Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer

Inclusion Criteria

• Histological confirmation of colorectal cancer that is metastatic and/or unresectable
• Documented mutation in KRAS or NRAS (codon 12, 13, 59, 61, 117, or 146) in tumor tissue from primary or metastatic site, tested by a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• Measurable disease
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Previously treated with fluoropyrimidine, oxaliplatin, and irinotecan based chemotherapy, and an anti-VEGF biological therapy
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained = = 75 x 10^9/L without transfusions (obtained = = 9 g/dL (obtained = = 50 mL/min using the Cockcroft-Gault formula (obtained = = 1.5 x 10^9/L (obtained = = 75 x 10^9/L without transfusion (obtained = = 9 g/dL (obtained = = 50 mL/min using the Cockcroft-Gault formula (obtained = = 42 days prior to registration/randomization. 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
• Sexually active males
• NOTE: unless they agree to use highly effective methods of contraception throughout the study and for 12 weeks after study drug discontinuation and should not father a child in this period
• Any symptomatic brain metastasis
• NOTE: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for >= 4 weeks prior to registration/randomization, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at registration/randomization
• Prior treatment = = 150 mmHg or diastolic blood pressure >= 100mmHg despite current therapy
• History of thromboembolic or cerebrovascular events = = 3 years prior to registration/randomization
• NOTE: If there is a history or prior malignancy, must not be receiving other specific anti-cancer treatment such as anti-estrogen, anti-androgen, or other tyrosine kinase inhibitor therapy
• CROSSOVER EXCLUSION CRITERIA: Prior treatment with drug targeting BRAF, MEK, ERK, or CDK family
• NOTE: For the purpose of this protocol, prior treatment with regorafenib is allowed
• CROSSOVER EXCLUSION CRITERIA: 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 hCG laboratory test
• CROSSOVER EXCLUSION CRITERIA: Women of child-bearing potential
• NOTE: Defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception throughout the study and for 8 weeks after study drug discontinuation
• NOTE: 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 have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation >= 42 days of re-registration. 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
• CROSSOVER EXCLUSION CRITERIA: Sexually active males
• NOTE: unless they agree to use highly effective methods of contraception throughout the study and for 12 weeks after study drug discontinuation and should not father a child in this period
• CROSSOVER EXCLUSION CRITERIA: Any symptomatic brain metastasis
• NOTE: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for >= 4 weeks, with imaging (e.g., MRI or CT) demonstrating no current evidence of pro