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Immunologic Factors

Patients receive cobimetinib PO QD on days 1-21 of each cycle, 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.

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.

Biopsy

Biospecimen Collection

Cobimetinib

Computed Tomography

Magnetic Resonance Imaging

Varlilumab

Nilofer S Azad

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.

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.

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

A Randomized Phase 2 Study of Combination Atezolizumab and CDX-1127 (Varlilumab) With or Without Addition of Cobimetinib in Previously Treated Unresectable Biliary Tract Cancers

NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Immunological variables will be examined in plots and summary statistics, to characterize distributions, identify outliers and other potential problems in the data. Joint exploratory analysis will identify associations and potential interactions. Variables may be transformed on the basis of these investigations, to reduce skewness, minimize the influence of outliers and/or to regularize relationships between predictors and response for better model fit. Exploratory analysis of the molecular markers, including visualizations and statistical summaries such as hierarchical cluster analysis, heat maps, multidimensional scaling, and principle component analysis will offer important views of the structural characteristics of the expression data.

Will be defined as the proportion of response evaluable subjects who have a complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria at any time during the study.

Will be summarized descriptively using Kaplan-Meier plots, and compared between arms using log-rank tests.

Will be summarized descriptively using the Kaplan-Meier method. Median overall survival will be reported and the associated 95% confidence interval will be estimated.

The density of CD8+ T cells in each treatment group, at baseline and after treatment, will be visualized using boxplots, and described using summary statistics including means and standard deviation presented with 95% confidence intervals. A student t-test or nonparametric Wilcoxon rank-sum test will be used to determine whether the increase in CD8+ T cells is greater in treatment arm B (combination atezolizumab and CDX-1127 (varlilumab) plus cobimetinib) than in treatment arm A (atezolizumab and CDX-1127 \[varlilumab\]).

Analysis of the activity of drugs in the body over a period of time, including the processes by which drugs are absorbed, distributed in the body, localized in the tissues, and excreted.

Analysis of an agent's ability to provoke an immune response (humoral and/or cell-mediated) in the subject.

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
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	NCT04941287	Metastatic Dist... Metastatic Gall... Metastatic Intr... Recurrent Dista... Recurrent Gallb... Recurrent Intra... Stage IV Distal... Stage IV Gallbl... Stage IV Intrah... Unresectable Li...	Atezolizumab Biopsy Biospecimen Col... Cobimetinib Computed Tomogr... Magnetic Resona... Varlilumab	18 Years -	National Cancer Institute (NCI)
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	NCT04941287	Metastatic Dist... Metastatic Gall... Metastatic Intr... Recurrent Dista... Recurrent Gallb... Recurrent Intra... Stage IV Distal... Stage IV Gallbl... Stage IV Intrah... Unresectable Li...	Atezolizumab Biopsy Biospecimen Col... Cobimetinib Computed Tomogr... Magnetic Resona... Varlilumab	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for metastatic distal bile duct adenocarcinoma