Low Dose Chemotherapy (Gemcitabine, Nab-Paclitaxel, Capecitabine, Cisplatin and Irinotecan) followed by Olaparib and Pembrolizumab for the Treatment of Untreated Metastatic Pancreatic Ductal Adenocarcinoma

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent document
• Age ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Metastatic histologically or cytologically confirmed pancreatic ductal adenocarcinoma. Subjects with islet cell neoplasms and mixed histology will be excluded
• Patients must not have received prior treatment for pancreatic cancer
• Have measurable disease based on RECIST 1.1
• Patient agreeable to a biopsy of an accessible lesion post 6 cycles of GAX-CI chemotherapy and after one cycle of maintenance pembrolizumab and olaparib. Biopsy will only be obtained if lesion is accessible and felt to be reasonably safe to biopsy
• Leukocytes ≥ 3,000/mm^3
• Absolute neutrophil count ≥ 1,500/ mm^3
• Platelets ≥ 100,000/mm^3
• Hemoglobin ≥ 8 g/dL
• Total bilirubin ≤ 1.5 upper limit of normal (ULN) OR direct bilirubin ≤ ULN if total bilirubin > 1.5 x ULN
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x ULN
• Creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 60 mL/min (if using the Cockroft-Gault formula)
• A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) OR * A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 120 days after the last dose of study treatment
• A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period
• Participant understands the study regimen, its requirements, risks and discomforts and is able and willing to sign the informed consent form in accordance with regulatory and institutional guidelines must be obtained before the performance of any protocol related procedures that are not part of normal patient care. Subjects must be competent to report adverse events(AE), understand the drug dosing schedule and use of medications to control AE

Exclusion Criteria

• Patients who will be considered for surgery are ineligible
• Subjects who have had prior chemotherapy for pancreatic cancer or prior chemotherapy within 5 years of enrollment for other cancer diagnoses
• Subjects who are receiving or have received any investigational agents within 28 days prior to day 1 of treatment in this study
• Subject has undergone major surgery, other than diagnostic surgery (i.e. surgery done to obtain a biopsy for diagnosis or an aborted Whipple), within 28 days prior to day 1 of treatment in this study
• Has history of central nervous system (CNS) metastases and/or carcinomatous meningitis
• Is expected to require any other form of systemic or localized antineoplastic therapy while on study
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
• Has received prior therapy with gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan, or PARP inhibitor
• History of severe hypersensitivity reaction to gemcitabine, nab-paclitaxel, capecitabine, cisplatin, irinotecan, PARP inhibitor or related compounds and/or to any of their components
• Is taking a moderate or strong CYP3A4 or CYP2C9 inhibitor
• Has uncontrolled acute or chronic medical illness
• Has known additional malignancy that is progressing and requires active treatment * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or other cancers that have undergone potentially curative therapy are not excluded
• Has received radiotherapy for pancreatic cancer
• Has received a live vaccine or live-attenuated within 30 days prior to the first dose of study drug. Administration of killed vaccine is allowed. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines are live attenuated vaccines and are not allowed
• Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment * Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent
• Has active autoimmune disease. Subjects with Graves or Hashimoto’s disease, vitiligo, type I diabetes mellitus, psoriasis or other conditions not requiring systemic treatment are permitted to enroll. Subjects requiring systemic treatment for autoimmune disease in the past must be approved by the principal investigator (PI)
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
• Prior tissue or organ allograft regardless of need for immunosuppression, including corneal allograft. Exceptions can be approved by the PI if loss of the graft is not a clinical concern. Patients with history of allogeneic bone marrow transplantation will be excluded
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator
• Requirement for daily supplemental oxygen
• Patients with a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or current pneumonitis/interstitial lung disease
• Subject with clinically significant wound
• Has a confirmed history of encephalitis, meningitis, or uncontrolled seizures in the year prior to informed consent
• Has a known history of human immunodeficiency virus (HIV)
• Has known active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as HCV ribonucleic acid [RNA] [qualitative] is detected) infection. Patients who are hepatitis C antibody positive and viral load negative will be permitted to enroll
• Has uncontrolled infection
• Subjects unable to undergo venipuncture and/or tolerate venous access
• Has known psychiatric or substance use disorder that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment
• A WOCBP who has a positive urine pregnancy test within 72 hours prior to study drug initiation. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. In the case of a positive serum human chorionic gonadotropin (HCG) test, a transvaginal ultrasound must be used to confirm lack of pregnancy