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

Phase I/II Trial of Encorafenib, Binimetinib, and Nivolumab in Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer

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.

Study Overview

• Status: Terminated
• Conditions: Stage IIIA Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer; Metastatic Colorectal Adenocarcinoma; Metastatic Colon Adenocarcinoma; Metastatic Rectal Adenocarcinoma; Stage IIIA Colon Cancer; Stage IIIB Colon Cancer; Stage IIIC Colon Cancer; Stage IV Colon Cancer; Stage IV Rectal Cancer; Stage IV Colorectal Cancer; Stage IVA Colorectal Cancer; Stage IVB Colorectal Cancer; Stage III Colon Cancer; Stage III Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer; Metastatic Microsatellite Stable Colorectal Carcinoma; Stage III Colorectal Cancer; Stage IIIA Colorectal Cancer; Stage IIIB Colorectal Cancer; Stage IIIC Colorectal Cancer; Stage IVC Colon Cancer; Stage IVC Colorectal Cancer; Stage IVC Rectal Cancer
• Intervention / Treatment: Biological: Nivolumab; Other: Questionnaire Administration; Drug: Binimetinib; Drug: Encorafenib

Detailed Description

This was intended to be a phase I/II study of Encorafenib, Binimetinib, and Nivolumab for treating participants with Microsatellite Stable BRAF V600E Metastatic Colorectal Cancer. The study was terminated before Phase II was initiated. The study did not open Phase II for enrollment.

PRIMARY OBJECTIVES:

I. To describe overall response rate (ORR) upon treatment with encorafenib, binimetinib, and nivolumab in patients with BRAFV600E, microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

II. To determine the safety and tolerability of nivolumab, encorafenib, and binimetinib in patients with BRAFV600E, MSS mCRC.

SECONDARY OBJECTIVES:

I. To estimate median progression-free survival (PFS) upon treatment with encorafenib, binimetinib, and nivolumab.

II. To estimate median overall survival (OS) upon treatment with encorafenib, binimetinib, and nivolumab.

III. To estimate median time to response (TTR) upon treatment with encorafenib, binimetinib, and nivolumab.

IV. To estimate median duration of response (DoR) upon treatment with encorafenib, binimetinib, and nivolumab.

V. To estimate disease control rate (DCR) upon treatment with encorafenib, binimetinib, and nivolumab.

EXPLORATORY (CORRELATIVE) OBJECTIVES:

I. To assess genomic and immune changes upon treatment with encorafenib, binimetinib, and nivolumab in tumor tissue, blood and stool.

II. To correlate genomic and immune changes upon treatment with encorafenib, binimetinib, and nivolumab in tumor tissue, blood and stool with radiographic response.

III. To evaluate contrast-enhanced computed tomography (CT) imaging for disease burden that is not measurable by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) and to correlate location and patterns of metastatic disease with clinical outcomes.

OUTLINE:

Participants in received encorafenib orally (PO) once daily (QD) on days 1-28, binimetinib PO twice daily (BID) on days 1-28, and nivolumab intravenously (IV) on day 1. Cycles repeat every 28 days for a maximum of 24 cycles of treatment. If disease progression or recurrence occurs, treatment may be resumed outside of the context of the clinical trial.

After completion of study treatment, patients are followed up at 30 and 100 days, then every 3 months thereafter.

Only participants in Phase 1 were enrolled.

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94115
      • Kaiser Permanente Northern California
    • San Francisco, California, United States, 94115
      • Univeristy of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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

  • Female participants of childbearing potential (WOCBP) must agree to use adequate contraception: *see list below this paragraph* for the duration of study participation and for 5 months (i.e., 30 days [duration of ovulatory cycle] plus the time required for the investigational drug to undergo approximately five half-lives) after last administration of study treatment. Only for all females of childbearing potential, the pregnancy test result must be negative within 24 hours of starting treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception *see list below this paragraph* for the duration of study treatment with nivolumab and 7 months after the last dose of study treatment (i.e., 90 days [duration of sperm turnover] plus the time required for the investigational drug to undergo approximately five half-lives.)

  • Accepted means of contraception:

    • Complete abstinence from sexual intercourse when this is in line with the preferred and usual lifestyle of the patient
    • Double barrier methods
    • Condom with spermicide in conjunction with use of an intrauterine device
    • Condom with spermicide in conjunction with use of a diaphragm
    • Birth control patch or vaginal ring
    • Oral, injectable, or implanted contraceptives
    • Due to the potential of encorafenib to induce CYP3A4, hormonal agents (including but not limited to birth control patch, vaginal ring, oral, injectable, or implanted contraceptives) are permissible only when combined with other highly effective or acceptable methods
    • Surgical sterilization (bilateral oophorectomy with or without hysterectomy, tubal ligation or vasectomy) at least 6 weeks prior to taking study treatment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up levels of luteinizing hormone, follicle-stimulating hormone, and/or estradiol
  • Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 100 days after last administration of study treatment
• Able to take oral medications

Exclusion Criteria:

• 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
  • 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 screening (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia)
  • Left ventricular ejection fraction (LVEF) < 50% as determined by multi-gated acquisition (MUGA) or echocardiogram (ECHO)
• Uncontrolled hypertension defined as persistent elevation of systolic blood pressure >= 160 mmHg or diastolic blood pressure >= 100 mm Hg, despite current therapy
• Known positive serology for HIV (human immunodeficiency virus), active hepatitis B, and/or active hepatitis C infection
• Known history of acute or chronic pancreatitis (history of acute pancreatitis with no recurrent events in the prior 24 months are permitted)
• Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn?s disease, are excluded from this study, as are patients with a history of symptomatic autoimmune disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener?s granulomatosis]); central nervous system (CNS) or motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and myasthenia gravis, multiple sclerosis). Patients with Graves? disease will be allowed
• Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
• Concurrent neuromuscular disorder that is associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease

• History of thromboembolic or cerebrovascular events =< 12 weeks prior to the first dose of study treatment. 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 related to indwelling catheters or other procedures may be enrolled
• Any other condition that would, in the investigator?s judgment, contraindicate the patient?s participation in the clinical study due to safety concerns or compliance with clinical study procedures
• Major surgery =< 6 weeks prior to starting study drug or failure to recover from side effects of such procedure at the discretion of the treating investigator
• Pregnant or nursing (lactating) females, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test
• Prisoners or persons who are involuntarily incarcerated
• Medical, psychiatric, cognitive or other conditions that may compromise the patient's ability to understand the patient information, give informed consent, comply with the study protocol or complete the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (encorafenib, binimetinib, nivolumab); 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.

Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Other: Questionnaire Administration; Ancillary studies; Drug: Binimetinib; Given PO; Other Names: ARRY-162; ARRY-438162; MEK162; Mektovi; Drug: Encorafenib; Given PO; Other Names: Braftovi; LGX 818; LGX-818; LGX818

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Will be defined by irRECIST criteria for the evaluable population. Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from start of treatment until death or PD	Up to 3 years
Overall survival	Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from start of treatment until death occurs	Up to 3 years
Time (in days) to response criteria	Will be defined by irRECIST criteria. Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from start of treatment until time of response.	Up to 3 years
Duration of response	Will be estimated by Kaplan-Meier method and summarized with Kaplan-Meier curves and log rank test from first partial or CR to time of PD or death for subjects with a response	Up to 3 years
Disease control rate (DCR)	The proportion of patients with CR, PR, or SD defined by irRECIST criteria in the evaluable population. The point estimate of DCR and its 95% confidence interval will be obtained.	Up to 3 years

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Bristol-Myers Squibb; Pfizer
• Investigators: Principal Investigator: Chloe E Atreya, MD, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): August 31, 2020
• Primary Completion (Actual): July 31, 2022
• Study Completion (Actual): July 31, 2022

Study Registration Dates

• First Submitted: August 1, 2019
• First Submitted That Met QC Criteria: August 1, 2019
• First Posted (Actual): August 5, 2019

Study Record Updates

• Last Update Posted (Estimate): January 9, 2023
• Last Update Submitted That Met QC Criteria: January 5, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Colon Cancer; BRAF V600E; Metastatic Colorectal Cancer (mCRC); Microsatellite Status (MSS)
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Adenocarcinoma; Rectal Neoplasms; Colonic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 19457; NCI-2019-04601 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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