Trifluridine/Tipiracil in Combination with Talazoparib for the Treatment of Patients with Locally Advanced or Metastatic Colorectal or Gastroesophageal Cancer

Inclusion Criteria

• Age ≥ 18 years
• Histologically or cytologically confirmed CRC or EGC that is locally advanced or metastatic (cohort A); histologically or cytologically confirmed p53mt/RASonc (cohort B1) or p53mt/RASwt CRC (cohort B2) that is locally advanced or metastatic. Patients with adenocarcinoma histology only are allowed to participate
• Has received at least one prior line of therapy with progression or intolerance
• Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
• Life expectancy >= 3 months by investigator assessment
• Hemoglobin >= 9 g/dL
• Absolute neutrophil count >= 1500/mm^3
• Platelet count >= 100,000/mm^3 without transfusion or growth factor support
• Creatinine < 1.5 upper limit of normal (ULN) or creatinine clearance > 60 mL/min
• Total bilirubin < 1.5 x ULN
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN or < x 5 ULN in the presence of liver metastasis
• Albumin > 3 g/dL
• Ability to swallow oral medications
• Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure
• NOTE: For blood Chemistry labs, Roswell Park clinical blood chemistries are performed on plasma unless otherwise indicated

Exclusion Criteria

• Systemic antineoplastic therapy within 2 weeks prior to day -14 (dose escalation, cohort A) or cycle 1 day 1 (dose expansion, cohorts B1 and B2) or within the past 6 weeks if this treatment is mitomycin C or nitrosourea
• Radiotherapy within the past 2 weeks excluding palliative radiotherapy to painful bone lesions
• Prior treatment with PARP inhibitor or FTD/TPI
• Any condition that in the investigator’s opinion can limit absorption of FTD/TPI or talazoparib from the gastrointestinal (GI) tract
• Gastrointestinal obstruction (without diversion) or perforation within 4 weeks from initiation of day -14 (dose escalation, cohort A) or cycle 1 cay 1 (dose expansion, cohorts B1 and B2)
• Refractory ascites (requiring weekly or more frequent paracentesis or permanent indwelling peritoneal catheter)
• Untreated central nervous system (CNS) disease. Patients with leptomeningeal disease are ineligible but patients with treated, stable CNS metastasis for at least 4 weeks are allowed to participate
• Significant cardiac disease defined as congestive heart failure stage III or IV (New York Heart Association [NYHA]), acute coronary event, cerebrovascular event, peripheral arterial embolic event, venous thromboembolic event (pulmonary embolism or lower extremity deep vein thrombosis), or ventricular arrhythmia within the past 3 months
• Other malignancy requiring active therapy
• Presence of toxicities from prior therapy of grade 2 or higher
• Active infection requiring antibiotic therapy
• Known human immunodeficiency virus (HIV) or hepatitis B infection or untreated hepatitis C infection. Patients with treated hepatitis C infection and undetectable viral load are allowed to participate
• Any history of myelodysplastic syndrome, acute leukemia, or bone marrow transplant
• Pregnant or nursing female participants
• Unwilling or unable to follow protocol requirements
• Any condition which in the investigator’s opinion deems the participant an unsuitable candidate to receive study drug