A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab

Inclusion Criteria

• Histologically- or cytologically-confirmed ovarian cancer, colorectal cancer, non-triple negative breast cancer, renal cell carcinoma and cervical cancer, with at least one lesion measurable by the immune-related Response Criteria (irRC) not previously irradiated. NOTE: Per Amendment 5, the disease states of non-small cell lung cancer and head and neck cancer were removed from the study and were replaced by non-triple negative breast cancer.
• Failed to respond to or relapsed following standard treatment or declined or was not eligible for standard treatment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
• Anticipated lifespan greater than 6 months.
• At the time of Day 1 of the study, subjects with brain metastases must have been asymptomatic for at least 4 weeks and:
• at least 8 weeks without tumor progression after any whole brain radiotherapy;
• at least 4 weeks since craniotomy and resection or stereotactic radiosurgery;
• at least 3 weeks without new brain metastases as evidenced by magnetic resonance imaging (MRI)/computed tomography (CT).
• Adequate organ and marrow function, as defined below:
• hemoglobin ≥ 9 g/dL
• absolute neutrophil count ≥ 1500/mm^3
• platelet count ≥ 100,000/mm^3
• total bilirubin within normal ranges unless associated with hepatobiliary metastases or Gilbert syndrome, then total bilirubin ≤ 2 × the upper limit of normal (ULN)
• alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN unless associated with hepatic metastases, then ALT and AST ≤ 5 × ULN
• creatinine ≤ 2.0 mg/dL
• Have been informed of other treatment options.
• Age ≥ 18 years.
• Able and willing to give valid written informed consent.
• Able and willing to give valid written consent for archival tumor samples.
• Able and willing to give valid written consent for biopsy samples (subjects with biopsiable tumors, and if clinically appropriate, in the expansion phase only).

Exclusion Criteria

• Prior exposure to tremelimumab or durvalumab or other anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), anti-programmed cell death-1 (PD-1), anti-programmed cell death ligand-1 (PD-L1) antibodies.
• History of severe allergic reactions to any unknown allergens or any components of the study drugs.
• Active or prior autoimmune disease except for autoimmune thyroiditis or vitiligo.
• Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior corticosteroid-refractory irAE.
• Known active or chronic viral hepatitis or history of any type of hepatitis within the last 6 months.
• History of sarcoidosis syndrome.
• Active or history of inflammatory bowel disease (colitis, Crohn's), diverticulitis, irritable bowel disease, celiac disease, or other serious, chronic, gastrointestinal conditions associated with diarrhea. Active or history of systemic lupus erythematosus or Wegener's granulomatosis.
• Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may have been available.
• Known immunodeficiency or active human immunodeficiency virus (HIV).
• Other active serious illnesses (e.g., serious infections requiring antibiotics).
• If a subject previously received investigational treatment, the last dose of investigational treatment was administered within 4 weeks of Day 1 of the study or AE(s) attributable to investigational treatment had not resolved to Grade 1 or better.
• Major surgical procedure (as defined by the Investigator) within 30 days prior to Day 1 or still recovering from prior surgery.
• Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study.
• Lack of availability for immunological and clinical follow-up assessments.
• Women who were breast feeding or pregnant as evidenced by positive serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [