| Eligibility |
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 =< 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 (B-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 fluoropyrimidine, oxaliplatin,
and irinotecan based chemotherapy, and an anti-VEGF biological therapy
- 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) in the opinion of the investigator
- 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 in the opinion of the investigator
- 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 pressure >= 150 mmHg or diastolic blood pressure >= 100
mmHg despite current therapy
- CROSSOVER EXCLUSION CRITERIA: History of thromboembolic or cerebrovascular events =<
12 weeks prior re-registration. Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (i.e. massive or sub-massive)
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 relat
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