Clinical Trials /

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

NCT03981614

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Binimetinib and Palbociclib or TAS-102 in Treating Patients With KRAS and NRAS Mutant Metastatic or Unresectable Colorectal Cancer
  • Official Title: Combination of MEK Inhibitor Binimetinib and CDK4/6 Inhibitor Palbociclib in KRAS and NRAS Mutant Metastatic Colorectal Cancers

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-GI-1618
  • SECONDARY ID: NCI-2019-03480
  • SECONDARY ID: ACCRU-GI-1618
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03981614

Conditions

  • 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

Interventions

DrugSynonymsArms
BinimetinibARRY-162, ARRY-438162, MEK162, MektoviArm A (binimetinib, palbociclib)
Palbociclib6-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-0332991Arm A (binimetinib, palbociclib)
Trifluridine and Tipiracil HydrochlorideLonsurf, TAS 102, TAS-102, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102Arm B (trifluridine and tipiracil hydrochloride)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (binimetinib, palbociclib)ExperimentalPatients 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.
  • Binimetinib
  • Palbociclib
Arm B (trifluridine and tipiracil hydrochloride)ExperimentalPatients 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.
  • Trifluridine and Tipiracil Hydrochloride

Eligibility 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Overall response rate
Time Frame:Up to 24 months
Safety Issue:
Description: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.
Measure:Overall survival (OS)
Time Frame:Time from first dose of study treatment to death from any cause, assessed for up to 24 months
Safety Issue:
Description:Will use Kaplan-Meier methods to evaluate time to event endpoints, and will report median OS and its 95% confidence interval.
Measure:Incidence of adverse events
Time Frame:Up to 24 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Academic and Community Cancer Research United

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