Please select the eligibility criteria that correspond to the clinical trial below.
Title: Randomized, Phase II Study of Pembrolizumab (MK-3475) Versus Chemotherapy in Patients With Advanced Melanoma (KEYNOTE 002)
Brief Summary: This study was conducted to compare survival using pembrolizumab (SCH 900475, MK-3475) or standard chemotherapy in participants with advanced melanoma (MEL) who had progressed after prior therapy.

Initial Treatment Period:

Participants were initially randomized to receive either low-dose (2 mg/kg) pembrolizumab, higher dose (10 mg/kg) pembrolizumab or Investigator-choice chemotherapy (ICC). The four standard chemotherapy choices were: carboplatin + paclitaxel, paclitaxel alone, dacarbazine, or temozolomide. The randomization to either pembrolizumab or ICC was conducted in an open-label fashion.

The starting pembrolizumab dose was initially blinded to Investigators and participants until Amendment 03. With Amendment 03, all ongoing pembrolizumab participants were to be treated with open label, fixed dose pembrolizumab 200 mg, instead of a weight-based dosing of pembrolizumab.

Switch-to-Pembrolizumab Treatment Period:

Participants who were initially randomized to receive ICC and experienced progressive disease (PD) may have been eligible to switch to receiving pembrolizumab provided they met protocol-specified requirements for switching. Qualified participants were re-randomized to receive either pembrolizumab 2 mg/kg or pembrolizumab 10 mg/kg in a double-blind fashion. Participants who qualified to switch to pembrolizumab must have completed a washout period of ≥28 days from last dose of chemotherapy before receiving pembrolizumab. With Amendment 03, all switched-to-pembrolizumab participants were to be treated with open-label, fixed dose pembrolizumab 200 mg instead of a weight-based dosing of pembrolizumab.


Options:
A: Inclusion Criteria:

* Histologically or cytologically confirmed diagnosis of unresectable Stage III or metastatic MEL not amenable to local therapy
* Participants must be refractory to ipilimumab
* Participants with BRAF gene mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF gene and/or mitogen-activated protein kinase (MEK) protein inhibitor
* Must consent to allow correlative studies; must provide a newly obtained tissue/biopsy specimen (or specimen obtained within 60 days of consenting)
* Radiographically measurable disease
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

* Chemotherapy, radiation therapy, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or not recovered from the AEs due to cancer therapies administered more than 4 weeks earlier
* Disease progression within 24 weeks of last dose of ipilimumab
* Participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug
* Expected to require any other form of systemic or localized antineoplastic therapy while on study
* Chronic systemic steroid therapy within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication
* Known history of any other than the current malignancy excepting adequately treated basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cervical cancer, breast cancer, or other in situ cancers
* Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
* Active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
* Prior treatment with any other anti-programmed cell death (PD) agent
* Active infection requiring systemic therapy
* Known history of Human Immunodeficiency Virus (HIV)
* Active Hepatitis B or Hepatitis C
* Regular user (including recreational use of) illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol)
* Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study through 120 days after last dose of study drug
B: Inclusion Criteria:

1. Histologically documented diagnosis of melanoma metastases.
2. Stage IIIB/IIIC (N2b, N2c and N3) or stage IV (M1a) melanoma patients with measurable and potentially resectable metastases without clinical and radiological evidence of other distant metastases.
3. An Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4. Age 18 or older.
5. Adequate organ function defined as follows: a.) Absolute granulocytes greater than or equal to 1,000/mm\^3 and Platelets greater than or equal to 100,000/mm\^3, b.) Serum bilirubin and serum creatinine of less than or equal to 1.5 times upper limit of laboratory normal. If serum creatinine is greater than 1.5 times upper limit of laboratory normal, the urine creatinine clearance must be greater than 60 ml/min., c.) serum glutamate oxaloacetate transaminase (SGOT) (AST), serum glutamate pyruvate transaminase (SGPT) (ALT) and alkaline phosphatase less than or equal to 3 times upper limit of laboratory normal.
6. Patients have not had any previous systemic chemotherapy for metastatic melanoma. Prior biologic therapy, targeted therapy or immunotherapy are allowable, but must be at least 2 weeks since prior therapy before starting study drugs. No other concurrent chemotherapy, immunotherapy, or radiotherapy.
7. Prior radiation therapy used to enhance local regional control is permitted, but must be at least 2 weeks since prior therapy before starting study drugs. In addition, the patient must have unirradiated metastatic sites for response evaluation and has fully recovered from its toxicity. Lesions within the prior field of radiation may only be used as indicator lesions if there has been recent evidence of disease progression after .
8. Ability to understand and sign an informed consent form, indicating awareness of the investigational nature of this study.

Exclusion Criteria:

1. Significant cardiac or pulmonary dysfunction, such as a history of severe cardiovascular disease, myocardial infarction within 6 months of the start of treatment, unstable angina, Class III or Class IV congestive heart failure, ventricular arrhythmia, or any uncontrolled arrhythmia.
2. Current significant psychiatric illness.
3. Serious infection requiring intravenous antibiotics, or any non-malignant medical illnesses that are uncontrolled or whose control may be jeopardized by complications of this therapy.
4. Frequent vomiting or any medical condition (e.g. partial bowel obstruction) that could interfere with oral medication intake.
5. Autoimmune or immunosuppressive disorders (e.g. HIV or AIDS-related illness).
6. Patients who require therapy with systemic corticosteroids.
7. No evidence of active secondary malignancy that requires chemotherapy within the past 2 years (excluding non-melanoma skin cancer, and/or all carcinoma in-situ)
8. Pregnant or lactating women are ineligible. Women of childbearing potential must have a negative urine pregnancy test within a week of initiation of therapy. All patients must agree to use medically approved contraceptive measures to prevent pregnancy during treatment.
9. Any other medical condition or reason that, in the principal investigator's opinion, makes the patient unsuitable to participate in a clinical trial.
C: Inclusion Criteria:

* written informed consent for the study
* ≥ 18 years of age
* histologically or cytologically confirmed diagnosis of cutaneous or unknown primary melanoma (excluding uveal/choroidal and mucosal melanoma; although acral melanoma is included) belonging to one of the following AJCC 8th edition TNM stages:

  1. Tx or T1-4 AND
  2. N1b, or N1c, or N2b, or N2c, or N3b, or N3c AND/OR
  3. M1a or M1b

Patients are eligible for this trial either at presentation for primary melanoma with concurrent regional nodal and/or in-transit metastasis and/or oligometastasis; AND/OR at the time of clinical detected nodal and/or in-transit and/or oligometastatic recurrence; and may belong to any of the following groups:

Primary melanoma with clinically apparent regional lymph node metastases; Clinically detected recurrent melanoma at the proximal regional lymph node(s) basin; Clinically detected primary melanoma involving multiple regional nodal groups; Clinical detected nodal melanoma (if single site) arising from an unknown primary; In-transit and/or satellite metastases with or without regional lymph node involvement; Distant skin and/or in-transit and/or satellite metastases with or without regional lymph node involvement; Oligometastatic lung disease with or without regional lymph node involved permitted if deemed resectable at baseline NOTE: Determination of resectability must be made at baseline to be eligible for this neoadjuvant study.

* measurable disease based on RECIST 1.1
* must provide tumor tissue from a newly obtained core, punch, incisional or excisional tumor biopsy
* 0 or 1 on the ECOG Performance Scale
* Demonstrate adequate organ function on screening labs obtained within 14 days of registration
* negative serum pregnancy test (females of childbearing potential)
* females of non-childbearing potential must be ≥45 years of age and has not had menses for \>1 year; if amenorrhoeic for \<2 years without history of a hysterectomy and oophorectomy must have an FSH value in the postmenopausal range; post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation (documented hysterectomy or oophorectomy)
* male subjects should agree to use an adequate method of contraception

Exclusion Criteria:

* Patients with uveal and/or mucosal melanoma histology are excluded (Patients with melanoma of unknown histology are permitted to enroll after discussion with Principal Investigator)
* Is currently participating in or has participated in a study of an investigational agent or using an investigational device within 4 weeks of the first dose of treatment.
* Is receiving systemic immunosuppression with either corticosteroids (\>10mg daily prednisone equivalent) or other immunosuppressive medications) for active autoimmune disease: history of active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids (\>10mg daily prednisone or equivalent) or systemic immunosuppressive agents
* ≥ CTCAE grade 3 immune-related AE (irAE) experienced with prior immunotherapy (except, non-clinically significant lab abnormalities (elevations in lipase, amylase not associated with clinically significant disease etc.) even if ≥ CTCAE grade 3 may enroll if resolved at this time, or, development of autoimmune disorders of Grade ≤ 3 may enroll if the disorder has resolved to Grade ≤ 1)
* received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks 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 (except ≤ Grade 2 neuropathy)
* autoimmune disorders of Grade 4 while on prior immunotherapy
* active (i.e., symptomatic or growing) central nervous system (CNS) and/or leptomeningeal metastases (CNS lesions that are treated and deemed stable (repeat imaging study done at least 2 weeks prior to first dose of study treatment) are NOT permitted to enroll even if other inclusion criteria are met and patients are neurologically asymptomatic)
* known additional malignancy that is progressing or requires active treatment (except, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy)
* invasive cancer diagnosed and treated less than 2 years prior to current presentation (other indolent malignancies that are not progressing and/or deemed to require active therapy are not exclusionary)
* evidence of interstitial lung disease or active, non-infectious pneumonitis
* active infection requiring systemic therapy
* history or current evidence of any condition, therapy, or laboratory abnormality determined to be significant, in the opinion of the treating investigator
* known psychiatric or substance abuse disorders that would interfere with study compliance
* is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial
* had a live vaccine within 30 days of initiating protocol therapy
* received prior therapy with an IDO inhibitor, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 and/or combination (including nivolumab, pembrolizumab or ipilimumab/nivolumab). Prior treatment with ipilimumab or interferon alfa is allowed.
* history of allergic or hypersensitivity reaction to components or excipients of Dostarlimab (TSR-042) and TSR-022, interferon alfa or ipilimumab
* known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
* known history of or screening test that is positive for hepatitis B virus (HBV; eg, HBsAg reactive or HBV DNA detected) or hepatitis C virus (HCV; HCV antibody positive and/or HCV RNA quantitative is detected). Hepatitis C antibody - positive subjects who received and completed treatment for hepatitis C that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. Hepatitis B positive subjects who received and completed treatment for hepatitis B that was intended to eradicate the virus may participate if hepatitis B DNA levels are undetectable.
D: For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

* Men and women ≥18 years of age
* Eastern Cooperative Oncology Group Performance Status of 0 or 1
* Untreated and histologically confirmed unresectable Stage III or Stage IV melanoma, as per the staging system of the American Joint Committee on Cancer
* Measurable disease as per Response Evaluation Criteria in Solid Tumors 1.1
* Tumor tissue from an unresectable or metastatic site of disease must be provided for biomarker analyses
* Known BRAF wild-type, as per regionally acceptable V600 mutational status testing. BRAF mutant patients and those with indeterminate or unknown BRAF status are not permitted to randomize

Exclusion Criteria:

* Active brain metastases or leptomeningeal metastases
* Ocular melanoma
* Any active, known, or suspected autoimmune disease

Answer: A