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

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ClinicalTrials.gov Identifier: NCT01991379
Recruitment Status : Recruiting
First Posted : November 25, 2013
Last Update Posted : August 5, 2019
Sponsor:
Collaborators:
Array BioPharma
University of Pittsburgh
Information provided by (Responsible Party):
Memorial Sloan Kettering Cancer Center

Tracking Information
First Submitted Date  ICMJE November 18, 2013
First Posted Date  ICMJE November 25, 2013
Last Update Posted Date August 5, 2019
Study Start Date  ICMJE November 2013
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2018)
  • maximum tolerated dose (MTD) (phase 1b portion) [ Time Frame: 1 year ]
    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.
  • Best Response Rate (phase II portion) [ Time Frame: 2 years ]
    Response Rate (CR+PR, RECIST 1.1). Response rate (RECIST 1.1) will be determined as the proportion of evaluable patients who have complete response or partial response defined by the RECIST 1.1.
Original Primary Outcome Measures  ICMJE
 (submitted: November 18, 2013)
  • maximum tolerated dose (MTD) (phase 1b portion) [ Time Frame: 1 year ]
    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.
  • Response Rate (phase II portion) [ Time Frame: 1 year ]
    Response Rate (CR+PR, RECIST 1.1). Response rate (RECIST 1.1) will be determined as the proportion of evaluable patients who have complete response or partial response defined by the RECIST 1.1 criteria with a one-sided 90% confidence interval (CI) and a two-sided 95% CI provided.
Change History Complete list of historical versions of study NCT01991379 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2013)
  • Response Rate (RR) (phase 1b portion) [ Time Frame: 1 year ]
    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.
  • Progression Free Survival (PFS) [ Time Frame: 1 year ]
    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.
  • RR by CHOI criteria (phase II portion) [ Time Frame: 1 year ]
    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.
  • RR by EORTC criteria [ Time Frame: 1 year ]
    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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)
Official Title  ICMJE A Phase Ib/II Study of MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)
Brief Summary

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

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Gastrointestinal Stromal Tumor (GIST)
Intervention  ICMJE
  • Drug: MEK162
    Patients should take the study drug with a glass of water. MEK162 can be taken with or without food.
  • Drug: Imatinib Mesylate (Gleevec®; STI571; NSC #716051)
  • Other: Blood draws
  • Procedure: biopsy
    Following informed consent, the first 20 mandatory patients, except for patients who have already been treated with imatinib prior to consent, and subsequent voluntary patients enrolled on the phase II portion of the trial will undergo research biopsies. Patients should hold both imatinib and MEK162 doses on the day they undergo a biopsy.
Study Arms  ICMJE Experimental: MEK162 in Combination With Imatinib Mesylate
Pts 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.
Interventions:
  • Drug: MEK162
  • Drug: Imatinib Mesylate (Gleevec®; STI571; NSC #716051)
  • Other: Blood draws
  • Procedure: biopsy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 18, 2013)
62
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date November 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Ping Chi, MD PhD 646-888-4166
Contact: William Tap, MD 646-888-4163
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01991379
Other Study ID Numbers  ICMJE 13-162
R01FD005731 ( U.S. FDA Grant/Contract )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Memorial Sloan Kettering Cancer Center
Study Sponsor  ICMJE Memorial Sloan Kettering Cancer Center
Collaborators  ICMJE
  • Array BioPharma
  • University of Pittsburgh
Investigators  ICMJE
Principal Investigator: Ping Chi, MD, PhD Memorial Sloan Kettering Cancer Center
PRS Account Memorial Sloan Kettering Cancer Center
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP