Vilastobart+Retifanlimab in BRCA or PALB2 Deficient PC (EKLAVYA-HRD)

A Phase 2 Study of Fc Enhanced checKpoint bLockade With CTLA4 Antibody Vilastobart in Combination With PD-1 antibodY RetifAnlimab in BRCA or PALB2 Deficient Pancreatic Adenocarcinoma (EKLAVYA-HRD)

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).

Study Overview

• Status: Not yet recruiting
• Conditions: Pancreatic Cancer Metastatic
• Intervention / Treatment: Drug: vilastobart (XTX101); Drug: Retifanlimab

Detailed Description

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
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Harshabad Singh, MBBS MD; Phone Number: 617-724-4000; Email: sharshabad@mgb.org

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
      • Contact: Harshabad Singh, MBBS MD; Phone Number: 617-724-4000; Email: sharshabad@mgb.org
      • Principal Investigator: Harshabad Singh, MBBS MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 therapy, if indicated.
• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• It is not known what effects study treatment has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age group and male patients should use effective methods of contraception through defined periods during and after study treatment as specified below:

Female patients must meet 1 of the following:

• Postmenopausal for at least 1 year before the screening visit, or
• Surgically sterile, or

• Women of childbearing potential must:

  • agree to practice 1 effective method of contraception from the time of signing of the informed consent form through 5 months after the last dose of study drug.
  • Agree not to breastfeed from the time of signing of the informed consent form through 5 months after the last dose of study drug
  • Have a serum or urine pregnancy test to rule out pregnancy within 2 weeks prior to registration.
• Male patients must agree to practice 1 effective method of contraception from the time of signing of the informed consent form through 7 months after the last dose of study drug.

Highly effective methods of contraception include:

• Sexual abstinence (no sexual intercourse)
• Hormonal birth control
• Intrauterine device (IUD) or intrauterine system (IUS)
• Bilateral tubal ligation (both tubes tied)
• Vasectomy - Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Participants with neuroendocrine tumors of the pancreas are excluded.

• Prior anticancer therapy:

  • Received prior treatment with anti-CTLA-4 therapy
  • Received prior immune-checkpoint anti-PD-1/PD-L1 therapy
  • Received prior approved systemic anticancer therapy within 2 weeks or within its 5 half-lives prior to study treatment, whichever is shorter. Note: Long-standing hormonal therapy for prostate, breast, uterine, and adrenal cancer may be permitted to continue if it is deemed to be in the best interest of the patient, after discussion with the Sponsor Investigator.
  • Received prior radiotherapy within 2 weeks prior to study treatment. Note: Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease
• Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia or stable, Grade ≤ 2 non-autoimmune chemotherapy-induced peripheral neuropathy.
• Participants with uncontrolled intercurrent illness that would interfere with ability to participate in the opinion of the treating investigator.
• Participants with psychiatric illness/social situations that would limit compliance with study requirements.
• Has an active infection requiring systemic intravenous or oral therapy within 7 days of cycle 1 day 1.
• Has received a live or live-attenuated vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. COVID-19 vaccination should not be given within 7 days of trial drug initiation.

• Active autoimmune disease requiring systemic immunosuppression in excess of physiologic maintenance doses of corticosteroids (> 10 mg/day of prednisone or equivalent).

  • Physiologic corticosteroid replacement therapy at doses ≤ 10 mg/day of prednisone or equivalent for adrenal or pituitary insufficiency and in the absence of active autoimmune disease is permitted.
  • Participants with asthma that requires intermittent use of bronchodilators, inhaled corticosteroids, or local corticosteroid injections may participate.
  • Participants using topical, ocular, intra-articular, or intranasal corticosteroids (with minimal systemic absorption) may participate.
  • Brief courses of corticosteroids for prophylaxis (eg, contrast dye allergy) or study treatment-related standard premedications are permitted.
  • Replacement therapy (e.g. thyroxine, insulin) is not considered a form of systemic therapy and is allowed.
• Has a history of immune-related (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease regardless of etiology.
• Subjects with any condition requiring systemic treatment with either corticosteroids (>10mg/day of prednisone or equivalent) or other immunosuppressive medications within 14 days of treatment. Premedication for hypersensitivity reactions (e.g. to contrast for CT or gadolinium for MRI) or for prophylaxis of infusion related reactions is allowed.

Exceptions: use of inhaled, intranasal, intraocular, topical, and intraarticular joint injections are allowed

• Participants with a known history of Human Immunodeficiency Virus (HIV) infection are excluded unless they meet all of the following criteria:

  • Stable antiretroviral therapy (ART) for at least 12 weeks prior to enrollment
  • No history of AIDS-defining conditions.
  • CD4+ T-cell count ≥ 350 cells/mm^3 at screening
  • HIV viral load ≤ 50 copies/mL at screening.
  • No significant comorbidities associated with HIV infection that could interfere with the safety or efficacy of the investigational treatment.
  • No concurrent use of prohibited medications that may interfere with the study drug or cancer therapy
• Has a history of severe hypersensitivity reaction (≥ Grade 3) to any study intervention and/or any of its excipients (refer to the IBs and/or approved product label for a list of excipients)
• Participants with brain metastases (active brain metastases) or leptomeningeal disease are not eligible. Patients with treated brain metastases who are off systemic steroids > 2 weeks and have documented radiographic stability over 4 weeks since initial brain metastasis diagnosis may be considered in discussion with the Sponsor Investigator.
• Has a history of allogeneic bone marrow/stem, cell or solid organ transplantation.
• Unstable angina, myocardial infarction, congestive heart failure (New York Heart Association [NYHA] classification ≥ grade 2) or unstable vascular disease (eg, aortic aneurysm at risk of rupture, Moyamoya disease) that required hospitalization within 6 months prior to randomization, or other cardiac impairment that may affect the safety evaluation of the study drug (eg, poorly controlled arrhythmias, myocardial ischemia).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vilastobart + Retifanlimab; 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.

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).; Other Names: XTX101; 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.; Other Names: INCMGA00012; MGA012; ZYNYZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 1 year from baseline.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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).	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.	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.	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.	From screening to on-treatment biopsy (estimated to be up to 2 months).

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: Incyte Corporation; Lustgarten Foundation; Xilio Development, Inc.
• Investigators: Principal Investigator: Harshabad Singh, MBBS MD, Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2027
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: August 10, 2026
• First Submitted That Met QC Criteria: August 10, 2026
• First Posted (Actual): August 14, 2026

Study Record Updates

• Last Update Posted (Actual): August 14, 2026
• Last Update Submitted That Met QC Criteria: August 10, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: metastatic pancreatic cancer; BRCA1, BRCA2, or PALB2 mutation
• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Fanconi Anemia, Complementation Group D1
• Other Study ID Numbers: 26-466

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Request may be directed to: sharshabad@mgb.org. The protocol and statistical analysis plan will be made available on ClinicalTrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.
• IPD Sharing Time Frame: Data can be shared no earlier than 1 year following the date of publication.
• IPD Sharing Access Criteria: Contact the Partners Innovations team at http://www.partners.org/innovation
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No