Colon Cancer Clinical Trial
Trametinib and Trifluridine and Tipiracil Hydrochloride in Treating Patients With Colon or Rectal Cancer That is Advanced, Metastatic, or Cannot Be Removed by Surgery
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.
I. Determine the maximum tolerated dose (MTD) for the combination of trametinib and trifluridine and tipiracil hydrochloride (TAS-102) in patients with chemotherapy-resistant metastatic colorectal cancer.
I. Describe the safety of the combination of trametinib and TAS-102 across all investigated dose levels.
II. Describe the clinical activity including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) of the combination in an expansion cohort using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.
Patients receive trifluridine and tipiracil hydrochloride orally (PO) twice daily (BID) on days 1-5 and 8-12 and trametinib PO once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then bi-annually thereafter.
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)
Hemoglobin (Hgb) >= 8 g/dL without transfusions (to be performed within 28 days prior to day 1 of protocol therapy)
Total serum bilirubin < upper limit of normal (ULN) (to be performed within 28 days prior to day 1 of protocol therapy)
Aspartate aminotransferase (AST) =< 2.5 x ULN if no liver metastases or =< 5 x ULN if liver metastases (to be performed within 28 days prior to day 1 of protocol therapy)
Alanine aminotransferase (ALT) =< 2.5 x ULN if no liver metastases or =< 5 x ULN if liver metastases (to be performed within 28 days prior to day 1 of protocol therapy)
Creatinine < 1.5 x ULN or creatinine clearance of >= 60 mL/min per the Cockcroft-Gault formula (to be performed within 28 days prior to day 1 of protocol therapy)
Female of childbearing potential: negative urine or serum pregnancy test (to be performed within 28 days prior to day 1 of protocol therapy)
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Corrected QT (QTc) interval =< 480 ms (12 lead-electrocardiography [ECG]) (to be performed within 28 days prior to day 1 of protocol therapy)
Left ventricular ejection fraction >= 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (to be performed within 28 days prior to day 1 of protocol therapy)
Normal eye examination (to be performed within 28 days prior to day 1 of protocol therapy)
Women of childbearing potential must use highly effective methods of contraception throughout the study and for 4 months after study drug discontinuation
Sexually active men must use a condom during intercourse while taking study drug and for 60 days after study drug discontinuation; a condom is required for vasectomized men to prevent delivery of study drug via seminal fluid
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)
Gastrointestinal (GI) disease or impairment of GI function (e.g., active ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection)
Prior major surgery =< 3 weeks before study drug or not recovered from side effects of such procedure
Ongoing grade >= 3 neuropathy
Known hypersensitivity to any components of study drugs
Prior intolerance to a fluoropyrimidine
Any other condition that would, in the investigator's judgement, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures (e.g., infection/inflammation, intestinal obstruction, unable to swallow medications, social/psychological issues, etc.)
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Check Your Eligibility
Let’s see if you might be eligible for this study.
What is your age and gender ?
There are 8 Locations for this study
Corona California, 92879, United States
Duarte California, 91010, United States
Lancaster California, 93534, United States
Mission Hills California, 91345, United States
Rancho Cucamonga California, 91730, United States
Santa Clarita California, 91355, United States
South Pasadena California, 91030, United States
West Covina California, 91790, United States
How clear is this clinincal trial information?
Introducing, the Journey Bar
Use this bar to access information about the steps in your cancer journey.