Niraparib and Ipilimumab for the Treatment of Patients with Metastatic Pancreatic Cancer Whose Disease Has Not Progressed on Platinum-Based Therapy, ParpVax2 Trial

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of pancreatic adenocarcinoma with metastatic disease.
• ≥ 18 years of age.
• Patients must be able to understand the study procedures and agree to participate in the study by providing written informed consent.
• Participants must have received 8-12 cycles (4-6 months) of first-line FOLFIRINOX or modified FOLFIRINOX for metastatic disease with stable disease or better. Patients treated with liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) are also eligible. Patients who were initially treated with FOLFIRINOX or NALIRIFOX but stopped oxaliplatin because of toxicity are eligible for the trial. * Note: This requires at least stable imaging and a stable or decreasing tumor marker as applicable and as determined by the investigator.
• Measurable disease is not a requirement for study entry * Note: The study will require that at least 80% of enrolled patients (i.e., 55 of all patients) are biopsiable at enrollment. The investigators may require measurable/biopsiable disease as the study progresses in order to achieve this goal.
• Participants must be willing to undergo a pre-treatment fresh tumor biopsy (if medically feasible).
• Participants must be willing to undergo an on-treatment tumor biopsy (if medically feasible).
• Female participant has a negative serum pregnancy test within 24 hours prior to taking study treatment if of childbearing potential and agrees to abstain from activities that could result in pregnancy from screening through 6 months (females) or 30 days (males) after the last dose of study treatment, or is of nonchildbearing potential.
• Male patient agrees to use an adequate method of contraception starting with the first dose through 90 days after the last dose of study treatment.
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (obtained ≤ 7 days prior to the first day of study therapy).
• Platelets >100 x 10^9/L (obtained ≤ 7 days prior to the first day of study therapy).
• Hemoglobin ≥ 9g/dL (obtained ≤ 7 days prior to the first day of study therapy).
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN); if liver metastases, then ≤ 5 x ULN (obtained ≤ 7 days prior to the first day of study therapy).
• Serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate (GFR) ≥ 45 mL/min using Cockcroft Gault formula (obtained ≤ 7 days prior to the first day of study therapy).
• Eastern Cooperative Oncology (ECOG) performance status of 0 to 1.

Exclusion Criteria

• Prior treatment with a PARP inhibitor, ipilimumab, or other cytotoxic T- lymphocyte-associated-4 protein (CTLA-4) inhibitor.
• Patients who have demonstrated resistance to FOLFIRINOX are not eligible to participate in this study.
• Patients with known pathogenic/likely pathogenic germline or somatic alteration(s) in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D.
• Patients with known mismatch repair deficiency or microsatellite instability-high cancer.
• Clinical evidence of uncontrolled malabsorption and/or any other gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with the absorption of niraparib.
• Patients with uncontrolled hypertension, defined as systolic blood pressure (BP) > 140mmHg and/or diastolic BP > 90mmHg.
• Patients with a prior history of posterior reversible encephalopathy syndrome (PRES).
• Acute infection requiring intravenous antibiotics, intravenous antiviral or intravenous antifungal agents during the 14 days prior to first dose of study therapy.
• Patients will be excluded if they have a history of or active autoimmune disease, defined as: patients with a history of inflammatory bowel disease are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g. rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis e.g. Wegener’s Granulomatosis); motor neuropathy considered of autoimmune origin (e.g. Guillain-Barre Syndrome). * NOTE: Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Has a history of interstitial lung disease or active, non-infectious pneumonitis.
• Has received a live vaccine within 4 weeks prior to the first dose of trial therapy. (Note: seasonal influenza vaccines for injection are generally inactivated and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist registered trademark) are live attenuated vaccines and are not allowed).
• For fertile patient (female able to become pregnant or male able to father a child), refusal to use effective contraception during the period of the trial and: * Female patients refusing to use effective contraception for 6 months after the last dose of study drug. * Male patients refusing to use effective contraception for 90 days after the last dose of study drug.
• Received any systemic treatment for pancreatic cancer ≤ 14 days prior to first dose of therapy. Patients must not have had investigational therapy administered ≤ 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study.
• Patients will be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Patient has had any known grade 3 or 4 anemia, neutropenia or thrombocytopenia due to prior chemotherapy that persisted > 4 weeks and was related to the most recent treatment.
• Non-study related minor surgical procedure ≤ 5 days, or major surgical procedure ≤ 21 days, prior to the first dose of therapy; in all cases, patients must be sufficiently recovered and stable before treatment administration.
• Active drug or alcohol use or dependence that would interfere with study compliance.
• Presence of any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results, and, in the opinion of the investigator, would make the patient inappropriate for entry into the study.
• Patient must not have any known history of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
• Patients must not be simultaneously enrolled in any therapeutic clinical trial.
• Patients must not have had radiotherapy within 4 weeks of the first dose of study treatment.
• Patients must not have a known hypersensitivity to the components of niraparib or the excipients.
• Patients must not have received a transfusion (platelets or red blood cells) ≤ 4 weeks of the first dose of study treatment.
• Patients must not be undergoing treatment for a second active cancer at the time of randomization. Exceptions include: (1) local therapies for skin cancers, (2) hormonal therapies for breast or prostate cancer without evidence of active disease Patients may have a history of: (1) adequately treated nonmelanoma skin cancers, (2) curatively treated in situ cancer of the cervix, (3) curatively treated ductal carcinoma in situ (DCIS), (4) curatively treated stage I, grade 1 endometrial carcinoma, (5) other solid tumors and lymphomas (without bone marrow involvement) diagnosed at least five years prior to randomization and treated with no evidence of disease recurrence.
• Patients with active hepatitis B or hepatitis C infections, as defined by positive polymerase chain reaction (PCR) testing, may not enroll.
• Patients with HIV may enroll, but must have an undetectable viral load at the time of enrollment and must be receiving a stable regimen of highly active antiretroviral therapy (HAART).
• Patients must not have known, symptomatic brain or leptomeningeal metastases.