Vilastobart+Retifanlimab in BRCA or PALB2 Deficient PC

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.

Drug: vilastobart (XTX101). 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).

Drug: Retifanlimab. 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.

Vilastobart + Retifanlimab (experimental): This arm involves screening, study treatment with the study drugs, study visits, and follow-up visits for up to 3 years from time of joining study. Participants will receive up to 4 doses of Vilastobart, and Retifanlimab every three weeks until disease progression, intolerable side effects, or for a total of one year. Premedication for all vilastobart doses is required. For participants who experience disease progression on retifanlimab monotherapy or after completion of therapy on trial may be considered for re-induction with vilastobart and retifanlimab. Treatment beyond disease progression will be permitted for first instance of progressive disease by RECIST only if patients remain clinically stable from their disease and ongoing treatment is considered appropriate by patient, treating physician, and Sponsor Investigator.

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). Time frame: From Day 1 through end of follow up (up to 3 years from registration).

Overall survival (OS). Time frame: Up to 3 years from registration.

Duration of response (DoR). Time frame: From Day 1 through end of follow up (up to 3 years from registration).

Overall clinical benefit. Time frame: From baseline through up to 1 year..

Safety and tolerability of vilastobart and retifanlimab. Time frame: From baseline through up to 1 year.

Treatment-associated depletion of regulatory T cells. Time frame: From screening to on-treatment biopsy (estimated to be up to 2 months)..

Inclusion Criteria: * Participant must have histologically proven metastatic pancreatic cancer. Histologies including acinar cell carcinoma, carcinoma, ductal carcinoma, ductal adenocarcinoma, poorly differentiated or adenosquamous carcinoma are allowed. * Participant must have a germline or somatic pathogenic alteration in BRCA1, BRCA2, or PALB2 on tumor next generation sequencing (NGS) performed using a CLIA certified assay. Somatic pathogenic alterations detected on circulating tumor DNA need confirmation on tumor tissue NGS. Germline pathogenic alterations in BRCA1, BRCA2 or PALB2 do not require further confirmation on tumor NGS. All genomic reports be verified in writing (via email) by site and/or overall PI. * Participants must have measurable disease per RECIST version 1.1. * Participant must have at least one disease site which is amenable to safe biopsy and must agree to pre- and on-treatment biopsies (core, incisional, or excisional biopsy) of tumor site. In select cases biopsies can be waived after discussion with the Sponsor Investigator. * Participant must have had at least one but not more than two lines of cytotoxic chemotherapy for metastatic disease. Receipt of neoadjuvant or adjuvant therapy within the last 12 months may count as one line of therapy in metastatic setting for patients with recurrent disease who are being considered for the study. Receipt of targeted therapy such as KRAS inhibitor, or PARP inhibitor is not counted line of therapy. Recycling of the same agents from prior lines of cytotoxic chemotherapy after disease progression does not count as a new line of therapy. * Participant must have had prior platinum containing chemotherapy with at least a best response of stable disease. Participants with primary disease progression on platinum chemotherapy are ineligible. * Age ≥18 years * ECOG performance status of 0-2. * Participants must meet the following organ and marrow function as defined below: * absolute neutrophil count ≥1,000/mcL * platelets ≥75,000/mcL * total bilirubin ≤ 1.5x institutional upper limit of normal (ULN). For patients with liver metastases or confirmed/suspected Gilbert syndrome, total bilirubin ≤ 3 × ULN * AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional ULN. For patients with liver metastases, AST and ALT ≤ 5 × ULN * glomerular filtration rate (GFR) ≥30 mL/min/1.73 m\^2 * For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive …

Enrollment: 40 participants (estimated).