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
Overview
- Phase
- Phase 2
- Intervention
- Atezolizumab
- Conditions
- Metastatic Distal Bile Duct Adenocarcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 57
- Locations
- 29
- Primary Endpoint
- Number of Participants Experiencing a Response
- Status
- Active, Not Recruiting
- Last Updated
- 11 months ago
Overview
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Arms & Interventions
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Atezolizumab
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Biopsy
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Biospecimen Collection
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Cobimetinib
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Computed Tomography
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Magnetic Resonance Imaging
Arm A (cobimetinib, atezolizumab, varlilumab)
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.
Intervention: Varlilumab
Arm B (atezolizumab, varlilumab)
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.
Intervention: Atezolizumab
Arm B (atezolizumab, varlilumab)
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.
Intervention: Biopsy
Arm B (atezolizumab, varlilumab)
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.
Intervention: Biospecimen Collection
Arm B (atezolizumab, varlilumab)
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.
Intervention: Computed Tomography
Arm B (atezolizumab, varlilumab)
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.
Intervention: Magnetic Resonance Imaging
Arm B (atezolizumab, varlilumab)
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.
Intervention: Varlilumab
Outcomes
Primary Outcomes
Number of Participants Experiencing a Response
Time Frame: Up to 2 years
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.
Duration of Progression Free Survival (PFS)
Time Frame: Up to 2 years
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.
Secondary Outcomes
- 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)