Stereotactic Body Radiation Therapy plus Zimberelimab with or without Quemliclustat and Etrumadenant before Surgery for the Treatment of Borderline Resectable or Locally Advanced Pancreatic Cancer, The AIRPanc Trial

Inclusion Criteria

• Histological or pathological confirmation of pancreatic adenocarcinoma * Cytologic or histologic proof of PDAC needs to be verified by the treating institution pathologist. A pathological report from non-treating institutions is sufficient to consent and to initiate investigational therapy if tissue sample is unavailable for evaluation at time of consent or enrollment. However, in such a case, PDAC diagnosis should be confirmed by the treating institution pathologist at a later time.
• Completed at least 8 cycles of neoadjuvant modified FOLFIRINOX and no more than 10 cycles of neoadjuvant modified FOLFIRINOX. Omission of oxaliplatin due to adverse events may be allowed in cycles 5-8/10 with consultation with the principal investigator.
• Patients with surgically resectable PDAC who are considered appropriate to undergo the applicable operation. * Patients with surgically resectable PDAC on diagnostic abdominal CT scan or MRI are eligible to participate in the study. Resectable PDAC confirmed as a surgical candidate with the designated site radiologist and surgeon at the treating institution who must meet the below criteria: ** If needed, venous involvement amenable to reconstruction ** If relevant, tumor <180° of the celiac and superior mesenteric arteries ** No arterial reconstruction or resection required except for involvement of the celiac artery allowing for Appleby resection. A consultation with the study principal investigators (PIs) required for Appleby resection ** No involvement of the inferior vena cava ** No involvement of the aorta
• Eligible to undergo SBRT.
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• No prior surgical, systemic, or radiotherapy for PDAC except for mFOLFIRINOX.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Age ≥ 18 years.
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L without granulocyte colony-stimulating factor support (within 14 days prior to initiation of investigational treatment).
• White blood cell (WBC) count ≥ 2.5 x 10^9/L (2500/µL) (within 14 days prior to initiation of investigational treatment).
• Lymphocyte count ≥ 0.5 x 10^9/L (500/µL) (within 14 days prior to initiation of investigational treatment).
• Platelet count ≥ 100 x 10^9/L (100,000/µL) without transfusion within 4 weeks (within 14 days prior to initiation of investigational treatment).
• Hemoglobin (Hgb) > 9.0 g/dL without transfusion within 1 week (within 14 days prior to initiation of investigational treatment).
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN) unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to initiation of therapy (within 14 days prior to initiation of investigational treatment). Prior to initiation of therapy, AST, ALT, and ALP ≤ 2.5 x ULN.
• Serum total bilirubin ≤ 1.5 x ULN unless elevated secondary to biliary obstruction from the pancreas mass and amenable to decompression prior to administration of investigational therapy (within 14 days prior to initiation of investigational treatment). A functioning biliary stent as evidenced by declining total bilirubin and ≤ 2 x ULN is required prior to initiation of therapy.
• Albumin ≥ 3.0 g/dL (within 14 days prior to initiation of investigational treatment).
• Creatinine within ULN or calculated creatinine clearance (CrCl) > 50 mL/min using the Cockcroft-Gault formula (within 14 days prior to initiation of investigational treatment).
• International normalized ratio (INR) and activated partial prothrombin time (aPTT) ≤ 1.5 x ULN (within 14 days prior to initiation of investigational treatment).
• Women of child-bearing potential must have a negative serum pregnancy test at screening and must agree to use two forms of effective contraception from the time of the negative pregnancy test and for a minimum of 5 months after the last dose of study drug. Effective forms of contraception include abstinence, hormonal contraceptive (injectable or implantable) in conjunction with a barrier method, or a double barrier method. Women will be considered not of child-bearing potential if amenorrheic for at least one year or if they have undergone surgical sterilization.
• Fertile men must agree to remain abstinent or use an effective method of birth control during the study and for up to 120 days after the last dose of study drug.
• Willingness and ability to provide written informed consent prior to any study- related procedures and to comply with all study requirements.
• Able to comply with the study protocol, in the investigator’s judgment.
• On stable full dose anticoagulation for 8 weeks. Initiation of prophylactic dose anticoagulation is allowed if not deemed to be at increased risk of bleeding under the view of the treating physician and Principal Investigator.

Exclusion Criteria

• Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies, including but not limited to anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies.
• Patients who are receiving any other investigational agents concurrently.
• Concomitant treatment with other anti-neoplastic agents (hormonal therapy acceptable).
• Corrected QT (QTc) ≥ 480 msec using Fridericia’s QT correction formula (based on an average of triplicate recordings).
• Prior treatment with an agent targeting the adenosine pathway.
• Due to the potential risk for drug-drug interactions with etrumadenant, participants must not have had: * Oral treatment with strong inhibitors of breast cancer resistance protein (BCRP) (e.g., cyclosporin A, eltrombopag) or BRCP substrates with a narrow therapeutic window, administered orally (e.g., prazosin, rosuvastatin) within 4 weeks or 5 drug-elimination half- lives of the drug (whichever is longer) prior to initiation of study treatment. * Oral treatment with strong inhibitors of P-glycoprotein (P-gp) substrates (e.g., itraconazole, quinidine, verapamil, dronedarone, ranolazine) or P-gp with a narrow therapeutic window, administered orally (e.g., digoxin) within 4 weeks or 5 drug-elimination half-lives of the drug (whichever is longer) prior to initiation of study treatment. * Treatment with known strong CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s Wort) or strong CYP3A4 inhibitors (e.g., clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, and voriconazole) within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to initiation of study treatment. * Treatment with known strong UDP-glucuronosyltransferases (UGTs) of UGT1A1, 1A4, 1A9 and 2B4 inhibitors (e.g., atazanavir) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment. * Treatment with known sensitive substrates of BSEP within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment. * Treatment with known sensitive substrates of OCT2 within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment. * Treatment with known sensitive substrates of MATE1 within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to the initiation of study treatment.
• Uncontrolled pleural effusion, pericardial effusion, or ascites.
• Uncontrolled hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL, or corrected serum calcium > ULN) or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy.
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease (Crohn’s disease or ulcerative colitis), antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: * Patients with a history of autoimmune-related hypothyroidism who are on thyroid- replacement hormone are eligible for the study. * Patients with controlled Type 1 diabetes mellitus who are on a stable insulin regimen are eligible for the study. * Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: ** Rash must cover < 10% of body surface area. ** Disease is well controlled at baseline and requires only low-potency topical corticosteroids. ** No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
• History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. * History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Positive HIV test at screening or at any time prior to screening. * Patients without a prior positive HIV test result will undergo an HIV test at screening, unless not permitted per local regulations.
• Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. * Note: Patients with a past or resolved HBV infection, defined as having a negative HBV surface antigen (HBsAg) test and a positive total hepatitis B core antibody test at screening, are eligible for the study.
• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test at screening. The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
• Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty liver disease, and inherited liver disease.
• Known active tuberculosis.
• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. However, patients who were admitted for biliary tract infection due to bile duct obstruction at time of diagnosis must have a functioning biliary stent (as evidenced by declining total bilirubin and ≤ 2 X ULN) and resolved infection (defined by normalization of elevated white blood cell count, absence of signs of infection) and completion of an antibiotic course (at least a seven-day course) prior to initiation of therapy.
• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment except for biliary tract infection due to bile duct obstruction from the pancreas mass. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 months prior to initiation of study treatment, seizure disorder, uncontrolled hypertension, unstable arrhythmia, or unstable angina within 3 months prior to initiation of study treatment.
• Grade ≥ 3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment.
• Prior autologous stem cell, allogeneic stem cell, or solid organ transplantation.
• History of malignancy other than PDAC within 2 years prior to screening, with the exception of those with a negligible risk of metastasis or death (e.g., 5-year overall survival of > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. Patients with history of prior malignancies should have risk of recurrence within 3 years after screening to be less than 90% (to be discussed with the principal investigator [PI] for final determination of eligibility).
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during treatment with zimberelimab or within 5 months after the last dose of zimberelimab.
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
• Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies.
• Known allergy or hypersensitivity to any of the study drugs or any of their excipients.
• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to initiation of study treatment.
• Treatment with systemic immunosuppressive medication administered at > 10mg/day prednisone or equivalent (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the course of the study, with the following exceptions: * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study if receiving equivalent to less than 10 mg of prednisone daily. * Patients who received a one-time pulse dose of systemic immunosuppressant medication are eligible for the study after approval from the PI has been obtained.
• Inability to swallow medication or malabsorption condition that would alter the absorption of orally administered medications.
• Major surgical procedure or significant traumatic injury within 14 days of initiating study, except for procedures which may be required to rule out metastatic disease (thoracentesis, biopsies including laparoscopy, and paracentesis). Placement of central venous access catheter (eg, port or similar) is not considered a major surgical procedure and is therefore permitted.
• Previous radiotherapy to 25% or more of the bone marrow.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications in the opinion of the treating investigator.
• Considered ineligible to receive the full standard dose modified FOLFIRINOX therapy in the adjuvant setting. Up to 25% dose reduction of oxaliplatin due to chemotherapy-induced neuropathy will be allowed during initiation of adjuvant therapy in consultation with the principal investigator. If dose reduced oxaliplatin is not tolerated during initiation of adjuvant therapy, oxaliplatin may be omitted after discussion with the principal investigator.
• Peripheral neuropathy > Grade 2.
• History of allergy or hypersensitivity to oxaliplatin, irinotecan, leucovorin, fluorouracil, pegfilgrastim, or any excipients.
• History of Gilbert’s disease or known genotype UGT1A1 *28/*28.
• Inflammatory disease of the colon or rectum, or severe uncontrolled diarrhea.
• Active or history of celiac disease.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.