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

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ClinicalTrials.gov Identifier: NCT03981614
Recruitment Status : Not yet recruiting
First Posted : June 11, 2019
Last Update Posted : June 11, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Academic and Community Cancer Research United

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
KRAS Gene Mutation Metastatic Colorectal Carcinoma NRAS Gene Mutation Stage III Colorectal Cancer AJCC v8 Stage IIIA Colorectal Neuroendocrine Tumor AJCC v8 Stage IIIB Colorectal Cancer AJCC v8 Stage IIIC Colorectal Cancer AJCC v8 Stage IV Colorectal Cancer AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Unresectable Carcinoma Drug: Binimetinib Drug: Palbociclib Drug: Trifluridine and Tipiracil Hydrochloride Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 112 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination of MEK Inhibitor Binimetinib and CDK4/6 Inhibitor Palbociclib in KRAS and NRAS Mutant Metastatic Colorectal Cancers
Estimated Study Start Date : June 28, 2019
Estimated Primary Completion Date : December 28, 2020
Estimated Study Completion Date : December 28, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Arm A (binimetinib, palbociclib)
Patients receive binimetinib PO BID on days 1-28 and palbociclib PO QD on days 1-21. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
Drug: Binimetinib
Given PO
Other Names:
  • ARRY-162
  • ARRY-438162
  • MEK162
  • Mektovi

Drug: Palbociclib
Given PO
Other Names:
  • 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)-8h-pyrido(2,3-d)pyrimidin-7-one
  • Ibrance
  • PD 0332991
  • PD 332991
  • PD 991
  • PD-0332991

Experimental: Arm B (trifluridine and tipiracil hydrochloride)
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.
Drug: Trifluridine and Tipiracil Hydrochloride
Given PO
Other Names:
  • Lonsurf
  • TAS 102
  • TAS-102
  • Tipiracil Hydrochloride Mixture with Trifluridine
  • Trifluridine/Tipiracil
  • Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102




Primary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: Time from randomization date to either disease progression or death from any cause, whichever occurs first, assessed for up to 24 months ]
    Disease progression will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and will be documented at each enrolling site with no central review planned. PFS will be compared between treatment arms using the stratified log rank test at one-sided level 0.05. Kaplan-Meier methodology will be used to estimate the median PFS for each treatment arm, and Kaplan-Meier curves will be produced.


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: Up to 24 months ]
    Assessment of response data will be performed on the basis of definitions of responses according to RECIST version (v)1.1. Objective response is defined as a complete or partial response by RECIST v1.1. This will be reported as a proportion with a 95% confidence interval for the true proportion.

  2. Overall survival (OS) [ Time Frame: Time from first dose of study treatment to death from any cause, assessed for up to 24 months ]
    Will use Kaplan-Meier methods to evaluate time to event endpoints, and will report median OS and its 95% confidence interval.

  3. Incidence of adverse events [ Time Frame: Up to 24 months ]
    Adverse events (AEs) will be described by grade for grade 1 and above with and without attribution considered. The maximum grade for each type of adverse event will be recorded for each patient, and described using frequency tables. The adverse events will be compared by arm to determine any differences. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03981614


Locations
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United States, Arizona
Mayo Clinic in Arizona Not yet recruiting
Scottsdale, Arizona, United States, 85259
Contact: Laurie A. Mihalik    480-342-3256    mihalik.laurie@mayo.edu   
Principal Investigator: Tanios S. Bekaii-Saab         
United States, California
City of Hope Comprehensive Cancer Center Not yet recruiting
Duarte, California, United States, 91010
Contact: Marwan G. Fakih    626-256-4673    mfakih@coh.org   
Principal Investigator: Marwan G. Fakih         
United States, Florida
Cleveland Clinic-Weston Not yet recruiting
Weston, Florida, United States, 33331
Contact: Sharon Lew       Lews2@ccf.org   
Principal Investigator: Zeina A. Nahleh         
United States, Georgia
Emory University Hospital/Winship Cancer Institute Not yet recruiting
Atlanta, Georgia, United States, 30322
Contact: Christina S. Wu    404-778-0202    christina.wu@emoryhealthcare.org   
Principal Investigator: Christina S. Wu         
United States, Kansas
University of Kansas Cancer Center Not yet recruiting
Kansas City, Kansas, United States, 66160
Contact: Amanda Ho    316-613-4326    amanda.ho@cancercenterofkansas.com   
Principal Investigator: Shaker R. Dakhil         
United States, Massachusetts
Dana-Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02215
Contact: Michele Vincitore    617-632-3125    michele_vincitore@dfci.harvard.edu   
Principal Investigator: Kimmie Ng         
United States, North Carolina
UNC Lineberger Comprehensive Cancer Center Not yet recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Catherine A. Griffin    919-962-2621    catherine_griffin@med.unc.edu   
Principal Investigator: Michael S. Lee         
United States, Texas
M D Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Contact: Scott Kopetz    507-266-0800    skopetz@mdanderson.org   
Principal Investigator: Scott Kopetz         
Sponsors and Collaborators
Academic and Community Cancer Research United
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Scott Kopetz Academic and Community Cancer Research United

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Responsible Party: Academic and Community Cancer Research United
ClinicalTrials.gov Identifier: NCT03981614     History of Changes
Other Study ID Numbers: ACCRU-GI-1618
NCI-2019-03480 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ACCRU-GI-1618 ( Other Identifier: Academic and Community Cancer Research United )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: June 11, 2019    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Carcinoma
Colorectal Neoplasms
Colonic Neoplasms
Neuroendocrine Tumors
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Palbociclib
Trifluridine
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antimetabolites
Antiviral Agents
Anti-Infective Agents