| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAF V600E -mutant Metastatic Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metatstatic Colorectal Cancer with a mutation of the BRAF V600E gene |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
- 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 2 mg/dL. Note: Total bilirubin > 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 other study procedures.
16. Female subjects 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.
Notes:
(a) Precautions to avoid pregnancy must be conducted from screening through 6 months after the last dose of cetuximab or through 30 days after the last dose of encorafenib or binimetinib, whichever is later if of childbearing potential.
(b) Permitted methods of contraception as provided (in Section 5.3.1) should be communicated to the subjects and their understanding confirmed. For all females, the pregnancy test must be negative at screening and baseline.
17. Male subject must agree to take appropriate precautions to avoid fathering a child
Notes:
(a) from screening through 6 months after the last dose of cetuximab or through 90 days after the last dose of encorafenib or binimetinib, whichever is later.
(b) permitted methods of contraception as provided (in Section 5.3.1) should be communicated to the subjects and their understanding confirmed.
18. Patients under guardianship or partial guardianship will be eligible unless prohibited by local laws or by local/central ethic committees.
Note: where allowed, all procedures prescribed by law must be followed.
19. Affiliated to a social security system, or is a beneficiary (if applicable in the national regulation). |
|
| E.4 | Principal 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 potential of elevated Creatin Kinase e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy.
17. Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy.
18. Known history of human immunodeficiency virus infection.
19. Active hepatitis B or hepatitis C infection.
20. Known contraindication to receive cetuximab at the planned doses.
21. Subjects who have any medical condition that would, in the Investigator’s judgment, prevent the subject’s participation in the clinical study due to safety concerns or compliance with study procedures.
22. Any medical or psychiatric condition or laboratory abnormality that may increase the risk with study participation or study drug administration or that may interfere with the interpretation of study.
23. Pregnancy, confirmed by a positive human chorionic gonadotropin laboratory test result, or breastfeeding.
24. Is a family member of the Investigator or any associate, colleague, or employee assisting in the conduct of the study
25. Is in a position likely to represent a conflict of interest.
26. Participation in a clinical study with administration of an investigational product within 4 weeks before the first dose of study treatment.
27. Is mentally unable to understand the nature, objectives and possible consequences of the trial; or he/she refuses to its constraints. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| cORR as assessed by local radiologist/investigator review as per Response Evaluation Criteria in Solid Tumors (RECIST 1.1). |
|
| E.5.1.1 | 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); |
|
| E.5.2 | 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. |
|
| E.5.2.1 | 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 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Belgium |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is defined as the time point when all subjects have been followed for at least 1 year after the start of study treatment of the last subject enrolled (including survival status). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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