Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Phase 3, Open Label, Randomized, Comparative Study Of CP-675,206 And Either Dacarbazine Or Temozolomide In Patients With Advanced Melanoma
Brief Summary: This is a Phase 3, multi-national, open-label, 2-arm randomized study in patients with surgically incurable metastatic melanoma who have received no prior chemotherapy, or biochemotherapy for the treatment of metastatic disease. The primary objective of this trial is to compare overall survival for patients with advanced melanoma who are randomized to receive CP-675,206 with that of patients who are randomized to receive either dacarbazine or temozolomide (investigator choice)


Options:
A: Inclusion Criteria

* In Part A: Histological or cytological diagnosis of MEL or any type of carcinoma, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy. In Parts B and D of the study, histological or cytological diagnoses of metastatic MEL with progressive locally advanced or metastatic disease. In Parts C and F, histological or cytological diagnosis of NSCLC. In Part F1, participants with Stage IV NSCLC without prior systemic therapy may be eligible.
* Failure of established standard medical anti-cancer therapies for a given tumor type or intolerance to such therapy.
* In Parts B, C, D, or F of the study, MEL or NSCLC must be measurable by imaging.
* In Part F of the study, NSCLC with PD-L1 gene expression.
* Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
* Adequate organ function.
* Female participants of childbearing potential should have a negative urine or serum pregnancy test prior to receiving study medication
* Female participants of childbearing potential must be willing to use adequate contraception from study start, through the course of the study, and for 120 days after the last dose of study medication
* Male participants of childbearing potential must agree to use adequate contraception from the first dose of study medication through 120 days after the last dose of study medication

Exclusion Criteria

* Chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study therapy, or not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better from the adverse events caused by therapy administered more than 4 weeks prior to first dose.
* Participation in a study of an investigational agent or using an investigational device within 30 days of administration of pembrolizumab, with the exception of participants in the follow-up phase.
* Other form(s) of antineoplastic therapy anticipated during the period of the study.
* History of non-infectious pneumonitis requiring treatment with steroids, or has a history of interstitial lung disease.
* Medical condition that requires chronic systemic steroid therapy, or on any other form of immunosuppressive medication, excepting use of inhaled steroids.
* Risk factors for bowel obstruction or bowel perforation (including a history of acute diverticulitis, intra-abdominal abscess, abdominal carcinomatosis).
* History of a hematologic malignancy, malignant primary brain tumor, malignant sarcoma, or another malignant primary solid tumor, unless no evidence of that disease for 5 years.
* Active central nervous system (CNS) metastases and/or carcinomatous meningitis.
* Previous severe hypersensitivity reaction to another monoclonal antibody (mAb).
* Active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents, except vitiligo or resolved childhood asthma/atopy.
* Prior therapy with another anti-programmed cell death (PD)-1 agent or previously enrolled in any pembrolizumab trial.
* Active infection requiring therapy.
* Positive for Human Immunodeficiency Virus (HIV), Hepatitis B (Hepatitis B Surface Antigen \[HBsAg\] reactive), or Hepatitis C virus (Hepatitis C Virus Ribonucleic Acid \[HCV RNA\] (qualitative) is detected).
* Regular use of illicit drugs or a recent history (within the last year) of substance abuse (including alcohol).
* Symptomatic ascites or pleural effusion.
* Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study.
B: Inclusion Criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be \>/= 18 years of age on day of signing informed consent.
3. Present with a resectable head and neck mucosal melanoma.
4. Be eligible for surgical treatment (without any contraindications).
5. Be eligible for adjuvant radiotherapy.
6. Have measurable disease based on RECIST 1.1.
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor.
8. Have a performance status of 0 or 1 on the ECOG Performance Scale.
9. Demonstrate adequate organ function as defined in table 1, all screening labs should be performed within 10 days of treatment initiation.
10. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
11. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
12. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
13. Patient affiliated to a social security system or beneficiary of the same

    For the cohort B, patients must met the following additional criteria :
14. Not having any contraindication for lenvatinib treatment

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a metastatic disease.
3. Has a non resectable melanoma.
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (except topical or inhaled steroids) or any other form of immunosuppressive therapy within 2 weeks prior to the first dose of trial treatment.
5. Has a known history of active TB (Bacillus Tuberculosis)
6. Hypersensitivity to pembrolizumab or any of its excipients.
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to D1 of study treatment or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
8. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 4 weeks or 5 half-life times (whatever the shorter) prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent.

   * Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.
   * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
9. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
11. Has active autoimmune and/or immune mediated inflammatory disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
12. Has known history of, or any evidence of active, non-infectious pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD L2 agent.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
20. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
21. Major injuries and/or surgery within the past 4 weeks prior to start of study treatment with incomplete wound healing
22. Has a prior history of organ transplant including allogeneic stem cell transplant
23. Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (ECHO)
24. Has an uveal melanoma

    For the cohort B, patients must be excluded if one of the following additional criteria is met :
25. Uncontrolled blood pressure (Systolic BP\>140 mmHg or diastolic BP \>90 mmHg) in spite of an optimized regimen of antihypertensive medication
26. Electrolyte abnormalities that have not been corrected
27. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 12 months of the first dose of study drug, or cardiac arrhythmia requiring medical treatment at Screening
28. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor invasion/infiltration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy
29. Subjects having \> 1+ proteinuria on urine dipstick testing unless a 24-hour urine collection for quantitative assessment indicates that the urine protein is \<1 g/24 hours.
30. Subjects who have not recovered adequately from any toxicity from other anti- cancer treatment regimens and/or complications from major surgery prior to starting therapy. Withhold lenvatinib for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing.
31. The participant has severe hypersensitivity (≥Grade 3) to lenvatinib and/or any of its excipients.
32. Has presence of a gastrointestinal condition including malabsorption, gastrointestinal, anastomosis, or any other condition that might affect the absorption of lenvatinib.
33. Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
34. Has clinically significant hemoptysis or significant tumor bleeding within 3 weeks prior to the first dose of study drug.
35. Prolongation of QTcF interval to \>480 ms
C: Inclusion Criteria:

* Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
* Patients must have histologically or cytologically confirmed stage IIIB/C or stage IV oligometastatic melanoma; oligometastatic melanoma is defined as three or fewer areas of resectable disease excluding central nervous system and bone involvement; patients with cutaneous, mucosal, acral, ocular or unknown primary melanomas are eligible for enrollment; for patients with stage IV disease with distant lymph nodes (stage M1a), a maximum of three separate lymph node sites fit the definition of oligometastatic disease; resectable tumors are defined as having no significant vascular, neural or bony involvement; only cases where a complete surgical resection with tumor-free margins can safely be achieved are defined as resectable
* Patients will have at least one melanoma deposit that can undergo serial biopsy (at least 2 time points) during the neoadjuvant phase of the protocol; patients must be willing to provide tumor samples at the time points specified in the Study Procedure Tables
* All patients must undergo a baseline tumor biopsy; in Arms A and B, tumor biopsy for PD-L1 testing (PD-L1 positivity is determined by greater than or equal to 1% of cells staining in the membrane by immunohistochemistry) is required for stratification; PD-L1 status is not required for enrollment on Arm C; the 28-8 clone for PD-L1 testing is required for assessment of PD-L1 status; for patients with stage IV disease, site of tumor biopsy will preferably be from non-lymph node disease site; for PD-L1 testing, the biopsy should contain sufficient tumor content (\> 100 tumor cells/4-micron tissue section); if a sample contains insufficient tumor content, a re-biopsy will be required to obtain a sample with sufficient tumor content prior to treatment
* Patients must be medically fit enough to undergo surgery as determined by the treating medical and surgical oncology team
* Patients who have been previously treated in the adjuvant setting for melanoma will be eligible for treatment after a 28 day wash-out period
* Patients must have measurable disease, defined by RECIST 1.1
* Age \>/= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Absolute neutrophil count (ANC) \>= 1.5 X 10\^9/L (within 28 days of first study treatment)
* Hemoglobin \>= 8.5 g/dL (within 28 days of first study treatment)
* Platelets \>= 100 X 10\^9/L (\>= 60 for hepatocellular carcinoma \[HCC\]) (within 28 days of first study treatment)
* Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =\< 1.5 X upper limit of normal (ULN) (within 28 days of first study treatment)
* White blood cells (WBC) \>= 2.0 X 10\^9/L (within 28 days of first study treatment)
* Total bilirubin =\< 1.5 X ULN (except subjects with Gilbert's syndrome who must have normal direct bilirubin) \[3 mg/dL for HCC\] (within 28 days of first study treatment)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 3.0 x upper limit of normal (ULN) (=\< 5 x ULN for HCC) (within 28 days of first study treatment)
* Albumin \>= 2.5 g/dL (within 28 days of first study treatment)
* Creatinine =\< 1.5 x ULN OR calculated creatinine clearance \>= 40 mL/min OR 24-hour urine creatinine clearance \>= 50 mL/min (within 28 days of first study treatment)
* Lipase \< 1.5 X ULN (within 28 days of first study treatment)
* Amylase \< 1.5 X ULN (within 28 days of first study treatment)
* Normal thyroid function (or stable on hormone supplementation) 0.27 - 10 X 10\^9/L (within 28 days of first study treatment)
* Left ventricular ejection fraction (LVEF) \>= 50% by transthoracic echocardiography (TTE) (preferred) or multigated acquisition (MUGA) within 6 months from first study drug administration
* Women are eligible to participate if: non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] \> 40 MlU/mL and estradiol \< 40 pg/mL \[\< 140 pmol/L\] is confirmatory); females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study; otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment; for most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT; following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
* A woman of childbearing potential (WOCBP) agrees to use method(s) of contraception; for a teratogenic study drug and/or when there is insufficient information to assess teratogenicity, a highly effective method(s) of contraception (failure rate of \< 1% per year) is required; the individual methods of contraception and duration should be determined in consultation with the investigator; WOCBP must follow instructions for birth control when the half-life of the study drug is \> 24 hours; contraception should be continued for a period of 30 days plus the time required for the study drug to undergo 5 half-lives; WOCBP should use an adequate method to avoid pregnancy for 24 weeks (30 days plus the time required for study drug to undergo 5 half-lives) after the last dose of study drug; WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin \[HCG\]) within 24 hours prior to the start of investigational product
* Women must not be breastfeeding
* Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of \< 1% per year; the investigator shall review contraception methods and the time period that contraception must be followed; men who are sexually active with WOCBP must follow instructions for birth control when the half-life of the study drug is \> 24 hours, contraception should be continued for 90 days plus the time required for the study drug to undergo 5 half-lives; therefore, men who are sexually active with WOCBP must continue contraception for 33 weeks (90 days plus the time required for nivolumab and/or relatlimab to undergo 5 half-lives) after the last dose of study drug; in addition, male participants must be willing to refrain from sperm donation during this time; men who are sexually active with women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile and azoospermic men) do not require contraception
* For Arm C: Cardiac assessment at baseline by trans- thoracic echocardiogram (TTE) with LVEF 50%

Exclusion Criteria:

* Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) or investigational anti-cancer drug
* Any major surgery within the last 3 weeks
* Brain metastases, leptomeningeal disease or bone metastases
* Pregnant or lactating female
* Unwillingness or inability to follow the procedures required in the protocol
* Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at therapeutic levels
* Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
* Prior malignancy active within the previous 3 years except for patient's prior diagnosis of melanoma and 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 prostate, cervix, or breast with local control measures (surgery, radiation)
* Subjects with active, known or suspected autoimmune disease; subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
* Subjects with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
* Prior treatment with an anti-PD-1, anti-PD-L1, anti-LAG-3, or anti-CTLA-4 antibody
* Any positive test result for hepatitis B or C virus indicating acute or chronic infection
* Known history of testing positive for human immunodeficiency virus or known acquired immunodeficiency syndrome
* History of severe hypersensitivity reaction to any monoclonal antibody
* Prisoners or subjects who are involuntarily incarcerated
* Subjects who are compulsorily detained for treatment of either a psychiatric or physical (infection disease) illness
* A known or underlying medical condition that, in the opinion of the Investigator, could make the administration of the study drug hazardous to the subject or could adversely affect the ability of the subject to comply with or tolerate the study
* A confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
* Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy 7 days prior to initiation of study drug therapy
* Any other acute or chronic medical illness
* Subjects who are unable to undergo venipuncture and/or tolerate venous access
* Any other sound medical, psychiatric, and/or social reason as determined by the Investigator
* Any of the following procedures or medications:

  * Within 2 weeks prior to time of study treatment:

    * Systemic or topical corticosteroids at immunosuppressive doses (\> 10 mg/day of prednisone or equivalent); inhaled or topical steroids, and adrenal replacement steroid doses of \> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
    * Palliative radiation or gamma
  * Within 4 weeks prior to study drug administration:

    * Any investigational cytotoxic drug; exposure to any non-cytotoxic drug within 4 weeks or 5 half-lives (whichever is shorter) is prohibited; if 5 half-lives is shorter than 4 weeks, agreement with sponsor/medical monitor is mandatory
* Subjects with history of life-threatening toxicity related to prior immune therapy (e.g., anti-CTLA-4 or anti-PD-1/PD-L1 treatment or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) except those that are unlikely to re-occur with standard countermeasures (e.g., hormone replacement after endocrinopathy)
* Troponin T (TnT) or I (TnI) \> 2 x institutional upper limit of normal (ULN); subjects with TnT or TnI levels between \> 1 to 2 x ULN will be permitted if repeat levels within 24 hours are \</= 1 x ULN; if TnT or TnI levels are \> 1 to 2 x ULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the investigator or designee; when repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible; if TnT or TnI repeat levels beyond 24 hours are \< 2 x ULN, the subject may undergo a cardiac evaluation and be considered for treatment, following a discussion with the investigator or designee
* For Arm C: Uncontrolled or significant cardiovascular disease including, but not limited to, any of the following:

  * Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 6 months prior to consent
  * Uncontrolled angina within the 3 months prior to consent
  * Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes)
  * Corrected QT interval (QTc) prolongation \> 480 msec
  * History of other clinically significant cardiovascular disease (i.e., cardiomyopathy, congestive heart failure with New York Heart Association \[NYHA\] functional classification III-IV, pericarditis, significant pericardial effusion, significant coronary stent occlusion, deep venous thrombosis, etc )
  * Cardiovascular disease-related requirement for daily supplemental oxygen
  * History of two or more MIs OR two or more coronary revascularization procedures
  * Subjects with history of myocarditis, regardless of etiology
D: Inclusion Criteria:

* Surgically incurable melanoma, either Stage IV or IIIC with N3 status for regional lymph nodes and in-transit or satellite lesions.
* Serum lactic acid dehydrogenase (LDH) \<= 2 x ULN
* ECOG performance status of 0 or 1

Exclusion Criteria:

* Received any systemic therapy for metastatic melanoma except post-surgical adjuvant treatment with cytokines (eg, alpha-interferon or GM-CSF) or with vaccines after complete resection of melanoma.
* History of brain metastases

Answer: D