bowel cancer Colorectal cancer
Conditions
Interventions
The investigational products in this study are encorafenib and binimetinib,
which will be administered orally (PO) in combination with cetuximab (i.e.,
encorafenib + binimetinib + cetuximab [Safety
Sponsors
Array BioPharma Inc.
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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 = 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
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 = 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety Lead-in Primary: • Incidence of dose-limiting toxicities (DLTs) • Incidence and severity of adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (v.4.03), and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations • Incidence of dose interruptions, dose modifications and discontinuations due to AEs Randomized Phase 3 Primary: • OS, defined as the time from randomization to death due to any cause, of Triplet Arm vs. Control Arm | — |
Secondary
| Measure | Time frame |
|---|---|
| Safety Lead-in Secondary: • ORR per the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (v1.1), defined as the number of patients achieving an overall best response of complete response (CR) or partial response (PR) divided by the total number of patients • DOR, defined as the time from first radiographic evidence of response to the earliest documented disease progression or death due to underlying disease • Time to response, defined as the time from first dose to first radiographic evidence of response • Plasma PK parameters of encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032) Exploratory • OS, defined as the time from first dose to death due to any cause Randomized Phase 3 Key Secondary: • OS of Doublet Arm vs. Control Arm Other Secondary: • Confirmed ORR per RECIST, v1.1 of Triplet Arm vs. Control Arm • Confirmed ORR per RECIST, v1.1 of Doublet Arm vs. Control Arm • PFS, defined as the time from randomization to the earliest documented disease progression or death due to any cause, of Triplet Arm vs. Control Arm • PFS of Doublet Arm vs. Control Arm • OS of Triplet Arm vs. Doublet Arm • Confirmed ORR per RECIST, v1.1 of Triplet Arm vs. Doublet Arm • PFS of Triplet Arm vs. Doublet Arm • DOR of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm • Time to response, defined as the time from randomization to first radiographic evidence of response, of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm • Incidence and severity of AEs, graded according to NCI CTCAE, v 4.03, and changes in clinical laboratory parameters, vital signs, ECGs, ECHO/MUGA scans and ophthalmic examinations • Change from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer Patients (QLQ-C30), Functional Assessment of Cancer Therapy-Colon Cancer (F | — |
Countries
Netherlands
Outcome results
None listed