Trifluridine/Tipiracil and Talazoparib for the Treatment of Patients With Locally Advanced or Metastatic Colorectal or Gastroesophageal Cancer
Study Details
Study Description
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:
- 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: 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. |
Drug: Trifluridine and Tipiracil Hydrochloride
Given PO
Other Names:
Drug: Talazoparib Tosylate
Given PO
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Incidence of Adverse Events [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.
- Maximum tolerated dose/ recommended phase II dose [Up to 14 days]
Will utilize the keyboard design - a novel model- assisted dose-finding method to find the maximum tolerated dose
Secondary Outcome Measures
- Plasma Concentration (Cmax) [Day -13 post dose]
The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose
- Plasma Concentration (Cmax) [day -14 pre dose]
The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose
- Plasma Concentration (Cmax) [day -14 post dose]
The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose
- Plasma Concentration (Cmax) [day -13 pre dose]
The pharmacokinetic parameters between Trifluridine/Tipiracil and Talazoparib will be evaluated on Day -14: pre-dose, 0.5, 1, 2, 4, 6, 8 hours (hr) post-dose; day-13: 24 hr post-initial dose and day -13 pre-dose
- Overall Response Rate (ORR) [Up to 3 years]
Will be summarized using frequencies and relative frequencies.
- CEA response rate (colorectal cancer patients) [Up to 3 years]
ill be summarized using frequencies and relative frequencies. .
- Progression Free Survival (PFS) [From treatment until disease progression UP to 3 years]
Will be summarized using standard Kaplan-Meier methods
- Overall Survival (OS) [From treatment until death or up to 3 years]
Will be summarized using standard Kaplan-Meier methods
- Progressive Disease Assessment (PD) [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]
Tumor biopsies will be summarized by dose level and time-point using means and standard deviations.
Eligibility Criteria
Criteria
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 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Roswell Park Cancer Institute | Buffalo | New York | United States | 14263 |
Sponsors and Collaborators
- Roswell Park Cancer Institute
- Pfizer
Investigators
- Principal Investigator: Christos Fountzilas, MD, Roswell Park Cancer Institute
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- I 650120