Study Of OX40 Agonist PF-04518600 Alone And In Combination With 4-1BB Agonist PF-05082566

Primary Purpose: Treatment

• Drug: PF-04518600
  
  Part A1 - PF-04518600 will be administered intravenously every 14 days in cohorts of 2 or more patients starting at a dose of 0.01 mg/kg. Increases in dose will continue until MTD is determined
• Drug: PF-04518600
  
  Part A2 - patients with hepatocellular carcinoma will be randomized to receive treatment with PF-04518600 at various doses administered intravenously
• Drug: PF-04518600 plus PF-05082566
  
  Part B1 -In cohorts of 2 or more patients, PF-04518600 will be administered intravenously every 2 weeks starting at a dose of 0.1 mg/kg and PF-05082566 will be administered intravenously 4 weeks starting at a dose of 20 mg. Increases in dose will continue until MTD is determined.
• Drug: PF-04518600 plus PF-05082566
  
  Part B2 - patients with select tumor types (ocular melanoma, cutaneous/acral melanoma or non-small cell lung cancer) will be treated at dose levels based on the OBD selected in Part 1.

• Experimental: PF-04518600
  
  OX40 agonist
  Interventions:
  

  • Drug: PF-04518600
  • Drug: PF-04518600
• Experimental: PF-04518600 plus PF-05082566
  
  OX40 (CD134) agonist plus 4-1BB (CD137) agonist
  Interventions:
  

  • Drug: PF-04518600 plus PF-05082566
  • Drug: PF-04518600 plus PF-05082566

Inclusion Criteria:

• Part A1 only: Patients with histological or cytological diagnosis of HNSCC, HCC, melanoma, or clear cell RCC who progressed on or are intolerant to standard therapy, for which no standard therapy is available or who decline standard therapy.
• Part A2 only: Patients with histological or cytological diagnosis of HCC who have had 0 to 2 prior lines of systemic therapy (progressed or intolerant to approved HCC standard of care treatment).
• Part B1 only: Patients with histological or cytological diagnosis of NSCLC, HNSCC, melanoma, urothelial bladder carcinoma (including renal pelvis, ureters, urinary bladder, and urethra), gastric or squamous cell carcinoma of the uterine cervix who progressed on or are intolerant to standard therapy, for which no standard therapy is available, or who decline standard therapy.
• Part B2

Arm 1 only:

1. Ocular melanoma; and have received no more than one line of systemic therapy for metastatic disease. Patients must not have received immune modifying agents (eg. anti PD-L1, anti PD-1, anti CTLA4, TNF agonist, etc.) for metastatic disease, or
2. Cutaneous/acral melanoma; and have 1) only previously received systemic therapy for advanced/metastatic disease with the following therapies: BRAF and MEK inhibitors, anti PD-L1, anti PD-1, or anti-CTLA4 and 2) have received checkpoint inhibitor (anti PD-L1, anti PD-1, or anti-CTLA4) based treatment as most recent line of therapy on which disease progressed, as long as progression did not occur in the first 3 months of receiving checkpoint inhibitor treatment.

Arm 2 only:

• Histological or cytological diagnosis of NSCLC. Patients must have 1) previously received prior anti-PD-L1 or anti-PD-1 mAb as most recent therapy, AND 2) did not have progressive disease as best overall response on recent PD-L1/PD-1 therapy (ie, stable disease 3 months, PR, or CR), AND 3) who subsequently progressed on anti-PD-L1 or anti-PD-1 mAb.
• Performance Status of 0 or 1 - Adequate bone marrow, kidney and liver function

Exclusion Criteria:

• Brain metastases requiring steroids
• Major surgery, radiation therapy, or systemic anti-cancer therapy within 4 weeks of study treatment start (6 weeks for mitomycin C or nitrosoureas)
• Active and clinically significant bacterial, fungal, or viral infection
• History of active autoimmune disorders
• History of immune-mediated adverse events requiring immunosuppressive therapy or were grade 3 or higher related to prior immune-modulatory therapy
• Prior treatment with an OX40 agonist and 4-1BB agonist (for Part B1/B2)
• Prior anthracycline treatment and at risk of cardiac failure (New York Heart Association Class 2)