The Miami "EMPIRE" Trial - Eradication of Metastatic Pancreatic Cancer With Immuno-Radiation

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.
• Patients must have the following lab values obtained <4 weeks prior to starting protocol treatment:

• absolute neutrophil count (ANC) ≥1,000 cells/μL
• white blood count (WBC) ≥2,000 cells/μL
• platelets ≥75,000 per μL
• hemoglobin ≥8.0 g/dL
• creatinine clearance ≥40 mL/min)
• serum total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤3 × ULN (or ≤5 × ULN in patients with liver metastases)
• international normalized ratio or prothrombin time ≤1.5 × ULN
• activated partial thromboplastin time ≤2.5 × ULN
• absolute lymphocyte count (ALC) ≥1000 cells/μL at baseline
• 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)

a. Females of non-childbearing potential are defined as: i. ≥ 50 years of age and has not had menses for greater than 1 year ii. 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 iii. 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. See Section 4.11, Contraception.

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.

a. QT interval corrected using Fridericia's formula (QTcF) of > 480 ms.

• Prior allogeneic organ transplantation.
• Treatment with chemotherapy or targeted therapy within 2 weeks prior to initiating 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 (SARS) coronavirus 2 (CoV 2) (SARS-CoV-2) vaccine or booster < 7 days before Cycle 1 Day 1 (C1D1). 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.