Binimetinib and Erlotinib Hydrochloride in Treating Patients with Stage IV Non-small Cell Lung Cancer

Inclusion Criteria

• Eligible patients will have a histologic or cytologic diagnosis of NSCLC of the advanced stage (IV), with no known curative treatment options
• Patients must have a tissue or blood proven KRAS or EGFR mutation confirmed in a Clinical Laboratory Improvement Amendments (CLIA) certified lab (only required in the Phase IB expansion cohort)
• For Phase I/Ib enrollment, patients with a CLIA confirmed EGFR mutation may be treatment naive; all other patients must have received at least one previous line of therapy; there will be no limits to prior lines of treatment for the Phase 1 portion
• Eastern Cooperative Oncology Group (ECOG) performance status of either 0 or 1
• There will be no limits to prior lines of treatment
• At least one measurable site of disease (as defined by Response Evaluation Criteria in Solid Tumors), or other disease specific response assessment criteria, as appropriate (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)
• Patients must have discontinued all previous systemic therapies and recovered from side effects due to systemic treatment for more than 14 days prior to starting on treatment
• Patients must have discontinued all previous biologic therapies and recovered from side effects due to biologic treatment for more than 14 days prior to starting on treatment
• Patients must have discontinued all previous external beam radiation therapy and recovered from side effects due to radiation therapy for more than 14 days starting on treatment
• Patients must have archival tissue sample (if available) or be willing to undergo a repeat biopsy (if feasible)
• Negative serum pregnancy test within 72 hours prior to the first study dose in all women of childbearing potential
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Hemoglobin (Hgb) >= 9.0 g/dL
• Platelets >= 100 x 10^9/L
• Serum total bilirubin =< 2.0 x ULN (upper limit of normal)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN or =< 5 x ULN if liver metastases are present
• Plasma creatine phosphokinase (CK) < 1.5 x ULN
• Serum creatinine =< 1.5 x ULN or 24-hour clearance >= 50 ml/min

Exclusion Criteria

• Patient do not have adequate cardiac function defined as: * Left ventricular ejection fraction (LVEF) =< 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram * Corrected QT (QTc) interval >= 480 ms * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting [CABG], coronary angioplasty, or stenting) < 6 months prior to screening * Symptomatic chronic heart failure; evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities < 6 months prior to screening
• Patients with documented central nervous system or leptomeningeal metastasis (brain metastasis) at the time of study entry; patients with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic
• Any other serious uncontrolled medical disorder or active infection that would impair the patient’s ability to receive study treatment (at the discretion of the investigator)
• Prior use of MEK162 or concurrent use of other approved anticancer or investigational agents is not allowed; patients treated with prior EGFR tyrosine kinase inhibitor (TKI) therapy (including erlotinib) are allowed to enroll
• Gastrointestinal disease that precludes absorption
• History or current evidence of central serous retinopathy (CSR) or retinal vein occlusion (RVO)
• Any ophthalmopathy visible at screening that would be considered a risk factor for CSR or RVO by the ophthalmologist (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, history of hyperviscosity or hypercoagulability syndromes)
• History of another malignancy within 2 years, except cured basal cell carcinoma of the skin or excised carcinoma in situ of the cervix
• Patients who have received prior anti-cancer treatment within the following time frames: * Received systemic therapies less than 14 days prior to starting on treatment * Received radiation therapy less than 14 days prior to starting on treatment * Received biologic therapy less than 14 days prior to starting on treatment
• Patients who have not recovered from side effects of prior anti-cancer treatment to less than or equal to grade 1 toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 within the following time frames: * Received previous systemic therapy and has not recovered from side effects for more than 14 days prior to starting on treatment * Received previous radiation therapy and has not recovered from side effects for more than 14 days prior to starting on treatment * Received previous biologic therapy and has not recovered from side effects for more than 14 days prior to starting on treatment
• Patients who have undergone major surgery < 4 weeks of initiation of study medication or who have not recovered from side effects of such procedure
• Patients with concurrent uncontrolled medical conditions that may interfere with their participation in the study or potentially affect the interpretation of the study data
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test (> 5 mIU/mL)
• Women of child-bearing potential defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means and males who have not been sterilized by vasectomy or other means with partners who are women of child-bearing potential (WOCBP), UNLESS the women are using two birth control methods; the two methods can be a double barrier method or a barrier method plus a hormonal method; adequate barrier methods of contraception include: * Diaphragm, condom (by the partner/patient where appropriate), intrauterine device (copper or hormonal), sponge or spermicide; hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent; reliable contraception should be maintained throughout the study and for 3 months after study drug discontinuation
• Patients unwilling or unable to comply with the protocol
• Known positive serology for human immunodeficiency virus (HIV), active hepatitis B, and/or active hepatitis C infection
• History of Gilbert’s syndrome
• Patients who have neuromuscular disorders that are associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment; muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment
• Previous treatment with any substrate of CYP2B6 enzyme < 14 days prior to initiation of investigational products