A Phase 1 Study of the Combination of Cabozantinib With Trifluridine/Tipiracil (TAS-102) in Patients With Metastatic Colorectal Adenocarcinoma (mCRC)
Overview
- Phase
- Phase 1
- Intervention
- Cabozantinib
- Conditions
- Colorectal Cancer
- Sponsor
- University of California, Irvine
- Enrollment
- 15
- Locations
- 2
- Primary Endpoint
- Dose Limiting Toxicity [DLT]
- Status
- Completed
- Last Updated
- 8 days ago
Overview
Brief Summary
This is a phase I clinical trial assessing the safety and recommended phase II dose of cabozantinib in combination with trifluridine/tipiracil (TAS102) in patients with metastatic colorectal carcinoma (mCRC).
Detailed Description
Patients with histologically proven colorectal adenocarcinoma not amenable to curative treatment will be eligible to participate for this study. After meeting the eligibility criteria, patients will be given a IP regimen consisting of cabozantinib 20 - 40 mg given orally everyday for 28 days, trifluridine/tipiracil (TAS102) 25 - 35 mg/m2 on Days 1 - 5 and Days 8 - 12 every 28 days, and peg-filgrastim 6 mg subcutaneously on Day 13 every 28 days. Tumor assessments will be completed by CT/MRI every 8 weeks during the first year of treatment and every 3 months after the first year until patient comes off treatment.
Investigators
Farshid Dayyani
Professor of Clinical Medicine
University of California, Irvine
Eligibility Criteria
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed colorectal adenocarcinoma
- •Must have locally advanced, recurrent, or metastatic disease not amenable to curative intent surgery or radiation.
- •Must have progressed, or not tolerated, a fluoropyrimidine, irinotecan, oxaliplatin, and cetuximab or panitumumab (only for RAS wild-type). Prior exposure to bevacizumab or ramucirumab is allowed. Patients who have exhausted all other standard of care options are also eligible.
- •Age ≥ 18 years
- •Performance status: ECOG performance status ≤2 (Appendix A).
- •Life expectancy of greater than 3 months
- •Adequate organ and marrow function as defined below:
- •leukocytes ≥ 3,000/mcL
- •absolute neutrophil count ≥ 1,500/mcL
- •platelets ≥ 100,000/mcl
Exclusion Criteria
- •Patients who have chemotherapy within 2 weeks prior to entering the study
- •All toxicities attributed to prior anti-cancer therapy other than alopecia must have resolved to grade 1 or baseline
- •Patients may not be receiving any other investigational agents.
- •Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
- •Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to TAS-102, cabozantinib or other agents used in study.
- •Uncontrolled intercurrent illness including, but not limited to, the following conditions:
- •ongoing or active infection
- •Cardiovascular disorders: Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias; uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment; Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #3.2.8) for at least 1 week before first dose of study treatment.
- •Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation:The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose of study treatment. Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose of study treatment.
Arms & Interventions
Cabozantinib in Combination with TAS-102 (trifluridine/tipiracil)
Subjects will receive cabozantinib in combination with TAS-102. Patients will receive cabozantinib on Days 1 - 28 and TAS-102 on Days 1-5 and Days 8-12, for a cycle length of 28 days.
Intervention: Cabozantinib
Cabozantinib in Combination with TAS-102 (trifluridine/tipiracil)
Subjects will receive cabozantinib in combination with TAS-102. Patients will receive cabozantinib on Days 1 - 28 and TAS-102 on Days 1-5 and Days 8-12, for a cycle length of 28 days.
Intervention: TAS-102
Outcomes
Primary Outcomes
Dose Limiting Toxicity [DLT]
Time Frame: From the start date of treatment until 4 weeks after the last patient has started treatment, an average of 1 year.
To determine the Dose Limiting Toxicity (DLT) at Cycle 1 Day 28. A DLT is defined as the occurrence of specific toxicities within the DLT treatment period if judged by the Investigator to be possibly, probably, or definitely related to cabozantinib or TAS-102.
Recommended Phase 2 Dose [RP2D]
Time Frame: From the start date of treatment until 4 weeks after the last patient has started treatment, an average of 1 year.
To determine the recommended Phase 2 Dose (RP2D) of cabozantinib in combination with TAS-102 in patients with metastatic colorectal carcinoma (mCRC) based on a 3+3 study design.
Secondary Outcomes
- Progression-Free Survival of Patients who Received Cabozantinib with TAS-102(From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.)
- Overall Survival of Patients who Received Cabozantinib with TAS-102(From date of registration for up to 18 months after last patient is enrolled or until death from any cause, whichever came first)
- Number of Participants with Objective Response Rate(From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability](From the start date of treatment until 4 weeks after removal of treatment due to disease progression, toxicity, delay of treatment, or withdrawal of treatment, whichever came first, an average of 1 year.)