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

PRIMARY OBJECTIVE:

I. To determine the safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) of trifluridine and tipiracil hydrochloride (trifluridine/tipiracil [FTD/TPI]) in combination with talazoparib tosylate (talazoparib) in patients with advanced colorectal (CRC) or gastroesophageal (EGC) adenocarcinoma.

• Advanced Malignant Solid Neoplasm
• Clinical Stage III Gastroesophageal Junction Adenocarcinoma
• Clinical Stage IV Gastroesophageal Junction Adenocarcinoma
• Clinical Stage IVA Gastroesophageal Junction Adenocarcinoma
• Clinical Stage IVB Gastroesophageal Junction Adenocarcinoma A
• Locally Advanced Colorectal Carcinoma
• Locally Advanced Gastroesophageal Junction Adenocarcinoma
• Metastatic Colorectal Adenocarcinoma
• Metastatic Gastroesophageal Junction Adenocarcinoma
• Pathologic Stage III Gastroesophageal Junction Adenocarcinoma
• Pathologic Stage IIIA Gastroesophageal Junction Adenocarcinoma
• Pathologic Stage IIIB Gastroesophageal Junction Adenocarcinoma
• Pathologic Stage IV Gastroesophageal Junction Adenocarcinoma
• Pathologic Stage IVA Gastroesophageal Junction Adenocarcinoma
• Pathologic Stage IVB Gastroesophageal Junction Adenocarcinoma
• Postneoadjuvant Therapy Stage III Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IIIB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IV Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IVA Gastroesophageal Junction Adenocarcinoma AJCC v8
• Postneoadjuvant Therapy Stage IVB Gastroesophageal Junction Adenocarcinoma AJCC v8
• Stage III Colorectal Cancer AJCC v8
• Stage IIIA Colorectal Cancer AJCC v8
• Stage IIIB Colorectal Cancer AJCC v8
• Stage IIIC Colorectal Cancer AJCC v8
• Stage IV Colorectal Cancer AJCC v8
• Stage IVA Colorectal Cancer AJCC v8
• Stage IVB Colorectal Cancer AJCC v8
• Stage IVC Colorectal Cancer AJCC v8

• Drug: Trifluridine and Tipiracil Hydrochloride
  Given PO
  Other Names:

  • 733030-01-8
  • Lonsurf
  • TAS 102,
  • Thymidine
  • Tipiracil Hydrochlorid Mixture with Trifluridine
  • Trifluridine/Tipiracil
  • Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102
• Drug: Talazoparib Tosylate
  Given PO
  Other Name: Talzenna

Inclusion Criteria:

• Histologically or cytologically confirmed CRC or EGC adenocarcinoma that is locally advanced or metastatic
• 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 or legal representative 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

Exclusion Criteria:

• Systemic antineoplastic therapy within 2 weeks prior to initiation of FTD/TPI run-in phase (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 FTD/TPI run-in
• 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