Rucaparib Plus Ramucirumab With or Without Nivolumab in Advanced Gastric and Esophageal Adenocarcinoma

Inclusion Criteria:

Half of the study population in phase 2 must have a deleterious tumor alteration in at least one protocol specified gene
Gastric or gastroesophageal junction adenocarcinoma
Advanced stage 4 or locally unresectable stage 3 disease
Must have measurable disease
Must consent to have a biopsy if archival tissue is not available or not enough for molecular testing
Must show evidence of progression or intolerance to at least one previous standard of care systemic therapy (not more than 2 lines of prior therapy)
Patients with human epidermal growth factor receptor 2 (HER2) positive disease must show progression on prior HER2 targeted therapy
Toxicities related to prior treatment should be recovered to baseline or less than grade 2 according to CTCAE
Adequate organ and marrow function
Absence of active autoimmune disease that has required systemic treatment in the past 2 years
Absence of conditions requiring systemic treatment with either corticosteroids or other immunosuppressive medications within 14 days of study drug administration. 10mg or less of prednisone or equivalent is acceptable
Evidence of post-menopausal status or negative serum pregnancy test for female pre-menopausal patients
Women of child-bearing potential and men with partners of child-bearing potential must agree to practice sexual abstinence, or to use two forms of adequate contraception prior to study entry, for the duration of study participation, and for 6 months following completion of therapy
Men of child-bearing potential must not father a child or donate sperm while on this study and for 7 months after their last study treatment

Exclusion Criteria:

Prior treatment with a programmed cell death protein 1 (PD1) or programmed death- ligand 1 (PD-L1) inhibitors
Prior treatment with poly-(ADP-Ribose)polymerase (PARP)
Patients with microsatellite instability (MSI) high or mismatch repair (MMR) deficient tumors
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose
Evidence of active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
Inability to swallow tablets
Uncontrollable ascites or pleural effusion
Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
Clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding within 12 weeks
Lesions invading any major blood vessels
Receipt of the last dose of anticancer therapy less than 28 days prior to the first dose of study drug
Major surgery within 8 weeks before first dose of study treatment
History of allogenic organ transplantation
Active infection including tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus. Patients with a past or resolved hepatitis B virus (HBV) infection are eligible. Patients positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for hepatitis C virus (HCV) RNA
Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or serious chronic gastrointestinal conditions
Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
Prolonged baseline QT interval corrected for heart rate greater than 470 ms
Brain metastases or spinal cord compression. Patients whose brain metastases have been treated may participate provided they show radiographic stability
Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
Current or anticipated use of other investigational agents while participating in this study

History of another primary malignancy except for:

Malignancy treated with curative intent and with no known active disease before the first dose of investigational product (IP) and of low potential risk for recurrence
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
Adequately treated carcinoma in situ without evidence of disease
Psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or breast feeding