This is a single arm, open-label, non-randomized multi-institution phase II trial of a Fc enhanced CTLA4 antibody, vilastobart, in combination with PD-1 antibody, retifanlimab, in patients with BRCA1, BRCA2 or PALB2 deficient pancreatic cancer (PC).
This is a single arm open label phase 2 clinical trial of a novel immunotherapy combination with Fc enhanced CTLA4 inhibitor, Vilastobart, in combination with PD-1 inhibitor, retifanlimab, in patients with metastatic pancreatic cancer who harbor a germline or somatic pathogenic alterations in BRCA1, BRCA2 or PALB2. The primary obejctive is to determine the efficacy of vilastobart in combination with retifanlimab in patients with BRCA1, BRCA2 or PALB2 altered pancreatic cancer as measured by objective response rate (ORR).This research study involves screening, study treatment with the study drugs, study visits, and follow-up visits. This study expects to enroll up to 40 participants. Participants will receive the study treatment for up to one year and will be followed for up to three years. The U.S. Food and Drug Administration (FDA) has not approved vilastobart as a treatment for any disease. The FDA has not approved retifanlimab (ZYNYZ) for this specific disease but it has been approved for other uses.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
40
100mg administered once every 6 weeks (Day 1 of every 6-week cycle) by intravenous infusion (IV) over about 90-140 minutes. This will continue for up to 4 6-week cycles (4 doses).
375 mg administered once every 3 weeks (Days 2 and 23 of every 6-week cycle) by intravenous infusion over about 30 minutes. This will continue for up to 12 months.
Massachusetts General Hospital
Boston, Massachusetts, United States
Objective response rate (ORR)
The primary endpoint is objective response rate for combination of vilastobart with retifanlimab. Response is measured using RECISTv1.1 and evaluated independently. Evaluation of the primary endpoint will follow a Simon's two-stage design. The objective response rate will be reported with an exact binomial 95% confidence interval.
Time frame: Up to 1 year from baseline.
Progression free survival (PFS)
Progression is measured using RECIST v1.1 defined as measured from the start of the treatment with vilastobart to the date of either documentation of disease progression or death. The Kaplan-Meier method will be used to estimate PFS.
Time frame: From Day 1 through end of follow up (up to 3 years from registration)
Overall survival (OS)
Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. The Kaplan-Meier method will be used to estimate OS.
Time frame: Up to 3 years from registration
Duration of response (DoR)
To measure the durability of response of the combination regimen as measured by duration of response (DoR), the duration of overall response is measured from the time RECIST v1.1 measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).
Time frame: From Day 1 through end of follow up (up to 3 years from registration)
Overall clinical benefit
Overall clinical benefit is defined as complete response (CR), or partial response (PR) or stable disease (SD) for at least 16 weeks as assessed by RECISTv1.1. They will be summarized using binomial proportions along with exact 95% CI.
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Time frame: From baseline through up to 1 year.
Safety and tolerability of vilastobart and retifanlimab
To determine safety and tolerability of the combination of vilastobart and retifanlimab, CTCAEv5.0 will be used to assess safety and tolerability. All patients who receive at least one dose of the study treatment regimen will be included in the assessment of adverse events (safety population). The number of patients experiencing new or worsening of each type of adverse event will be summarized according to the worst grade observed; incidence rates of adverse events and grade 3-5 adverse events will be summarized with 90% exact binomial confidence intervals.
Time frame: From baseline through up to 1 year
Treatment-associated depletion of regulatory T cells
To assess treatment-associated depletion of regulatory T cells (Tregs) and association with clinical outcomes following vilastobart and retifanlimab, as measured by density of CD3+CD4+FOXP3+ T cells per mm\^2 in paired pre-treatment and on-treatment tumor biopsies. Treg density at each time point, as well as absolute and percent change from baseline, will be summarized descriptively. Within-patient change will be assessed using the Wilcoxon signed-rank test. Baseline Treg density and change in Treg density will be compared between patients with and without objective response, and between patients with and without clinical benefit, using the Wilcoxon rank-sum test. Associations with PFS and OS will be explored using Cox proportional hazards models.
Time frame: From screening to on-treatment biopsy (estimated to be up to 2 months).