Radiation Therapy with Dual Immune Checkpoint Inhibitor Therapy (Botensilimab and Balstilimab) for the Treatment of Metastatic Pancreatic Ductal Adenocarcinoma, Miami EMPIRE Trial

Inclusion Criteria

• ≥ 18 years old
• Histologically or cytologically confirmed diagnosis of pancreatic ductal adenocarcinoma
• Microsatellite stable (MSS) disease by pathologic assessment
• Patients must have measurable disease as defined by RECIST 1.1
• Progression on ≥ 1 line of systemic therapy
• No concomitant therapy with any of the following: interleukin (IL)-2, interferon, non-study immunotherapy regimens, cytotoxic chemotherapy, immunosuppressive agents, other investigational therapies, and/or chronic use of systemic corticosteroids
• No known infection with human immunodeficiency virus (HIV) or active infection with hepatitis B
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Life expectancy ≥ 3 months
• Absolute neutrophil count (ANC) ≥ 1,000 cells/μL (obtained < 4 weeks prior to starting protocol treatment)
• White blood count (WBC) ≥ 2,000 cells/μL (obtained < 4 weeks prior to starting protocol treatment)
• Platelets ≥ 75,000 per μL (obtained < 4 weeks prior to starting protocol treatment)
• Hemoglobin ≥ 8.0 g/dL (obtained < 4 weeks prior to starting protocol treatment)
• Creatinine clearance ≥ 40 mL/min (obtained < 4 weeks prior to starting protocol treatment)
• Serum total bilirubin ≤ 1.5 times the upper limit of normal (obtained < 4 weeks prior to starting protocol treatment)
• Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3 × upper limit of normal (ULN) (or ≤ 5 × ULN in patients with liver metastases) (obtained < 4 weeks prior to starting protocol treatment)
• International normalized ratio or prothrombin time ≤ 1.5 × ULN (obtained < 4 weeks prior to starting protocol treatment)
• Activated partial thromboplastin time ≤ 2.5 × ULN (obtained < 4 weeks prior to starting protocol treatment)
• Absolute lymphocyte count (ALC) ≥ 1000 cells/μL at baseline (obtained < 4 weeks prior to starting protocol treatment)
• At least 1 previously unirradiated lesion amenable to pre-treatment biopsy
• No limit on overall numbers of lesions, but liver tumor burden ≤ 25% of total liver volume
• Women of childbearing potential (WOCBP): negative serum pregnancy test (within 7 days prior to day 1 of protocol therapy) * Females of non-childbearing potential are defined as: ** ≥ 50 years of age and has not had menses for greater than 1 year ** Amenorrheic for ≥ 2 years without a hysterectomy and bilateral oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation ** Status is post-hysterectomy, bilateral oophorectomy, or tubal ligation
• Male and female patients of reproductive potential must use effective methods of contraception or abstain from sexual activity for the course of the study through at least 6 months after the last dose of balstilimab and/or botensilimab

Exclusion Criteria

• Liver tumor burden exceeding 25% of total liver volume
• Active, untreated central nervous system (CNS) metastases
• Active autoimmune disease or history of autoimmune disease that required systemic treatment within 2 years of the start of study treatment (i.e., with use of disease-modifying agents or immunosuppressive drugs)
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or another immunosuppressive medication within 30 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses (≤ 10 mg daily prednisone equivalent) are permitted in the absence of active autoimmune disease
• Previous external beam radiation therapy to the liver or radioisotope therapy directed to the liver or any liver embolization
• Clinically significant ascites requiring a paracentesis in the last 4 weeks, or clinically significant history of liver failure defined as any prior episode of hepatic encephalopathy and/or any prior history of an elevated serum ammonia level
• Partial or complete bowel obstruction within the last 3 months prior to study enrollment, signs/symptoms of bowel obstruction, or known radiologic evidence of impending obstruction
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke or myocardial infarction within 6 months of study enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥ III), or serious uncontrolled cardiac arrhythmia requiring medication * QTcF (QT interval corrected using Fridericia’s formula) of > 480 ms
• Prior allogeneic organ transplantation
• Treatment with chemotherapy or targeted therapy within 2 weeks prior to initiating Eradication of Metastatic Pancreatic Cancer with Immuno-Radiation (EMPIRE) treatment
• Persistent grade ≥ 2 adverse events (aEs) from prior therapy (except neuropathy)
• Known additional malignancy requiring active treatment
• History of non-infectious pneumonitis
• Active infection requiring antibiotic
• Live vaccine within 30 days of protocol treatment
• Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine or booster < 7 days before cycle (C) 1 day (D) 1. For vaccines requiring more than 1 dose, the full series should be completed prior to C1D1, when feasible. Booster shot not required but also must be administered > 7 days from C1D1 or > 7 days from future cycle on study
• History of severe hypersensitivity reaction to monoclonal antibody
• Participants with impaired decision-making capacity