Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer
Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer
This phase II trial studies how well binimetinib and palbociclib work compared to TAS-102 in
 treating patients with KRAS and NRAS mutation positive colorectal cancer that has spread to
 other places in the body or cannot be removed by surgery. Binimetinib and palbociclib may
 stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs
 used in chemotherapy, such as TAS-102, work in different ways to stop the growth of tumor
 cells, either by killing the cells, by stopping them from dividing, or by stopping them from
 spreading. Giving binimetinib and palbociclib may work better compared to TAS-102 alone in
 treating patients with colorectal cancer.
PRIMARY OBJECTIVES:

 I. The primary objective is to compare the progression-free survival (PFS) between those
 randomized to palbociclib/binimetinib and those randomized to trifluridine and tipiracil
 hydrochloride (TAS-102) in patients with refractory KRAS- or NRAS-mutant metastatic
 colorectal cancer (CRC).

 SECONDARY OBJECTIVES:

 I. To compare the overall response rate by Response Evaluation Criteria in Solid Tumors
 (RECIST) 1.1 criteria between those randomized to palbociclib/binimetinib and those
 randomized to TAS-102 in patients with refractory KRAS- or NRAS-mutant metastatic CRC.

 II. To compare the overall survival (OS) between those randomized to palbociclib/binimetinib
 and those randomized to TAS-102 in patients with refractory KRAS- or NRAS-mutant metastatic
 CRC.

 III. To determine the safety and tolerability of the recommended phase II dose of palbociclib
 in combination with binimetinib in patients with refractory KRAS- or NRAS-mutant metastatic
 CRC.

 CORRELATIVE RESEARCH OBJECTIVES:

 I. To determine the tumor mutational profiles that characterize groups of patients that
 predict for response or resistance to combination of palbociclib/binimetinib.

 II. To determine the correlation between circulating tumor deoxyribonucleic acid (DNA) and
 tumor response or resistance to therapy with palbociclib/binimetinib or TAS-102.

 III. To determine the association between Consensus Molecular Subtype based on gene
 expression profiling and response or resistance to combination of palbociclib/binimetinib.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM A: Patients receive binimetinib orally (PO) twice daily (BID) on days 1-28 and
 palbociclib PO once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 24
 cycles in the absence of disease progression or unacceptable toxicity.

 ARM B: Patients receive trifluridine and tipiracil hydrochloride PO BID on days 1-5 and 8-12.
 Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or
 unacceptable toxicity. Patients with disease progression may optionally crossover to Arm A.

 After completion of study treatment, patients are followed up within 30-37 days and then
 every 12 weeks for up to 24 months.
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 >= 2 prior regimens of systemic chemotherapy for metastatic or
 locally advanced, unresectable disease

 -  NOTE: Maintenance regimens, such as 5-fluorouracil or capecitabine, with or
 without bevacizumab, should not be counted as separate lines of treatment

 -  NOTE: For patients who experienced disease recurrence during or within 6 months
 of completion of adjuvant chemotherapy, only one regimen of systemic chemotherapy
 for metastatic disease is required

 -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained =< 14 days prior to
 registration/randomization unless otherwise noted)

 -  Platelet count >= 75 x 10^9/L without transfusions (obtained =< 14 days prior to
 registration/randomization unless otherwise noted)

 -  Hemoglobin (Hgb) >= 9 g/dL (obtained =< 14 days prior to registration/randomization
 unless otherwise noted)

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to
 registration/randomization unless otherwise noted)

 -  Aspartate transaminase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN; =< 5.0 x
 ULN if known liver metastases (obtained =< 14 days prior to registration/randomization
 unless otherwise noted)

 -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance >= 50 mL/min using
 the Cockcroft-Gault formula (obtained =< 14 days prior to registration/randomization
 unless otherwise noted)

 -  Negative serum beta-human chorionic gonadotropin (HCG) pregnancy test done =< 7 days
 prior to registration/randomization for women of childbearing potential only

 -  Able to swallow capsules with no surgical or anatomic conditions that would preclude
 the patient from swallowing and absorbing oral medications

 -  Able and willing to provide informed written consent and able to comply with protocol
 requirement

 -  Able and willing to return to enrolling institution for follow-up (during the active
 monitoring phase of the study)

 -  NOTE: During the active monitoring phase of a study (i.e., active treatment and
 observation), participants must be willing to return to the consenting
 institution for follow-up

 -  Willing to provide blood and tissue samples for mandatory correlative research
 purposes

 -  Patient is deemed by the investigator to have the initiative and means to be compliant
 with the protocol (treatment and follow-up)

 -  CROSSOVER INCLUSION CRITERIA: Histological confirmation of colorectal cancer that is
 metastatic and/or unresectable

 -  CROSSOVER INCLUSION CRITERIA: 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
 CLIA-certified laboratory

 -  CROSSOVER INCLUSION CRITERIA: Measurable disease

 -  CROSSOVER INCLUSION CRITERIA: ECOG performance status (PS) of 0 or 1

 -  CROSSOVER INCLUSION CRITERIA: Previously treated with >= 2 prior regimens of systemic
 chemotherapy for metastatic or locally advanced, unresectable disease

 -  NOTE: Maintenance regimens, such as 5-fluorouracil or capecitabine, with or
 without bevacizumab, should not be counted as separate lines of treatment

 -  NOTE: For patients who experienced disease recurrence during or within 6 months
 of completion of adjuvant chemotherapy, only one regimen of systemic chemotherapy
 for metastatic disease is required

 -  CROSSOVER INCLUSION CRITERIA: ANC >= 1.5 x 10^9/L (obtained =< 28 days of
 re-registration unless otherwise noted)

 -  CROSSOVER INCLUSION CRITERIA: Platelet count >= 75 x 10^9/L without transfusion
 (obtained =< 28 days of re-registration unless otherwise noted)

 -  CROSSOVER INCLUSION CRITERIA: Hgb >= 9 g/dL (obtained =< 28 days of re-registration
 unless otherwise noted)

 -  CROSSOVER INCLUSION CRITERIA: Total bilirubin =< 1.5 x ULN (obtained =< 28 days of
 re-registration unless otherwise noted)

 -  CROSSOVER INCLUSION CRITERIA: AST and ALT =< 2.5 x ULN; =< 5.0 x ULN if known liver
 metastases (obtained =< 28 days of re-registration unless otherwise noted)

 -  CROSSOVER INCLUSION CRITERIA: Serum creatinine =< 1.5 mg/dL OR calculated creatinine
 clearance >= 50 mL/min using the Cockcroft-Gault formula (obtained =< 28 days of
 re-registration unless otherwise noted)

 -  CROSSOVER INCLUSION CRITERIA: Negative serum beta-HCG pregnancy test done =< 7 days
 prior to re-registration for women of childbearing potential only

 -  CROSSOVER INCLUSION CRITERIA: Able to swallow capsules with no surgical or anatomic
 conditions that would preclude the patient from swallowing and absorbing oral
 medications

 -  CROSSOVER INCLUSION CRITERIA: Able and willing to provide informed written consent and
 able to comply with protocol requirements

 -  CROSSOVER INCLUSION CRITERIA: Able and willing to return to enrolling institution for
 follow-up (during the Active Monitoring Phase of the study)

 -  NOTE: During the Active Monitoring phase of a study (i.e., active treatment and
 observation), participants must be willing to return to the consenting
 institution for follow-up

 -  CROSSOVER INCLUSION CRITERIA: Willing to provide blood samples for mandatory
 correlative research purposes

 -  CROSSOVER INCLUSION CRITERIA: Patient is deemed by the investigator to have the
 initiative and means to be compliant with the protocol (treatment and follow-up)

 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

 -  Prior treatment with trifluridine/tipiracil (TAS-102)

 -  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

 -  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 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 =< 21 days prior to registration/randomization with any other
 chemotherapy, small molecule inhibitor (e.g. regorafenib), monoclonal antibody,
 immunotherapy, or radiotherapy

 -  NOTE: All toxicities from prior therapy must be =< grade 1 (or =< grade 2 for
 peripheral neuropathy or alopecia)

 -  Impaired cardiovascular function or clinically significant cardiac 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 registration/randomization

 -  Symptomatic chronic heart failure (i.e. grade 2 or higher), history or current
 evidence of clinically significant cardiac arrhythmia and/or conduction
 abnormality < 6 months prior to registration/randomization except atrial
 fibrillation and paroxysmal supraventricular tachycardia

 -  Left ventricular ejection fraction (LVEF) < 50% as determined by a multigated
 acquisition (MUGA) scan or echocardiogram =< 28 days prior to
 registration/randomization

 -  Uncontrolled hypertension, defined as persistent elevation of systolic blood pressure
 >= 150 mmHg or diastolic blood pressure >= 100mmHg despite current therapy

 -  History of thromboembolic or cerebrovascular events =< 12 weeks prior
 registration/randomization. Examples include transient ischemic attacks,
 cerebrovascular accidents, hemodynamically significant (i.e. massive or submassive)
 deep vein thrombosis or pulmonary emboli

 -  Note: Patients with either deep vein thrombosis or pulmonary emboli that does not
 result in hemodynamic instability are allowed to enroll as long as they are on a
 stable dose of anticoagulants for at least 4 weeks

 -  Note: Patients with thromboembolic events related to indwelling catheters or
 other procedures may be enrolled

 -  Known history of acute or chronic pancreatitis =< 6 months prior to
 registration/randomization

 -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,
 and/or active hepatitis C infection

 -  Patients who have neuromuscular disorders that are associated with elevated creatine
 phosphokinase (CPK) (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic
 lateral sclerosis, spinal muscular atrophy)

 -  History of chronic inflammatory bowel disease or Crohn?s disease requiring medical
 intervention (immunomodulatory or immunosuppressive medications or surgery) =< 12
 months prior to registration/randomization

 -  Impaired gastrointestinal (GI) function or disease that may significantly alter the
 absorption of binimetinib or palbociclib (e.g., ulcerative disease, uncontrolled
 vomiting, malabsorption syndrome, small bowel resection with decreased intestinal
 absorption)

 -  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)

 -  Leptomeningeal disease

 -  Known hypersensitivity to the components of study drugs or its analogs

 -  Known medical, psychiatric, substance abuse, or cognitive disorder that may compromise
 the patient's ability to understand the patient information, give informed consent,
 comply with the study protocol or complete the study

 -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
 infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
 arrhythmia, or psychiatric illness/social situations that would limit compliance with
 study requirements

 -  Patients who have undergone major surgery =< 21 days prior to
 registration/randomization or who have not recovered from side effects of such
 procedures

 -  Any other co-morbid, systemic illnesses or other severe concurrent disease which, in
 the judgment of the investigator, would make the patient inappropriate for entry into
 this study or interfere significantly with the proper assessment of safety and
 toxicity of the prescribed regimens

 -  Previous or concurrent malignancy =< 3 years prior to registration/randomization with
 the following exceptions:

 -  Adequately treated basal cell or squamous cell carcinoma of the skin

 -  Superficial bladder cancer

 -  Prostate intraepithelial neoplasm

 -  In situ carcinoma of the cervix

 -  Other solid tumors treated curatively without evidence of recurrence for >= 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 progressive brain metastases at
 re-registration

 -  CROSSOVER EXCLUSION CRITERIA: Impaired cardiovascular function or clinically
 significant cardiac 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 re-registration

 -  Symptomatic chronic heart failure (i.e., grade 2 or higher), history or current
 evidence of clinically significant cardiac arrhythmia and/or conduction
 abnormality < 6 months prior to re-registration except atrial fibrillation and
 paroxysmal supraventricular tachycardia

 -  Left ventricular ejection fraction (LVEF) < 50% as determined by a MUGA scan or
 echocardiogram

 -  CROSSOVER EXCLUSION CRITERIA: Uncontrolled hypertension, defined as persistent
 elevation of systolic blood pres