Encorafenib used with binimetinib versus placebo in BRAF mutant stage II melanoma after surgery to evaluate the efficacy and safety in preventingmelanoma recurrence
- Conditions
- Resected BRAF V600E/K stage II melanomaMedDRA version: 21.1Level: LLTClassification code 10053571Term: MelanomaSystem Organ Class: 100000004864Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-000743-41-IT
- Lead Sponsor
- PIERRE FABRE MéDICAMENT
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 900
Molecular pre-screening
1. Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations ;
2. Male or female = 18 years of age;
3. Surgically resected, with tumor free margins, and histologically/pathologically confirmed new diagnosis of stage II (pT2bpT4bN0) cutaneous melanoma per AJCC 8th edition;
4. Sentinel node (SN) staged node negative (pN0);
5. Sentinel node (SN) biopsy within 14 weeks from initial diagnosis of melanoma;
Screening
1. Melanoma determined locally to be V600E/K mutation-positive. Note: only PCR and NGS-based local assay results will be acceptable;
2. Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed within 6 weeks from the randomization (Day 1);
3. Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations;
4. Randomization within 12 weeks from SN biopsy;
5. Able to provide a sufficient amount of representative tumor specimen (diagnostic biopsy) for retrospective central testing of BRAFV600E/K mutation status. FFPE tumor tissue block or a minimum of 10 slides, optimally up to 15 slides;
6. Recovered from definitive surgery (e.g. complete wound healing, no uncontrolled wound infections or indwelling drains);
7. ECOG performance status of 0 or 1;
8. Adequate bone marrow function:
i. Absolute neutrophil count (ANC) = 1.5 x 1000000000/L
ii. Platelets = 100 x1000000000 /L
iii. Hemoglobin = 9.0 g/dL
9. Adequate renal function:
Serum creatinine = 1.5 × ULN; or calculated creatinine clearance = 50 mL/min by Cockcroft-Gault formula;
10. Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits.
11. Adequate hepatic function:
i. Serum total bilirubin = 1.5 x ULN and < 2 mg/dL
ii. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) = 2.5 x ULN
12. Adequate cardiac function:
i. Left ventricular ejection fraction (LVEF) = 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
ii. Mean triplicate QT interval corrected for heart rate according to Fridericia's formula (QTcF) value = 480 msec and no history of QT syndrome
13. Negative serum ß-HCG test (female patient of childbearing potential only) performed within 3 days prior to Day 1;
14. Participants of childbearing / reproductive potential should use adequate birth control measures (see Appendix 4, section 10.4.2):
Female participants are either postmenopausal for at least 1 year, surgically sterile for at least 6 weeks or must agree to take appropriate precautions to avoid pregnancy.
Male participants must agree to take appropriate precautions to avoid
fathering a child.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 720
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 180
Molecular pre-screening
1. Unknown ulceration status;
2. Uveal and mucosal melanoma;
3. Clinically apparent metastases (N+/M1);
4. Microsatellites, satellites and/or in-transit metastases;
5. Local (scar) recurrences.
Screening
1. Breast feeding women;
2. 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 or hypercoagulability syndromes);
3. History of thromboembolic or cerebrovascular events = 12 weeks prior to randomization;
i. Note 1: Thromboembolic or cerebrovascular events include stroke, transient ischemic attacks, cerebrovascular accidents, hemodynamically significant (i.e massive or sub-massive) deep vein thrombosis, pulmonary emboli, aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis;
ii. Note 2: Participants with thromboembolic events related to indwelling catheters or other procedures may be enrolled;
4. Previous or concurrent malignancy for the past 3 years (must be free from disease for at least 3 years). Except for non-melanoma skin cancer (Basal Cell Carcinomas or Squamous Cell Carcinomas) and any in situ
cancer;
5.Participants with a prior cancer associated with RAS mutation;
6. Previous treatment for melanoma beyond complete surgical resection (any prior systemic anticancer therapy; prior radiotherapy);
7. Hypersensitivity to the study drugs or to any of the excipients;
8. Participants with severe lactose intolerance (e.g Rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption);
9.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
iii. History of acute myocardial infarction, acute coronary syndromes (including unstable angina, coronary artery bypass graft, coronary angioplasty or stenting) = 6 months prior to randomization;
iv. Congestive heart failure requiring treatment (New York Heart Association Grade = 2);
v. Uncontrolled hypertension defined as persistent systolic blood pressure = 150 mmHg or diastolic blood pressure = 100 mmHg despite optimal therapy;
vi. Presence of clinically significant cardiac arrhythmias including uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia (stable controlled atrial fibrillation or paroxysmal supraventricular tachycardia is accepted);
10. Neuromuscular disorders that are associated with CK > ULN (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy);
11. Non-infectious pneumonitis and Interstitial Lung Disease;
12. Positive SARs-CoV-2 or variants of SARs-CoV2 RT-PCR test at screening or suspected to be infected with SARs-CoV2 or variants of SARsCoV2 with confirmation pending;
13. Known history of a positive serology for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), known history of a positive serology for active hepatitis B, and/or
hepatitis C;
14. Unable to ingest or digest tablets and capsules. This can be caused by any impaired gastrointestinal function or disease, such as for example: ulcerative diseases, malabsorption syndrome, small bowel
resection, ileus, etc. Or any condition causing uncontrolled nausea, vomiting or diarrhea;
15. Presence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up s
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To prospectively assess whether treatment with encorafenib and binimetinib prolongs recurrence-free survival as compared to placebo in resected pT2b-4bN0M0 BRAF V600E/K melanoma participants.;Secondary Objective: 1.To prospectively assess whether treatment with encorafenib and binimetinib prolongs distant metastasis-free survival (DMFS) as compared to placebo.<br>2.To prospectively assess whether treatment with encorafenib and binimetinib prolongs overall survival (OS) as compared to placebo.<br>3.To characterize the safety and tolerability.<br>4.To compare the patient-reported health-related (HRQoL) between the two arms during the treatment duration and after treatment completion.;Primary end point(s): Recurrence-free survival (RFS);Timepoint(s) of evaluation of this end point: Approximately 4.7 years from the accrual of the first patient.The longterm evaluation will take place 10 years from the randomization of the last patient.
- Secondary Outcome Measures
Name Time Method Secondary end point(s): 1.Distant metastasis-free survival (DMFS)<br>2.Overall survival (OS)<br>3.•Severity of adverse events and SAEs on-study graded according to NCI CTCAE Version 5.0<br>•Changes from baseline and worst value on-study for clinical safety laboratory assessments, physical examinations, vital signs, ECGs, ECHO, dermatological examinations, ophthalmic examinations and ECOG performance status<br>•Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy<br>4. •The change in the HRQoL from baseline to the average of the scores during the treatment<br>•The change in the HRQoL from baseline to week 48;Timepoint(s) of evaluation of this end point: 1. 6.9 years from first patient in<br>2.At the time of the DMFS analysis (6.9 years from first patient in)<br>3.At the time of the RFS analysis (4.7 years from first patient in)<br>4.At the time of the RFS analysis (4.7 years from first patient in)