Binimetinib and Imatinib Mesylate in Treating Patients with Untreated Advanced Gastrointestinal Stromal Tumors

Status: Active

Description

This phase Ib / II trial studies the side effects and the best dose of binimetinib when given together with imatinib mesylate and to see how well they work in treating patients with untreated gastrointestinal stromal tumors that have spread from where they started to nearby tissue or lymph nodes or to other places in the body. Binimetinib and imatinib mesylate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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 naive, 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
  • Disease must be measurable by RECIST 1.1
  • Eastern Cancer Oncology Group (ECOG) performance status 0 or 1
  • Serum creatinine =< 1.5 mg/dL
  • Total serum bilirubin =< 1.5 x upper limit of normal (ULN)
  • Serum aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and/or alanine aminotransferase (ALT) (serum glutamate pyruvate aminotransferase [SGPT]) =< 2.5 x ULN (or =< 5.0 x ULN if considered due to tumor)
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin >= 9 g/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
  • Patients must have adequate cardiac function (left ventricular ejection fraction [LVEF]) >= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
  • Corrected QT (QTc) interval =< 480 ms by electrocardiogram (EKG)
  • 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 active brain metastasis
  • Patients have known chronic liver disease (i.e., cirrhosis)
  • Known positive serology for human immunodeficiency virus (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: * History of acute coronary syndrome including myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty or stenting < 6 months prior to screening * Symptomatic chronic heart failure (New York Heart Association criteria, class II-IV) * 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
  • Patient with any significant history of non-compliance to medical regimens or with inability to grant reliable informed consent

Locations & Contacts

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Ping Chi
Phone: 646-888-4166
Email: chip@mskcc.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of treatment with binimetinib (MEK162) (a mitogen-activated protein kinase kinase [MEK] inhibitor) in combination with imatinib mesylate (imatinib) and to determine the maximum-tolerated dose (MTD) and the recommended phase II dose (RP2D) of the combination therapy in locally advanced or metastatic gastrointestinal stromal tumor (GIST) patients. (Phase Ib)

II. To assess the efficacy (response rate [RR] = complete response [CR] + partial response [PR]) of the combination therapy of MEK162 and imatinib in patients with untreated locally advanced or metastatic GIST, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. (Phase II)

SECONDARY OBJECTIVES:

I. To estimate RR (CR + PR) by both RECIST 1.1 and CHOI criteria, progression free survival (PFS) and clinical benefit rate (CR + PR + stable disease [SD]) of the combination therapy of MEK162 and imatinib in all locally advanced or metastatic GIST patients. (Phase Ib)

II. To assess the RR (CR + PR) of the combination therapy of MEK162 and imatinib by CHOI criteria, and by European Organization for Research and Treatment of Cancer (EORTC) criteria for partial response on fludeoxyglucose F 18 (FDG) positron emission tomography (PET) (25% reduction in PET maximum standardized uptake value [SUVmax]), PFS, overall survival (OS), clinical benefit rate (CR + PR + SD) and resectability rates in patients with untreated locally advanced or metastatic untreated GIST. (Phase II)

TERTIARY OBJECTIVES:

I. Analyze the pharmacodynamic effects of MEK162 in combination with imatinib on the following and correlate with clinical response to develop predictive and prognostic biomarkers: ets variant 1 (ETV1) protein level by western blot (WB); ETV1-dependent transcriptome (expression profile of ETV1-dependent gene targets) by nanostring; cell proliferation (marker of proliferation Ki-67 [Ki-67]) and apoptosis (cleaved caspase-3) by immunohistochemistry (IHC); mitogen-activated protein (MAP) kinase pathway and other pathways downstream of v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling using standard antibodies (phosphorylated [phospho]-mitogen-activated protein kinase 1 [ERK], phospho-KIT, phospho-MEK, phospho-v-akt murine thymoma viral oncogene homolog 1 [AKT]) by IHC; KIT/platelet-derived growth factor receptor, alpha polypeptide (PDGFRA) mutational status in matched tumor biopsy specimens collected prior to therapy, after combination therapy and upon disease progression.

II. Monitor the effect of MEK162 on imatinib serum levels by measuring the steady-state imatinib serum trough levels at the end of the 2-week lead in imatinib alone phase and after the combination of MEK162 and imatinib therapy at week 3 and week 5.

OUTLINE: This is a phase I, dose escalation study of binimetinib, followed by a phase II study.

Patients receive imatinib mesylate orally (PO) once daily (QD) and binimetinib PO twice daily (BID). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Trial Phase & Type

Trial Phase

Phase I/II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Ping Chi

Trial IDs

Primary ID 13-162
Secondary IDs NCI-2013-02281
Clinicaltrials.gov ID NCT01991379