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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 (BEACON CRC)

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ClinicalTrials.gov Identifier: NCT02928224
Recruitment Status : Active, not recruiting
First Posted : October 10, 2016
Last Update Posted : June 21, 2019
Sponsor:
Collaborators:
Merck KGaA, Darmstadt, Germany
Pierre Fabre Medicament
Ono Pharmaceutical Co. Ltd
Information provided by (Responsible Party):
Array BioPharma

Study Description
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Brief 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.

Condition or disease Intervention/treatment Phase
BRAF V600E-mutant Metastatic Colorectal Cancer Drug: Encorafenib Drug: Binimetinib Drug: Cetuximab Drug: Irinotecan Drug: Folinic Acid Drug: 5-Fluorouracil Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 645 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : October 2016
Actual Primary Completion Date : February 2019
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
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 Name: FA

Drug: 5-Fluorouracil
Standard of care.
Other Name: 5-FU


Outcome Measures
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Primary Outcome Measures :
  1. (Safety Lead-in) Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Cycle 1 (up to 28 days) ]
  2. (Safety Lead-in) Incidence and severity of adverse events (AEs) and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
  3. (Safety Lead-in) Incidence of dose interruptions, dose modifications and discontinuations due to adverse events (AEs) [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
  4. (Phase 3) Overall Survival (OS) of Triplet Arm vs. Control Arm [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  5. (Phase 3) Response Rate (ORR) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST), v1.1 of Triplet Arm vs. Control Arm [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]

Secondary Outcome Measures :
  1. (Safety Lead-in) Response Rate (ORR) [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
  2. (Safety Lead-in) Duration of Response (DOR) [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
  3. (Safety Lead-in) Time to Response [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
  4. (Safety Lead-in) Progression-free Survival (PFS) [ Time Frame: Duration of safety lead-in, approximately 6 months (up to 28 days per cycle) ]
  5. (Phase 3) Overall Survival (OS) in Doublet Arm vs. Control Arm and Triplet Arm vs. Doublet Arm [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  6. (Phase 3) Comparison of Progression-free Survival (PFS) in study arms [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  7. (Phase 3) Comparison of Objective Response Rate (ORR) in study arms [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  8. (Phase 3) Comparison of Duration of Response (DOR) in study arms [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  9. (Phase 3) Comparison of Time to Response in study arms [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  10. (Phase 3) Incidence and severity of adverse events (AEs) and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  11. (Phase 3) Comparison of the Quality of Life in study arms [ Time Frame: Duration of Phase 3, approximately 6 months (up to 28 days per cycle) ]
  12. (Safety Lead-in) Evaluation of the area under the concentration-time curve (AUC) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 ]
  13. (Safety Lead-in) Evaluation of the maximum concentration (Cmax) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 ]
  14. (Safety Lead-in) Evaluation of the time of maximum observed concentration (Tmax) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 ]
  15. (Safety Lead-in) Evaluation of the steady-state concentration measured just before the next dose of study drug (Ctrough) for cetuximab, encorafenib, binimetinib, and a metabolite of binimetinib [ Time Frame: Predose and 1, 2, 4 and 6 hours post-dose on Day 1 of Cycles 1 and 2 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
  • Residual 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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02928224


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Sponsors and Collaborators
Array BioPharma
Merck KGaA, Darmstadt, Germany
Pierre Fabre Medicament
Ono Pharmaceutical Co. Ltd
Investigators
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Study Director: Array BioPharma, Inc. 303-381-6604
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Array BioPharma
ClinicalTrials.gov Identifier: NCT02928224     History of Changes
Other Study ID Numbers: ARRAY-818-302
2015-005805-35 ( EudraCT Number )
First Posted: October 10, 2016    Key Record Dates
Last Update Posted: June 21, 2019
Last Verified: June 2019
Keywords provided by Array BioPharma:
Colorectal cancer
BRAF
BRAFV600E
Additional relevant MeSH terms:
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Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Colonic Diseases
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Rectal Diseases
Leucovorin
Folic Acid
Irinotecan
Fluorouracil
 Cetuximab
Levoleucovorin
Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antimetabolites
Antimetabolites, Antineoplastic
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antidotes
Protective Agents