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

NCT03981614 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: ACCRU-GI-1618NCI-2019-03480P30CA015083
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 7

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 (metastatic) or cannot be removed by surgery (unresectable). 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.

Conditions

Metastatic Colorectal Carcinoma; 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

Outcome Measures

Primary Outcomes (1)

• Progression Free Survival (PFS)

  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.

  Time from randomization date to either disease progression or death from any cause, whichever occurs first, assessed for up to 16 months

Secondary Outcomes (3)

• Overall Response Rate

  Up to 16 months

• Overall Survival (OS)

  Time from first dose of study treatment to death from any cause, assessed for up to 24 months

• Number of Participants With Adverse Events

  Up to 24 months

Study Arms (2)

Arm A (binimetinib, palbociclib)

EXPERIMENTAL

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; Drug: Palbociclib

Arm B (trifluridine and tipiracil hydrochloride)

EXPERIMENTAL

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

Interventions

Binimetinib DRUG

Given PO

Also known as: ARRY-162, ARRY-438162, MEK162, Mektovi

Arm A (binimetinib, palbociclib)

Palbociclib DRUG

Given PO

Also known as: 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

Arm A (binimetinib, palbociclib)

Trifluridine and Tipiracil Hydrochloride DRUG

Given PO

Also known as: Lonsurf, TAS 102, TAS-102, Tipiracil Hydrochloride Mixture with Trifluridine, Trifluridine/Tipiracil, Trifluridine/Tipiracil Hydrochloride Combination Agent TAS-102

Arm B (trifluridine and tipiracil hydrochloride)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Academic and Community Cancer Research United: lead
• National Cancer Institute (NCI): collaborator

Study Sites (7)

Mayo Clinic in Arizona

Scottsdale, Arizona, 85259, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Cancer Center of Kansas - Wichita

Wichita, Kansas, 67214, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, 37232, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

binimetinib; palbociclib; Trifluridine; trifluridine tipiracil drug combination

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Thymidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Scott Kopetz, M.D.
• Organization: University of Texas; MD Anderson Cancer Center

SKopetz@mdanderson.org

(507) 266-0800

Study Officials

• Scott Kopetz

  Academic and Community Cancer Research United

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 7, 2019
• First Posted: June 11, 2019
• Study Start: October 29, 2019
• Primary Completion: August 23, 2021
• Study Completion: July 2, 2024
• Last Updated: August 22, 2024
• Results First Posted: December 29, 2022

Record last verified: 2024-07

Locations

US (7)