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
Condition: BRAF V600E-mutant Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Encorafenib; Binimetinib; Cetuximab; Irinotecan; Folinic Acid; 5-Fluorouracil
Intervention description: Orally, once daily.; Orally, twice daily.; Standard of care.; Standard of care.; Standard of care.; Standard of care.
Intervention MeSH terms: Leucovorin; Folic Acid; Fluorouracil; Irinotecan; Cetuximab; Levoleucovorin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 702.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Colorectal cancer; BRAF; BRAFV600E

Summary:

      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.
    

Eligibility criteria:

        Key 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

        Key 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