A Phase I Study of Trifluridine/ Tipiracil Plus the Poly (ADP) Ribose Polymerase Inhibitor Talazoparib in Advanced Cancers
Overview
- Phase
- Phase 1
- Intervention
- Trifluridine and Tipiracil Hydrochloride
- Conditions
- Advanced Malignant Solid Neoplasm
- Sponsor
- Roswell Park Cancer Institute
- Enrollment
- 45
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose/ recommended phase II dose
- Status
- Recruiting
- Last Updated
- 6 months ago
Overview
Brief Summary
This phase I trial investigates the side effects and best dose of talazoparib when given together with trifluridine/tipiracil for the treatment of patients with colorectal or gastroesophageal cancer that has spread to nearby tissue or lymph nodes (locally advanced) or other places in the body (metastatic). Drugs used in the chemotherapy, such as trifluridine/tipiracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving talazoparib with trifluridine/ tipiracil may inhibit certain enzymes in the cells that are responsible for tumor cell growth.
Detailed Description
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. SECONDARY OBJECTIVES: I. To determine the pharmacokinetics (PK) and pharmacodynamic (PD) markers of activity. II. To evaluate the preliminary antineoplastic efficacy of the combination.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically confirmed CRC or EGC adenocarcinoma 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
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, FUDR 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 Day 1 (Dose Expansion, Cohorts B1 and B
- •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
Arms & Interventions
Treatment Arm
Patients receive trifluridine/tipiracil PO BID and talazoparib tosylate PO QD on days 1-5. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Intervention: Trifluridine and Tipiracil Hydrochloride
Treatment Arm
Patients receive trifluridine/tipiracil PO BID and talazoparib tosylate PO QD on days 1-5. Cycles repeat every 14 days in the absence of disease progression or unacceptable toxicity.
Intervention: Talazoparib Tosylate
Outcomes
Primary Outcomes
Maximum tolerated dose/ recommended phase II dose
Time Frame: Up to 14 days
Will utilize the keyboard design - a novel model- assisted dose-finding method to find the maximum tolerated dose
Incidence of Adverse Events
Time Frame: after each cycle of treatment ( 1 cycle = 14 days)
All adverse events will be evaluated using Common Terminology Criteria for All Adverse Events (CTCAE) version (v.) 5.
Secondary Outcomes
- CEA response rate (colorectal cancer patients)(Up to 3 years)
- Plasma Concentration (Cmax)(day -13 pre dose)
- Progressive Disease Assessment (PD)(Up to 3 years)
- Overall Response Rate (ORR)(Up to 3 years)
- Progression Free Survival (PFS)(From treatment until disease progression UP to 3 years)
- Number of subjects with DNA damage response(Up to 28 days prior to first drug dose, on treatment and between cylce 1-day 8 and cycle 1 day 12)
- Overall Survival (OS)(From treatment until death or up to 3 years)