Clinical Trials /

Trametinib and TAS-102 in Treating Patients With Colon or Rectal Cancer That is Advanced, Metastatic, or Cannot Be Removed by Surgery

NCT03317119

Description:

This phase I trial studies the side effects and best dose of trametinib and TAS-102 in treating patients with colon or rectal cancer that has spread to other places in the body 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 TAS-102, 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 TAS-102 may prevent cancer cells from dividing and work better in treating patients with colon and rectal cancer.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Trametinib and TAS-102 in Treating Patients With Colon or Rectal Cancer That is Advanced, Metastatic, or Cannot Be Removed by Surgery
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 17212
  • SECONDARY ID: NCI-2017-01923
  • NCT ID: NCT03317119

Conditions

  • 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

Interventions

DrugSynonymsArms
Trametinib871700-17-3, GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist, N-(3-{3-cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamideTreatment (TAS-102, trametinib)
Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102Lonsurf, TAS-102, Trifluridine/TipiracilTreatment (TAS-102, trametinib)

Purpose

This phase I trial studies the side effects and best dose of trametinib and TAS-102 in treating patients with colon or rectal cancer that has spread to other places in the body 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 TAS-102, 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 TAS-102 may prevent cancer cells from dividing and work better in treating patients with colon and rectal cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Determine the maximum tolerated dose (MTD) for the combination of trametinib and
      trifluridine/tipiracil hydrochloride combination agent TAS-102 (TAS-102) in patients with
      chemotherapy-resistant metastatic colorectal cancer.

      SECONDARY OBJECTIVES:

      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.

      OUTLINE:

      Patients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 orally (PO)
      twice daily (BID) on days 1-5 and 8-12 and trametinib PO once daily (QD) on days 1-28.
      Courses 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (TAS-102, trametinib)ExperimentalPatients receive trifluridine/tipiracil hydrochloride combination agent TAS-102 PO BID on days 1-5 and 8-12 and trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Trametinib
  • Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  To be performed within 28 days prior to day 1 of protocol therapy: Absolute neutrophil
             count (ANC) >= 1500/mm^3

             * NOTE: Growth factor is not permitted within 14 days of ANC assessment unless
             cytopenia is secondary to disease involvement

          -  To be performed within 28 days prior to day 1 of protocol therapy: 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

             * If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
             test will be required

          -  To be performed within 28 days prior to day 1 of protocol therapy: 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 >= 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

          -  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

        Exclusion Criteria:

          -  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 or 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 and 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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose defined as the highest dose level at which 0-1 out of 6 patients experience dose limiting toxicities
Time Frame:Up to 28 days
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 4.0
Time Frame:Up to 30 after last dose
Safety Issue:
Description:Will be summarized in terms of type and severity, along with dose modification/delays that resulted.
Measure:Objective response rate using Response Evaluation Criteria in Solid Tumor guideline, version 1.1
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Time to progression using Response Evaluation Criteria in Solid Tumor guideline, version 1.1
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:From start treatment to death (any cause), assessed up to 1 year
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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