Binimetinib, Encorafenib, And Cetuximab Combined to Treat BRAF-mutant ColoRectal Cancer

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2015-005805-35-HU
• Date of registration: 10/08/2016
• Prospective Registration: Yes
• Primary sponsor: Array BioPharma Inc.
• Public title: Binimetinib, Encorafenib, And Cetuximab Combined to Treat BRAF-mutant ColoRectal Cancer
• Scientific 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 - BEACON CRC (Binimetinib, Encorafenib, And Cetuximab Combined to Treat BRAF-mutant Colorectal Cancer)
• Date of first enrolment: 23/09/2016
• Target sample size: 651
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005805-35
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: yes; Placebo: no; Other: no; Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, Czech Republic, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Norway, Poland, Russian Federation, Spain, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: Ashwin Gollerkeri
• Affiliation: Array BioPharma Inc.

• Name: Ashwin Gollerkeri
• Affiliation: Array BioPharma Inc.

Key inclusion & exclusion 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, additional samples may be submitted.
d. If at any time in the Phase 3 portion of the study there is lack of BRAFV600E confirmation by the central laboratory (for any reason including discordance and inadequate available tissue) in 37 total patients or discordance (a valid result of "no BRAFV600E mutation" as determined by central laboratory) 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 (section 7.1.1)
e. Results from local laboratories with more than 1 discordant result leading to patient enrollment will not be accepted for further patient enrollment.
f. Sites with more than 2 randomized patients having indeterminate results after initiation of protocol version 6 will be required to enroll all subsequent patients based only on central laboratory assay results.
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 6 slides; optimally up to 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. Patients who have received 2 prior regimens (i.e., those entering the study in the 3rd line setting), must have received or have been offered and refused prior oxaliplatin unless it was contraindicated due to underlying conditions.
c. Maintenance therapy given in the metastatic setting will not be considered a separate regimen.
d. 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. Tr
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 = 1 week prior to the start of study treatment
7.Known history of acute or chronic pancreatitis
8.History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) =12 months prior to randomization
9.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes = 6 months prior to start of study treatment;
b. Symptomatic congestive heart failure (i.e., Grade 2
or higher), history or current evidence of clinically
significant cardiac arrhythmia and/or conduction
abnormality = 6 months prior to start of study
treatment, except atrial fibrillation and paroxysmal
supraventricular tachycardia
10.Uncontrolled hypertension defined as persistent systolic blood pressure = 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 = 5 half-lives (t1/2) or = 4 weeks (whichever is shorter) prior to starting study tr

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Cancer [C04]

BRAF V600E-mutant Metastatic Colorectal Cancer
MedDRA version: 20.0 Level: SOC Classification code 10029104 Term: Neoplasms benign, malignant and unspecified (incl cysts and polyps) System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Intervention(s)

Product Name: Encorafenib
Product Code: LGX818
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ENCORAFENIB
CAS Number: 1269440-17-6
Current Sponsor code: LGX818
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-

Product Name: Binimetinib
Product Code: MEK162
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: BINIMETINIB
CAS Number: 606143-89-9
Current Sponsor code: MEK162
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 15-

Trade Name: Erbitux
Product Name: Cetuximab
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: CETUXIMAB
CAS Number: 205923-56-4
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Trade Name: Campto
Product Name: Irinotecan
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: IRINOTECAN HYDROCHLORIDE
CAS Number: 100286-90-6
Other descriptive name: IRINOTECAN HYDROCHLORIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 20-

Trade Name: Fluorouracil
Product Name: Fluorouracil
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: FLUOROURACIL
CAS Number: 51-21-8
Other descriptive name: FLUOROURACIL
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-

Trade Name: Rescuvolin
Product Name: Calcium folinate
Pharmaceutical Form: Solution for injection
INN or Proposed INN: CALCIUM FOLINATE
CAS Number: 1492-18-8
Other descriptive name: CALCIUM FOLINATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 5-

Trade Name: Calcium Folinate
Product Name: Calcium Folinate
Product Code: V03AF03
Pharmaceutical Form: Solution for injection
INN or Proposed INN: CALCIUM FOLINATE
CAS Number: 1492-18-8
Other descriptive name: CALCIUM FOLINATE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concen

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Safety Lead-in:
The Data Monitoring Committee (DMC) will evaluate the safety data at pre-specified intervals and at additional points during the conduct of the Safety Lead-in, if necessary.
Randomized Phase III:
Interim analysis at approximately 30 months. End-of-study evaluations at approximately 48 months.

Main Objective: Safety Lead-in: Assess the safety/tolerability of the combination of encorafenib + binimetinib + cetuximab

Randomized Phase III:
- Compare the acitivity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan + cetuximab or 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab (Control Arm) as measured by overall survival (OS)
- Compare the activity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by ORR (objective response rate) per BICR (blinded independent central review)

Primary end point(s): Safety Lead-in:
- 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 III:
- OS, defined as the time from randomization to death due to any cause, of Triplet Arm vs. Control Arm
- Confirmed ORR (by BICR) per RECIST, v1.1 of Triplet Arm vs. Control Arm

Secondary Objective: Safety Lead-in:
- Assess the activity of encorafenib + binimetinib + cetuximab as measured by blinded independent central review (BICR) determined and Investigator-determined objective response rate (ORR), duration of response (DOR), progression-free survival (PFS) and time to response
- Characterize the pharmacokinetics (PK) of encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032)
Exploratory:
- Assess the activity of encorafenib + binimetinib + cetuximab as measured by overall survival (OS)
Randomized Phase III:
- Compare the activity of encorafenib + cetuximab (Doublet Arm) vs. irinotecan + cetuximab or FOLFIRI/cetuximab (Control Arm) as measured by OS
- Other Secondary as per Protocol

Secondary Outcome(s)

Secondary end point(s): Safety Lead-in:
- ORR (by BICR and Investigator) 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 (by BICR and Investigator), defined as the time from first radiographic evidence of
response to the earliest documented disease progression or
death due to underlying disease
- PFS (by BICR and Investigator), defined as the time from first dose to the earliest documented disease progression or death due to any cause
- Time to response (by BICR and Investigator), defined as the time from first dose to first
radiographic evidence of response
- 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 III:
1. Key Secondary:
- OS of Doublet Arm vs. Control Arm
2. Other Secondary:
- Confirmed ORR (by Investigator) per RECIST, v1.1 of Triplet Arm vs. Control Arm
- Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Doublet Arm vs. Control Arm
- PFS (by BICR and Investigator), 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 (by BICR and Investigator) of Doublet Arm vs. Control Arm
- OS of Triplet Arm vs. Doublet Arm
- Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Triplet Arm vs. Doublet
Arm
- PFS (by BICR and Investigator) of Triplet Arm vs. Doublet Arm
- DOR (by BICR and Investigator) of Triplet Arm vs. Control Arm, of Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm
- Time to response (by BICR and Investigator), 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 (FACT-C),
EuroQol-5D-5L (EQ-5D-5L), and Patient Global Impression of
Change (PGIC) of Triplet Arm vs. Control Arm, of Doublet
Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm
- Model-based PK parameters of encorafenib, cetuximab,
binimetinib and the active metabolite of binimetinib (AR00426032)
- Model-based PK assessment of drug-drug interactions between encorafenib, cetuximab, binimetinib and the active metabolite of binimetinib (AR00426032)
3. Exploratory:
- Changes in CEA and CA19-9
- Genomic and proteomic analysis of blood and tissue samples at baseline and at end of treatment (optional for tumor samples at end of treatment)

Timepoint(s) of evaluation of this end point: In addition to end-of-study evaluations at approximately 48 months, interim safety reviews will be performed by an independent DMC as detailed in the protocol, and an interim analysis will be performed at approximately 30 months.

Secondary ID(s)

ARRAY-818-302

2015-005805-35-GB

NCT02928224

Source(s) of Monetary Support

Merck KGaA

Pierre Fabre

Ono Pharmaceuticals Co., Ltd.

Ethics review

Status: Approved
Approval date:
Contact: