Combination Chemotherapy and Binimetinib in Treating Patients with RAS Positive Metastatic Colorectal Cancer

Inclusion Criteria

• Patients with histologically confirmed RAS (HRAS, NRAS, or KRAS) positive metastatic colorectal cancer
• Patients must have progressed during or after first-line treatment for metastatic disease with oxaliplatin and fluoropyrimidines based chemotherapy (with failure within six months) or not be a candidate for oxaliplatin (i.e. neuropathy)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Hemoglobin (Hgb) >= 9 g/dL (transfusions are not permitted =< two weeks prior to screening)
• Platelets (PLT) >= 75 x 10^9/L (transfusions are not permitted =< two weeks prior to screening)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN); patient with liver metastases =< 5 x ULN
• Total bilirubin =< 1.5 x ULN and < 2 mg/dl * Note: patients who have a total bilirubin level > 1.5 x ULN will be allowed if their indirect bilirubin level is =< 1.5 x ULN
• Creatinine =< 1.5 mg/dL x ULN, or > 50 mL/min
• Adequate cardiac function as defined by the following: * Left ventricular ejection fraction (LVEF) >= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram * Corrected QT interval by Fridericia's formula (QTcF) interval =< 480 ms (if a single QTcF interval is prolonged, the mean from triplicate electrocardiogram [ECG]s may be used)
• Must have recovered from adverse effects of any prior surgery, radiotherapy or other antineoplastic therapy; Common Terminology Criteria for Adverse Events (CTCAE) adverse events less than or equal to grade 1 are acceptable; CTCAE adverse events grade 2 or greater may be acceptable as determined by the principal investigator
• Willingness and ability to comply with all study procedures and able to take oral medications
• DOSE EXPANSION PHASE ADDITIONAL INCLUSION CRITERIA
• Patients must be willing to undergo biopsy according to the institute’s own guidelines and requirements for such procedures unless deemed unsafe by the investigator
• Patients must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (at least one lesion >= 10 mm in at least one dimension when assessed by computed tomography [CT] or magnetic resonance imaging [MRI], or a cutaneous lesion with clearly defined margins that measures >= 10 mm in at least one dimension)
• Patients must be irinotecan refractory; patients must have progressed on prior irinotecan therapy but must be able to tolerate standard irinotecan doses

Exclusion Criteria

• Uridine diphosphate (UDP) glycosyltransferase 1 family, polypeptide A1 (UGT1A1) *28 homozygous patients
• Previous treatment with any MEK inhibitor
• Treatment with systemic antineoplastic therapy (including unconjugated therapeutic antibodies and toxin immunoconjugates) or any investigational therapy =< 4 weeks (< 6 weeks for nitrosourea or mitomycin-C, antibodies except for trastuzumab) or =< 5-half lives of the investigational therapy prior to starting study treatment, whichever is longer
• Patient received radiotherapy =< 2 weeks prior to the first dose of study treatment except localized radiation therapy for symptomatic bone metastasis
• Have had a diagnosis of another malignancy, unless the patient has been disease-free for at least 3 years following the completion of curative intent therapy, with the following exceptions: * Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed * Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
• Personal history of Gilbert’s syndrome
• Uncontrolled arterial hypertension defined by blood pressure > 150 mmHg systolic and/or 100 mmHg diastolic at rest (average 3 consecutive readings at least 5 minutes apart) despite appropriate medical therapy
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: * History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, 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 except atrial fibrillation and paroxysmal supraventricular tachycardia
• Known positive serology for human immunodeficiency virus (HIV), active hepatitis B, and/or active hepatitis C infection (note: if not suspected, testing is not required at baseline)
• Patients who have neuromuscular disorders that are associated with elevated creatinine kinase (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
• Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection that under the judgment of the principal investigator [PI] may impair absorption of study drugs)
• Any other condition that would, in the investigator’s judgment, contraindicate the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., infection/inflammation, intestinal obstruction, unable to swallow medication; (patients may not receive drug through a feeding tube, social/psychological issues, etc.)
• Patients who have undergone major surgery =< 3 weeks prior to starting study drug or who have not recovered from side effects of such procedure
• 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 beta-human chorionic gonadotropin (hCG) laboratory test * A positive beta-hCG result will not be exclusionary if it is suspected to originate from a malignancy and the patient has undergone a confirmatory ultrasound within 72 hours prior to starting MEK162 therapy
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception from screening through 30 days after the last dose of study drug/treatment; highly effective contraception methods include: * Total abstinence * Female sterilization-bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks before starting study treatment; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential * Male sterilization of subject partner- vasectomy at least 6 months prior to screening * Combination of any two of the following: ** Use of oral, injected, or implanted hormonal methods of contraception ** Placement of an intrauterine device (IUD) or intrauterine system (IUS) ** Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) levels > 40 mIU/mL (for United States [US] only: and estradiol < 20 pg/mL) * In addition, female participants must refrain from donating ova during the study through 30 days after the end of systemic exposure of study drug/treatment
• Sexually active males, unless they use a condom during intercourse while taking the drug through 90 days after the end of systemic exposure to study drug/treatment; in addition, male participants should not father a child in this period and must refrain from donating sperm during the study through 90 days after the end of systemic exposure of study drug/treatment; a condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid
• Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study