Clinical Trials /

MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)

NCT01991379

Description:

The purpose of this study is to evaluate the effects, good and/or bad, of MEK162 and imatinib on the patient and on Gastrointestinal Stromal Tumor (GIST). Funding Source - FDA OOPD

Related Conditions:
  • Gastrointestinal Stromal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)
  • Official Title: A Phase Ib/II Study of MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)

Clinical Trial IDs

  • ORG STUDY ID: 13-162
  • SECONDARY ID: R01FD005731
  • NCT ID: NCT01991379

Conditions

  • Gastrointestinal Stromal Tumor (GIST)

Interventions

DrugSynonymsArms
MEK162MEK162 in Combination With Imatinib Mesylate
Imatinib Mesylate (Gleevec®; STI571; NSC #716051)MEK162 in Combination With Imatinib Mesylate

Purpose

The purpose of this study is to evaluate the effects, good and/or bad, of MEK162 and imatinib on the patient and on Gastrointestinal Stromal Tumor (GIST). Funding Source - FDA OOPD

Trial Arms

NameTypeDescriptionInterventions
MEK162 in Combination With Imatinib MesylateExperimentalPts will be treated with the combination therapy of MEK162 & imatinib. The phase Ib portion of the study, pts will receive imatinib at 400 mg once daily & MEK162 at the standard 3+3 escalation doses. Phase Ib expansion cohort, pts will receive the RP2D: imatinib 400 mg once daily (standard of care first line imatinib dose) & MEK162 at the RP2D twice daily. The phase II portion of the study, pts will receive imatinib at 400 mg once daily & MEK162 at the RP2D. The MEK162 RP2D was originally determined based on the phase Ib escalation data & it was established as 45 mg BID. After the completion of the phase Ib dose expansion & initiation of phase II, the MEK162 RP2D was reduced to 30 mg BID30 for better long term tolerability. Patient's will now begin MEK162 at the revised RP2D of 30 mg BID. 1 cycle is 28 days. If no progression of the tumor is seen, pts will continue on therapy. Pts who have progression of disease will proceed directly to second line therapy as per standard of care.
  • MEK162
  • Imatinib Mesylate (Gleevec®; STI571; NSC #716051)

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have pathologically confirmed GIST.

          -  In the Phase Ib portion, must have locally advanced or metastatic GIST and have
             progressed on imatinib.

          -  In the Phase II portion, patients must be newly diagnosed or treatment naïve, or have
             been off adjuvant imatinib therapy for at least 3 months. Patients with newly
             diagnosed GIST and who had been on imatinib for up to 4 weeks prior to signing the
             consent are allowed to enroll in order to expedite accrual.

          -  Patients must be at least 18 years of age.

          -  Disease must be measurable by RECIST 1.1.

          -  ECOG Performance Status 0 or 1.

          -  Adequate renal, hepatic, and hematologic function as the following: Serum Creatinine ≤
             1.5 mg/dL, Total Serum Bilirubin ≤ 1.5 x upper limit of normal (ULN), Serum AST (SGOT)
             and/or ALT (SGPT) ≤ 2.5 x ULN (or ≤ 5.0 x ULN if considered due to tumor)ANC ≥
             1500/mm3, Platelets ≥ 100,000/mm3, and hemoglobin ≥ 10g/dL.

          -  Patients of childbearing potential must have a negative serum pregnancy test within 14
             days of treatment. Patients must agree to use a reliable barrier method of birth
             control during and for 3 months following the last dose of study drug.

          -  Patient must have adequate cardiac function (left ventricular ejection fraction (LVEF)
             ≥50% as determined by a multigated acquisition (MUGA) scan or echocardiogram; and QTc
             interval≤480 ms.

          -  Patient must be able to take oral medications.

          -  Patients must sign an informed consent document.

        Exclusion Criteria:

          -  In the phase II portion of the study, patients that have been previously treated with
             any systemic therapy for GIST are not permitted to enroll, with the exception of
             adjuvant imatinib systemic therapy or exposure to imatinib within 4 weeks of signing
             consent.

          -  Patients have a severe and/or uncontrolled medical disease (i.e., uncontrolled
             diabetes, chronic renal disease, or active uncontrolled infection).

          -  Patients have known brain metastasis.

          -  Patients have known chronic liver disease (i.e., cirrhosis)

          -  Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C
             infection.

          -  Other active malignancy (other than malignancies, which the investigator determines
             are unlikely to interfere with treatment and safety analysis).

          -  Patients have a history or current evidence of Central Serous Retinopathy (CSR) or
             retinal vein occlusion (RVO) or predisposing factors to CSR or RVO (i.e. uncontrolled
             glaucoma or ocular hypertension, uncontrolled diabetes mellitus, hyperviscosity or
             hypercoagulability syndromes).

          -  History of retinal degenerative disease.

          -  History of Gilbert's syndrome.

          -  Patients have clinically significant cardiovascular disease, including any of the
             following:

             1) History of acute coronary syndrome including myocardial infarction, unstable
             angina, CABG, coronary angioplasty or stenting < 6 months prior to screening; 2)
             symptomatic chronic heart failure (New York Heart Association Criteria, Class II-IV);
             3) evidence of clinically significant cardiac arrhythmias and/or conduction
             abnormalities < 6 months prior to screening except atrial fibrillation (AF) and
             paroxysmal supraventricular tachycardia (PSVT).

          -  Uncontrolled arterial hypertension despite appropriate medical therapy.

          -  Patients who have neuromuscular disorders that are associated with elevated creatinine
             phosphokinase (i.e. inflammatory myopathies, muscular dystrophy, amyotrophic lateral
             sclerosis, spinal muscular atrophy).

          -  Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).

          -  Prior therapy with a MEK inhibitor.

          -  Patients had a major surgery within 3 weeks prior to study entry or who have not
             recovered from side effects of such procedure.

          -  Women who are pregnant or lactating.

          -  Sexually active males unless they use a condom during intercourse while taking the
             drug and for 15 days after stopping treatment and should not father a child in this
             period. A condom is required to be used also by vasectomized men in order to prevent
             delivery of the drug via seminal fluid.

          -  Patients with any significant history of non-compliance to medical regimens or with
             inability to grant reliable informed consent.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:maximum tolerated dose (MTD) (phase 1b portion)
Time Frame:1 year
Safety Issue:
Description:The first three patients will be enrolled at Dose Level 1. If dose level 1 is not found to be tolerable, then the next cohort will be enrolled at dose level -1. If dose level -1 is not found to be tolerable, then the study may be terminated based on discussions with the sponsor and the combination may be deemed intolerable. If 0/3 patients or 1/6 patients experience a DLT on dose level 2, this will be the RP2D.

Secondary Outcome Measures

Measure:Response Rate (RR) (phase 1b portion)
Time Frame:1 year
Safety Issue:
Description:defined by RECIST 1.1 criteria and by CHOI criteria RR will be estimated as the proportion of patients who have complete response or partial response for each criterion.
Measure:Progression Free Survival (PFS)
Time Frame:1 year
Safety Issue:
Description:PFS will be calculated using Kaplan-Meier estimate among all patients enrolled. Patients who have not experienced the event of interest by the end of the study will be censored at the time of the last follow-up.
Measure:RR by CHOI criteria (phase II portion)
Time Frame:1 year
Safety Issue:
Description:It will be determined as the proportion of patients who have complete response or partial response defined by the CHOI criteria with a two-sided 95% CI provided.
Measure:RR by EORTC criteria
Time Frame:1 year
Safety Issue:
Description:It will be determined as the proportion of patients who have complete response or partial response defined by the EORTC criteria with a two-sided 95% CI provided.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Memorial Sloan Kettering Cancer Center

Trial Keywords

  • MEK162
  • Imatinib
  • 13-162

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