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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Memorial Sloan-Kettering Cancer Center
Sponsor:
Collaborators:
Novartis
University of Pittsburgh
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT01991379
First received: November 18, 2013
Last updated: October 2, 2014
Last verified: October 2014
  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).


Condition Intervention Phase
Gastrointestinal Stromal Tumor (GIST)
Drug: MEK162
Drug: Imatinib Mesylate (Gleevec®; STI571; NSC #716051)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib/II Study of MEK162 in Combination With Imatinib Mesylate in Patients With Untreated Advanced Gastrointestinal Stromal Tumor (GIST)

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • maximum tolerated dose (MTD) (phase 1b portion) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Response Rate (RR) (phase 1b portion) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 62
Study Start Date: November 2013
Estimated Primary Completion Date: November 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MEK162 in Combination With Imatinib Mesylate
Patients will be treated with the combination therapy of MEK162 and imatinib. In the phase Ib portion of the study, patients will receive imatinib at 400 mg once daily and MEK162 at the standard 3+3 escalation doses .In the phase Ib expansion cohort, the patients will receive the RP2D: imatinib 400 mg once daily (standard of care first line imatinib dose) and MEK162 at the RP2D twice daily. In the phase II portion of the study, patients will receive imatinib at 400 mg once daily and MEK162 at the RP2D twice daily. One cycle is 28 days. If no progression of the tumor is seen, patients will continue on therapy. Those patients who have progression of disease will proceed directly to second line therapy as per standard of care.
Drug: MEK162 Drug: Imatinib Mesylate (Gleevec®; STI571; NSC #716051)

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 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 have been previously treated with any systemic therapy except for adjuvant imatinib systemic therapy.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01991379

Contacts
Contact: Ping Chi, MD PhD 646-888-3338
Contact: William Tap, MD 646-888-4163

Locations
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York, New York, United States, 10065
Contact: Ping Chi, MD    646-888-3338      
Contact: William Tap, MD    646-888-4163      
Principal Investigator: Ping Chi, MD, PhD         
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Novartis
University of Pittsburgh
Investigators
Principal Investigator: Ping Chi, MD, PhD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT01991379     History of Changes
Other Study ID Numbers: 13-162
Study First Received: November 18, 2013
Last Updated: October 2, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
MEK162
Imatinib
13-162

Additional relevant MeSH terms:
Gastrointestinal Stromal Tumors
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Imatinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014