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 | Active Not Recruiting Phase 2 Results FDA Drug

• 4 other identifiers: NCI-2021-06445ETCTN1047610476UM1CA186691
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 29

Brief 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.

Conditions

Metastatic Distal Bile Duct Adenocarcinoma; Metastatic Gallbladder Carcinoma; Metastatic Intrahepatic Cholangiocarcinoma; Recurrent Distal Bile Duct Adenocarcinoma; Recurrent Gallbladder Carcinoma; Recurrent Intrahepatic Cholangiocarcinoma; Stage IV Distal Bile Duct Cancer AJCC v8; Stage IV Gallbladder Cancer AJCC v8; Stage IV Intrahepatic Cholangiocarcinoma AJCC v8; Unresectable Liver Carcinoma

Outcome Measures

Primary Outcomes (2)

• Number of Participants Experiencing a Response

  Response is defined as a complete response (CR) (disappearance of all lesions) or partial response (PR) (\>= 30% decrease in the sum of target lesions) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria after receiving at least one dose of the assigned study regimen.

  Up to 2 years

• Duration of Progression Free Survival (PFS)

  Time from the date of enrollment to the date of documented tumor progression (\>= 20% increase in the sum of target lesions, measurable increase in a non-target lesion, or appearance of a new lesion) by RECIST v1.1 or death due to any cause, whichever occurs first for participants who received at least one dose of their assigned study regimen.

  Up to 2 years

Secondary Outcomes (5)

• The Number of Participants Experiencing Grade 3, 4 and 5 Adverse Events

  Up to 2 years

• Duration of Overall Survival (OS)

  Up to 2 years

• Change in T-cell Populations

  Baseline up to 2 years

• The Change in Clearance Rates

  At 6 weeks

• The Amount of Anti-drug Antibodies With Treatment

  Up to 2 years

Other Outcomes (1)

• Tumor Microenvironment Modulation and Immunologic Response

  Up to 2 years

Study Arms (2)

Arm A (cobimetinib, atezolizumab, varlilumab)

EXPERIMENTAL

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.

Biological: Atezolizumab; Procedure: Biopsy; Procedure: Biospecimen Collection; Drug: Cobimetinib; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Varlilumab

Arm B (atezolizumab, varlilumab)

EXPERIMENTAL

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.

Biological: Atezolizumab; Procedure: Biopsy; Procedure: Biospecimen Collection; Procedure: Computed Tomography; Procedure: Magnetic Resonance Imaging; Drug: Varlilumab

Interventions

Atezolizumab BIOLOGICAL

Given IV

Also known as: MPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG 7446, RG-7446, RG7446, RO 5541267, RO-5541267, RO5541267, Tecentriq

Arm A (cobimetinib, atezolizumab, varlilumab); Arm B (atezolizumab, varlilumab)

Biopsy PROCEDURE

Undergo tumor biopsy

Also known as: BIOPSY_TYPE, Bx

Arm A (cobimetinib, atezolizumab, varlilumab); Arm B (atezolizumab, varlilumab)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Arm A (cobimetinib, atezolizumab, varlilumab); Arm B (atezolizumab, varlilumab)

Cobimetinib DRUG

Given PO

Also known as: Cotellic, GDC 0973, GDC-0973, GDC0973, MEK Inhibitor GDC-0973, XL 518, XL-518, XL518

Arm A (cobimetinib, atezolizumab, varlilumab)

Computed Tomography PROCEDURE

Undergo a CT scan

Also known as: CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, tomography

Arm A (cobimetinib, atezolizumab, varlilumab); Arm B (atezolizumab, varlilumab)

Magnetic Resonance Imaging PROCEDURE

Undergo MRI

Also known as: Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI

Arm A (cobimetinib, atezolizumab, varlilumab); Arm B (atezolizumab, varlilumab)

Varlilumab DRUG

Given IV

Also known as: CDX 1127, CDX-1127, CDX1127, Immunoglobulin G1, Anti-(Human CD Antigen CD27) (Human Monoclonal CDX-1127 Clone 1f5 Heavy Chain), Disulfide with Human Monoclonal CDX-1127 Clone 1f5 Kappa-chain, Dimer

Arm A (cobimetinib, atezolizumab, varlilumab); Arm B (atezolizumab, varlilumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
• 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
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1 (Karnofsky \>= 80%)
• Absolute neutrophil count \>= 1,500/mcL
• Hemoglobin \>= 9.0 g/dl
• Platelets \>= 100,000/mcL
• 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)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) =\< 3 x institutional ULN
• Serum creatinine =\< 1.5 x institutional ULN OR
• Creatinine clearance \> 30 mL/min/1.73 m\^2 (calculated by Cockcroft-Gault method) for patients with creatinine levels above institutional normal
• Albumin \>= 3.0 g/dL
• 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)
• Creatine kinase (CK)/creatine phosphokinase (CPK) \< 5 x ULN

You may not qualify if:

• Patients with prior allogeneic bone marrow transplantation within the past 5 years or prior solid organ transplantation at any point
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events (other than alopecia or neuropathy) due to agents administered more than 4 weeks earlier. However, the following therapies are allowed:
• Hormone-replacement therapy or oral contraceptives
• Herbal therapy \> 1 week prior to randomization (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to randomization)
• Palliative radiotherapy for bone metastases \> 2 weeks prior to randomization
• Prior treatment with anti-CTLA-4, anti-PD-1, or anti-PD-L1or other immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents with the following exceptions:
• Patients who have only received previous durvalumab (anti-PD-L1) as part of first line in combination with gemcitabine and cisplatin (TOPAZ-1 regimen \[NCT03875235\]) are eligible.
• Patients who have only received previous pembrolizumab (anti-PD-1) as part of first line in combination with gemcitabine and cisplatin (KEYNOTE-966 regimen \[NCT04003636\]) are eligible.
• Prior treatment with MEK or ERK inhibitors
• Treatment with any other investigational agent within 4 weeks prior to randomization
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon \[IFN\]-alpha or interleukin \[IL\]-2) within 6 weeks prior to randomization
• Treatment with systemic immunosuppressive medications (including, but not limited to, prednisone (\> 10 mg), cyclophosphamide, tacrolimus, sirolimus, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor \[anti-TNF\] agents) within 2 weeks prior to randomization
• Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled
• The use of physiologic doses of systemic corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency is allowed
• The use of topical and inhaled corticosteroids are allowed due to low systemic absorption

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (29)

Mayo Clinic Hospital in Arizona

Phoenix, Arizona, 85054, United States

Location

City of Hope Comprehensive Cancer Center

Duarte, California, 91010, United States

Location

Los Angeles General Medical Center

Los Angeles, California, 90033, United States

Location

USC / Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California, 92868, United States

Location

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

UM Sylvester Comprehensive Cancer Center at Aventura

Aventura, Florida, 33180, United States

Location

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida, 33146, United States

Location

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida, 33442, United States

Location

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida, 33136, United States

Location

UM Sylvester Comprehensive Cancer Center at Kendall

Miami, Florida, 33176, United States

Location

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida, 33324, United States

Location

Emory University Hospital Midtown

Atlanta, Georgia, 30308, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Emory Saint Joseph's Hospital

Atlanta, Georgia, 30342, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York, 10016, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin, 53792, United States

Location

MeSH Terms

Conditions

Gallbladder Neoplasms; Cholangiocarcinoma

Interventions

atezolizumab; Biopsy; Specimen Handling; cobimetinib; Magnetic Resonance Spectroscopy; varlilumab; Immunoglobulin G; Disulfides

Condition Hierarchy (Ancestors)

Biliary Tract Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Biliary Tract Diseases; Digestive System Diseases; Gallbladder Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Spectrum Analysis; Chemistry Techniques, Analytical; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals

Results Point of Contact

• Title: Grants Administrative Manager
• Organization: Johns Hopkins University/SKCCC

jmurra33@jhmi.edu

4439273568

Study Officials

• Nilofer S Azad

  JHU Sidney Kimmel Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 25, 2021
• First Posted: June 28, 2021
• Study Start: December 15, 2021
• Primary Completion: January 2, 2024
• Study Completion (Estimated): April 29, 2026
• Last Updated: May 23, 2025
• Results First Posted: May 23, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

US (29)