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

• Drug: Encorafenib
  Orally, once daily.
• Drug: Binimetinib
  Orally, twice daily.
• Drug: Cetuximab
  Standard of care.
• Drug: Irinotecan
  Standard of care.
• Drug: Folinic Acid
  Standard of care.
  Other Name: FA
• Drug: 5-Fluorouracil
  Standard of care.
  Other Name: 5-FU

• Experimental: Safety Lead-in, Triplet Arm
  Encorafenib + binimetinib + cetuximab.
  Interventions:

  • Drug: Encorafenib
  • Drug: Binimetinib
  • Drug: Cetuximab
• Experimental: Doublet Arm
  Encorafenib + cetuximab.
  Interventions:

  • Drug: Encorafenib
  • Drug: Cetuximab
• Active Comparator: Control Arm
  Investigator's choice of either irinotecan/cetuximab or FOLFIRI/cetuximab.
  Interventions:

  • Drug: Cetuximab
  • Drug: Irinotecan
  • Drug: Folinic Acid
  • Drug: 5-Fluorouracil

• Kopetz S, Grothey A, Yaeger R, Van Cutsem E, Desai J, Yoshino T, Wasan H, Ciardiello F, Loupakis F, Hong YS, Steeghs N, Guren TK, Arkenau HT, Garcia-Alfonso P, Pfeiffer P, Orlov S, Lonardi S, Elez E, Kim TW, Schellens JHM, Guo C, Krishnan A, Dekervel J, Morris V, Calvo Ferrandiz A, Tarpgaard LS, Braun M, Gollerkeri A, Keir C, Maharry K, Pickard M, Christy-Bittel J, Anderson L, Sandor V, Tabernero J. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer. N Engl J Med. 2019 Oct 24;381(17):1632-1643. doi: 10.1056/NEJMoa1908075. Epub 2019 Sep 30.
• Van Cutsem E, Huijberts S, Grothey A, Yaeger R, Cuyle PJ, Elez E, Fakih M, Montagut C, Peeters M, Yoshino T, Wasan H, Desai J, Ciardiello F, Gollerkeri A, Christy-Bittel J, Maharry K, Sandor V, Schellens JHM, Kopetz S, Tabernero J. Binimetinib, Encorafenib, and Cetuximab Triplet Therapy for Patients With BRAF V600E-Mutant Metastatic Colorectal Cancer: Safety Lead-In Results From the Phase III BEACON Colorectal Cancer Study. J Clin Oncol. 2019 Jun 10;37(17):1460-1469. doi: 10.1200/JCO.18.02459. Epub 2019 Mar 20.

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

• Merck KGaA, Darmstadt, Germany
• Pierre Fabre Medicament
• Ono Pharmaceutical Co. Ltd