Encorafenib, Binimetinib, and Nivolumab in Treating Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer

NCT04044430 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: 19457NCI-2019-04601
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 2

Brief Summary

This phase I/II trial studies the side effects and how well encorafenib, binimetinib, and nivolumab work in treating patients with microsatellite stable, BRAFV600E gene-mutated colorectal cancer that has spread to other places in the body (metastatic). Encorafenib and binimetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving encorafenib, binimetinib, and nivolumab may work better in treating patients with colorectal cancer compared to standard treatments.

Conditions

Metastatic Colon Adenocarcinoma; Metastatic Colorectal Adenocarcinoma; Metastatic Microsatellite Stable Colorectal Carcinoma; Metastatic Rectal Adenocarcinoma; Stage III Colon Cancer; Stage III Colorectal Cancer; Stage III Rectal Cancer; Stage IIIA Colon Cancer; Stage IIIA Colorectal Cancer; Stage IIIA Rectal Cancer; Stage IIIB Colon Cancer; Stage IIIB Colorectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Colon Cancer; Stage IIIC Colorectal Cancer; Stage IIIC Rectal Cancer; Stage IV Colon Cancer; Stage IV Colorectal Cancer; Stage IV Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Colorectal Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Colorectal Cancer; Stage IVB Rectal Cancer; Stage IVC Colon Cancer; Stage IVC Colorectal Cancer; Stage IVC Rectal Cancer

Keywords

BRAF V600E; Metastatic Colorectal Cancer (mCRC); Microsatellite Status (MSS); Colon Cancer

Outcome Measures

Primary Outcomes (3)

• Radiographic Response

  Will be measured according to immune-related Response Evaluation Criteria in Solid Tumors (irRECIST). The point estimate of the objective response rate (ORR) and its 95% confidence interval will be obtained.

  Up to 3 years

• Best investigator-assessed response

  Will be assessed in the following order of importance: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and not evaluable. The point estimate of the ORR and its 95% confidence interval will be obtained

  Up to 3 years

• Incidence of treatment-related grade 3 or higher adverse events (AEs)

  Will be graded according to the Common Terminology Criteria for Adverse Events version 5.0. Safety data will be tabulated.

  100 days after last dose

Secondary Outcomes (5)

• Progression-free survival

  Up to 3 years

• Overall survival

  Up to 3 years

• Time (in days) to response criteria

  Up to 3 years

• Duration of response

  Up to 3 years

• Disease control rate (DCR)

  Up to 3 years

Study Arms (1)

Treatment (encorafenib, binimetinib, nivolumab)

EXPERIMENTAL

Participants in Phase 1 receive encorafenib PO QD on days 1-28, binimetinib PO BID on days 1-28, and nivolumab IV on day 1. Cycles repeat every 28 days for a maximum of 24 cycles of treatment in the absence of disease progression or unacceptable toxicity. The study was terminated before Phase II was initiated. The study did not open Phase II for enrollment.

Drug: Binimetinib; Drug: Encorafenib; Biological: Nivolumab; Other: Questionnaire Administration

Interventions

Binimetinib DRUG

Given PO

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

Treatment (encorafenib, binimetinib, nivolumab)

Encorafenib DRUG

Given PO

Also known as: Braftovi, LGX 818, LGX-818, LGX818

Treatment (encorafenib, binimetinib, nivolumab)

Nivolumab BIOLOGICAL

Given IV

Also known as: BMS-936558, MDX-1106, NIVO, ONO-4538, Opdivo

Treatment (encorafenib, binimetinib, nivolumab)

Questionnaire Administration OTHER

Ancillary studies

Treatment (encorafenib, binimetinib, nivolumab)

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically or cytologically confirmed diagnosis of adenocarcinoma of the colon or rectum, with clinical confirmation of unresectable and/or metastatic disease that is measurable according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria
• Confirmation of BRAFV600E tumor as detected from testing performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory
• Confirmation of MSS status from testing performed in a CLIA-certified laboratory
• Prior treatment with at least one systemic chemotherapy regimen for mCRC, or recurrence/progression with development of unresectable or metastatic disease within 6 months of adjuvant chemotherapy for resected CRC
• Eastern Cooperative Oncology Group performance status (ECOG PS) =\< 1 (Karnofsky \>= 70%)
• Absolute neutrophil count (ANC) \>= 1.0 x 10\^9/L
• Hemoglobin (Hgb) \>= 9 g/dL with or without transfusions
• Platelets (PLT) \>= 100 x 10\^9/L without transfusions
• Total bilirubin =\< 1.5 x upper limit of normal (ULN) and \< 2 mg/dL
• Note: Patients who have a total bilirubin level \> 1.5 x ULN and/or have Gilbert's disease will be allowed if their direct bilirubin level is =\< 0.5 mg/dl or ULN, whichever is higher.
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =\< 3 x ULN
• Serum creatinine =\< 1.5 x ULN, or calculated creatinine clearance (determined as per Cockcroft-Gault) \>= 50 mL/min at screening
• Corrected QT (QTc) interval =\< 480 ms (preferably the mean from triplicate electrocardiograms \[ECGs\])
• Ability to understand a written informed consent document, and the willingness to sign it
• The effects of the study drugs on the developing human fetus are unknown. Female patients must either be postmenopausal for at least 1 year, surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through 5 months after discontinuation of study treatment if of childbearing potential

You may not qualify if:

• Concurrent corticosteroid therapy or concurrent use of any other immunosuppressive medication (corticosteroid use on study as a pre-medication for IV contrast allergies/reactions is allowed). Subjects who are receiving daily steroid replacement therapy (the equivalent of prednisone =\< 10 mg daily) serve as an exception to this rule
• Prior immune checkpoint therapy including, but not limited to, an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody, or any other prior immunotherapy agent administered with antineoplastic intent
• Prior B-raf (BRAF)- or mitogen-activated extracellular kinase (MEK)-targeted therapy
• Known hypersensitivity or contraindication to any component of binimetinib or encorafenib or their excipients
• Prior allogeneic tissue/solid organ transplant
• Interstitial lung disease (ILD) or history of pneumonitis that has required oral or IV steroids
• Receipt of a live vaccine within 30 days prior to the first administration of study medication. Seasonal flu vaccines that do not contain a live virus are permitted
• History of a grade 3 or 4 allergic reaction attributed to humanized or human monoclonal antibody therapy
• Active infection requiring concurrent antibiotic use
• 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., magnetic resonance imaging \[MRI\] or computerized tomography \[CT\]) demonstrating no current evidence of progressive brain metastases at screening
• Leptomeningeal disease
• Previous or concurrent malignancy within 3 years of study entry, with the following exceptions: adequately treated basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy; other solid tumors treated curatively without evidence of recurrence for at least 3 years prior to study entry
• Impaired cardiovascular function or clinically significant cardiovascular 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 screening

Sponsors & Collaborators

• University of California, San Francisco: lead
• Pfizer: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (2)

Kaiser Permanente Northern California

San Francisco, California, 94115, United States

Location

Univeristy of California, San Francisco

San Francisco, California, 94115, United States

Location

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms; Colorectal Neoplasms

Interventions

binimetinib; encorafenib; Nivolumab

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)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Chloe E Atreya, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 1, 2019
• First Posted: August 5, 2019
• Study Start: August 31, 2020
• Primary Completion: July 31, 2022
• Study Completion: July 31, 2022
• Last Updated: January 9, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)