Testing A New Combination of Anti-cancer Immune Therapies, Atezolizumab and CDX-1127 (Varlilumab) With or Without the Addition of a Third Anti-cancer Drug, Cobimetinib, for Advanced-Stage Biliary Tract Cancer

PRIMARY OBJECTIVES: I. To assess the response rate (ORR) of patients with unresectable, pre-treated biliary cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib. II. To assess the progression free survival (PFS) of patients with unresectable, pre-treated biliary cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib. SECONDARY OBJECTIVES: I. To assess the safety and tolerability of combination of atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib in patients with unresectable, pre-treated biliary cancers. II. To assess overall survival (OS) of patients with unresectable, pre-treated biliary cancers treated with the combination of atezolizumab and CDX-1127 (varlilumab) with or without cobimetinib. III. To determine the effect of combination atezolizumab and CDX-1127 (varlilumab) +/- cobimetinib on T cell subpopulations systemically and intratumorally. CORRELATIVE OBJECTIVES: I. To explore the effect of atezolizumab and CDX-1127 (varlilumab) +/- cobimetinib on local and systemic immune activation pathways, immune suppressive pathways, and cytokine/chemokine signaling in peripheral blood and within the tumor microenvironment. II. To assess whether atezolizumab and CDX-1127 (varlilumab) clearance at baseline and over time correlate with clinical outcomes (ORR, PFS and OS) and the presence of cachexia. III. To assess immunogenicity by monitoring for the presence of anti-drug antibodies (ADA) to both atezolizumab and CDX-1127 (varlilumab). OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: Patients receive cobimetinib orally (PO) once daily (QD) on days 1-21 of each cycle, atezolizumab intravenously (IV) over 30-60 minutes on days 1 and 15 of each cycle, and varlilumab IV over 90 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a computed tomography (CT) or magnetic resonance imaging (MRI) at baseline, every 8 weeks while on treatment, and at end of treatment or progression. Patients also undergo a tumor biopsy at baseline and on day 21 of cycle 1. Patients also undergo blood sample collection on study. ARM B: Patients receive atezolizumab IV over 30-60 minutes on days 1 and 15 of each cycle and varlilumab IV over 90 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo a CT or MRI at baseline, every 8 weeks while on treatment, and at end of treatment or progression. Patients also undergo a tumor biopsy at baseline and on day 21 of cycle 1. Patients also undergo blood sample collection on study. After completion of study treatment, patients are followed up at 30 days and then every 3 months until death, withdrawal of consent, or study closure.