mass > 1/3 max transverse diameter thorax and/or extranodal lesion(s)
Stage III - IV
Consent to participation in translational research:
Archival tumor tissue available (15 blank formalin fixed paraffin embedded tissue samples mounted on APES slides or a tissue block).
Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 72 hours prior to the first dose of study treatment.
Patients of childbearing / reproductive potential should use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last dose of treatment. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1 percent per year) when used consistently and correctly.
Female subjects who are breast feeding should discontinue nursing prior to the first dose of study treatment and until 6 months after the last study treatment.
Absence of any medical, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:
Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of Progressive Multifocal Leukoencenphalopathy
Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
Sensory or motor peripheral neuropathy greater than or equal to grade 2 according to CTCAE version 4.0
Any of the following cardiovascular conditions or values:
within 6 months before registration:
A left-ventricular ejection fraction <50 percent (at registration)
New York Heart Association (NYHA) Class III or IV heart failure.
Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
symptomatic coronary heart disease (stable angina pectoris is allowed)
severe uncontrolled hypertension within 2 years before registration
Myocardial infarction
Patients with poorly controlled diabetes mellitus (HbA1c > 7.5 percent or a fasting blood sugar > 200 mg/dL).
Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 2 weeks prior to registration.
Known HIV infection, chronic active hepatitis C, HBV positivity (HBsAg + patients; HBsAg -/HBcAb+/HBV DNA+ patients).
Note: HBsAg-/HBV DNA - patients are eligible; patients who are seropositive due to vaccination are eligible
Concomitant or previous malignancies within the past 5 years with the exception of adequately treated carcinoma in situ of the cervix , nonmelanoma skin cancer.
Previous treatment with anti CD30 antibodies
Known hypersensitivity to any excipient contained in Brentuximab Vedotin formulation and other study drugs. Refer to Summary Product Characteristics for list of excipients.
Concurrent anti-cancer treatment or use of any investigational agent(s)

Inclusion criteria:

newly diagnosed lymphoblastic lymphoma
age <18 years
patient enrolled in a participating center
written informed consent of patient (>14 years of age or according to local law and regulation) and parents to trial participation and transfer and processing of data
willingness of patients and the investigator/pathologist to provide adequate slides/blocks for reference (molecular) pathology and international pathology panel and/or fresh or fresh frozen samples for genetic risk group stratification if these samples are available after standard diagnostic procedures.

Exclusion criteria:
lymphoblastic lymphoma as secondary malignancy
non-lymphoma related relevant medical, psychiatric or social conditions incompatible with trial treatment, including among others
prior organ transplant
severe immunodeficiency
demyelinating Charcot-Marie Tooth syndrome
serious acute or chronic infections, such as HIV, VZV and tuberculosis
urinary tract infection, cystitis, urinary outflow obstruction, severe renal impairment (creatinine clearance less than 20 ml/min)
severe hepatic impairment (bilirubin >3 times ULN, transaminases >10 times ULN)
myocardial insufficiency, severe arrhythmias
ulcers of the oral cavity and known active gastrointestinal ulcer disease
known hypersensitivity to any IMP and to any excipient (listed in section 6.1 of the respective SmPC)
steroid pre-treatment with ≥ 1 mg/kg/d for more than two weeks during the last month before diagnosis
vaccination with live vaccines within 2 weeks before start of protocol treatment
treatment started according to another protocol or pre-treatment with cytostatic drugs
participation in another clinical trial that interferes with the protocol, except NHL-BFM Registry 2012 and trials with different endpoints, involving aspects of supportive treatment, which can run parallel to LBL 2018 without influencing the outcome of this trial (e.g. trials on antiemetics, antibiotics, strategies for psychosocial support)
evidence of pregnancy or lactation period
sexually active adolescents not willing to use highly effective contraceptive method (pearl index < 1) until 12 months after end of cytostatic therapy

Inclusion Criteria:
Eligible for continuing atezolizumab-based therapy at the time of roll-over from the parent study, as per the parent study protocol or
Eligible for continuing the comparator agent(s) in a Genentech- or Roche-sponsored study as per the parent study protocol, with no access to commercially available comparator agent
Time between the last dose of treatment received in parent study and first dose in extension study is no longer than the interruption period allowed in the parent study. First dose of study treatment in this extension study will be received within 7 days of the treatment interruption window allowed by the parent study
Continue to benefit from atezolizumab-based study treatment or from the comparator at the time of roll-over from the parent study as assessed by the investigator
Negative serum pregnancy test within 7 days prior to start of study treatment in women of childbearing potential
For women of childbearing potential: agreement to remain abstinent or use contraceptive methods, and agreement to refrain from donating eggs
For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Exclusion Criteria:
Meet any of the study treatment discontinuation criteria specified in the parent study at the time of enrollment in this extension study
Study treatment or comparator agent is commercially marketed in the patient's country for the patient-specific disease and is accessible to the patient
Treatment with any anti-cancer treatment during the time between last treatment in the parent study and the first dose of study treatment in this extension study
Permanent discontinuation of atezolizumab for any reason during the parent study or during the time between last treatment in the parent study and the first dose of study treatment in this extension study (if applicable)
Ongoing serious adverse event(s) that has not resolved to baseline level or Grade ≤1 from the parent study or during the time between the last treatment in the parent study and the first dose of study treatment in this extension study
Any condition that, in the opinion of the investigator, would interfere with the interpretation of patient safety or place the patient at high risk for treatment-related complications
Concurrent participation in any therapeutic clinical trial (other than the parent study)
Pregnant or lactating, or intending to become pregnant during this extension study and for the period after the last dose of study treatment specified in the designated referenced safety information (RSI)

Principal inclusion criteria
1. Age of 18 years or more
2. Not currently participating in another study
3. Able and willing to sign informed consent and to comply with study procedures
4. Biopsy-proven locally advanced resectable oesophago-gastric adenocarcinoma (Siewert I – III) with T3N0, T4N0, T2 – T4N+, stage Ib – IIIc I. Adenocarcinoma of distal part of the oesophagus II. Adenocarcinoma of the real cardia III. Adenocarcinoma of the subcardial stomach
5. Staging procedures include endoscopy, endoscopic ultrasound and FDG-PET
6. Eligible patients have to be fit for platinum-containing chemotherapy
7. Tumours must be potentially R0 resectable tumours during consecutive operation.
1. Vek 18 a viac rokov
2. Pacient sa v súčasnej dobe nezúčastňuje inej štúdie
3. Pacient je schopný a ochotný podpísať informovaný súhlas a plniť štúdijné postupy
4. Biopticky potvrdený lokálne pokročilý operabilný adenokarcinóm oesophago-gastrického spojenia T3N0, T4N0, T2-T4N+, typ I - III podľa Siewerta: I. Adenokarcinóm distálnej časti pažeráka
II. Adenokarcinóm kardie
III. Adenokarcinóm subkardiálneho žalúdka
5. Prevedený staging zahrňujúci endoskopiu, endoskopický ultrazvuk a PET/CT
6. Pacient musí byť vhodný pre chemoterapiu obsahujúcu platinu
7. Nádor musí byť potenciálne R0 operabilný pri nadväzujúcej operácii

Principal exclusion criteria
1. Participation in another clinical trial of a therapeutic drug during the past 14 days
2. Addiction to alcohol or drugs
3. Women of child-bearing potential who are not using a commonly accepted effective means of contraception; women of child-bearing potential will have negative blood pregnancy test before enrollment
4. Pregnant women and nursing mothers are not allowed to enroll on this study
5. Eastern Cooperative Oncology Group score >2
6. Previous or secondary malignancy in past 5 years (Excluding skin cancer and early cervical carcinoma)
7. Life expectancy of less than 3 months
8. Uncontrolled bleeding from the tumour
9. Uncontrolled diabetes
10. Patients are also ineligible if they have undergone previous chemotherapy, radiotherapy, or endoscopic laser therapy for EGJ
1. Účasť v liekovom klinickom skúšaní behom posledných 14 dní
2. Závislosť na alkohole alebo drogách
3. Ženy v plodnom veku, ktoré nepoužívajú efektívne antikoncepčné prostriedky (pred zaradením do štúdie musí byť u žien v plodnom veku doložený negatívny tehotenský test z krvi)
4. Tehotné ženy a dojčiace matky
5. Eastern Cooperative Oncology Group skóre > 2
6. Predchádzajúce alebo sekundárne malígne ochorenie v posledných 5 rokoch (okrem kožného karcinómu a včasného karcinómu cervixu)
7. Očakávané prežitie kratšie ako 3 mesiace
8. Nekontrolované krvácanie z nádora
9. Neliečený diabetes
10. Pacienti nemôžu byť do štúdie zaradení, pokiaľ podstúpili predchádzajúcu chemoterapiu, rádioterapiu alebo endoskopickú laserovú terapiu EGJ

Inclusion Criteria:

Aged ≥ 18 years
ECOG performance status of 0-1
Histologically-confirmed metastatic or recurrent non-squamous non-small cell lung cancer
At least one measurable lesion according to RECIST v1.1.
Able to receive bevacizumab, carboplatin and paclitaxel based on adequate laboratory and clinical parameters
Exclusion Criteria:

Diagnosis of small cell carcinoma of the lung or squamous cell carcinoma
Sensitizing EGFR mutations or ALK rearrangements
Increased risk of bleeding determined by investigator based on radiographic / clinical findings
History of systemic chemotherapy administered in the first-line setting for metastatic or recurrent disease of NSCLC.

Principal inclusion criteria
In order to be eligible to participate in this study, all individual must meet all of the following criteria:
1. Male or female over 18 years of age with histologicaly confirmed metastatic cancer of the colon or rectum fulfilling the following criteria :
a) Scheduled for treatment including antiangiogenic agent
b) At least one measurable lesions according to RECIST 1.1 criteria (>10mm in long axis for non-lymph node lesions and >15mm in short axis for lymph node lesions).
c) Availability of following examination data in DICOM III format performed less than 31 days prior inclusion:
- Diagnostic CT of thorax, abdomen and pelvis
- Fludeoxyglucose (18F) PET/CT
2. Capable of staying still in lying position for the duration of the PET/CT acquisition which can last up to 30 min in all, a "whole body" acquisition
3. ECOG performance status ≤ 2 at inclusion
4. Patient with a life expectancy ≥ 24 weeks from baseline
5. For women of childbearing age, the possibility of pregnancy should be ruled out at inclusion
6. Volunteer and able to follow the instructions necessary for the study
7. Having signed an informed consent to participate in the study
Na zaradenie do tejto štúdie musí každý jednotlivec spĺňať všetky nasledovné kritériá:
1. Muž alebo žena staršia ako 18 rokov s histologicky potvrdeným pokročilým metastatickým karcinómom hrubého čreva alebo konečníka spĺňajúcim nasledovné kritériá:
a) Plánovaná na liečba zahŕňajúca inhibítor angiogenézy
b) Aspoň jedna merateľná lézia podľa kritérií RECIST 1.1 (> 10 mm v dlhej osi pre lézie mimo lymfatických uzlín a> 15 mm v krátkej osi pre uzlinové lézie).
c) Dostupnosť nasledujúcich údajov o vyšetrení vo formáte DICOM III vykonaných menej ako 31 dní pred zaradením:
- CT hrudníka, brucha a panvy
- PET/CT s fludeoxyglukózou (18F)
2. Pacient schopný zostať v ležiacej polohe počas snímania obrazov PET/CT, čo môže trvať do 30 minút pre celotelové snímanie
3. Stav výkonnosti ECOG ≤ 2 pri zaradení do štúdie
4. Pacient s očakávanou dĺžkou života ≥ 24 týždňov od zaradenia do štúdie
5. U žien vo fertilnom veku sa má pri začlenení vylúčiť možnosť tehotenstva
6. Pacient ochotný a schopný dodržať pokyny potrebné pre realizáciu štúdie
7. Podpis informovaného súhlasu s účasťou na štúdii

Principal exclusion criteria
An individual who meets any of the following criteria will be excluded from participation in this study:
- Pregnancy or lactation
- Known allergy to components of the study product
- Treatment scheduled does not include antiangiogenic agent
- Life expectancy less than 6 months
- ECOG Performance Status >2 or Karnofsky Performance Status <50%
Jednotlivec spĺňajúci niektoré z nasledujúcich kritérií bude vylúčený z účasti na tejto štúdii:
- Tehotenstvo alebo laktácia
- Známa alergia na niektorú zo zložiek skúmaného produktu
- Plánovaná liečba nezahŕňa liek s antiangiogénnym účinkom
- Očakávaná dĺžka života je kratšia ako 6 mesiacov
- Stav výkonnosti ECOG> 2 alebo stav výkonnosti Karnofsky <50%

Inclusion Criteria:
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Participants enrolled in any Bayer-sponsored darolutamide feeder study at the time of study closure or primary completion, who are currently receiving darolutamide and are experiencing clinical benefit from treatment.
Participants who have not met any treatment discontinuation criteria in the feeder study protocol.
Willingness to continue practicing acceptable methods of birth control during the study.

Exclusion Criteria:
Participant is unable to comply with the requirements of the study.
Negative benefit/ risk ratio as determined by the investigator.
Meet any criteria for treatment discontinuation of the feeder study the participant is coming from.

Inclusion Criteria:
Histologically proven primary high risk leiomyosarcoma (LMS) or Liposarcoma (LPS) of retroperitoneal space or infra-peritoneal spaces of pelvis.
LMS:
Any grade LMS can be included
Minimum size of LMS tumor should be 5 cm
LPS:
Diagnosis should be confirmed based on MDM2 (Mouse double minute 2 homolog) and CDK4 (Cyclin-dependent kinase 4) expression on IHC (immunohistochemistry), while proof of MDM2 amplification is highly recommended.
All grade 3 DDLPS can be included.
DDLPS with confirmed grade 2 on biopsy can be included when:
The grade 2 DDLPS has an FNCLCC score=5 (Fédération Nationale des Centres de Lutte Contre Le Cancer), has no necrosis on the biopsy but clear necrosis on imaging.
The tumors carry a high risk gene profile as determined by the Complexity INdex in SARComas (CINSARC-high)
Representative formalin fixed, paraffin embedded tumor blocks or unstained tissue slides must be available at baseline for histological central review.
Unifocal tumor
Absence of extension through the sciatic notch or across the diaphragm
Resectable tumor: resectability is based on pre-operative imaging (CT-abdomen, potentially also with MRI) and has to be defined by the local treating sarcoma team. A patients is not considered resectable when the expectation is that only an R2 resection is feasible.

Criteria for non-resectability are:
Involvement of the superior mesenteric artery, aorta, coeliac trunk and/or portal vein
Involvement of bone
Growth into the spinal canal
Progression of retro-hepatic inferior vena cava leiomyosarcoma towards the right atrium
Infiltration of multiple major organs like liver, pancreas and/or major vessels
Tumor not previously treated (no previous surgery (excluding diagnostic biopsy), radiotherapy or systemic therapy)
Patient must have radiologically measurable disease (RECIST 1.1), as confirmed by imaging within the 28 days prior to randomization. CT thorax abdomen pelvis with IV contrast is the preferred imaging modality. In case of any contra-indications (medical or regulatory), it is allowed to perform a non-contrast CT thorax + MRI abdomen & pelvis.
≥ 18 years old (no upper age limit)
WHO (World Health Organization) performance status ≤ 2
Adequate haematological and organ function:
Haematological: haemoglobin > 9.0 g/dL or 5.6 mmol/L, absolute neutrophils > 1.5 x 109/L, platelets > 100 x 109/L Note: Platelet transfusions is allowed to achieve these baseline values
Renal: estimated glomerular filtration rate (eGFR) > 50 ml/min/m2; No proteinuria CTCAE ≥ grade 2;
Hepatic: Bilirubin ≤ 1.0 times upper limit of normal (1.0xULN) of institutional limits, ALT (alanine aminotransferase) and/or AST (aspartate transaminase) ≤1.5 x ULN. If isolated elevated bilirubin <2 x ULN and Gilberts syndrome suspected, suggest repeating bloods after food. If bilirubin improves to meet the criteria above this is acceptable. More severe persistent hepatic impairment of whatever cause would exclude the patient from treatment till resolved.
Heart: Clinically normal cardiac function based on left ventricular ejection fraction (LVEF ≥ 50%) as assessed either by multi-gated acquisition scan (MUGA) or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities.
American Society of Anesthesiologist (ASA) score < 3
Women of child bearing potential (WOCBP) must have a negative serum pregnancy test within 7 days prior to the first dose of study treatment or surgery.
Note: a woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post menopausal unless permanently sterile.
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient..
Patients of childbearing / reproductive potential should use highly effective birth control measures, as defined by the investigator, during the study treatment period and for at least 6 months after the last dose of treatment or date of surgery. A highly effective method of birth control is defined as a method which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly. Such methods include:

Combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal)
Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable)
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
Bilateral tubal occlusion
Vasectomized partner
Sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient)
Female subjects who are breast feeding should discontinue nursing prior to the first day of study treatment and until 6 months after the last study treatment.
Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:
Sarcoma originated from bone structure, abdominal or gynecological viscera
Metastatic disease
Tumors with extension through the sciatic notch or across the diaphragm
Hypersensitivity to doxorubicin, ifosfamide, dacarbazine or to any of their metabolites or to any of their excipients
Persistent myelosuppression
Myocardial infarction within the last 6 months
Uncontrolled cardiac arrhythmia
Previous treatment with maximum cumulative doses (450mg/m² Doxorubicin or equivalent 900mg/m² EpiADM) of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones
Active and uncontrolled infections
Vaccination with live vaccines within 30 days prior to study entry
Inflammation of the urinary bladder (interstitial cystitis) and/or obstructions of the urine flow.
Other invasive malignancy within 5 years, with the exception of adequately treated non-melanoma skin cancer, localized cervical cancer, localized and presumably cured prostate cancer.
Uncontrolled severe illness, infection,medical condition (including, uncontrolled diabetes or hypertension), other than the Primary LPS or LMS of the retroperitoneum.
Female patients who are pregnant or breastfeeding or female and male patients of reproductive potential who are not willing to employ effective birth control method.
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before randomization in the trial
Known contraindication to imaging tracer and to MRI

Inclusion Criteria:
-Male or female ≥ 18 years age at the time of consent.
-Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
-Has the ability to understand informed consent and provided signed written informed consent.
-Life expectancy of > 3 months.
-Histologically and/or cytologically confirmed advanced metastatic or unresectable solid tumors has progressed after treatment for which there are no standard therapies available OR histologically and/or cytologically confirmed hematological malignancies that have relapsed, or refractory disease following at least 2 standard lines of systemic therapy for which there are no standard therapies available.
-Must have evaluable or measurable disease.
-Has all prior treatment (i.e., chemotherapy, immunotherapy, radiotherapy) related clinically significant toxicities resolve to ≤ Grade -1 per NCI CTCAE, Version 5.0 or are clinically stable and not clinically significant, at time of consent.
-All subjects must have completed any prior chemotherapy, targeted therapy and major surgery, ≥ 28 days before study entry. For daily or weekly chemotherapy without the potential for delayed toxicity, a washout period of 14 days may be acceptable, and questions related to this can be discussed with the Medical Monitor.
-Has adequate hematologic (bone marrow [BM] and coagulation factors), and renal function.
-Able to swallow and retain orally-administered medication and without clinically significant gastrointestinal abnormalities that could alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
-Subjects with abnormal hepatic function will be eligible and will be grouped according to established criteria. Subjects with active hemolysis will be excluded.
-Manual differential with no significant morphologic abnormalities on complete blood count (CBC) testing.
-Male subjects must have had a successful vasectomy OR must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a female of childbearing potential from the first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.
-Females of childbearing potential must have a negative serum pregnancy test at screening and within 24 hours prior to the first dose of study drug. All females will be considered of childbearing potential unless they are naturally postmenopausal or have been sterilized.
-Females of childbearing potential (FCBP) must either practice complete abstinence or agree to use a highly effective method of contraception beginning at least 28 days prior to the first dose of study drug, during study treatment (including during dose interruptions), and for 6 months after study drug discontinuation.
-Has a QT interval corrected by Fridericia's formula (QTcF) ≤480 msec.
-Subjects with diagnosed human immunodeficiency virus (HIV) are eligible to participate in the study if they meet established criteria.

Exclusion Criteria:
-Prior exposure to tazemetostat or other inhibitor(s) of EZH2.
-Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression as documented by CT or MRI scan, analysis of cerebrospinal fluid or neurological exam. Subjects with primary glioblastoma multiforme are excluded.
-Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders. Subjects on anticoagulation with low molecular weight heparin are allowed.
-Known hypersensitivity to any of the components of tazemetostat.
-Concurrent investigational agent or anticancer therapy. NOTE: Megestrol (Megace) if used as an appetite stimulant is allowed.
-Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders, symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmias, or psychiatric illness/social situations that would limit compliance with study requirements.
-Have a known active infection with hepatitis B virus (HBV, as measured by positive hepatitis B surface antigen, hepatitis C virus (HCV, as measured by positive hepatitis C antibody), OR human T-cell lymphotropic virus 1.
-Subjects taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's Wort).
Is unwilling to exclude grapefruit juice, Seville oranges and grapefruit from the diet and all foods that contain those fruits from 24 hours prior to the first dose of study drug until the last dose of study drug.
-Any condition or medical problem in addition to the underlying malignancy and organ dysfunction that the Investigator feels would pose unacceptable risk.
-Has thrombocytopenia, neutropenia, or anemia of grade ≥3 (per CTCAE 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS).
-Has abnormalities known to be associated with MDS and myeloproliferative neoplasms (MPN) observed in cytogenetic testing and DNA sequencing.
-Has a prior history of T-LBL/T-ALL.
-Ingestion of alcohol and smoking is not permitted any time during the study.
-History of drug abuse (including alcohol) within the last 6 months prior to screening.
-Severe hepatic encephalopathy (Grade >2) or degree of CNS impairment which the Investigator considers sufficiently serious to interfere with the informed consent, the conduct, the completion, or the results of this trial, or constitutes an unacceptable risk to the subject.
-History of liver transplantation.
-Advanced ascites or ascites that require drainage and albumin supplementation, as judged by the Investigator.
-Acute damage of the liver with Grade 4 AST/ALT values at screening or admission.

Principal inclusion criteria
- Asymptomatic or mildly symptomatic, histologically-confirmed de novo metastatic hormone-sensitive prostate adenocarcinoma without small-cell tumours
- Provide a FFPE tissue block (preferred) or slides. Tissue from bone metastases is not acceptable
- A valid PTEN IHC result indicating PTEN deficiency (centralized testing)
- Metastatic disease documented prior to randomisation by clear evidence of ≥ 1 bone
lesion and/or ≥ 1 soft tissue lesion accurately assessed at baseline and suitable for repeated assessment with CT and/or MRI. PSMA PET identification only will not be eligible
- Candidate for abiraterone and steroid therapy
- Ongoing ADT with GnRH analogue, or LHRH agonists or antagonist, or bilateral orchiectomy
- Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0 to 1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
- Able and willing to swallow and retain oral medication
- 7-day Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory(BFI) questionnaires and the analgesic diary during screening completed
- Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm

Principal exclusion criteria
-Radiotherapy with a wide field of radiation within 4 weeks(wks) before start of study treatment (capivasertib/placebo)
-Major surgery (excl.placement of vascular access,transurethral resection of prostate,bilateral orchiectomy,internal stents) within 4 wks of start of study treatment
-Brain metastases,or spinal cord compression (unless spinal cord compression is asymptomatic, treated and stable and not requiring steroids for at least 4 wks prior to start of study treatment)
-Past medical history of interstitial lung disease,drug-induced interstitial lung disease,radiation pneumonitis which required steroid treatment,or any evidence of clinically active interstitial lung disease
-Any of the following cardiac criteria:
i.Mean resting corrected QT interval (QTc) >470 msec from 3 consecutive ECGs
ii.Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG
iii.Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure,hypokalaemia,potential for torsades de pointes,congenital long QT syndrome,family history of long QT syndrome or unexplained sudden death under 40 years of age,or any concomitant medication known to prolong the QT interval
iv.Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months,severe or unstable angina,or NYHA or Class II to IV heart failure or cardiac ejection fraction measurement of <50%
v.Experience of any of the following procedures or conditions in the preceding 6months: coronary artery bypass graft,angioplasty,vascular stent,myocardial infarction,angina pectoris,congestive heart failure NYHA Grade ≥2
vi.Uncontrolled hypotension - systolic blood pressure <90 mmHg and/or diastolic blood pressure <50 mmHg
vii.Cardiac ejection fraction outside institutional range of normal or <50% (whichever is higher) as measured by echocardiogram (or multiple-gated acquisition scan if an echocardiogram cannot be performed or is inconclusive)
viii.Uncontrolled hypertension (SBP ≥160 mmHg or DBP ≥95 mmHg).
-Clinically significant abnormalities of glucose metabolism as defined by any of the following:
i.Patients with diabetes mellitus (MS) type 1 or MS type 2 requiring insulin treatment
ii.HbA1c ≥8.0% (63.9 mmol/mol)
-Inadequate bone marrow reserve or organ function
-As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses,or known active infection including hepatitis B and C,and HIV
-Unevaluable for both bone and soft tissue progression as defined by meeting both of the following criteria:
i.a "superscan" of bone scan,and
ii.no soft tissue lesion that can be assessed by RECIST criteria
-Refractory nausea and vomiting, malabsorption syndrome,chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection,or other condition that would preclude adequate absorption of capivasertib
-Any other disease,metabolic dysfunction,physical examination finding,or clinical laboratory finding that,in the investigator’s opinion,gives reasonable suspicion of a disease or condition that contra-indicates the use of an investigational drug,may affect the interpretation of the results,render the patient at high risk from treatment complications or interferes with obtaining informed consent
-Evidence of dementia,altered mental status,or any psychiatric condition that would prohibit understanding or rendering of informed consent
-Previous allogeneic bone marrow transplant or solid organ transplant
-Known additional malignancy that has had progression or has required active treatment in the last 3 years.Exceptions include basal cell carcinoma of the skin and squamous cell carcinoma of the skin that has undergone potentially curative therapy
-Treatment with any of the following:
i.Nitrosourea or mitomycin C within 6 wks of the start of study treatment
ii.Any investigational agents or study drugs from a previous clinical study within 30 days or 5 half-lives (whichever is longer) of the start of study treatment
iii.Any other chemotherapy,immunotherapy,immunosuppressant medication (other than corticosteroids) or anticancer agents within 3 wks of the first dose of study treatment.A longer washout may be required for drugs with a long half-life (eg,biologics)
iv.Potent inhibitors or inducers of CYP3A4 within 2 weeks before the start of study treatment (3 weeks for St John’s wort), or sensitive substrates of CYP3A4,CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 wk before the start of study treatment
-Drugs known to prolong the QT interval within 5 half-lives of the first dose of study treatment
-History of hypersensitivity to active or inactive excipients of capivasertib,abiraterone,or drugs with a similar chemical structure or class

INCLUSION CRITERIA

Full list of inclusion criteria

Pre-/peri-menopausal women or men can be enrolled if amenable to be treated with concomitant, approved LHRH agonists for the duration of the study treatment.
De novo Stage 4 disease, or recurrence from early stage disease after at least 24 months of standard adjuvant endocrine therapy. Note that at least 12 months must have elapsed since the patient's last dose of adjuvant AI therapy without disease progression on treatment. Note that a 2-week washout period is required after the last dose of tamoxifen prior to randomisation.
Histologically or cytologically documented diagnosis of ER+, HER2-negative breast cancer based on local laboratory results.
Previously untreated with any systemic anti-cancer therapy for their locoregionally recurrent or metastatic ER+ disease.
Measurable disease as defined per RECIST v.1.1 OR at least one lytic or mixed (lytic + sclerotic) bone lesion with a soft tissue component that can be assessed by CT or MRI.
Eastern Cooperative Oncology Group performance status of 0 or 1.
Adequate organ and marrow function.
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
INFORMATION FOR TRIAL PARTICIPANTS

Participants can join the trial if they:

Have breast cancer that cannot be treated with surgery or radiation
Have breast cancer that has already spread into other parts of the body at the time of diagnosis, or has come back after at least 2 years of a standard endocrine treatment
Have ER proteins but not overexpression of HER2 protein in their tumors
Have never received any type of cancer therapy that affects the whole body for advanced breast cancer
Are able to do their daily activities
EXCLUSION CRITERIA

Full list of exclusion criteria

Previous neoadjuvant or adjuvant treatment with an AI treatment +/- CDK4/6 inhibitor with disease recurrence while on or within 12 months of completing treatment.
Prior exposure to AZD9833, other investigational SERDs/endocrine agents or fulvestrant.
Participation in another clinical study with a study treatment or investigational medicinal device administered in the last 4 weeks prior to randomization or concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.
Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term and/or impending visceral crisis
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease.
Any clinically important and symptomatic heart disease .
Currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, renal transplant and active bleeding diseases) which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
Any concurrent anti-cancer treatment.
Active infection including tuberculosis, HBV and HCV.
INFORMATION FOR TRIAL PARTICIPANTS

Participants cannot join the trial if they:

Have uncontrolled cancer that has spread to the brain or the spinal cord
Have received certain treatments for cancer in the past but the cancer came back within 1 year
Had certain types of tumors in the past, which the study doctors think could come back
Are currently taking any treatment for cancer or are taking medications or supplements that affect certain proteins in the body
Have any major health problem, infection, or surgery that could make it difficult or dangerous to participate in this trial, such as tuberculosis, HIV, heart problems, or a kidney transplant
The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Inclusion Criteria:

Histologically confirmed adenocarcinoma of the prostate
Previously treated with radical prostatectomy with or without lymph node dissection and either: a) for biochemical recurrence after radical prostatectomy (RP): any post-operative prostate-specific antigen (PSA) measurement of less than (<) 0.1 nanogram/milliliter (ng/mL) within 12 months after RP and without any PSA greater than and equal to (>=) 0.1 ng/mL within the 4 to 8-week period after RP or b) for persistent PSA after RP: PSA >=0.1 ng/mL within the 4 to 8-week period after RP, confirmed by additional measurement at least 3 weeks later
Be able to swallow whole the study drug tablets or follow the instructions for admixing with apple sauce
Results of the Prostate specific membrane antigen-positron emission tomography (PSMA-PET) at screening as determined by blinded independent, central review (BICR), must be: PSMA-PET-negative for any prostate cancer lesions (that is, no loco-regional lesion and no distant lesions); or PSMA-PET-positive for at least one loco-regional (pelvic) lesion without distant extra-pelvic lesion; or PSMA PET- positive for at least one loco--regional (pelvic) lesion with extra-pelvic lesion(s).
High risk of developing metastasis defined as; a) for biochemical recurrence after RP: pathological Gleason score greater than or equal to (>=) 8 evaluated from prostate tissue specimen at radical prostatectomy, or prostate-specific antigen doubling time (PSADT) less than or equal to (<=) 12 months at the time of screening; b) for persistent PSA after RP: pathological Gleason score >=8, evaluated from prostate tissue specimen at radical prostatectomy
Participants with evidence of distant metastasis on screening PSMA-PET scan must have no evidence of prostate cancer metastases on screening CT/MRI of the chest/abdomen/pelvis, Technetium 99m [99mTc] whole-body bone scan. Participants with a single bone lesion on 99mTc whole-body bone scan should have confirmatory imaging by CT or MRI; if the confirmatory scan confirms the bone lesion, the participant should be excluded from the study. Conventional images (99mTc-bone scan and CT/MRI) from the screening will be evaluated locally before randomization
Eastern Cooperative Oncology Group Performance Status Grade 0 or 1

Exclusion Criteria:
History of pelvic radiation for malignancy
Previous treatment with androgen deprivation therapy (ADT) for prostate cancer
Previously treated for biochemical recurrence (BCR) or persistent PSA after RP (previous surgical treatment of one or more loco-regional lesions is allowed)
Prior treatment with a CYP17 inhibitor (example, oral ketoconazole, orteronel, abiraterone acetate, galeterone) or any androgen receptor (AR) antagonist including bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide or darolutamide and any other medications that may lower androgen levels (estrogens, progestins, aminoglutethimide, etc.), including bilateral orchiectomy
Known or suspected contraindications or hypersensitivity to apalutamide, Luteinizing Hormone-Releasing Hormone (LHRH) agonist or any of the components of the formulations
Prior chemotherapy for prostate cancer
Any evidence of prostate cancer metastasis on computed tomography/magnetic resonance imaging (CT/MRI) of the chest/abdomen/pelvis or 99mTc whole-body bone scan, at any time prior to screening

Inclusion Criteria:

Documented estrogen receptor (ER)-positive and HER2-negative breast tumor, as assessed locally on a primary disease specimen
Participants who have multicentric (the presence of two of more tumor foci within different quadrants of the same breast) and/or multifocal (the presence of two or more tumor foci within a single quadrant of the breast) breast cancer are also eligible if all examined tumors meet pathologic criteria for ER positivity and HER2 negativity
Participants must have undergone definitive surgery of their primary breast tumor(s) and axillary lymph nodes (axillary lymph node dissection [ALND] and/or sentinel lymph node biopsy [SLNB])
Participants who received or will be receiving adjuvant chemotherapy must have completed adjuvant chemotherapy prior to randomization. Participants may also have received neoadjuvant chemotherapy. A washout period of at least 21 days is required between last adjuvant chemotherapy dose and randomization.
Resolution of all acute toxic effects of prior anti-cancer therapy or surgical procedures to NCI CTCAE v5.0 Grade 1 or better (except alopecia, Grade ≤2 peripheral neuropathy, arthralgia or other toxicities not considered a safety risk for the participant per the investigator's judgment)
Participants have received (neo)adjuvant chemotherapy and/or had surgery and had no prior endocrine therapy are eligible, provided that they are enrolled within 12 months following definitive breast cancer surgery
Participants who have confirmed availability of an untreated primary breast tumor tissue specimen suitable for biomarker testing (i.e., representative archived formalin-fixed, paraffin-embedded [FFPE] tissue block [preferred] or 15-20 slides containing unstained, freshly cut, serial sections), with associated de-identified pathology report is required. Although 15-20 slides are preferred, if only 10-14 slides are available, the individual may still be eligible for the study.
Participants with node-positive and node-negative disease are eligible provided they meet additional risk criteria as defined in the protocol
Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2
Able and willing to swallow, retain, and absorb oral medication
Adequate organ function
Exclusion Criteria:

Pregnant or breastfeeding, or intending to become pregnant during the study or within 10 days after the final dose of giredestrant, or within the time period specified per local prescribing guidelines after the final dose of the endocrine therapy of physician's choice
Received treatment with investigational therapy within 28 days prior to initiation of study treatment or is currently enrolled in any other type of medical research judged by the sponsor not to be scientifically or medically compatible with this study
Receiving or planning to receive a CDK4/6 inhibitor as (neo)adjuvant therapy. A short course of up to 12 weeks of neoadjuvant or adjuvant treatment with CDK4/6 inhibitor therapy prior to randomization is allowed.
Active cardiac disease or history of cardiac dysfunction
Diagnosed with Stage IV breast cancer
A history of any prior (ipsilateral and/or contralateral) invasive breast cancer or ductal carcinoma in situ (DCIS). Participants with a history of contralateral DCIS treated by only local regional therapy at any time may be eligible.
A history of any other malignancy within 3 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, or Stage I uterine cancer
Any prior endocrine treatment with selective ER modulators (e.g., tamoxifen), degraders, or aromatase inhibitors. A short course of neoadjuvant or adjuvant endocrine therapy (up to 12 weeks) is allowed.
Clinically significant liver disease consistent with Child-Pugh Class B or C, including active hepatitis (e.g., hepatitis B virus [HBV] or hepatitis C virus [HCV]), current alcohol abuse, cirrhosis, or positive test for viral hepatitis
Treatment with strong CYP3A4 inhibitors or inducers within 14 days or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment
Known allergy or hypersensitivity to any of the study drugs or any of their excipients
Pre- and perimenopausal participants or male participants who have a known hypersensitivity to LHRH agonists
A documented history of hemorrhagic diathesis, coagulopathy, or thromboembolism
Renal dysfunction that requires dialysis
A major surgical procedure unrelated to breast cancer within 28 days prior to randomization
A serious infection requiring oral or IV antibiotics within 14 days prior to screening or other clinically significant infection (e.g., COVID-19) within 14 days prior to screening
Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
Unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator

Inclusion Criteria:

Able to understand and comply with the study procedures, understand the risks involved in the study, and provide legally effective informed consent before the first study-specific procedure; specifically able to comply with the PK assessment schedule during the first treatment cycle.
Participants must have histologically or cytologically confirmed solid tumor or hematologic malignancy that is metastatic or unresectable and for which standard life-prolonging measures are not available.
For participants with AML/MDS only:

Cytologically or histologically confirmed diagnosis of AML (except M3 acute promyelocytic leukemia) or MDS according to the 2008 World Health Organization (WHO) classification with the disease being refractory, relapsed, or unresponsive to standard treatment;
Participants with frontline MDS or treatment naïve AML not suitable for induction therapy (eg, age of >75 years, Eastern Cooperative Oncology Group [ECOG] performance status ≥ 2, severe pulmonary disorder, total bilirubin > 1.5x upper limit of normal [ULN]);
Platelet count ≥ 25,000/μL;
Absolute neutrophil count (ANC) ≥ 100 cells/μL.
For participants with solid tumors only:

Platelet count ≥ 100,000/μL;
ANC ≥ 1000 cells/μL.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Hepatic function defined per the National Cancer Institute Cancer Therapy Evaluation Program (NCI CTEP) Organ Dysfunction Working Group (ODWG) as:

Normal hepatic function: total bilirubin ≤1x ULN aspartate aminotransferase (AST): ≤1x ULN;
Moderate hepatic impairment: total bilirubin >1.5x to 3x ULN AST: any value;
Severe hepatic impairment: total bilirubin >3x ULN AST: any value.
Adequate renal function defined as creatinine clearance (CLcr, according to the Cockcroft-Gault equation) >50mL/min.
No major surgery within 30 days of first administration of oral decitabine and cedazuridine.
Life expectancy of at least 3 months.
Women of childbearing potential (according to recommendations of the Clinical Trial Facilitation Group) must not be pregnant or breastfeeding and must have a negative pregnancy test at Screening.
Women of childbearing potential must agree to practice 1 highly effective contraceptive measure of birth control with low user dependency and must agree not to become pregnant for 6months after completing treatment
Male participants with female partners of childbearing potential must agree to use a male condom and advise his partner to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) and must agree not to father a child while receiving treatment with oral decitabine and cedazuridine and for at least 3 months after completing treatment.
Exclusion Criteria:

Treatment with azacitidine or decitabine within 4 weeks before Screening. Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.
Hospitalization for more than 2 days for documented febrile neutropenia, pneumonia, sepsis, or systemic infection 30 days prior to first dose.
Treatment with any investigational medicinal product (IMP), investigational therapy, chemotherapy, immunotherapy, or targeted therapy within 2 weeks or 5 half-lives, whichever is longer, before the first dose of study treatment, or ongoing clinically significant adverse events from previous treatment.
Concurrent MDS therapies, including lenalidomide, cyclosporine/tacrolimus, granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor, etc. Prior treatment with these agents is permitted, provided that completion is at least 1 week before the first dose of study treatment. Short-term use of G-CSF for febrile neutropenia is permitted at the discretion of the treating physician and should be guided by accepted practice or institutional guidelines. Hematopoietic growth factors will not be routinely used unless cleared by Astex medical expert.
Administration of live (attenuated) vaccines within 4 weeks before the first administration of oral decitabine and cedazuridine until after the follow-up visit. Other vaccines, eg, inactivated or RNA-based, may be administered but should not occur from 7 days before first administration of oral decitabine and cedazuridine until after the follow-up visit.
High medical risk because of other conditions such as uncontrolled systemic diseases, active uncontrolled infections, or comorbidities that may put the participant at risk of not being able to complete at least 2 cycles of treatment.
Conditions which likely promote delayed ventricular repolarization (QT prolongation):

Corrected QT interval (QTc) using Bazett's correction (QTcB) or QTc using Fridericia correction (QTcF) at Screening or Day -1 > 450 ms;
History or disposition for torsades des pointes (TdP) (eg, heart failure, hypokalemia, family history of long QT Syndrome);
Concomitant medication that prolong the QT/QTc interval.
Cardiac abnormalities or unstable cardiovascular conditions:

Unstable ischemic heart disease or severe heart failure (New York Heart Association Class III or IV);
Uncontrolled treated/untreated hypertension (defined as a mean of 3 repeated measurements for systolic blood pressure ≥ 180 mmHg and/or diastolic blood pressure ≥ 110 mmHg; current or documented history of repeated clinically significant hypotension or severe episodes of orthostatic hypotension (systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg).
Known significant mental illness or other condition, such as active alcohol or other substance abuse or addiction, that in the opinion of the investigator predisposes the participant to high risk of noncompliance with the protocol.
In participants with AML/MDS, rapidly progressive or highly proliferative disease or other criteria that render the participant at high risk of requiring intensive cytotoxic chemotherapy within the next 3 months.
Life-threatening illness or severe organ system dysfunction, such as uncontrolled congestive heart failure or chronic obstructive pulmonary disease, or other reasons including laboratory abnormalities, which, in the investigator's opinion, could compromise the participant's safety, interfere with the absorption or metabolism of oral decitabine and cedazuridine, or compromise completion of the study or integrity of the study outcomes.
Untreated central nervous system (CNS) metastases. Participants with treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks before screening.
Positive nasopharyngeal test for SARS-CoV-2 at Screening or Day -1. Participants may be rescreened if they become SARS-CoV-2 negative.
Participants infected with human immunodeficiency virus (HIV).
Positive blood screen for hepatitis C antibody (HCV+) and positive RNA polymerase chain reaction (PCR). Participant can be included if HCV+ but negative for RNA PCR.
Positive blood screen for hepatitis B surface antigen (HBsAg+). Participants with positive blood screen for hepatitis B surface antibody (HBsAb+) and negative hepatitis B core antibody (HBcAb-) can be included if negative for hepatitis B surface antigen (HBsAg-).
Average intake of more than 24 units of alcohol per week for male subjects and 17 units per week for female subjects (1 unit of alcohol equals 10 mL of pure alcohol, ie, approximately 250 mL of beer, 75 mL of wine, or 25 mL of spirits).
Positive drugs of abuse or alcohol test at Screening and Day -1, except for the use of prescribed and medically indicated drugs (eg, benzodiazepines, opiates, or cannabinoids).
Donation or loss of more than 500 mL of blood within 60 days prior to the first study drug administration.
Hypersensitivity to decitabine, cedazuridine, or any of the excipients in oral decitabine and cedazuridine.

Principal inclusion criteria
1) Previous participation in an Astex-sponsored ASTX727 clinical trial (including but not limited to studies ASTX727-01, ASTX727-02, ASTX727-04, ASTX727-17, ASTX727-18, and the food effect substudy of ASTX727-06) in which the subject was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Astex.
2) Subject is considered to be benefitting from ASTX727 treatment in the opinion of the treating Investigator at the time of parent study completion. (Subjects must not be withdrawn from the parent study until eligibility for this study is confirmed.)
3) Subject is able to understand and comply with the study procedures and understands the risks involved in the study.
4) Subject provides legally effective informed consent before undergoing any study-specific procedure.

FE Substudy inclusion criteria:
1) Be 18 years of age or older, at the time of signing the informed consent.
2) Have MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, CMML), and subjects with MDS IPSS int-1, -2, or high-risk MDS, or AML, as diagnosed according to the 2016 World Health Organization (WHO) guidelines on acute leukemia, of any subtype except M3 (acute promyelocytic leukemia), who are not candidates for intensive chemotherapy, including subjects receiving HMA treatment, who have a confirmed diagnosis and a prior confirmatory bone marrow report. Subjects who are currently receiving HMA treatment must complete the ongoing (at the time of Screening) treatment cycle before enrolling in this study; timing of start of treatment cycle with ASTX727 is at the principal investigator’s discretion.
3) Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
4) Have adequate organ function defined as follows:
a. Hepatic: Total bilirubin ≤1.5× upper limit of normal (ULN); aspartate aminotransferase/serum glutamicoxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤5× ULN.
b. Renal: Calculated creatinine clearance ≥60 mL/min.
5) Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 1 highly effective contraceptive measure of birth control (with a failure rate of <1% per year; with low user dependency) during the substudy and for 6 months after the last dose of study treatment and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to use a condom and advise their partners to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) while receiving treatment with ASTX727 and for at least 3 months after completing treatment and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment.

Principal exclusion criteria
1) Any subject who, in the opinion of the investigator, may have other conditions, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits.

FE Substudy Exclusion Criteria:
1) Known or suspected hypersensitivity to decitabine, cedazuridine, or any of the excipients in the ASTX727 tablets.
2) Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
3) Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the Investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of decitabine + cedazuridine, or compromise the integrity of the study outcomes.
4) Prior gastric surgery for ulcer disease, weight loss, etc., that would impair normal motility or absorption.
5) Second malignancy currently requiring active chemotherapy. To clarify, patients with breast or prostate cancer stable on or responding to endocrine therapy, are eligible.
6) Known history of human immunodeficiency virus or known seropositive for hepatitis C virus or hepatitis B virus.
7) Active uncontrolled gastric or duodenal ulcer.
8) Subjects with acute promyelocytic leukemia.
9) Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.
10) Treated with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant AEs from previous treatment with investigational drug or therapy.
11) Sensitivity to any of the study interventions or components thereof, or drug or other allergy that, in the opinion of the Investigator or medical monitor, contraindicates participation in the study.
12) Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the Investigator, predisposes the subject to high risk of noncompliance with the protocol.

Principal inclusion criteria
Molecular Prescreening Inclusion Criteria
Age and Sex:
1. SLI: Male or female participants age ≥18 years at the time of informed consent.
Phase 3 and Cohort 3: Male or female participants age ≥16 years at the time of informed consent/assent in all countries where permitted. In countries or sites where enrollment of adolescents is not permitted (eg, Germany), male or female participants age ≥18 years at the time of informed consent.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
Weight:
2. Body weight ≥40 kg.
Type of Participant and Disease Characteristics:
3. Participants with histologically or cytologically confirmed colorectal adenocarcinoma.
4. Participants with evidence of Stage IV metastatic disease.
Note: Patients with oligometastatic disease previously treated with curative intent are eligible to participate in the study as long as they have baseline measurable disease per RECIST 1.1. Oligometastatic
colorectal cancer is characterized by a limited metastatic spread of
disease. Oligometastatic disease is defined as the involvement of up to 3
sites with 5 or sometimes more metastases that for their anatomic
localization is amenable to local therapies, thus rendering the patient
free of disease.
5. Able to provide a sufficient amount of representative tumor specimen for central testing of BRAF V600E mutation status and tumor tissue assessment
Note: Tumor sample can be archival or de novo (newly collected fixed biopsy sample) and must be in an FFPE block, or provide a minimum of 15 unstained slides of analyzable tissue. This tissue specimen should be obtained from a biopsy or surgery that was performed within 2 years
prior to study enrollment. Participants with fewer than the required number of slides with analyzable tissue may be considered eligible if the Sponsor determines that the slides are sufficient for central testing.
Informed Consent/Assent:
6. Capable of giving signed informed consent/assent as described in 54TAppendix 154T, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol.
Note: Participants ≥16 years old that are under guardianship may participate with the consent of their legally authorized guardian if permitted by local regulations. When appropriate, adolescent participants will be included in all discussions (see Section 10.1.3).
5.1.2. Screening Inclusion Criteria
Type of Participant and Disease Characteristics:
7. Participants who have met all Molecular Prescreening inclusion criteria.
8. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
9. Presence of a BRAF V600E mutation in tumor tissue or blood (eg, ctDNA genetic testing). The following are acceptable:
a. Local laboratory assay (PCR or NGS-based only) performed at any time prior to Screening using either tumor tissue or blood.
b. Central laboratory assay performed during the Screening period using tumor tissue alone (not blood).
Note: For participants enrolled on the basis of a local BRAF mutation assay, tumor samples must be submitted to the central laboratory for BRAF testing as soon as possible following signing of the ICD. The BRAF status must be confirmed no later than 30 days following first dose of study intervention.
10. The Investigator must obtain prior to Cycle 1 Day 1 (SLI) or date of randomization (Phase 3 and Cohort 3) adequate tumor tissue (primary or metastatic, archival or newly obtained) for submission to a central laboratory for confirmation of BRAF V600E and tumor tissue assessment.
Note: Once BRAF V600E mutation status is determined by the central laboratory (tumor tissue), the results will be considered definitive for eligibility. No repeat testing will be performed.
Note: Lack of BRAF V600E confirmation by the central laboratory may be due to discordance between the local assay and central laboratory results (potential false positive local assay results), or due to inadequate or poor sample condition for central testing (indeterminate results). If at any time in the study there is lack of BRAF V600E confirmation in a total of 6% of the total planned enrollment of the randomized portion of the trial (42 participants) or a discordance between the local assay and the central laboratory of 3% of the total planned enrollment (21 participants), all subsequent participants will be required to have BRAF V600E determined by the central laboratory for treatment (ie, local BRAF testing will no longer be accepted for trial eligibility).
Note: Participants whose sample is determined to be inadequate or who have an indeterminate result on central testing may have additional tumor samples submitted for testing.

For a full list please see section 5.1 of the protocol.

Principal exclusion criteria
Molecular Prescreening Exclusion Criteria
Medical Conditions:
1. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
2. Presence of acute or chronic pancreatitis.
3. Leptomeningeal disease.
4. History of chronic inflammatory bowel disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization.
5. Known DPD deficiency; refer to local fluorouracil or capecitabine label or local clinical guidances, for DPD status recommendation prior to starting treatment.
6. Gilbert’s syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype:
a. SLI: Participants with documented Gilbert’s syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype will be excluded from Cohort 1 (EC + FOLFIRI) of the SLI.
b.Phase III: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype may be enrolled, but may not receive FOLFOXIRI if randomized to the Control Arm.
c. Cohort 3: Participants with documented Gilbert's syndrome or known homozygous UGT1A1*28/*28 or UGT1A1*6/*6 genotypes or double heterozygous UGT1A1*6/*28 genotype will be excluded from Cohort 3 Arm D and Arm E (EC + FOLFIRI and FOLFIRI ± bevacizumab).
Other Exclusions:
7. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
8. Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown.
9. Locally confirmed dMMR or MSI-H colorectal carcinoma or unknown MSI/MMR status. If participant is locally confirmed dMMR or MSI-H and unable to receive immune checkpoint inhibitors due to a pre existing medical condition, they may be enrolled.
5.2.2. Screening Exclusion Criteria
Medical Conditions:
10. Impaired gastrointestinal function (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, small bowel resection) or disease which may significantly alter the absorption of oral study intervention or recent changes in bowel function suggesting current or impending bowel obstruction.
11. Clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤6 months prior to randomization;
b. Congestive heart failure requiring treatment (New York Heart Association Class II and above);
c. Recent history (within 1 year prior to randomization) or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
d. History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization. Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli.
Note: Participants with either deep vein thrombosis or pulmonary emboli that do not result in hemodynamic instability are allowed to enroll as long as they are on a stable dose of anticoagulants for at least 4 weeks.
Note: Participants with thromboembolic events related to indwelling catheters (including PICC lines) or other procedures may be enrolled.
e. Triplicate average QTcF interval ≥480 ms or a history of prolonged QT syndrome.
Note: Participants with bundle-branch block (BBB) or with an implanted cardiac pacemaker, may enroll into the study following consultation with the Sponsor.
f. Congenital LQTS.
12. Evidence of active noninfectious pneumonitis.
13. Evidence of active and uncontrolled bacterial or viral infection, with certain exceptions, as noted below, for chronic infection with HIV,
hepatitis B or hepatitis C, within 2 weeks prior to start of study
intervention.
14. Participants positive for HIV are ineligible unless they meet all of the following:
a. A stable regimen of highly active anti-retroviral therapy that is not contraindicated (see Section 6.5);
b. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections;
c. A CD4 count >250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests.

For a full list please see section 5.2 of the protocol.

Principal inclusion criteria
1) Previous participation in an Astex-sponsored ASTX727 clinical trial (including but not limited to studies ASTX727-01, ASTX727-02, ASTX727-04, ASTX727-17, ASTX727-18, and the food effect substudy of ASTX727-06) in which the subject was treated with ASTX727 and was still on active treatment with ASTX727 at the time of study completion as determined by Astex.
2) Subject is considered to be benefitting from ASTX727 treatment in the opinion of the treating Investigator at the time of parent study completion. (Subjects must not be withdrawn from the parent study until eligibility for this study is confirmed.)
3) Subject is able to understand and comply with the study procedures and understands the risks involved in the study.
4) Subject provides legally effective informed consent before undergoing any study-specific procedure.

FE Substudy inclusion criteria:
1) Be 18 years of age or older, at the time of signing the informed consent.
2) Have MDS, including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, CMML), and subjects with MDS IPSS int-1, -2, or high-risk MDS, or AML, as diagnosed according to the 2016 World Health Organization (WHO) guidelines on acute leukemia, of any subtype except M3 (acute promyelocytic leukemia), who are not candidates for intensive chemotherapy, including subjects receiving HMA treatment, who have a confirmed diagnosis and a prior confirmatory bone marrow report. Subjects who are currently receiving HMA treatment must complete the ongoing (at the time of Screening) treatment cycle before enrolling in this study; timing of start of treatment cycle with ASTX727 is at the principal investigator’s discretion.
3) Have Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
4) Have adequate organ function defined as follows:
a. Hepatic: Total bilirubin ≤1.5× upper limit of normal (ULN); aspartate aminotransferase/serum glutamicoxaloacetic transaminase (AST/SGOT) and alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) ≤5× ULN.
b. Renal: Calculated creatinine clearance ≥60 mL/min.
5) Women of childbearing potential must not be pregnant or breastfeeding and must have a negative pregnancy test at screening. Women of childbearing potential must agree to practice 1 highly effective contraceptive measure of birth control (with a failure rate of <1% per year; with low user dependency) during the substudy and for 6 months after the last dose of study treatment and must agree not to become pregnant for 6 months after completing treatment; men with female partners of childbearing potential must agree to use a condom and advise their partners to practice 1 highly effective contraceptive measure of birth control (user dependent or with low user dependency) while receiving treatment with ASTX727 and for at least 3 months after completing treatment and must agree not to father a child while receiving ASTX727 and for at least 3 months after completing ASTX727 treatment.

Principal exclusion criteria
1) Any subject who, in the opinion of the investigator, may have other conditions, or for whom safety data from parent study participation suggests the risks of continuing treatment with ASTX727 may outweigh the benefits.

FE Substudy Exclusion Criteria:
1) Known or suspected hypersensitivity to decitabine, cedazuridine, or any of the excipients in the ASTX727 tablets.
2) Poor medical risk because of other conditions such as uncontrolled systemic diseases or active uncontrolled infections.
3) Life-threatening illness, medical condition or organ system dysfunction, or other reasons including laboratory abnormalities, which, in the Investigator’s opinion, could compromise the subject’s safety, interfere with the absorption or metabolism of decitabine + cedazuridine, or compromise the integrity of the study outcomes.
4) Prior gastric surgery for ulcer disease, weight loss, etc., that would impair normal motility or absorption.
5) Second malignancy currently requiring active chemotherapy. To clarify, patients with breast or prostate cancer stable on or responding to endocrine therapy, are eligible.
6) Known history of human immunodeficiency virus or known seropositive for hepatitis C virus or hepatitis B virus.
7) Active uncontrolled gastric or duodenal ulcer.
8) Subjects with acute promyelocytic leukemia.
9) Prior cytotoxic chemotherapy for AML except for hydroxyurea to control high white blood cell (WBC) counts.
10) Treated with any investigational drug or therapy within 2 weeks of study treatment, or 5 half-lives, whichever is longer, before the protocol-defined first dose of study treatment, or ongoing clinically significant AEs from previous treatment with investigational drug or therapy.
11) Sensitivity to any of the study interventions or components thereof, or drug or other allergy that, in the opinion of the Investigator or medical monitor, contraindicates participation in the study.
12) Known significant mental illness or other condition such as active alcohol or other substance abuse or addiction that, in the opinion of the Investigator, predisposes the subject to high risk of noncompliance with the protocol.

Principal inclusion criteria
•Age ≥ 18 years
•Histologically- or cytologically-confirmed diagnosis of advanced or recurrent (Stage IIIB/C, not amenable for radical treatment) or metastatic (Stage IV) NSCLC that harbors a documented ROS1 gene rearrangement
•No prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
•Prior radiotherapy is allowed if more than 14 days have elapsed between the end of treatment and randomization. Patients who received brain irradiation must have completed whole brain radiotherapy at least 14 days prior and/or stereotactic radiosurgery at least 7 days prior to the start of entrectinib treatment
•Measurable systemic disease according to RECIST v1.1
•Patients with measurable and non-measurable CNS lesions per RECIST v1.1, including leptomeningeal carcinomatosis, are eligible, provided that the patient is neurologically stable for at least 1 week prior to the first dose of study treatment.Note: Previously irradiated CNS lesions cannot be selected as target (measurable) lesions
•Life expectancy of at least 12 weeks
•Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
•Adequate hematologic, renal, liver function
•Recovery from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
•Patients must have recovered from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
•Ability to comply with the study protocol, in the investigator’s judgment
•Ability to swallow entrectinib and crizotinib intact without chewing, crushing, or opening the capsules
•For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs
during the treatment period and for up to 5 weeks after the final dose of entrectinib or for at least 90 days after the final dose of crizotinib
•For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm

Principal exclusion criteria
•Current participation in another therapeutic clinical trial
•Prior treatment with a ROS1 tyrosine kinase inhibitor, chemotherapy or other systemic therapy for advanced or recurrent (Stage IIIB/C not amenable for radical treatment) or metastatic (Stage IV) NSCLC
•NCI-CTCAE v5.0 Grade 3 or higher toxicities due to any prior therapy (excluding alopecia, fatigue, nausea and lack of appetite), which have not shown improvement and are strictly considered to interfere with current study drug
•History of recent (within the past 3 months) symptomatic congestive heart failure or ejection fraction ≤ 50% observed during screening for the study
•History of prolonged corrected QT interval
•History of additional risk factors for torsades de pointes
•Grade ≥2 peripheral sensory neuropathy
•Known interstitial lung disease, interstitial fibrosis, or history of tyrosine kinase inhibitor-induced pneumonitis
•Previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal (GI) cancer by endoscopic resection, in situ carcinoma of the cervix, or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
•Incomplete recovery from any surgery prior to the start of study treatment that would interfere with the determination of safety or efficacy
•Active GI disease or other malabsorption syndrome that would reasonably impact drug absorption
•History of prior therapy-induced pneumonitis
•Any condition (in the past 3 months) that would interfere with the determination of safety or efficacy of study treatments
•Known active infections that would interfere with the assessment of safety or efficacy of study treatments (bacterial, fungal or viral) , with the exceptions of HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV) infections
•History of hypersensitivity to any of the additives in the entrectinib and/or crizotinib drug formulations
•Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of entrectinib or crizotinib
•Known human immunodeficiency virus (HIV) positivity or acquired immunodeficiency syndrome (AIDS)-related illness
•Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the patient in this study
•Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures; those conditions should be discussed with the patient before trial entry

Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

Male or female patients ≥ 18 years of age.
Participants with CML-CP within 3 months of diagnosis.
Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of Philadelphia chromosome
Documented chronic phase CML will meet all the below criteria (Hochhaus et al 2020):

< 15% blasts in peripheral blood and bone marrow,
< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
< 20% basophils in the peripheral blood,
Platelet count ≥ 100 x 109/L (≥ 100,000/mm3),
No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0,or 1. 5. Adequate end organ function as defined by:

Total bilirubin < 3 x ULN; patients with Gilbert's syndrome may only be included if total bilirubin ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN
Creatinine clearance (CrCl) ≥ 30 mL/min as calculated using Cockcroft-Gault formula,
Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis 6. Participants must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization:
Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)
Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)
Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min)
For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be ≥ LLN or corrected to within normal limits with supplements prior to randomization.
*CrCl as calculated using Cockcroft-Gault formula 7. Ability to provide written informed consent prior to any study related screening procedures being performed.

8. Evidence of typical BCR-ABL1 transcript [e14a2 and/or e13a2] at the time of screening which is amenable to standardized Real time quantitative polymerase chain reaction (RQ-PCR) quantification.

Exclusion Criteria:

Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide. Treatment with either imatinib, or nilotinib, or dasatinib or bosutinib for ≤2 weeks is allowed, but no other treatment with other tyrosine kinase inhibitors prior to randomization is permitted.
Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following:

History within 6 months prior to starting study treatment of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG)
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block)
QTc ≥ 450 ms (male patients), ≥460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula) as determined by central reading. If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc.
Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia
Concomitant medication(s) with a "Known risk of Torsades de Pointes" per www.crediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.•Inability to determine the QTcF interval
Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia). Please refer to Section 6.3.1
History of significant congenital or acquired bleeding disorder unrelated to cancer.
Major surgery within 4 weeks prior to study entry or who have not recovered from prior surgery.
History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively
History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
Other protocol-defined Inclusion/exclusion criteria will apply.

Inclusion Criteria:

Histologically confirmed, treatment naïve, locally advanced or metastatic (stage IIIB IV per AJCC version 8), squamous or non-squamous NSCLC with documented high PD L1 expression (TC ≥ 50%) as determined by the VENTANA SP263 IHC assay, as assessed by central laboratories).
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
Must have at least 1 measurable lesion per RECIST v1.1
Adequate organ and marrow function
If a participant has brain or meningeal metastases, the participant must meet the following criteria:

Have no evidence of progression by neurologic symptoms or signs for at least 4 weeks prior to the first dose.
Participants with previously treated brain metastases may participate provided they have stable central nervous system (CNS) disease for at least 4 weeks prior to enrollment. Stable CNS disease is defined as resolution of all neurologic symptoms to baseline, having no evidence of new or enlarging brain metastases, and not requiring use of corticosteroids for CNS disease for at least 14 days prior to the start of study treatment. Participants who have had brain metastases resected or have received whole brain radiotherapy ending at least 4 weeks (or stereotactic radiotherapy ending at least 2 weeks) prior to initiation of study treatment are permitted.
Carcinomatous meningitis is excluded regardless of clinical stability.
Exclusion Criteria:

Presence of any tumor genomic aberration or driver mutation for which a targeted therapy is approved by local health authority and available
Use of any live vaccines against infectious diseases within 28 days of first dose
Any active autoimmune disease or a documented history of autoimmune disease or syndrome that required systemic treatment in the past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), except for vitiligo or resolved childhood asthma/atopy.
Prior malignancy active within the previous 2 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix, breast, or prostate cancer
Prior treatment with any anti-PD-1, anti-PD-L1 or any other antibody targeting an immune checkpoint.
Other protocol defined Inclusion/Exclusion criteria may apply.

Principal inclusion criteria
1. Male or female participants ≥ 18 years at the time of informed consent. Refer to protocol appendix 4 for reproductive criteria for male (protocol section 10.4.1) and female (protocol section 10.4.2) participants.
2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
Note: Locally advanced disease must not be amenable for treatment with curative intent.
4. Presence of at least 1 measurable lesion as detected by radiological and/or photographic methods according to RECIST v1.1.
Note: Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional therapy, are not considered measurable unless there has been documented progression of the lesion.
Note: If baseline scans from an institution other than the investigational site are used, the site must obtain copies of the scans prior to enrolment of the participant, or the scans must be repeated at the investigational site and submitted for independent review (Phase 3 only).
Note: Clinical lesions will only be considered measurable when they are superficial and ≥ 10 mm diameter as assessed using calipers (eg, skin nodules). When lesions can be evaluated by both clinical exam and imaging, imaging evaluation should be performed and submitted for independent review (Phase 3 only).
5. ECOG performance status 0 or 1.
6. Documented evidence of a BRAF V600E or V600K mutation in melanoma tumor tissue as previously determined by either PCR or NGS-based local laboratory assay (eg, US FDA-approved test, CE-marked [European conformity] in vitro diagnostic in EU countries, or equivalent), obtained during the course of normal clinical care, in a CLIA- or similarly certified laboratory.
7. Submission of adequate tumor tissue (archival or newly obtained; block or slides; see protocol section 8.7.2) to the sponsor central laboratory(ies) during the screening period and prior to enrollment (SLI)/randomization (Phase 3).
Note: Whenever possible, the archival sample should be from the same tumor block that was used for local BRAF V600E/K mutation testing.
Note: A newly obtained tumour tissue biopsy must be provided prior to enrolment (SLI)/ randomization (Phase 3) for participants unable to provide adequate archival tumour tissue. If a newly obtained biopsy is taken, the biopsy should be taken from a nontarget lesion when possible.
Note: Confirmation of the BRAF V600E/K mutation from the central laboratory is required (see protocol section 8.7.2). If results from the central laboratory are indeterminate or indicate insufficient tissue, additional samples must be submitted (see protocol section 8.7.2).
8. SLI Participants: Have not received more than 1 prior systemic therapy for metastatic or locally advanced melanoma.
Note: Prior neoadjuvant therapy for early-stage disease does not count as prior systemic therapy.
Note: Participants who receive adjuvant therapy and had evidence of disease recurrence ≤ 6 months after the last dose of adjuvant treatment will be considered as having received prior first line therapy.
Phase 3 Participants: Have not received prior first-line systemic therapy for metastatic or unresectable locally advanced melanoma.
Note: Participants with complete surgical resection of locally advanced or metastatic disease (eg, definitive treatment of all sites of metastases), who receive up to 12 months of systemic adjuvant therapy are eligible for the study provided there is no evidence of disease recurrence ≤ 6 months after the last dose of adjuvant treatment.
Note: Participants who receive any neoadjuvant therapy for early stage disease are eligible for the study.
Note: Prior adjuvant therapy with a BRAFi and/or MEKi or anti-PD-1 or CTLA-4 agents is permitted.
Note: Participants who receive adjuvant treatment for up to 12 months, and have evidence of disease recurrence during treatment or ≤ 6 months after the last dose of treatment would be considered as receiving first-line therapy and are therefore not eligible for study participation.
9. Adequate bone marrow, hepatic and renal function, characterized by screening results specified in protocol section 5.1.
For a full list please see protocol section 5.1.

Principal exclusion criteria
1. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study (including, but not limited to, a participant who is rapidly progressing or has
clinically significant tumor related symptoms, in the judgment of the investigator).
2. Mucosal or ocular melanoma.
3. Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
Note: Participants with diabetes type I, controlled asthma, Graves’ disease, Hashimoto’s disease or hypo- or hyperthyroid disease are exceptions and may participate.
Note: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered a form of immunosuppressive agents and are permitted.
4. Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
5. Unable to swallow, retain, and absorb oral medications.
6. Impairment of GI function or disease which may significantly alter the absorption of oral study intervention (eg, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, including malabsorption syndrome secondary to prior GI surgery).
7. Clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) ≤ 6 months prior to enrollment (SLI)/randomization (Phase 3);
b. Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
c. LVEF < 50% as determined by ECHO or MUGA scan;
d. Uncontrolled hypertension, defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg, despite therapy;
e. History or presence of clinically significant cardiac arrhythmias (including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
f. Triplicate average QTcF interval ≥ 480 ms at Screening or a history of prolonged QT syndrome.
8. History of thromboembolic or cerebrovascular events ≤ 12 weeks prior to enrollment (SLI)/randomization (Phase 3). Examples include transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (ie, massive or sub-massive) deep vein thrombosis or pulmonary emboli.
9. History or current evidence of RVO or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes).
10. Concurrent neuromuscular disorder that is associated with the potential of elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
11. Current noninfectious pneumonitis/interstitial lung disease or history of noninfectious pneumonitis/interstitial lung disease requiring steroids, or history of radiation pneumonitis.
12. Evidence of HBV or HCV infection.
13. Known history of a positive test for HIV or known AIDS. Testing for HIV must be performed at sites where mandated locally.
14. Any active infection requiring systemic therapeutic treatment within 2 weeks prior to enrollment (SLI)/ randomization (Phase 3).
15. Participants with prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
16. Concurrent or previous other malignancy within 2 years of study entry, except curatively treated basal or squamous cell skin cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen’s disease and Gleason ≤ 6 prostate cancer. Participants with a history of other curatively treated cancers must be reviewed with the sponsor or designee prior to entering the study.

For a full list please see section 5.2 of the protocol.

Principal inclusion criteria
- Participant is an adult ≥ 18 years old at the time of informed consent and has signed informed consent before any trial related activities and according to local guidelines
- Participant has a histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory.
- Participant has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (Fluorescent in situ hybridization (FISH), Chromogenic in situ hybridization (CISH), or Silver-enhanced in situ hybridization (SISH)) test is required by local laboratory testing.
- Participant has at least one measurable lesion as per RECIST v1.1 criteria as assessed by Investigator (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation).
- Participant has recurrence or progression of disease during or after combined AI (i.e. letrozole, anastrozole, exemestane) and CDK4/6 inhibitor therapy. The combined AI and CDK4/6 inhibitor therapy does not need to be the latest treatment regimen (including adjuvant setting).
- Participant has received ≤ 2 prior lines of systemic therapies overall in
the metastatic setting, of which a maximum of 1 line of prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy) is
permitted.
- The presence of a PIK3CA mutation(s) determined in tumor tissue prior
to enrollment either by a Novartis designated laboratory or in tumor
tissue or plasma ctDNA by a local laboratory usinga Food and Drug
Administration (FDA)-approved PIK3CA Companion Diagnostics (CDx)
test for alpelisib or the CE IVD QIAGEN Therascreen® PIK3CA RGQ PCR test.
- If female, then the participant must be in postmenopausal status

Further inclusion criteria and details are described in the protocol

Principal exclusion criteria
- Participant with symptomatic visceral disease or any disease burden that makes the participant ineligible for endocrine therapy (ET) per the investigator’s best judgment.
- Participant who relapsed with documented evidence of progression more than 12 months from completion of (neo)adjuvant endocrine/endocrine-based therapy with no treatment for metastatic disease
- Participant has received prior treatment with fulvestrant, any oral
selective estrogen receptor degrader (SERD), any Phosphatidylinositol-3-Kinase (PI3K), mammalian Target of Rapamycin (mTOR) or Protein Kinase B (AKT) inhibitor

Further exclusion criteria and details are described in the protocol

Inclusion Criteria
• Part 1: Breast Cancer (BC)
o Refractory Hormone Receptor Positive (HR+), Human Epidermal Growth Factor Receptor 2 Negative (HER2-) BC
o Part 1A/Part 1D/Part1E also include: Refractory HR-positive/HER2-positive BC
• Part 1: Tumors other than BC (Part 1A/Part 1D/Part 1E): NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests
• Part 1F: prostate cancer
• Part 2A, 2B and 2C:
o HR-positive/HER2-negative BC
o Patients who are either postmenopausal women or pre/peri-menopausal (Part 2C only)
• Part 1D: metastatic castration resistant prostate cancer
• Lesion:
o Part 1: evaluable lesion (including skin or bone lesion only)
o Part 2A, 2B and 2C: measurable lesion per RECIST v1.1
o Part 2D: Participants with evaluable disease as per PCWG3; participants with bone metastases only are allowed. Participants with biochemical recurrence only are excluded.
• Prior systemic Treatment
o Part 1: HR-positive/HER2-negative BC
 At least 1 line of SOC, including CD4/6 inhibitor therapy for advanced or metastatic disease, or if CDK4/6 inhibitors are not considered appropriate in the opinion of the investigator
 At least 1 line of anti-endocrine in countries without CDK4/6 inhibitor approval or reimbursement, for advanced or metastatic disease
 HR-positive/HER2-positive BC (Parts 1A/1D/1E): at least 1 prior treatment of approved HER2 targeting therapy
 Tumors other than BC (Parts 1A/1D/1E/1F): tumor that is resistant to at least 2 lines of SOC for advanced or recurrent disease or for which no standard therapy is available
o Part 2A: participants must have received at least 1 line of standard of care (including prior CDK4/6i) for advanced/metastatic disease; Prior chemo is allowed; Prior fulvestrant, mTOR and/or PI3K inhibitors are allowed
o Part 2B: participants who have not received any prior systemic anti-cancer therapies for advanced/metastatic BC
o Part 2C:
 Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre or perimenopausal, or
 Progressed while on or within 1 month after the endo the prior aromatase inhibitor therapy for advanced/metastatic BC if postmenopausal or prior endocrine treatment for advanced/metastatic BC if pre or perimenopausal
 One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy
o Part 2D:
 Received prior abiraterone; enzalutamide and CDK4i naive
 0-1 line of chemotherapy is allowed General Inclusion Criteria
• All participants must be refractory to or intolerant of existing therapies known to provide clinical benefit for their condition.
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1
• Adequate renal, liver, and bone marrow function
Exclusion Criteria:
• Part 1D: participants who have had a gastrectomy or have dietary or other restrictions that preclude a 10 hour overnight fast or consumption of the high fat, high calorie meal
• Part 2B: prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor with disease recurrence while on or within 12 months of completing treatment. Prior treatment with any CDK4/6 inhibitor
• Part 2C: prior treatment with any CDK inhibitor, fulvestrant, everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway
• Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases carcinomatous meningitis, or leptomeningeal disease
• Other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ
• Major surgery or radiation within 4 weeks prior to study intervention
• Last anti-cancer treatment within 2 weeks prior to study intervention
• Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry
• Pregnant or breastfeeding female participant
• Active inflammatory gastrointestinal (GI) disease, known diverticular disease or previous gastric resection or lap band surgery including impairment of gastrointestinal function or GI disease

Inclusion Criteria:

- Histological or cytological diagnosis of SCCHN, RCC (clear cell and papillary cell), ovarian, gastric, esophageal (adeno and squamous), lung squamous cell, pancreatic and biliary duct, endometrial, melanoma, or urothelial cancer.

Part 2:

Arm A SCCHN:

Primary tumor location of the oral cavity, oropharynx, hypopharynx or larynx.
PDL-1 expression positive and CPS ≥1. No prior systemic therapy administered in the recurrent or metastatic setting (except for systemic therapy given as part of a multimodal treatment for locally advanced disease).
Arm B RCC (clear cell):

1 or 2 prior lines of therapy including PD-L1/PD-1 immunotherapy in combination or sequentially with antiangiogenic directed treatment
Adequate bone marrow, kidney and liver function.
Performance status of 0 or 1.
Exclusion Criteria:

Participant disease status is suitable for local therapy administered with curative intent.
Hypertension that cannot be controlled by medications.
Active or prior autoimmune disease
Active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) Hepatitis B, Hepatitis C, and known Human Immunodeficiency Virus infection or Acquired Immunodeficiency Syndrome-related illness

Inclusion Criteria:

Participants must have c-Met overexpressing non-small cell lung cancer (NSCLC) as assessed by an AbbVie designated immunohistochemistry (IHC) laboratory using the VENTANA MET (SP44) RxDx assay.
Archival or fresh tumor material must be submitted for assessment of c-Met levels during the Pre-Screening period. Tumor material from the primary tumor site and/or metastatic sites are allowed.

If a participant was prescreened for Study M14-239 but did not enroll, tumor material previously submitted for Study M14-239 may be used for Study M18-868 Pre-Screening upon confirmation from AbbVie that sufficient evaluable tumor material is available (Except China).
A histologically documented non-squamous cell NSCLC that is locally advanced or metastatic.
A known epidermal growth factor receptor (EGFR) activating mutation status.
Actionable alterations in genes other than EGFR .
Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
An Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 1.
Have received no more than 1 line of prior systemic cytotoxic chemotherapy in the locally advanced or metastatic setting.

Neoadjuvant and adjuvant systemic cytotoxic chemotherapy will count as a prior line for eligibility purposes if progression occurred within 6 months of the end of therapy.
Have progressed on at least 1 line of prior therapy for locally advanced/metastatic NSCLC:

Participants WITHOUT an actionable gene alteration: must have progressed on (or be considered ineligible for) platinum-based chemotherapy and immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy).
Participants WITH an actionable gene alteration for which immune checkpoint inhibitor therapy is not standard of care (e.g., anaplastic lymphoma kinase [ALK] translocation): must have progressed on (or be considered ineligible for) anti-cancer therapy targeting driver gene alterations and platinum-based chemotherapy.

Participants with actionable gene alterations for which immune checkpoint inhibitor is standard of care must have also progressed on (or be considered ineligible for) immune checkpoint inhibitor (as monotherapy or in combination with chemotherapy).
Must be considered appropriate for docetaxel therapy based on the assessment of the treating physician.
Participants with metastases to the central nervous system (CNS) are eligible only after definitive therapy (such as surgery or radiotherapy) is provided and:

There is no evidence of progression of CNS metastases at least 2 weeks after definitive therapy.
They are asymptomatic and off or on a stable or reducing dose of systemic steroids and/or anticonvulsants for at least 2 weeks prior to first dose of telisotuzumab vedotin.

Exclusion Criteria:
Participants with adenosquamous histology.
Actionable epidermal growth factor receptor (EGFR) activating mutations.
Participants who have received prior c-Met-targeted antibodies, prior telisotuzumab vedotin, or prior antibody-drug conjugates either targeting c-Met or consisting of monomethylauristatin E..
Participants who have received prior docetaxel therapy.
A history of other malignancies except:

Malignancy treated with curative intent and with no known active disease present for >=2 years before the first dose of study drug and felt to be at low risk for recurrence by investigator.
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
Adequately treated carcinoma in situ without current evidence of disease.
A history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. A history of prior radiation pneumonitis in the radiation field (fibrosis) is permitted.
Unresolved adverse event (AE) >= Grade 2 from prior anticancer therapy, except for alopecia or anemia.
Major surgery within 21 days prior to the first dose of telisotuzumab vedotin.
Clinically significant condition(s) as listed in the protocol.

Inclusion Criteria:
patients with ALL (except for patients with mature B-ALL) who fulfil the following criteria:
• Age at diagnosis ≤ 18 years or age at HSCT ≤ 21 years
• Indication for allogeneic HSCT
• Complete remission (CR) before SCT
• Written consent of the parents (legal guardian) and, if necessary, with minor patients via “Informed Consent Form“
• No pregnancy
• No secondary malignancy
• No previous HSCT
• HSCT is performed in a study participating centre
Exclusion Criteria:
• Patients who do not fulfill the inclusion criteria
• Non-Hodgkin-Lymphoma
• The whole protocol or essential parts are declined either by patient himself/ herself or the respective guardian
• No consent in given for saving and propagation of anonymous medical data for study success
• Severe concomitant disease that doesn’t allow treatment according the protocol at the investigators discretion (e.g. malformation syndromes, cardiac malformations, metabolic disorders)
• Karnofsky/ Lansky score < 50%
• Subject unwilling or unable to comply with the study procedures

Principal inclusion criteria
Patients must meet all the following inclusion criteria to be eligible for
enrollment in the study:
1. Histologically confirmed relapsed or refractory solid tumor as follows:
•For dose escalation and dose determination parts: Histologically
confirmed relapsed or refractory solid tumor (including CNS tumors but
not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not
require histological only radiographic confirmed relapse to enroll.
•For dose expansion cohorts: Histologically confirmed relapsed or
refractory solid tumor including but not limited to EWS, rhabdoid tumor,
rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with
Diffuse Intrinsic Pontine Glioma do not require histological only
radiographic confirmed relapse to enroll.
•For tumor-specific cohorts: Histologically confirmed relapsed or
refractory solid tumor including but not limited to EWS, rhabdoid tumor,
rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with
Diffuse Intrinsic Pontine Glioma do not require histological only
radiographic confirmed relapse to enroll.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma
at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS
rearrangement. Histopathology confirmation of both EWSR1-ETS or
FUSETS rearrangement partners is required OR availability of formalin
fixed paraffin embedded (FFPE) tumor tissue sample for central testing.
Patient must have relapsed or have refractory disease and at least
evaluable disease in at least one site other than bone marrow that can
be followed by imaging.
2. Age ≥2 and <21 years at the time of study entry. Refer to Section 4.3
for reproductive criteria for male and female participants.
3. Lansky performance status ≥50% for patients ≤16 years of age, or
Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16
years of age.
4. Adequate bone marrow function.
•Absolute neutrophil count ≥1000/mm3;
•Platelet count ≥75,000/mm3 (transfusion independent, no platelet
transfusion in
past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender
must be less than or equal to the following maximum upper limits as
shown in Table 10:
Table 10. Maximum Allowed Creatinine Levels
Age Maximum Serum Creatinine (mg/dL)
Male Female
2 to <6 years 0.8 0.8
6 to <10 years 1.0 1.0
10 to <13 years 1.2 1.2
13 to <16 years 1.5 1.4
16 to <21 years 1.7 1.4
The threshold creatinine values in this table were derived from the
Schwartz formula for estimating glomerular filtration rate utilizing child
length and stature data published by the CDC.
6. Adequate liver function, including:
•Aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable
to disease involvement of the liver;
•Total bilirubin ≤1.5 × ULN for age unless the patient has documented
Gilbert's syndrome. Patients with documented Gilbert's syndrome are
eligible if direct bilirubin is within normal ranges (≤ULN).
7. Patients enrolled to Phase 1 portion of the study and tumor specific
cohorts must have measurable disease as defined by RECIST version 1.1
or modified RANO criteria for CNS disease or at least evaluable disease
by INRC for neuroblastoma.
The eligible patients with neuroblastoma must have at least one of the
following at the time of study entry:
•Measurable tumor by CT or MRI that is avid on MIBG scan or
demonstrates increased FDG uptake on PET scan;
•Avid lesion on MIBG scan with positive uptake at a minimum of one
site;
•For disease that is not avid by MIBG-scan, at least one lesion that
demonstrates increased FDG uptake on PET scan AND viable
neuroblastoma confirmed by current or prior biopsy;
•bone marrow involvement with more than 5% neuroblastoma cells in at
least one sample from bilateral bone marrow biopsies;
•In non MIBG-avid refractory soft tissue disease that does not demonstrate increased FDG uptake; lesion biopsy is required to
document the presence of viable neuroblastoma, unless patient has a
new soft tissue lesion (radiographic
evidence of disease progression). Patients with EWS enrolled to Phase 2
portion of the study are eligible with at least evaluable disease (eg, bone
only disease with no soft tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any nonhematological
acute toxicities of prior surgery, chemotherapy,
immunotherapy, radiotherapy, differentiation therapy or biologic
therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at
screening and at the baseline visit.

Principal exclusion criteria
Patients with any of the following characteristics/conditions will not be
included in the study:
1. Phase 1 portion and tumor specific cohorts: For palbociclib with IRN
and TMZ combination, prior treatment with a CDK4/6 inhibitor or
progression while on treatment with an IRN-containing regimen that
includes TMZ. Patients who have
received the combination of IRN and TMZ and did not progress while on
these medications are eligible. For patients enrolling in the palbociclib
with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor
or progression while on treatment with a TOPO-containing regimen that
includes CTX. Patients who have received the combination of TOPO and
CTX and did not progress while on thesemedications are eligible. Phase 2
portion: prior treatment with a CDK4/6 inhibitor or progression while on
treatment with an IRN-containing or TMZ-containing regimen. Patients
who have received IRN and/or TMZ and did not progress while on these
medications are eligible.
2. Prior intolerability to IRN and/or TMZ for IRN and TMZ plus/minus
palbociclib combinations and prior intolerability to TOPO and/or CTX for
TOPO and CTX combination. For patients enrolled in the UK, any
contraindication for IRN and/or TMZ treatment, as per the local SmPC.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers within
12 days of study entry. Patients who are receiving strong uridine
diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12
days of C1D1 are not eligible for the palbociclib with IRN and TMZ
combination. Patients who are receiving strong UGT1A1 inhibitors within
12 days of C1D1 are eligible for the palbociclib with TOPO and CTX
combination
4. Systemic anticancer therapy within 2 weeks prior to study entry and 6
weeks for nitrosoureas.
5. Prior irradiation to >50% of the bone marrow
6. Participation in other studies involving investigational drug(s) within
2 weeks or 5 halflives, whichever is longer, prior to study entry
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or
central line placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or
suspected hypersensitivity to palbociclib, dacarbazine, IRN and/or TMZ.
For combination of palbociclib with TOPO and CTX: known or suspected
hypersensitivity to palbociclib, TOPO and/or CTX.
9. Patients with known symptomatic brain tumors or brain metastases
and require steroids, unless they have been on a stable or on a
decreasing steroid dose for >14 days.
10. Patients with previously diagnosed brain metastases are eligible if
they have completed their prior treatment and have recovered from the
acute effects of radiation therapy or surgery prior to study entry for
these metastases for at least 14 days postradiation and 4 weeks post surgery and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease,
including:
History of or active congestive heart failure; if patient had congestive
heart failure
resolve and >1 year from resolution, patient will be considered eligible;
•Clinically significant ventricular arrhythmia (such as ventricular
tachycardia,
ventricular fibrillation or Torsades de Pointes);
•Diagnosed or suspected congenital or acquired prolonged QT syndrome;
•Need for medications known to prolong the QT interval;
•Uncorrected hypomagnesemia or hypokalemia because of potential
effects on the QT interval;
•Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that
may interfere with absorption of orally administered drugs (eg,
gastrectomy).
15. Evidence of serious active or uncontrolled bacterial, fungal or viral
infection or known history of hepatitis B virus, hepatitis C virus, or
human immunodeficiency virus infection or acquired immunodeficiency
syndrome-related illness. Screening for viral hepatitis and HIV is under
discretion of investigator unless required by local regulation.
16. Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
17. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
18. Fertile male patients or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements as detailed in Section 4.3.
19. Pregnant or breastfeeding women.

Inclusion Criteria:

Locally confirmed microsatellite instability-high/ deficient mismatch repair (MSI-H/dMMR) stage IV colorectal carcinoma
Locally confirmed BRAF V600E mutation in tumor tissue or blood
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Have not received prior systemic regimens for metastatic disease.
Measurable disease per RECIST 1.1
Adequate organ function

Exclusion Criteria:

Colorectal adenocarcinoma that is RAS mutant or for which RAS mutation status is unknown
Known active central nervous system metastases and/or carcinomatous meningitis; leptomeningeal disease
Immunodeficiency or active autoimmune disease requiring systemic treatment in the past 2 years
Presence of acute or chronic pancreatitis
Clinically significant cardiovascular diseases (eg, thromboembolic or cerebrovascular accident events ≤ 12 wks prior)
Received a live or live-attenuated vaccine within 30 days of planned start of study medication
Previous treatment with any selective BRAF inhibitor (eg, encorafenib, dabrafenib, vemurafenib, XL281/BMS-908662) or any epidermal growth factor receptor (EGFR) inhibitor (eg, cetuximab, panitumumab).
Previous treatment with an immune checkpoint inhibitor (eg, anti-programmed cell death [PD-1], anti-PD-L1 or anti-PD-L2 agent); or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).

Inclusion Criteria:

Histologically and/or cytologically confirmed adenocarcinoma of the colon or rectum which is metastatic and/or unresectable
Able to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue blocks (or freshly sectioned slides) obtained prior to treatment initiation to a central laboratory

If archival tissue is not available, a newly-obtained baseline biopsy of an accessible tumor lesion is required within 35 days prior to start of study treatment
HER2+ disease as determined by a tissue based assay performed at a central laboratory.
Participant has rat sarcoma viral oncogene homolog wild-type (RAS WT) disease as determined by local or central testing
Radiographically measurable disease per RECIST v1.1 with:

At least one site of disease that is measurable and that has not been previously irradiated, or
If the participant has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
CNS Inclusion - based on contrast brain magnetic resonance imaging, participants may have any of the following:

No evidence of brain metastases
Previously treated brain metastases which are asymptomatic
Exclusion Criteria:

Prior systemic anticancer therapy for colorectal cancer (CRC) in the metastatic setting

May have received chemotherapy for CRC in the adjuvant setting if it was completed >6 months prior to enrollment
Radiation therapy within 14 days prior to enrollment (or within 7 days in the setting of stereotactic radiosurgery)
Previous treatment with anti-HER2 therapy
Ongoing Grade 3 or higher neuropathy
GI perforation within 12 months of enrollment

Inclusion Criteria:

Eastern Cooperative Oncology Group (ECOG) performance status score 0 to 2.
Participant has:

Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan demonstrating positive lesion compatible with computed tomography (CT) or magnetic resonance image (MRI)-defined anatomical tumor sites AND
>= 1 measurable nodal lesion (long axis > 1.5 cm) or >= 1 measurable extra-nodal lesion (long axis > 1.0 cm) on CT scan or MRI.
Histologically confirmed classic follicular lymphoma (FL) [previously Grade 1 to 3a FL] stage II, III, or IV with no evidence of histologic transformation to an aggressive lymphoma and CD20+ disease on most recent representative tumor biopsy based on the pathology report.
Relapsed or refractory (R/R) disease to at least one prior systemic regimen that contained an anti-CD20 monoclonal antibody (mAb) in combination with chemotherapy. (Participant who received only prior anti-CD20 mAb monotherapy and/or radiation therapy is not eligible.)
Eligible to receive R2 per investigator determination.
Exclusion Criteria:

Documented refractoriness to lenalidomide.
Have lenalidomide exposure within 12 months prior to randomization.

Key Inclusion Criteria:

Individuals, regardless of race and ethnic group, with previously untreated locally advanced, inoperable or metastatic triple-negative breast cancer (TNBC)

Individuals whose tumors are programmed cell death ligand 1 (PD-L1) negative at screening or individuals whose tumors are PD-L1 positive at screening if they have received an anti-PD-(L)1 inhibitor in the (neo)adjuvant setting
Centrally confirmed TNBC and PD-L1 status on fresh or archival tissue
Individuals must have completed treatment for Stage I-III breast cancer, if indicated, and ≥ 6 months must have elapsed between completion of treatment with curative intent and first documented local or distant disease recurrence
Individuals presenting with de novo metastatic TNBC are eligible
Measurable disease based on computed tomography (CT) or magnetic resonance imaging (MRI) in accordance with per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. as evaluated locally
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Demonstrates adequate organ function
Male individuals and female individuals of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception
Individuals with human immunodeficiency virus (HIV) must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease
Key Exclusion Criteria:

Positive serum pregnancy test or women who are lactating
Received systemic anticancer treatment within the previous 6 months or radiation therapy within 2 weeks prior to enrollment
Have not recovered from adverse events (AEs) due to a previously administered agent at the time study entry
May not be participating in a study with an investigational agent or investigational device within 4 weeks prior to randomization. Individuals participating in observational studies are eligible
Previously received topoisomerase 1 inhibitors or antibody drug conjugates containing a topoisomerase inhibitor
Active second malignancy
Active serious infection requiring antibiotics
Positive for HIV-1 or 2 with a history of Kaposi sarcoma and/or Multicentric Castleman Disease
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
Note: Other protocol defined Inclusion/Exclusion criteria may apply.

INCLUSION CRITERIA:

INFORMATION FOR TRIAL PARTICIPANTS - Participants can join the trial if they:

Have advanced breast cancer that is not able to be treated with surgery or radiation;
Have an ESR1 mutation in their cancer;
Have breast cancer that is HR-positive and HER2-negative;
Are currently being treated with a CDK4/6 inhibitor and an AI and have been taking these drugs for at least 6 months;
Have not had their cancer get worse after taking an AI and CDK4/6 inhibitor;
Are able to do their daily activities;
Are at least 18.
Full list of inclusion criteria:

Proven diagnosis of adenocarcinoma of the breast with evidence of locoregionally recurrent or metastatic disease not amenable to resection or radiation therapy with curative intent;
Documentation of histologically confirmed diagnosis of estrogen receptor positive (ER+) /HER2- breast cancer based on local laboratory results;
Currently on AI (letrozole or anastrozole) + CDK4/6 inhibitor (palbociclib or abemaciclib) ± LHRH as the initial endocrine based treatment for advanced disease;
Eastern Cooperative Oncology Group performance status of 0 or 1;
ESR1m detected by central testing of ctDNA;
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures;
Adequate organ and marrow function.
EXCLUSION CRITERIA:

INFORMATION FOR TRIAL PARTICIPANTS - Participants cannot join the trial if they:

Had certain types of tumors in the past that may come back;
Are currently taking any other treatments for their cancer or other conditions including hormone replacements, medications, or supplements that could interfere with the trial treatment;
Have or have had any major health problem, infection, or recent surgery that could make it difficult or dangerous to participate in this trial.
Full list of exclusion criteria:

Advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term;
Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease;
Any evidence of severe or uncontrolled systemic diseases which, in the investigator's opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol;
Patient with known or family history of severe heart disease;
Previous treatment with AZD9833, investigational SERDs or fulvestrant;
Currently pregnant (confirmed with positive pregnancy test) or breastfeeding;
Persistent non-haematological toxicities (CTCAE Grade > 2) caused by CDK4/6 inhibitor and/or AI treatment.

Inclusion Criteria:

Histologically confirmed unresectable or metastatic melanoma, per the American Joint Committee on Cancer (AJCC) staging system (unresectable Stage III or Stage IV)
Radiologically measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1
Known v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation status
Adequate cardiovascular, hematological, hepatic and renal function
Willingness to abide by contraceptive measures for the duration of the study
Participants must have known PD-L1 status
Exclusion Criteria:

Pregnancy, lactation, or breastfeeding
Known hypersensitivity to any of the components of RO7247669
Participants must not have ocular melanoma
Symptomatic central nervous system (CNS) metastases
Significant cardiovascular/cerebrovascular disease within 6 months prior to randomization
Known active or uncontrolled bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization within 28 days prior to randomization
Major surgical procedure or significant traumatic injury (excluding biopsies) within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study
Active or history of autoimmune disease or immune deficiency with some exceptions
Prior systemic anticancer therapy for unresectable or metastatic melanoma
Prior anticancer therapy with any-immunomodulatory agents including CPIs (such as anti-programmed death-ligand 1[PD-L1]/PD-1 and anti-cytotoxic T lymphocyte-associated antigen [CTLA-4]) with some exceptions if used as prior adjuvant or neoadjuvant melanoma therapies
Prior treatment with anti-LAG3 therapy

Inclusion Criteria:

Male or female participants between 1 and <18 years of age.
Morphologically confirmed diagnosis of first relapse HR BCP ALL; HR first relapse is defined as relapse occurring within 18 to 30 months of original diagnosis of ALL or within 6 months of completion of primary therapy, and lacking any identified very high-risk genetic abnormalities (ie, KMT2A-rearrangements, TCF3-HLF, TCF3-PBX1, hypodiploidy, TP53 alteration)

CD22-positive ALL as defined by local institution;
Bone marrow involvement of ≥ 5% leukemic blasts (≥ M2 status).
Adequate serum chemistry parameters:

An eGFR in participants 1 to <2 years of age, or eCrCl in those 2 to <18 years of age, ≥30 mL/min using the recommended formula in Section 10.10.2.
AST and ALT ≤5 × institutional ULN at the time of randomization or pre-cytoreduction/general anesthesia;
Total bilirubin ≤1.5 × institutional ULN unless the participant has documented Gilbert's syndrome;
Prior history of thrombosis during corticosteroid use and/or asparaginase are eligible provided the patient receives anti-coagulant prophylaxis per institutional guidelines.
Cardiac shortening fraction ≥ 30% by echocardiogram or ejection fraction >50% by MUGA.

Exclusion Criteria

Any history of prior or ongoing hepatic SOS or prior liver failure [defined as severe acute liver injury with encephalopathy and impaired synthetic function (INR of ≥1.5)].
Prior allo-HSCT or CAR T-cell therapy.
Isolated extramedullary leukemia.
Philadelphia-chromosome positive ALL, ie. BCR-ABL/t(9;22) present.
Prior therapy with a calicheamicin-conjugated antibody (eg, InO or gemtuzumab ozogamicin).
Participants with active, uncontrolled bacterial, fungal, or viral infection.

Inclusion Criteria:

Group 1: Must have newly diagnosed, pathologically confirmed classical Hodgkin Lymphoma (cHL) at Stages IA, IB and IIA without bulky disease. Group 2: Must have newly diagnosed, pathologically confirmed cHL at Stages IIEB, IIIEA,IIIEB, IIIB, IVA and IVB
Has measurable disease per investigator assessment.
Male participants are eligible to participate if they agree to the following during the intervention period: refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent or must agree to use contraception per protocol unless confirmed to be azoospermic.
Female participants who are not pregnant or breastfeeding, and who are either not a woman of childbearing potential (WOCBP), or are a WOCBP who agrees to use approved contraception during the intervention period and for at least 120 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period.
Performance status: Lansky Play-Performance Scale ≥50 for children up to 16 years of age OR Karnofsky score ≥50 for participants ≥ 16 years of age
Has adequate organ function

Exclusion Criteria:

Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic stem cell transplantation within the last 5 years
WOCBP who has a positive urine pregnancy test within 24 hours before the first dose of study treatment
Baseline left ventricular ejection fraction value <50% or shortening fraction of <27%
Has received prior therapy with an anti-Programmed Death (PD)-1, anti-Programmed Death-Ligand 1 (PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor or has previously participated in a MSD pembrolizumab (MK-3475) clinical study
Has received any prior systemic anti-cancer therapy,including investigational agents for current diagnosis before randomization
Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
Has a diagnosis of lymphocyte-predominant Hodgkin Lymphoma (HL)
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of pembrolizumab
Has a known additional malignancy that is progressing or requires active treatment within the past 3 years
Has radiographically detectable central nervous system metastases and/or carcinomatous meningitis as assessed by local site investigator at the time of diagnosis
Has severe hypersensitivity (≥Grade 3) to any study therapies including any excipients
An active autoimmune disease that has required systemic treatment in past 2 years
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease
Has an active infection requiring systemic therapy
Has a known history of human immunodeficiency virus (HIV) infection
Has a known history of Hepatitis B or known active Hepatitis C virus infection
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator
Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study
Participants who have not adequately recovered from major surgery or have ongoing surgical complications

Principal inclusion criteria
1. Subject must be a man in the age of 18 – 79 years
2. Each subject must sign an informed consent form (ICF) indicating that he understands the purpose and procedures required for the study and is willing to participate in the study. Subjects must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
3. Indicated and planned to receive primary RT for prostate cancer.
4. Histologically confirmed adenocarcinoma of an intact prostate and one of the following risk factors for EUA high-risk localized or locally prostate cancer (see Attachment 1) 14 at diagnosis:
• Localized high-risk prostate cancer: PSA >20 ng/ml or GS >7 (ISUP grade 4/5) or cT2c
• Locally advanced high-risk prostate cancer: cT3 – 4 or cN+, any PSA, any ISUP grade
5. Modified Charlson comorbidity index (CCI) ≤4 (Attachment 2)
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) grade 0 or 1 (Attachment 2)
7. Adequate organ function determined by the following local laboratory values:
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin within normal limits (WNL)
• Serum creatinine <133 umol/l
• Thrombocytes ≥140x109/l
• Hemoglobin ≥120 g/l (no transfusion is allowed within 3 months prior to enrollment)
8. To avoid risk of drug exposure through the ejaculate (even men with vasectomies), subjects must use a condom during sexual activity while on study drug and for 3 months following the last dose of study drug. Donation of sperm is not allowed during the Treatment Phase and for 3 months following the last dose of study drug.
9. Be able to swallow whole study drug tablets, undergo prostate MR, prostate seeds implantation and prostate radiotherapy in supine position.

Principal exclusion criteria
1. Presence of distant metastasis on conventional imaging or 68Ga PSMA/PET (clinical stage M1). Isolated pelvic nodal disease below the iliac vessels bifurcation (clinical stage N1) is not an exclusion.
2. Prior treatment with LHRH agonist/antagonist analogue or anti-androgen or both for >3 months prior to enrollment.
3. Bilateral orchiectomy
4. History of pelvic radiation
5. Prior systemic (e.g., chemotherapy) or local (e.g., radical prostatectomy, cryotherapy) treatment for prostate cancer.
6. Prior treatment with enzalutamide, abiraterone acetate, orteronel, galeterone, ketoconazole, aminoglutethimide, estrogens, megestrol acetate, and progestational agents (including cyproterone acetate) for prostate cancer.
7. Prior treatment with systemic glucocorticoids ≤4 weeks prior to enrollment or subject expected to require long-term use of corticosteroids during the study.
8. Use of first-generation antiandrogen (e.g., bicalutamide) ≤4 weeks prior to enrollment.
9. Use of 5-α reductase inhibitors (e.g., dutasteride, finasteride) ≤4 weeks prior to enrollment.
10. Use of any investigational agent ≤4 weeks prior to enrollment.
11. Current chronic use of opioid analgesics, for ≥3 weeks for oral or ≥7 days for non-oral formulations.
12. Major surgery ≤4 weeks prior to enrollment
13. History of seizure or any condition that may predispose to seizure (including, but not limited to prior stroke, transient ischemic attack or loss of consciousness ≤1 year prior to enrollment; brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect).
14. Current or prior treatment with anti-epileptic medications for the treatment of seizures.
15. Gastrointestinal conditions affecting absorption.
16. Known or suspected contraindications or hypersensitivity to apalutamide or LHRH agonists/antagonist or any of the components of the formulations.
17. Any condition for which, in the opinion of the investigator, participation would not be in the best interest of the subject.

Inclusion Criteria:

Male or female participants ≥18 years of age at the time of informed consent.
Histologically confirmed unresectable (Stage IIIB, IIIC, or IIID) or metastatic (Stage IV) cutaneous melanoma, according to the AJCC 8th edition.
Documented evidence of a BRAF V600E or V600K mutation.
Submission of adequate tumor tissue for central laboratory testing of BRAF V600E-mutation and biomarkers is required for all participants during the screening period and prior to randomization.
Must have received only 1 prior line of systemic therapy for melanoma (either adjuvant therapy or first-line anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab)
Must have anti-PD-1 resistant disease (primary or secondary) with confirmed disease progression per RECIST v1.1 either during or after receipt of an approved anti-PD-1 monotherapy (ie, nivolumab or pembrolizumab) for melanoma, defined according to the SITC Immunotherapy Resistance Taskforce (Kluger et al, 2020).
Have at least one measurable lesion per RECIST v1.1.
ECOG PS of 0-1, and adequate organ and cardiac function, including LVEF ≥50% by cardiac imaging.

Exclusion Criteria:

Mucosal or ocular melanoma.
Diagnosis of immunodeficiency or an active autoimmune disease that required systemic treatment with chronic systemic steroid therapy or any other form of immunosuppressive therapy within the past 2 years.
Clinically significant cardiovascular diseases.
History of thromboembolic or cerebrovascular events ≤12 weeks prior to randomization.
History or current evidence of RVO or current risk factors for RVO.
Concurrent neuromuscular disorder that is associated with the potential of elevated CK.
Active bacterial, fungal, or viral infection requiring systemic therapeutic treatment within 2 weeks prior to randomization.
Current non-infectious pneumonitis/interstitial lung disease or history of noninfectious pneumonitis/interstitial lung disease requiring steroids.
Prior or current symptomatic brain metastasis, leptomeningeal disease or other active CNS metastases.
Participants who permanently discontinued prior anti-PD-1 therapy due to toxicity or will be unable to tolerate combination therapy based on investigator judgement are excluded.
Prior treatment with ipilimumab; prior combined immunotherapy blockade with anti-PD-1/L-1; prior treatment with a BRAFi and/or MEKi; or previous administration of an investigational anti-cancer agent for the adjuvant or first-line treatment of melanoma prior to randomization.

Inclusion Criteria:

Any participant who is receiving study intervention and deriving clinical benefit (as determined by the principal investigator) in an encorafenib/binimetinib Parent Study, with no ongoing NCI CTCAE version 4.03 Grade ≥3 or intolerable Grade 2 AEs considered to be related to study treatment.
Participants must agree to follow the reproductive criteria as outlined in the applicable Encorafenib/Binimetinib Continuation Sub-Study Protocol.

Exclusion Criteria:

Any medical reason that, in the opinion of the investigator or sponsor, precludes the participant from inclusion in the study.

Key Inclusion Criteria:

Documented active diagnosis of non-small cell lung, pancreatic, colorectal cancer
Cachexia defined by Fearon criteria of weight loss
Serum GDF-15 concentrations
Signed informed consent
ECOG PS ≤3 with life expectancy of at least 4 months to be able to complete Part A.

Key Exclusion Criteria:

Receiving tube feedings or parenteral nutrition at the time of Screening or Randomization.
Current active reversible causes of decreased food intake.
Cachexia caused by other reasons.
History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody.
inadequate liver function
renal disease requiring dialysis

Inclusion Criteria:

Planned to receive treatment with 6 cycles of standard rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP) per investigator determination.
Must have newly diagnosed, histologically confirmed CD20+ diffuse large b-cell lymphoma [DLBCL] (de novo or histologically transformed from a diagnosis of follicular lymphoma) at most recent representative tumor biopsy based on the pathology report, with a World Health Organization (WHO) 2016 classification and including:

DLBCL, Not Otherwise Specified (NOS).
High grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangement with DLBCL morphology.
T-cell/histiocyte-rich large B-cell lymphoma.
Epstein Barr virus-positive DLBCL, NOS.
Follicular lymphoma Grade 3b.
Note: The local pathology report must be available at Screening to support CD20+ DLBCL histology.

Composite/intermediate histology with any of the following components is not allowed: high grade B-cell lymphoma, NOS; Hodgkin's lymphoma; primary mediastinal (thymic) large B-cell lymphoma; Burkitt; plasmablastic lymphoma or any CD20- lymphoma, such as anaplastic lymphoma kinase-positive large B-cell lymphoma, human herpesvirus type 8-positive DLBCL, or primary effusion lymphoma.

Availability of archival or freshly collected tumor tissue at Screening. Archival paraffin-embedded tissue must be obtained within 8 weeks prior to Cycle 1 Day 1.
Must have an IPI score of 2-5. The number of participants with IPI 2 will not exceed approximately 30% of the overall sample size.
Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 prior to initiating R-CHOP treatment. Note that participant with an initial ECOG performance status >= 3 may be screened if pre-phase treatment is planned. Participant may be eligible if ECOG performance status were to improve to 0-2 during pre-phase treatment.
Has at least one target lesion defined as:

>= 1 measurable nodal lesion (long axis > 1.5 cm ) or >= 1 measurable extra-nodal lesion (long axis > 1 cm) on computed tomography (CT) scan or magnetic resonance imaging (MRI). AND
Positron emission tomography (PET)-positive on PET-CT scan.
Laboratory values meeting the criteria laid out in the protocol.
Left ventricular ejection fraction must be >= 50% by multi-gated acquisition or transthoracic echocardiography at Screening.
Exclusion Criteria:

History of prior systemic anti-lymphoma therapy for diagnosed diffuse large b-cell lymphoma (DLBCL) including any definitive radiotherapy with curative intent] other than corticosteroids with or without vincristine during prephase treatment, or non-curative intent palliative radiotherapy with the stipulation that radiated lesions cannot be selected as target lesion for response assessment.
Clinically significant cardiovascular disease as per the protocol.

Inclusion Criteria:

Have a diagnosis of ER+, HER2- early-stage, resected, invasive breast cancer without evidence of distant metastasis.
Participants must have received at least 24 months but not more than 60 months of any adjuvant ET, from time of adjuvant ET initiation.
Participants may have received (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor.
Must have an increased risk of disease recurrence based on clinical-pathological risk features.
Have a Performance Status of 0 or 1 on the Eastern Cooperative Oncology Group scale.
Have adequate organ function.

Exclusion Criteria:
Have any evidence of metastatic disease (including contralateral ALN) or inflammatory breast cancer at primary breast cancer diagnosis.
Participants with more than a 6-month consecutive gap in therapy during the course of prior adjuvant ET.
Participants who have completed or discontinued prior adjuvant ET >6 months prior to screening.
Participants with a history of previous breast cancer are excluded, with the exception of ipsilateral DCIS treated by locoregional therapy alone ≥5 years ago.
Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study intervention.
Participant has previously received ET of any duration for breast cancer prevention (tamoxifen or AIs) or raloxifene.
Participants with a history of any other cancer.
Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study.

Inclusion Criteria:

Adult participants with loco-regional recurrent or metastatic breast disease not amenable to surgical resection or radiation therapy
Confirmed diagnosis of ER+/HER2- breast cancer
Prior therapies for locoregional recurrent or metastatic disease must fulfill all the following criteria:
One line of CDK4/6 inhibitor therapy in combination with endocrine therapy. Only one line of CDK4/6 inhibitor is allowed in any setting.
≤ 1 endocrine therapy in addition to CDK4/6 inhibitor with ET
Most recent endocrine treatment duration must have been given for ≥6 months prior to disease progression. This may be the endocrine treatment component of the CDK4/6 inhibitor line of therapy.
Radiological progression during or after the last line of therapy.
Measurable disease evaluable per Response Evaluation Criterion in Solid Tumors (RECIST) v.1.1 or non-measurable bone-only disease
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Participants should be willing to provide blood and tumor tissue

Exclusion Criteria:
Participants with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term
Prior treatment with:
ARV-471, fulvestrant, elacestrant, mTOR, PI3K, AKT pathway inhibitors, PARP inhibitor for any setting
other investigational agents (including novel endocrine therapy any SERDs, SERCAs, CERANs) for any setting
prior chemotherapy for advanced/metastatic disease
Inadequate liver, kidney and bone marrow function
Active brain metastases
Participants with significant concomitant illness

Inclusion Criteria:

Age ≥ 18 years at the date of signing the informed consent form.
Follicular lymphoma grade 1, 2, or 3A confirmed histologically after latest relapse (local assessment).
Relapsed or refractory disease after a second or later line of systemic therapy including an anti-CD20 antibody and an alkylating agent.
Disease that is both active on Positron emission tomography (PET) scan (defined as a score of 4 or 5 on the Deauville 5-point scale) and measurable on Computed tomography (CT) scan.
ECOG performance status of 0, 1 or 2 at screening.
Adequate hematologic, renal, hepatic and pulmonary organ function at screening.
Must meet the institutional criteria to undergo leukapheresis (unless historical leukapheresis is available).
Must be eligible for treatment with the selected standard of care regimen.

Exclusion Criteria:
Follicular lymphoma grade 3B or evidence of histologic transformation.
Prior treatment with anti-CD19 therapy, gene therapy, or adoptive T-cell therapy.
Active CNS involvement by malignancy.
Clinically significant active infection, presence of Human immunodeficiency virus (HIV) antibody or active hepatitis B or C.
Active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré syndrome).
Investigational medicinal product within the last 30 days or five half-lives (whichever is longer) prior to randomization.
Clinically significant cardiovascular conditions such as acute coronary syndrome, significant cardiac arrhythmias, heart failure or decreased LVEF.
Other protocol defined inclusion/exclusion criteria may apply

Inclusion Criteria:
Histologically confirmed nccRCC that is unresectable, advanced or metastatic. Histologic subtypes including papillary, unclassified, and translocation-associated are allowed. Among the eligible histologic subtypes, sarcomatoid features are allowed.
Measurable disease according to RECIST v1.1 as determined by the Investigator.
Available archival tumor biopsy material.
Recovery to baseline or ≤ Grade 1 per CTCAE v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy.
Age 18 years or older on the day of consent.
Karnofsky Performance Status (KPS) ≥ 70%.
Adequate organ and marrow function within 14 days prior to randomization.
Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception.
Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

Chromophobe, renal medullary carcinoma, and pure collecting duct histologic subtypes of nccRCC.
Prior systemic anticancer therapy for unresectable locally advanced or metastatic nccRCC including investigational agents.

Note: One prior systemic adjuvant therapy, including immune checkpoint inhibitor therapy and excluding sunitinib, is allowed for completely resected RCC and if recurrence occurred at least 6 months after the last dose of adjuvant therapy.
Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks prior to randomization.
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy (including radiosurgery) or surgically removed and stable for at least 4 weeks before randomization.
Concomitant anticoagulation with oral anticoagulants and platelet inhibitors. Subjects who are receiving oral anticoagulants at the time of screening must be transitioned to LMWH prior to randomization. Subjects who require treatment with platelet inhibitors are not eligible.
Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks prior to randomization. Prior laparoscopic nephrectomy within 4 weeks prior to randomization. Minor surgery (eg, simple excision, tooth extraction) within 10 days before randomization. Complete wound healing from major or minor surgery must have occurred at least prior to randomization.

Note: Fresh tumor biopsies should be performed at least 7 days before randomization. Subjects with clinically relevant ongoing complications from prior surgical procedures, including biopsies, are not eligible.
Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before randomization.
Pregnant or lactating females.
Administration of a live, attenuated vaccine within 30 days before randomization.

Note: If feasible, approved non-live vaccines for SARS-CoV-2 should be administered at least 2 weeks before randomization

Inclusion Criteria:

Patients with CML-CP within 3 months of diagnosis.
Diagnosis of CML-CP (ELN 2020 criteria) with cytogenetic confirmation of the Philadelphia chromosome

Documented chronic phase CML will meet all the below criteria Baccarani et al 2013:

< 15% blasts in peripheral blood and bone marrow,
< 30% blasts plus promyelocytes in peripheral blood and bone marrow,
< 20% basophils in the peripheral blood,
PLT count ≥ 100 x 10^9/L (≥ 100,000/mm3), except treatment induced thrombocytopenia
No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment.
ECOG performance status of 0 or 1.
Adequate end organ function as defined by:

Total bilirubin (TBL) < 3 x ULN; patients with Gilbert's syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN,
CrCl ≥ 30 mL/min as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis.
Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization:

Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min),
Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min),
Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min),
For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be within normal limits or corrected to within normal limits with supplements prior to randomization.

CrCl as calculated using Cockcroft-Gault formula.
Exclusion Criteria:

Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide.
Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following:

History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment.
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block).
QTcF ≥ 450 ms (male patients), ≥460 ms (female patients) on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF.
Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:
Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
Concomitant medication(s) with a "Known risk of Torsades de Pointes" per www.crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication.
Inability to determine the QTcF interval.
Severe and/or uncontrolled concurrent medical disease that in the opinion of the Investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia).
History of significant congenital or acquired bleeding disorder unrelated to cancer.
Major surgery within 4 weeks prior to study entry or patients who have not recovered from prior surgery.
History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively.
History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4.
History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.
Other protocol-defined Inclusion/exclusion criteria will apply.

Inclusion Criteria:

Signed informed consent must be obtained prior to participation in the study
Participants must be adults ≥18 years of age at the time of informed consent
ECOG performance status of 0 or 1 at screening
Participants must have a life expectancy ≥24 months as determined by the Investigator at screening
Histologically confirmed prostate cancer prior to randomization
Participants must have biochemically recurrent disease after definitive treatment to prostate by RP, (alone or with post-operative radiation to prostate bed/pelvic nodes) or XRT, (prostate alone or prostate with seminal vesicle and/or pelvic nodes) and/or brachytherapy prior to randomization. Biochemical recurrence is defined as: nadir PSA + 2 ng/mL post XRT (if participant received-radiation therapy to intact prostate) and PSA > 0.2 ng/mL and rising post RP (with or without post-operation RT)
Participants must have OMPC with ≤5 PSMA-positive metastatic lesions on screening PSMA PET/CT scan (with either gallium (68Ga) gozetotide or piflufolastat (18F)) as visually assessed by BIRC based on the methodology proposed in the Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) (Eiber et al 2018); for further details, please refer to Section 8.1 and Imaging Manual. Metastatic lesions may include regional/pelvic lymph nodes (N1), distant lymph nodes (M1a), bone (M1b), lung and others visceral (M1c) except liver and brain classified using AJCC 8. When counting the number of oligometastatic lesions, each lesion is counted as distinct metastasis irrespective of its anatomical location (e.g., one pelvic and one extra-pelvic lymph node will be counted as two metastatic lesions)
At least 1 PSMA-positive lesion should be a distant metastasis (M1) per AJCC8 classification at screening. For AJCC M staging, PSMA PET information should be used
Participants must have a negative conventional imaging for M1 disease at screening. Note:

For a participant not to be eligible, CI positive M1 lesions should be unequivocal in CI scans, i.e., potentially not attributable to findings thought to represent something other than tumor (e.g., degenerative, or post-traumatic changes or Paget's disease in bone lesions).
Prior knowledge of PSMA PET positivity should not influence the radiologist (reader) in determination of CI positivity. Two different readers will be involved, one reader for PSMA PET scan and one reader for CI: Reader will be blinded to PSMA PET scan results while reading CI scans. Readers should not modify their assessment of CI scans (e.g. changing a lesion previously identified as equivocal in CI to unequivocal) after reading the PSMA PET scan. Similarly, biopsy positivity should not influence the reader in the assessment of CI positivity. More details on the reading paradigm will be provided in the imaging charter.
MRI for radiation treatment planning may show M1 disease but this will not exclude the participant from the study if the lesion is deemed negative per baseline CT or bone scans.
Participants with pelvic disease (N1) seen in conventional imaging are allowed if the local spread is below common iliac bifurcation (per AJCC 8 definition of local disease).
Distant lymph node disease (M1a) that is visible per CI and less than 10mm in the short axis are not exclusionary irrespective of PSMA PET positivity.
All metastatic lesions detected at screening should be amenable to SBRT
If participants previously received SBRT for OMPC, progressive disease must be demonstrated prior to randomization (e.g., a new PSMA PET lesion). Previously treated lesions must be stable in baseline imaging scans and will not be counted towards 1-5 lesions required in this study. If a previously treated lesion was unequivocal for M1 by bone scan or CT before the previous SBRT, the participant is not eligible.
Confirmation of Controlled primary tumor at screening: If local recurrence is suspected, MRI is required to rule out local relapse. Participants with MRI or PET positive local lesions require biopsy to rule out local progression. These locally recurrent participants (with biopsy proven local disease or with MRI or PET positive local lesions without biopsy) may be eligible for the study after salvage therapy to local disease. Note: Participants who previously undergone pelvic RT (salvage pelvic RT) at local recurrence after RP are allowed in the study.
PSADT <10 months at screening [PSADT will be calculated using a linear regression model of the normal logarithm of PSA and time (Pound et al 1999)]
Non-castration testosterone level >100 ng/dL at screening
Human immunodeficiency virus (HIV)-infected participants at screening and during the study who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial
Participants must have adequate organ functions including the following laboratory values at the screening visit:
Bone marrow reserve

ANC ≥1.5 x 109/L
Platelets ≥100 x 109/L
Hemoglobin ≥9 g/dL Hepatic
Total bilirubin (TBIL) ≤2 x the institutional upper limit of normal (ULN). For participants with known Gilbert's Syndrome ≤3 x ULN is permitted
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN.
Albumin ≥2.5 g/dL Renal
eGFR ≥ 60mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
Exclusion Criteria:

Participants with de novo OMPC at screening
Unmanageable concurrent bladder outflow obstruction or urinary incontinence at screening. Note: participants with bladder outflow obstruction or urinary incontinence, which is manageable and controlled with best available standard of care (incl. pads, drainage) are allowed
Prior therapy with:

ADT including bilateral orchiectomy

Participants who had XRT or RP and completed adjuvant ADT (or ADT+ Androgen Receptor Pathway Inhibitor (ARPI)) prior to recurrence are eligible to participate if the last dose of ADT (or ADT+ARPI) was before 12 months from randomization
Participants who discontinued ADT due to disease progression are not allowed (i.e., CRPC participants)
Other hormonal therapy. e.g.,

Use of estrogens, 5-α reductase inhibitors (finasteride, dutasteride), other steroidogenesis inhibitors (aminoglutethamide)
First-generation anti-androgens (bicalutamide, flutamide, nilutamide, cyproterone).
Second generation anti-androgens (e.g., enzalutamide, apalutamide and darolutamide)
CYP17 inhibitors (e.g., abiraterone acetate, orteronel, galeterone, ketoconazole). Short term ketoconazole treatment (<28 days) is permitted.
Radiopharmaceutical agents (e.g., Strontium-89, PSMA-targeted radioligand therapy)
Immunotherapy (e.g., sipuleucel-T)
Chemotherapy, except if administered in the adjuvant/neoadjuvant setting completed > 12 months before randomization
Any other investigational or systemic agents for metastatic disease
Herbal and non-herbal products that may decrease PSA levels (i.e., saw palmetto, pomegranate juice) within 28 days before randomization
Use of other investigational drugs within 28 days prior to day of randomization
Radiation therapy, external beam radiation therapy (EBRT), and brachytherapy within 28 days before randomization
Systemic (oral/i.v./Intramuscular (IM)) corticosteroids within 28 days before randomization. Note: Short term use (≤ 4 weeks) of corticosteroids during the study is allowed if clinically indicated
Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, hormonal therapy (see ADT initiation guidance in Section 6.8.2), PARP inhibitor, biological therapy, or investigational therapy
Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
Transfusion during screening procedures for the sole purpose of making a participant eligible for study inclusion
Diagnosed at screening with other malignancies that are expected to alter life expectancy or may interfere with disease assessment. However, participants with a prior history of malignancy that has been adequately treated and who have been disease/treatment free for more than 3 years are eligible, as are participants with adequately treated non-melanoma skin cancer and superficial bladder cancer
Concurrent serious (as determined by the Investigator) medical conditions, including, but not limited to, uncontrolled infection, known active hepatitis B or C, or other significant co-morbid conditions that in the opinion of the Investigator would impair study participation or cooperation. Participants with an active documented COVID-19 infection (any grade of disease severity) at time of informed consent may be included only when completely recovered (in accordance with local guidance)
History or current diagnosis of ECG abnormalities indicating significant risk of safety for participants participating in the study such as:

Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker
History of familial long QT syndrome or known family history of Torsades de Pointe
Resting heart rate (physical exam or 12 lead ECG) <60 bpm
History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
Any condition that precludes raised arms position
Sexually active males unwilling to use a condom during intercourse

Inclusion Criteria:

Adult participants with loco-regional recurrent or metastatic disease not amenable to curative treatment
Confirmed diagnosis of ER+/HER2- breast cancer
No prior systemic treatment for loco-regional recurrent or metastatic disease
Measurable disease evaluable per Response Evaluation Criterion in Solid Tumors (RECIST) v.1.1 or non-measurable bone-only disease
Eastern Cooperative Oncology Group (ECOG) performance status 0-2
Phase 3 only: Participants should be willing to provide blood and tumor tissue
Exclusion Criteria:

Disease recurrence while on, or within 12 months of completion of adjuvant endocrine therapy
Prior treatment with cyclin dependent kinase 4/6 inhibitors (CDK4/6i), fulvestrant, elacestrant and other investigational drugs including novel endocrine therapies, any selective estrogen receptor degraders (SERDs), covalent antagonists (SERCAs) and complete ER antagonists (CERANs).
Inadequate liver, kidney and bone marrow function
Impaired cardiovascular function or clinically significant cardiovascular diseases
Refractory nausea and vomiting, inability to swallow capsules and tablets whole, chronic gastrointestinal diseases, significant gastric (total or partial) or bowel resection that would preclude adequate absorption of study interventions.
Current use or anticipated need for food, herbal supplements or drugs that are known strong CYP3A4 inhibitors or inducers.

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

Have histologically or cytologically confirmed adenocarcinoma of the prostate without small cell histology
Has current evidence of metastatic disease documented by either bone lesions on bone scan and/or soft tissue disease shown by computed tomography scan (CT)/magnetic resonance imaging (MRI)
Has prostate cancer progression while receiving androgen deprivation therapy (ADT) (or post bilateral orchiectomy) within 6 months before Screening
Has disease that progressed during or after treatment with one next-generation hormonal agent (NHA) for hormone sensitive prostate cancer (HSPC) metastatic hormone sensitive prostate cancer (mHSPC) or non metastatic hormone sensitive prostate cancer (nmHSPC), for at least 8 weeks (at least 14 weeks for participants with bone progression) Note: Participants may have received abiraterone acetate and docetaxel or darolutamide and docetaxel for HSPC. However, participants must have received no more than six cycles of docetaxel and had no radiographic disease progression while receiving docetaxel
Has an eastern clinical oncology group (ECOG) performance status of 0 or 1 assessed within 7 days before randomization
Has ongoing androgen deprivation with serum testosterone <50 ng/dL (<1.7 nM)
Has had prior treatment with Poly polymerase inhibitors (PARPi) or were deemed ineligible to receive treatment by the investigator or have refused PARPi treatment
Has adequate organ function
Has provided tumor tissue from a fresh core or excisional biopsy from soft tissue not previously irradiated. Samples from tumors progressing at a prior site of radiation are allowed
Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load before randomization.
Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at Screening
Participants who have adverse event (AEs) due to previous anticancer therapies must have recovered to ≤Grade 1 or baseline. Participants with endocrine-related AEs who are adequately treated with hormone replacement therapy (HRT) or participants who have ≤Grade 2 neuropathy are eligible
Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on antiretroviral therapy (ART)
Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

Has presence of gastrointestinal condition
Is unable to swallow capsules/tablets
Has history of pituitary dysfunction
Has poorly controlled diabetes mellitus
Has active or unstable cardio/cerebro-vascular disease, including thromboembolic events
Has clinically significant abnormal serum potassium or sodium level. Has any of the following at Screening Visit: Hypotension: systolic BP <110 mmHg, or Uncontrolled hypertension: systolic BP ≥160mmHg or diastolic BP ≥90 mmHg, in 2 out of 3 recordings with optimized antihypertensive therapy
History or family history of long QTc syndrome
Has a history of seizure(s) within 6 months prior to signing the IC or has any condition that may predispose to seizure within 12 months prior to the date of enrollment
Has a history of clinically significant ventricular arrhythmias or Mobitz II second degree or third-degree heart block without a permanent pacemaker in place
Has received a taxane-based chemotherapy and or NHA for metastatic castration-resistant prostate cancer (mCRPC)
Has not adequately recovered from major surgery or have ongoing surgical complications
Has received prior treatment with radium for prostate cancer
Is currently being treated with Cytochrome P450 (CYP450)-inducing antiepileptic drugs for seizures
Participants on an unstable dose of thyroid hormone therapy within 6 months before the start of the study intervention
Receives prior radiotherapy within 2 weeks before the first dose of study intervention, or radiation-related toxicities, requiring corticosteroids
Receives prior systemic anticancer therapy including investigational agents within 4 weeks before the first dose of study intervention
Has systemic use of strong Cytochrome P450 3A4 (CYP3A4) inducers and P-glycoprotein (P-gp) inhibitors within 2 weeks before the first dose of study intervention
Has received prior targeted small molecule therapy or NHA treatment within 4 weeks before the first dose of study intervention
Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration
Has known hypersensitivity to the components or excipients in abiraterone acetate, prednisone or prednisolone, or enzalutamide
Has a "superscan" bone scan defined as an intense symmetric activity in the bones and diminished renal parenchymal activity on baseline bone scan such that the presence of additional metastases in the future could not be evaluated
Has known additional malignancy that is progressing or has required active treatment within the past 3 years
Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication
Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days prior to the first dose of study intervention
Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy is allowed
Active infection requiring systemic therapy
Has concurrent active Hepatitis B virus and Hepatitis C virus infection

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

Has surgically resected and histologically confirmed diagnosis of Stage II, IIIA, IIIB (N2) squamous or nonsquamous NSCLC as per American Joint Committee on Cancer (AJCC) Eighth Edition guidelines.
Has no evidence of disease at the time of providing documented consent for the main study.
Has received at least one dose of adjuvant treatment with standard of care platinum doublet chemotherapy.
No more than 24 weeks have elapsed between surgical resection of curative intent and the first dose of pembrolizumab.
Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.
Human immunodeficiency virus (HIV)-infected participants must have well controlled HIV on anti-retroviral therapy (ART).
Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

Diagnosis of small cell lung cancer (SCLC) or, for mixed tumors, presence of small cell elements, or has a neuroendocrine tumor with large cell components or a sarcomatoid carcinoma.
HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.
Received prior neoadjuvant therapy for their current NSCLC diagnosis.
Received or is a candidate to receive radiotherapy for their current NSCLC diagnosis.
Received prior therapy with an anti-programmed cell death 1 protein (PD-1), anti-PD-ligand 1 (L1), or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor.
Received prior systemic anticancer therapy including investigational agents within 4 weeks before randomization.
Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
Has received an investigational agent or has used an investigational device within 4 weeks prior to study intervention administration.
Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication.
Known additional malignancy that is progressing or has required active treatment within the past 5 years.
Active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
Active infection requiring systemic therapy.