International multicenter study to test the use of 3 combined targeted therapy drugs for Colorectal cancer (encorafenib, binimetinib and cetuximab) in subjects with mutant Metastatic Colorectal Cancer

Phase 1

• Conditions: BRAF V600E -mutant Metastatic Colorectal Cancer; MedDRA version: 21.0Level: LLTClassification code 10052362Term: Metastatic colorectal cancerSystem Organ Class: 100000004864; Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2018-000271-32-AT
• Lead Sponsor: Pierre Fabre Médicament

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2018-11-28
• Last Update Posted: 19 April 2022

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 95

Inclusion Criteria

1. Provide a signed and dated informed consent form.
2. Male or female = 18 years of age at time of informed consent.
3. Histologically or cytologically confirmed CRC that is metastatic and unresectable at time of study entry (i.e. not suitable for complete surgical resection at screening).
4. Presence of BRAFV600E mutation in tumor tissue previously determined by a local assay at any time prior to screening.
Notes: a. Only PCR and NGS-based local assays results will be acceptable.
b. If at any time there is lack of confirmation of the BRAFV600E mutation in a total of 6 subjects 6% of the total targeted 90 treated subjects) or discordance between the local assay and the central laboratory in 3 subjects (= 3% of the total targeted 90 treated subjects), all subsequent subjects will be required to have BRAFV600E determined by the central lab. prior to study treatment assignment.
c. Central testing cannot be repeated to resolve discordances with a local result once the central lab. delivers a definitive result (positive or negative).
d. If the result from the central lab. is indeterminate or the sample is deemed inadequate for testing, additional samples may be submitted (archival material only).
e. If more than 1 discordant result from any local lab. lead to subject enrollment, subsequent results from this local lab. will not be accepted for further subject enrollment.
5. Eligible to receive cetuximab per locally approved label with regards to tumor RAS status
e.g.: In agreement with EU label, evidence of wild type RAS (KRAS and NRAS) status in EU countries
6. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for testing of BRAF and RAS mutation status. Note: (FFPE tumor tissue block or a minimum of 10 slides, optimally up to 15 slides)
7. Evidence of measurable disease, as per RECIST 1.1.
Note: Lesions in areas of prior radiotherapy or other loco-regional therapies are considered measurable only if progression has been documented in the region following therapy.
8. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. Adequate bone marrow function at screening and baseline:
i. Absolute neutrophil count (ANC) = 1.5 x 1 000 000 000 /L.
ii. Platelets = 100 x 1 000 000 000/L
iii. Hemoglobin = 9.0 g/dL.
Blood transfusions are allowed provided that the subject has not received more than 2 units of red blood cells in the 4 weeks prior to achieve the minimum required hemoglobin level.
10. Adequate renal function at screening and baseline:
i. Serum creatinine = 1.5x upper limit of normal (ULN).
ii. Calculated creatinine clearance (CrCl)= 50 mL/min by Cockroft-Gault formula.
11. Adequate electrolytes at screening and baseline, defined as serum potassium and magnesium levels within institutional normal limits.
Replacement treatment to achieve adequate electrolytes will be allowed
12. Adequate hepatic function at screening and baseline:
i. Serum total bilirubin = 1.5 x ULN and < 2 mg/dL.Total bilirubin > 1.5 x ULN is allowed if direct (conjugated) bilirubin is = 1.5 x ULN (and indirect (unconjugated) bilirubin is = 4.25 x ULN – Only applicable for France).
ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) = 2.5 x ULN, or = 5 x ULN in the presence of liver metastases.
13. Adequate cardiac function at screening:
i. Left ventricular ejection fraction (LVEF) = 50% as determined by MUGA scan or ECHO.
ii. Mean triplicate QT interval correcte

Exclusion Criteria

1. Prior systemic therapy for metastatic disease.
Note: previous adjuvant/neoadjuvant therapy is allowed provided that 1) the interval from the end of chemotherapy to relapse is >6 months OR 2) in the case of neoadjuvant therapy, complete surgical resection was achieved and the interval from the end of chemotherapy to relapse is >12 months. Prior locoregional radiotherapy is allowed.
2. Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab or other anti- EGFR treatment.
3. Symptomatic brain metastasis.
Note: subjects previously treated or untreated for these conditions who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for = 4 weeks with imaging
4. Leptomeningeal disease.
5. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity syndrome or hypercoagulability syndrome.
6. Use of any herbal medications/supplements or any medications or foods that are moderate or strong inhibitors or inducers of CYP3A4/5 = 1 week prior to the start of treatment.
Note: However, subjects who either discontinue moderate or strong inhibitors or inducers of CYP3A4/5 or switch to another medication at least 7 days prior to starting study treatment are eligible.
7. Known history of acute or chronic pancreatitis within 6 months prior to the start of the treatment.
8. History of chronic inflammatory bowel disease or Crohn’s disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) = 12 months prior to first dose.
9. Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
i. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) = 6 months prior to start of study treatment.
ii. Symptomatic congestive heart failure (Grade 2 or higher), history or current evidence of clinically significant 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 elevation of systolic blood pressure = 150 mmHg or diastolic blood pressure = 100 mmHg despite optimal therapy.
11. Impaired hepatic function, defined as Child-Pugh class B or C.
12. No more applicable from protocol V6
13. Impaired gastrointestinal function or disease which may significantly alter the absorption of encorafenib or binimetinib or recent changes in bowel function suggesting current or impending bowel obstruction.
14. Previous or concurrent malignancy within 5 years of study entry or other noninvasive or indolent malignancy without Sponsor approval except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix.
15. 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.
16. Concurrent neuromuscular disorder that is associated with the potential of elevated Creatine Kinase e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy.
17. Residual CTCAE = Grade 2 toxicity from any prior anticanc

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified