Trametinib and Trifluridine and Tipiracil Hydrochloride in Treating Patients With Colon or Rectal Cancer That is Advanced, Metastatic, or Cannot Be Removed by Surgery

NCT03317119 | Completed Phase 1 FDA Drug

• 3 other identifiers: 17212NCI-2017-01923P30CA033572
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 8

Brief Summary

This phase I trial studies the side effects and best dose of trametinib and trifluridine and tipiracil hydrochloride in treating patients with colon or rectal cancer that has spread to other places in the body (advanced/metastatic) or cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as trifluridine and tipiracil hydrochloride, 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. Giving trametinib and trifluridine and tipiracil hydrochloride may prevent cancer cells from dividing and work better in treating patients with colon and rectal cancer.

Conditions

Metastatic Colon Carcinoma; Metastatic Colorectal Carcinoma; Metastatic Rectal Carcinoma; RAS Family Gene Mutation; Stage III Colon Cancer AJCC v7; Stage III Colorectal Cancer AJCC v7; Stage III Rectal Cancer AJCC v7; Stage IIIA Colon Cancer AJCC v7; Stage IIIA Colorectal Cancer AJCC v7; Stage IIIA Rectal Cancer AJCC v7; Stage IIIB Colon Cancer AJCC v7; Stage IIIB Colorectal Cancer AJCC v7; Stage IIIB Rectal Cancer AJCC v7; Stage IIIC Colon Cancer AJCC v7; Stage IIIC Colorectal Cancer AJCC v7; Stage IIIC Rectal Cancer AJCC v7; Stage IV Colon Cancer AJCC v7; Stage IV Colorectal Cancer AJCC v7; Stage IV Rectal Cancer AJCC v7; Stage IVA Colon Cancer AJCC v7; Stage IVA Colorectal Cancer AJCC v7; Stage IVA Rectal Cancer AJCC v7; Stage IVB Colon Cancer AJCC v7; Stage IVB Colorectal Cancer AJCC v7; Stage IVB Rectal Cancer AJCC v7

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose defined for the combination of trametinib, and Trifluridine and Tipiracil Hydrochloride (TAS?102) as the highest dose level at which 0-1 out of 6 patients experience dose limiting toxicities

  Toxicities observed at each dose level will be categorized by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] 4.0 and nadir or maximum values for the laboratory measures), time of onset (i.e., course number), duration, and reversibility or outcome.

  Up to 28 days

Secondary Outcomes (4)

• Incidence of adverse events assessed using NCI) CTCAE 4.0

  Up to 30 after last dose

• Objective response rate using Response Evaluation Criteria in Solid Tumor (RECIST) guideline, version 1.1

  Up to 1 year

• Time to progression using RECIST guideline, version 1.1

  From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year

• Overall survival

  From start of treatment to death (any cause), assessed up to 1 year

Study Arms (1)

Treatment (TAS-102, trametinib)

EXPERIMENTAL

Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12 and trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Drug: Trametinib; Drug: Trifluridine and Tipiracil Hydrochloride

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (TAS-102, trametinib)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Treatment (TAS-102, trametinib)

Trifluridine and Tipiracil Hydrochloride DRUG

Given PO

Also known as: Lonsurf, TAS 102, TAS-102, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102

Treatment (TAS-102, trametinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects must have the ability to understand and the willingness to sign a written informed consent
• All patients must be able to take oral medications
• All patients must be deemed by investigator to have the initiative and means to be compliant with the study protocol (treatment and follow-up)
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2
• Pathologically confirmed advanced, unresectable, or metastatic colon or rectal cancer who have had intolerance to or progression after a fluoropyrimidine, oxaliplatin, irinotecan, and cetuximab or panitumumab in the event of wild-type RAS/BRAF tumors
• Of note, prior bevacizumab or regorafenib exposure is not mandated as some patients are deemed poor candidates for anti-angiogenesis therapy and never receive these agents
• Tumors must have undergone expanded molecular profiling with a Clinical Laboratory Improvement Act (CLIA)-certified platform that evaluates, at a minimum, RAS, PIK3CA, PTEN and BRAF mutations status
• Documented RAS-mutated tumor without activating PIK3CA mutations or PTEN mutation (loss of PTEN or silencing)
• Measurable disease by RECIST 1.1 guidelines
• Last chemotherapy at least 3 weeks from initiation of study treatment
• No investigational agents within 4 weeks from initiation of study treatment
• Negative serum or urine beta-human chorionic gonadotropin (HcG) test (female patient of childbearing potential only) performed within 72 hours of prior to first study dose
• Absolute neutrophil count (ANC) \>= 1500/mm\^3 (to be performed within 28 days prior to day 1 of protocol therapy)
• NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement
• Platelets \>= 75,000/mm\^3 without transfusions (to be performed within 28 days prior to day 1 of protocol therapy)

You may not qualify if:

• Prior chemotherapy, biologic, targeted, or radiotherapy within 3 weeks prior to entering study or not recovered from grade \>= 2 adverse events (AEs) due to agents administered more than 4 weeks earlier (except alopecia or neuropathy)
• Prior MEK inhibitor or prior TAS-102 therapy
• Use of other investigational drugs
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity, or hypercoagulability syndromes)
• History of retinal degenerative disease
• History of Gilbert's syndrome
• Previous or concurrent malignancy with the following exceptions:
• Adequately treated basal cell or squamous cell carcinoma of skin with adequate wound healing prior to study entry
• In situ carcinoma of the cervix treated curatively and without evidence of recurrence
• Primary malignancy completely resected and in complete remission \>= 1 year
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass graft, coronary angioplasty, or stenting) \< 6 months prior to screening
• Impaired cardiovascular function or clinically significant cardiovascular disease including any of the following: symptomatic congestive heart failure, clinically significant cardiac arrhythmias and/or conduction abnormalities \< 6 months prior to screening except for atrial fibrillation and paroxysmal supraventricular tachycardia
• Uncontrolled arterial hypertension despite appropriate medical therapy (systolic blood pressure \> 160 or diastolic blood pressure \> 100)
• Neuromuscular disorders associated with elevated creatine kinase (CK, e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, or spinal muscular atrophy)
• Started or planning to start on strenuous exercise regimen after first dose of study treatment (i.e., muscular activities, such as strenuous exercise, that can result in significant increase in plasma CK levels should be avoided while on trametinib treatment)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (8)

City of Hope Corona

Corona, California, 92879, United States

Location

City of Hope Medical Center

Duarte, California, 91010, United States

Location

City of Hope Antelope Valley

Lancaster, California, 93534, United States

Location

City of Hope Mission Hills

Mission Hills, California, 91345, United States

Location

City of Hope Rancho Cucamonga

Rancho Cucamonga, California, 91730, United States

Location

City of Hope - Santa Clarita

Santa Clarita, California, 91355, United States

Location

City of Hope South Pasadena

South Pasadena, California, 91030, United States

Location

City of Hope West Covina

West Covina, California, 91790, United States

Location

Related Publications (1)

• Chuang J, Gong J, Li SM, Wang C, Fakih M. A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer. Clin Colorectal Cancer. 2022 Sep;21(3):252-258. doi: 10.1016/j.clcc.2022.05.004. Epub 2022 May 23.

  PMID: 35738999 DERIVED

MeSH Terms

Conditions

Colonic Neoplasms; Colorectal Neoplasms; Rectal Neoplasms

Interventions

trametinib; Trifluridine; trifluridine tipiracil drug combination

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Marwan G Fakih

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 18, 2017
• First Posted: October 23, 2017
• Study Start: April 11, 2018
• Primary Completion: July 14, 2023
• Study Completion: July 14, 2023
• Last Updated: April 8, 2024

Record last verified: 2024-04

Locations

US (8)