A Multicenter, Randomized, Open-label, 3-Arm Phase 3 Study of Encorafenib + Cetuximab Plus or Minus Binimetinib vs. Irinotecan/Cetuximab or Infusional 5-Fluorouracil (5-FU)/Folinic Acid (FA) /Irinotecan (FOLFIRI)/Cetuximab with a Safety Lead-in of Encorafenib + Binimetinib + Cetuximab in Patients with BRAF V600E mutant Metastatic Colorectal Cancer

Phase 3

Completed

• Conditions: bowel cancer; Colorectal cancer; 10017991

• Registration Number: NL-OMON47693
• Lead Sponsor: Array BioPharma Inc.

Brief Summary

Trial is onging in other countries

Detailed Description

Not available

Study Timeline

• Study Completion: 2022-10-14
• Results First Posted: 2023-04-15
• Last Update Posted: 23 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 58

Inclusion Criteria

1. Provide a signed and dated informed consent document.;2. Age >= 18 years at time of informed consent.;3. Histologically or cytologically confirmed CRC that is metastatic.;4. Presence of BRAFV600E in tumor tissue previously determined by a local assay at any time prior to Screening or by the central laboratory;Notes:;a. Only PCR and NGS-based local assays results will be;acceptable.;b. Central testing cannot be repeated to resolve discordances with a local result once the central laboratory delivers a definitive result (positive or negative).;c. If the result from the central laboratory is indeterminate or the sample is deemed is inadequate for testing, a second sample may be submitted.;d. If at any time there is discordance in the results between the local assay and the central laboratory (potential false-positive local result), or lack of BRAFV600E confirmation in 18 patients, all subsequent patients will be required to have BRAFV600E determined by the central laboratory prior to enrollment;e. Results from local laboratories with more than 1 discordant result leading to patient enrollment will not be accepted for further patient enrollment.;5. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for confirmatory central laboratory testing of BRAF and KRAS mutation status (minimum of 15 slides);Note: Tumor samples must be submitted to the central laboratory for BRAF testing as soon as possible following the signing of the Molecular Prescreening informed consent. The BRAF status must be confirmed no later than 30 days following first dose of study drug.;6. Eligible to receive cetuximab per locally approved label with regard to tumor RAS status;7. Progression of disease after 1 or 2 prior regimens in the metastatic setting;Notes:;a. Disease relapse during treatment or within 6 months;following adjuvant therapy will be considered metastatic disease.;b. Maintenance therapy given in the metastatic setting will not be considered a separate regimen.;c. In the Phase 3 portion of study, the number of patients having received 2 prior regimens will be limited to 215 (35% of the total randomized). Patients with 2 prior regimens who have entered Screening at the time that the limit has been reached will be permitted to continue into the study if they are otherwise determined to be eligible.;8. Evidence of measurable or evaluable non measurable disease per RECIST, v1.1;9. ECOG PS of 0 or 1;10. Adequate bone marrow function characterized by the following at screening:;a. Absolute neutrophil count (ANC) >= 1.5 × 109/L;;b. Platelets >= 100 × 109/L;;c. Hemoglobin >= 9.0 g/dL;Note: Transfusions will be allowed to achieve this. Transfusions will be permitted provided the patient has not received more than 2 units red blood cells in the prior 4 weeks to achieve this criteria.;11. Adequate renal function characterized by serum creatinine <= 1.5 × upper limit of normal (ULN), or calculated by Cockroft-Gault formula or directly measured creatinine clearance >= 50 mL/min at screening;12.Adequate electrolytes at baseline, defined as serum potassium and magnesium levels within institutional normal limits;13. Adequate hepatic function characterized by the following at screening:;a. Serum total bilirubin <= 1.5 × ULN and < 2 mg/dL;Note: Patients who have a total bilirubin level > 1.5 × ULN will be allowed if their indirect bilirubin level is <= 1.5 × ULN;b. Alanine aminotransferase (ALT

Exclusion Criteria

1.Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors;2.Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks;3.Symptomatic brain metastasis;Notes: 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 computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening.;4.Leptomeningeal disease;5.History or current evidence of RVO or current risk factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes);6.Use of any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 <= 1 week prior to the start of study treatment;7.Known history of acute or chronic pancreatitis;8.History of chronic inflammatory bowel disease or Crohn*s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) <=12 months prior to randomization;9.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:;a. History of acute myocardial infarction, acute;coronary syndromes (including unstable angina,;coronary artery bypass graft [CABG], coronary angioplasty or stenting) <= 6 months prior to start of;study treatment;;b. Symptomatic congestive 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 start of study;treatment, except atrial fibrillation and paroxysmal;supraventricular tachycardia;10. Uncontrolled hypertension defined as persistent systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite current therapy;11.Impaired hepatic function, defined as Child-Pugh class B or C;12.Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption);13.Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy without Sponsor approval;14.History of thromboembolic or cerebrovascular events <= 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli;15.Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);16.Treatment with any of the following:;a. Cyclical chemotherapy within a period of time that was shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment;b. Biologic therapy (e.g., antibodies) except bevacizumab or aflibercept, continuous or intermittent small molecule therapeutics, or any other investigational agents within a period of time that is

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Safety Lead-in<br /><br>Primary:<br /><br>• Incidence of dose-limiting toxicities (DLTs)<br /><br>• Incidence and severity of adverse events (AEs) graded according to the<br /><br>National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events<br /><br>(CTCAE), version 4.03 (v.4.03), and changes in clinical laboratory parameters,<br /><br>vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated<br /><br>acquisition (MUGA) scans and ophthalmic examinations<br /><br>• Incidence of dose interruptions, dose modifications and discontinuations due<br /><br>to AEs<br /><br><br /><br>Randomized Phase 3<br /><br>Primary:<br /><br>• OS, defined as the time from randomization to death due to any cause, of<br /><br>Triplet Arm vs. Control Arm</p><br>