A Phase IB Dose Escalation and Expansion Trial of MEK 162 With Docetaxel in Previously Treated Stage IV, Non-small Cell Lung Cancer (NSCLC)
Overview
- Phase
- Phase 1
- Intervention
- Binimetinib
- Conditions
- Recurrent Non-Small Cell Lung Carcinoma
- Sponsor
- Jonsson Comprehensive Cancer Center
- Locations
- 1
- Primary Endpoint
- Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03
- Status
- Withdrawn
- Last Updated
- 5 years ago
Overview
Brief Summary
This phase Ib trial studies the safety and best dose of binimetinib when given in combination with docetaxel in treating patients with previously treated, stage IV non-small cell lung cancer. Binimetinib and docetaxel may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES: I. Evaluate the safety and tolerability of increasing doses of MEK162 (binimetinib) with docetaxel 75 mg/m2 every 21 days in patients with stage IV non-small cell lung cancer (NSCLC) that have progressed after at least one prior systemic therapy. SECONDARY OBJECTIVES: I. Determine objective tumor response rate (RR) as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 with MEK162 and standard doses of docetaxel in stage IV NSCLC. II. Determine progression free survival (PFS) of MEK162 and standard doses of docetaxel. III. Evaluate the pharmacokinetic profile of MEK162 when given along with docetaxel. TERTIARY OBJECTIVES: I. Evaluate tissue biomarkers in baseline tumors and at the time of progression to correlate with clinical outcome II. Assess the activation status of extracellular signal-regulated kinase (ERK), protein kinase B (Akt) and ribosomal protein S6 kinase (S6K) in tumor biopsy samples at baseline and at the time of progression. III. Determine the cytokine profile before and after treatment in patients. OUTLINE: This is a dose-escalation study of binimetinib. Patients receive binimetinib orally (PO) twice daily (BID) on days 1-21 and docetaxel intravenously (IV) on day 21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or better after completing 6 courses of binimetinib and docetaxel may continue receiving binimetinib PO BID in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days and then annually for up to 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed written informed consent
- •A histologically or cytologically confirmed diagnosis of stage IV NSCLC
- •Must have progressed on at least one prior line of platinum-based therapy for stage IV NSCLC (excluding docetaxel or mitogen activated protein kinase kinase \[MEK\] inhibitors)
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Measurable disease defined by RECIST criteria
- •Ability to provide adequate tissue from archival tumor specimen; confirmation of adequate tissue is required prior to enrollment
- •In expansion cohort only: patient's kirsten rat sarcoma viral oncogene homolog (KRAS) mutational status must be known prior to enrollment
- •Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
- •Hemoglobin (Hgb) \>= 9 g/dL without transfusions
- •Platelets (PLT) \>= 100 x 10\^9/L without transfusions
Exclusion Criteria
- •History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
- •History of Gilbert syndrome
- •Previous or concurrent malignancy within the last 3 years with the exception of adequately treated skin basal or squamous cell with adequate wound healing
- •Prior therapy with a MEK-inhibitor or docetaxel for metastatic non-small cell lung cancer (docetaxel in the adjuvant setting will be allowed)
- •Epidermal growth factor receptor (EGFR) mutant and/or anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearranged tumor
- •Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following within 6 months of enrollment: myocardial infarction, unstable angina, coronary artery bypass graft (CABG), coronary angioplasty, or stenting, symptomatic chronic heart failure, clinically significant cardiac arrhythmias and/or conduction (except atrial fibrillation and paroxysmal supraventricular tachycardia)
- •Uncontrolled arterial hypertension despite appropriate medical therapy
- •Known positive serology for human immunodeficiency virus (HIV), active hepatitis B, and/or active hepatitis C infection
- •Neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy)
- •Subjects planning on embarking on a new strenuous exercise regimen after first dose of study treatment that can result in significant increases in plasma CK levels
Arms & Interventions
Treatment (binimetinib and docetaxel)
Patients receive binimetinib PO BID on days 1-21 and docetaxel IV on day 21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or better after completing 6 courses of binimetinib and docetaxel may continue receiving binimetinib PO BID in the absence of disease progression or unacceptable toxicity.
Intervention: Binimetinib
Treatment (binimetinib and docetaxel)
Patients receive binimetinib PO BID on days 1-21 and docetaxel IV on day 21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or better after completing 6 courses of binimetinib and docetaxel may continue receiving binimetinib PO BID in the absence of disease progression or unacceptable toxicity.
Intervention: Docetaxel
Treatment (binimetinib and docetaxel)
Patients receive binimetinib PO BID on days 1-21 and docetaxel IV on day 21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients who have stable disease or better after completing 6 courses of binimetinib and docetaxel may continue receiving binimetinib PO BID in the absence of disease progression or unacceptable toxicity.
Intervention: Laboratory Biomarker Analysis
Outcomes
Primary Outcomes
Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.03
Time Frame: Up to 30 days post-treatment
Side effects will be tabulated according to grade and will do sub-analysis based on patient demographic categories such as age and ECOG performance status.
Maximum tolerated dose of binimetinib in combination with docetaxel
Time Frame: 21 days
Incidence of dose-limiting toxicities, graded according to the CTCAE v4.03
Time Frame: 21 days
Side effects will be tabulated according to grade and will do sub-analysis based on patient demographic categories such as age and ECOG performance status.
Secondary Outcomes
- Biomarker analyses(Up to 30 days post-treatment)
- Mutations in KRAS and NRAS(Up to 30 days post-treatment)
- Pharmacokinetic (PK) profile will assess binimetinib (MEK162) levels during treatment cycles(On days 1 and 8 of course 1 and on day 1 of course 2)
- Objective tumor response rate (the rate of complete response or partial response), as defined by RECIST 1.1(Up to 5 years)
- Progression free survival(Up to 5 years)