Summary

This phase II trial investigates the effect of combining two immune therapies, atezolizumab and CDX-1127 (varlilumab), with or without cobimetinib, in treating patients with biliary tract cancer that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Varlilumab is an immune agonist antibody that may further strengthen the immune system’s attack on the cancer. Cobimetinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps slow or stop the spread of cancer cells. Giving atezolizumab in combination with varlilumab and cobimetinib may work better than atezolizumab and varlilumab alone in treating patients with unresectable biliary tract cancer.

Objectives

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.

Eligibility

1. Pathologically confirmed biliary tract cancer, having received at least 1 prior line of systemic therapy, and received no more than 2 prior lines of therapy in the metastatic setting (disease recurrence =< 6 months from the last dose of perioperative therapy/day of surgery [whichever is more recent] in resected patients will be considered the first line of therapy) * Includes intrahepatic cholangiocarcinoma (IHC), extrahepatic cholangiocarcinoma (EHC), and gallbladder carcinoma (GBC), but not Ampulla of Vater cancers
2. Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
3. Age >= 18 years. Because no dosing or adverse event data are currently available on the use of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) in patients < 18 years of age, children are excluded from this study
4. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 80%)
5. Absolute neutrophil count >= 1,500/mcL
6. Hemoglobin >= 9.0 g/dl
7. Platelets >= 100,000/mcL
8. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (Patients with known Gilbert disease who have serum bilirubin level =< 3 x ULN may be enrolled)
9. Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN
10. Serum creatinine =< 1.5 x institutional ULN OR
11. Creatinine clearance > 30 mL/min/1.73 m^2 (calculated by Cockcroft-Gault method) for patients with creatinine levels above institutional normal
12. Albumin >= 3.0 g/dL
13. Prothrombin time (PT)/activated partial thromboplastin time (aPTT) =< 1.5 x ULN (This applies only to patients who do not receive therapeutic anticoagulation; patients receiving therapeutic anticoagulation, such as low-molecular-weight heparin or warfarin, should be on a stable dose)
14. Creatine kinase (CK)/creatine phosphokinase (CPK) < 5 x ULN
15. Oxygen saturation >= 92% on room air
16. Left ventricular ejection fraction > 50%
17. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
18. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
19. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
20. Patients must be willing to undergo 2 sets of core needle biopsies. If possible, biopsied sites should be different than those used for measurable disease/RECIST measurements, but this is not mandatory
21. Patients must have an estimated life expectancy of greater than 3 months
22. Patients must be able to swallow pills
23. Patients should not have evidence of retinal pathology on ophthalmologic examination; or neurosensory retinal detachment, retinal vein occlusion (RVO), or neovascular macular degeneration
24. The effects of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 5 months after the last dose of atezolizumab. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 5 months (150 days) after completion of atezolizumab, cobimetinib, and CDX-1127 (varlilumab) administration
25. Ability to understand and the willingness to sign a written informed consent document