Vanderbilt Clinical Trials

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

Purpose

This is a multicenter, randomized, open-label, 3-arm Phase 3 study to evaluate encorafenib + cetuximab plus or minus binimetinib versus Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab, as controls, in patients with BRAFV600E mCRC whose disease has progressed after 1 or 2 prior regimens in the metastatic setting. The study contains a Safety Lead-in Phase in which the safety and tolerability of encorafenib + binimetinib + cetuximab will be assessed prior to the Phase 3 portion of the study.

Condition

BRAF V600E-mutant Metastatic Colorectal Cancer

Eligibility

Eligible Ages: Over 18 Years
Eligible Genders: All
Accepts Healthy Volunteers: No

Inclusion Criteria

Age ≥ 18 years at time of informed consent - Histologically- or cytologically-confirmed CRC that is metastatic - Presence of BRAFV600E in tumor tissue as previously determined by a local assay at any time prior to Screening or by the central laboratory - Progression of disease after 1 or 2 prior regimens in the metastatic setting - Evidence of measurable or evaluable non-measurable disease per RECIST, v1.1 - Adequate bone marrow, cardiac, kidney and liver function - Able to take oral medications - Female patients are either postmenopausal for at least 1 year, are surgically sterile for at least 6 weeks, or must agree to take appropriate precautions to avoid pregnancy from screening through follow-up if of childbearing potential - Males must agree to take appropriate precautions to avoid fathering a child from screening through follow-up

Exclusion Criteria

Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other epidermal growth factor receptor (EGFR) inhibitors - Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks - Symptomatic brain metastasis or leptomeningeal disease - History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes) - Known history of acute or chronic pancreatitis - History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization - Uncontrolled blood pressure despite medical treatment - Impaired 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) - 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 - 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 - Concurrent neuromuscular disorder that is associated with the potential of elevated creatine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy) - Residual common terminology criteria for adverse events (CTCAE) ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy - Known history of HIV infection - Active hepatitis B or hepatitis C infection - Known history of Gilbert's syndrome - Known contraindication to receive cetuximab or irinotecan at the planned doses

Study Design

Phase: Phase 3
Study Type: Interventional
Allocation: Randomized
Intervention Model: Sequential Assignment
Primary Purpose: Treatment
Masking: None (Open Label)

Arm Groups

Arm	Description	Assigned Intervention
Experimental Safety Lead-in, Triplet Arm	Encorafenib + binimetinib + cetuximab.	Drug: Encorafenib Orally, once daily. Drug: Binimetinib Orally, twice daily. Drug: Cetuximab Standard of care.
Experimental Doublet Arm	Encorafenib + cetuximab.	Drug: Encorafenib Orally, once daily. Drug: Cetuximab Standard of care.
Active Comparator Control Arm	Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.	Drug: Cetuximab Standard of care. Drug: Irinotecan Standard of care. Drug: Folinic Acid Standard of care. Other names: FA Drug: 5-Fluorouracil Standard of care. Other names: 5-FU

More Details

Status: Completed
Sponsor: Pfizer