BRAF V600E -mutant Metastatic Colorectal Cancer MedDRA version: 20.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Interventions
Product Name: encorafenib
Product Code: W0090
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ENCORAFENIB
CAS Number: 1269440-17-6
Current Sponsor code: W0090
Concentration unit: mg milligram(
Sponsors
Pierre Fabre Médicament
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provide a signed and dated screening informed consent document. 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 discordance in the results between the local assay and the central laboratory (potential false-positive local result), or lack of BRAFV600E confirmation in 3 subjects, all subsequent subjects will be required to have BRAFV600E determined by the central laboratory prior to enrollment in the study. c. Central testing cannot be repeated to resolve discordances with a local result once the central laboratory delivers a definitive result (positive or negative). d. If the result from the central laboratory is indeterminate or the sample is deemed inadequate for testing, additional samples may be submitted. e. If more than 1 discordant result from any local laboratory lead to subject enrollment, subsequent results from this local laboratory will not be accepted for further subject enrollment. 5. Eligible to receive cetuximab per locally approved label with regards to tumor RAS status 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(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. Note: 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. iii. Directly measured CrCl = 50 mL/min. 11. Adequate electrolytes at screening and baseline, defined as serum potassium and magnesium levels within institutional normal limits. Note: 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 1.5 x ULN is allowed if indirect bilirubin is = 1.5 x ULN. 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 corrected for heart rate according to Fridericia’s formula (QTcF) value = 480 msec. 14. Subject able to take oral medications. 15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and
Exclusion criteria
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 for fluoropyrimidine alone or >12 months for oxaliplatin-based therapy 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 strong inhibitors or inducers of CYP3A4/5 = 1 week prior to the start of treatment. Note: However, subjects who either discontinue 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. Known history of Gilbert's syndrome or is known to have any of the following genotypes: UDP-glucoronosyl transferase (UGT)1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28. 13. Impaired gastrointestinal function or disease which may significantly alter the absorption of encorafenib or binimetinib e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection. 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 poten
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the antitumor activity of the combination of encorafenib, binimetinib and cetuximab by assessing the confirmed overall response rate (cORR) by local radiologist/investigator assessment in adult subjects with previously untreated BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC).;Secondary Objective: - To evaluate the cORR by central radiologist assessment. - To evaluate the unconfirmed ORR by local and central radiologist/investigator assessment. - To assess the effect of the combination of encorafenib, binimetinib and cetuximab on the duration of response (DOR). - To assess the effect of the combination of encorafenib, binimetinib and cetuximab on other time-related efficacy parameters: time to response (TTR), progression-free survival (PFS) and overall survival (OS). - To characterize the safety and tolerability of the combination of encorafenib, binimetinib and cetuximab. - To assess the effect on quality of life (QoL). - To explore potential health care resource utilization. - To describe the pharmacokinetics (PK) of encorafenib, binimetinib, a metabolite of binimetinib (AR00426032) and cetuximab.;Primary end point(s): cORR as assessed by local radiologist/investigator review as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1).;Timepoint(s) of evaluation of this end point: Every 6 weeks (±7 days) from first dose (study treatment initiation date) for the first 12 weeks, then every 8 weeks (±7 days); | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1.cORR as assessed by central radiologist review as per RECIST 1.1. 2. Unconfirmed ORR as per local and central radiologist/investigator assessment. 3.DOR assessed based on local and central radiologist/investigator review. 4. TTR assessed based on local and central radiologist/investigator review. 5. PFS assessed based on local and central radiologist/investigator review. 6.OS. 7.Type and severity of adverse events (AEs) and serious adverse events (SAEs), changes in hematology and chemistry values, physical examinations, vital signs, electrocardiogram (ECGs) and echocardiogram (ECHO)/ multi-gated acquisition (MUGA) scans and ophthalmological examinations graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 (NCI-CTCAE v4.03). 8.Change from baseline in the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire for Cancer subjects (QLQ-C30), EuroQol-5D-5L (EQ-5D-5L), and Patient Global Impression of Change (PGIC). 9.Analyses of resource utilization focused on descriptive statistics of hospitalizations occurring during the study treatment phase. 10.Plasma concentrations of encorafenib, binimetinib and the active metabolite of binimetinib (AR00426032) and serum concentration of cetuximab.;Timepoint(s) of evaluation of this end point: 1-5 Every 6 weeks (±7 days) from first dose (study treatment initiation date) for the first 12 weeks, then every 8 weeks (±7 days); 6. Every 3 months 7.Adverse events:continuously;Hemat:screening,Cycle1 D15,22subsequent cycels (Cn)D1,end of treatment,follow up;Chem:scren,C1 D15,Cn D1, EOT,F-up;Pysical exam:screen,CnD1,EOT,F-up;Vital signs:screen,C1,D8,15,22,Cn D1,8,15,22,EOT,F-up;ECG:screen,C1D1,15,Cn D1,EOT F-up;ECHO/MUGA:C2 D1,C5 D1,every 12 weeks,EOT;Ophthalmic examination:Cn D1,EOT,F-up 8. screening,Cn D1,EOT,F-up 9. continuously 10. C1 D1, C2 D1 | — |
Countries
Austria, Belgium, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactDr. David Paez Lopez-Bravo
HOSPITAL DE LA SANTA CREU I SANT
Outcome results
None listed