Trifluridine/Tipiracil and Talazoparib for the Treatment of Patients With Locally Advanced or Metastatic Colorectal or Gastroesophageal Cancer

Inclusion Criteria:

• Histologically or cytologically confirmed CRC or EGC adenocarcinoma that is locallyadvanced or metastatic (Cohort A); histologically or cytologically confirmedp53mt/RASonc (Cohort B1) or p53mt/RASwt CRC (Cohort B2) that is locally advanced ormetastatic. 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 contraceptivemethods (e.g., hormonal or barrier method of birth control; abstinence) prior tostudy entry. Should a woman become pregnant or suspect she is pregnant while she orher partner is participating in this study, she should inform her treating physicianimmediately

• Participant must understand the investigational nature of this study and sign anIndependent Ethics Committee/Institutional Review Board approved written informedconsent form prior to receiving any study related procedure

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 6weeks if this treatment is mitomycin C or nitrosourea

• Radiotherapy within the past 2 weeks excluding palliative radiotherapy to painfulbone lesions

• Prior treatment with PARP inhibitor or FTD/TPI

• Any condition that in the investigator's opinion can limit absorption of FTD/TPI ortalazoparib from the gastrointestinal (GI) tract

• Gastrointestinal obstruction (without diversion) or perforation within 4 weeks frominitiation of day -14 (Dose Escalation, Cohort A) or Cycle 1 Day 1 (Dose Expansion,Cohorts B1 and B2.

• Refractory ascites (requiring weekly or more frequent paracentesis or permanentindwelling peritoneal catheter)

• Untreated central nervous system (CNS) disease. Patients with leptomeningeal diseaseare ineligible but patients with treated, stable CNS metastasis for at least 4 weeksare allowed to participate

• Significant cardiac disease defined as congestive heart failure stage III or IV (NewYork Heart Association [NYHA]), acute coronary event, cerebrovascular event,peripheral arterial embolic event, venous thromboembolic event (pulmonary embolismor 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 untreatedhepatitis C infection. Patients with treated hepatitis C infection and undetectableviral 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 anunsuitable candidate to receive study drug