|Inclusion Criteria:||1) In Part B of the study, patients must have a histological or cytological diagnosis of MEL with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent. Ipilimumab-na´ve Patients: Patients naive to ipilimumab may not have received more than 2 prior systemic treatment regimens for treatment of MEL. Ipilimumab-treated Patients: After the first 13 patients are enrolled, patients who have had ipilimumab may be enrolled, provided the following requirements are met: Full resolution of ipilimumab related adverse effects (including immunerelated adverse effects) and no treatment for these adverse events (AEs) for at least 4 weeks prior to the time of enrollment. Minimum of 12 weeks from the first dose of ipilimumab and >6 weeks from the last dose.|
2) #1 Contd. No history of severe immune related adverse effects from ipilimumab (CTCAE Grade 4; CTCAE Grade 3 requiring treatment >4 weeks). Unequivocal PD within 6 months of the first dose of ipilimumab Ipilimumab
3) #1 Contd.Ipilimumab-refractory Patients: With Amendment 05 and 06, patients who have had ipilimumab may be enrolled, provided the following requirements are met (these patients are considered ipilimumab-refractory): Received at least two doses of ipilimumab. Progressive disease will be defined as increase in tumor burden >25% relative to nadir (minimum recorded tumor burden) which is confirmed by repeat assessment (investigator determination based on site radiology reading; SPONSOR will collect CT scans for retrospective analysis) no less than four weeks from the date of the first documented PD. Once PD is confirmed, initial date of PD documentation will be considered as the date of disease progression. Tumor burden is defined by irRC
4) #1 Contd: Documented disease progression within 24 weeks of the last dose of ipilimumab. Patients who were re-treated with ipilimumab and patients who were on maintenance ipilimumab will be allowed to enter the trial as long as there is documented PD within 24 weeks of the last treatment date (with ipilimumab). Full resolution of ipilimumab related AEs (including irAEs) back to baseline and <10 mg/day prednisone or equivalent dose for irAEs for at least two weeks prior to first dose of study drug.
5) contd #1: No history of severe irAEs from ipilimumab CTCAE Grade 4 requiring steroid treatment. o No history of CTCAE Grade 3 irAEs from ipilimumab requiring steroid treatment (>10 mg/day prednisone or equivalent dose) >12 weeks. o Minimum of four weeks (wash out period) from the last dose of ipilimumab. Patients with BRAF V600mutant melanoma must had a prior treatment regimen that included a BRAF and/or MEK inhibitor. Patient must have progressive disease after the most recent treatment regimen.
6) #1 contd. In Part D of the study, patients must have a histological or cytological diagnosis of MEL with progressive locally advanced or metastatic disease that is not amenable to definitive local therapy with curative intent. Patients must be naive to ipilimumab and may not have received more than 2 prior systemic treatment regimens for treatment of MEL. One of them may have included a BRAF or MEK inhibitor.
7) #1 contd. In Part F of the study, patients must have a histologically-confirmed or cytologicallyconfirmed diagnosis of non-small cell lung cancer, Patient has non-squamous NSCLC Patients' tumors must express PD-L1 as confirmed by a central vendor. Patients have tumor(s) amenable to biopsy. Patients in F-1 must be naive to systemic treatment for NSCLC (adjuvant therapy may not have been administered within 1 year of the relapse). Patients in F-2 have experienced progression of locally advanced or metastatic NSCLC after two or more prior systemic antineoplastic regimens (adjuvant therapy will count as a regimen if administered within 1 year before the relapse). Patient has an estimated life expectancy of at least 12 weeks.
8) #2. Measurable disease:In Part B, C, D, E and F of the study, patients must have measurable disease as defined per irRC (Appendix 6.5): i. Tumor mass: Must be accurately measurable in 2 perpendicular diameters, with both its longest diameter and its longest perpendicular must be greater than or equal to 10 mm or 2 times the axial slice thickness. Clinical lesions will only be considered measurable when they are superficial, such as skin or palpable lymph node. For patients who are being screened for enrollment in Part B, the ipilimumab-refractory cohort, clinical lesions alone will not be considered as sufficient for enrollment; there must be measurable disease evident on CT imaging. ii. Malignant lymph nodes: Must be measurable in 2 perpendicular diameters, with both its longest diameter and its longest perpendicular, must be greater than or equal to 15 mm or 2 times the axial slice thickness.
9) #3: Patient is male or female and ≥18 years of age on day of signing informed consent.
10) #4. Patient must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale
11) #5. Patient must have adequate organ function as indicated by the following laboratory values: Hematological: Absolute neutrophil count (ANC) >/=1,500 /mcL; Platelets >/=100,000 mcL; Hemoglobin >/=9 g/dL or >/=5.6 mmol/L. Renal: Serum creatinine </=1.5 X upper limit of normal (ULN). Hepatic: Serum total bilirubin </= 1.5 X ULN OR Direct bilirubin </= ULN for patients with total bilirubin levels > 1.5 ULN. AST (SGOT) and ALT (SGPT) </= 2.5 X ULN OR </= 5 X ULN for patients with liver metastases. Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) </=1.5 X ULN. Activated Partial Thromboplastin Time (aPTT) </=1.5 X ULN
12) #6. Patient (Parts A, B, C, D, E and F) has voluntarily agreed to participate by giving written informed consent. For Parts B, C, D, E and F, patient has agreed to a fresh biopsy of tumor (that can be biopsied based on investigator's assessment) and to providing the acquired tissue for biomarker analysis. Tissue obtained for the biopsy must not be previously irradiated. No systemic antineoplastic therapy may be received by the patient between the time of the biopsy and the first administration of MK-3475.
13) #7. Female patient of childbearing potential has a negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.
14) #8. Female patients enrolled in the study, who are not free from menses for >2 years, post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy or to abstain from heterosexual activity throughout the study, starting with Visit 1 through 90 days after the last dose of study therapy. Approved contraceptive methods include for example; intra uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception. Male patients must agree to use an adequate method of contraception starting with the first dose of study drug through 90 days after the last dose of study therapy.
15) #9. Subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.