Melanoma skin cancer
Conditions
Interventions
Subjects will be randomized 1:1 to receive either treatment with encorafenib
and binimetinib or placebo. The treatment will consist of a combination of
encorafenib 450 mg (6 capsules of 75 mg) once
Sponsors
Pierre Fabre
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 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 (pT3bpT4bN0) 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; 6.Available tumor sample for central determination of the BRAFV600E/K mutation. FFPE tumor tissue block or a minimum of 10 slides, optimally up to 20 slides. Screening 1.Before any related study activity, written informed consent must be given according to ICH/GCP, and national/local regulations; 2.Presence of BRAF V600E/K mutation in tumor tissue as determined by a local assay any time prior to screening (if done routinely in clinical practice) and/or the central laboratory i.If the participant is screened based on local assay result, the BRAF V600E/K mutation status must be confirmed by the central laboratory prior to randomization. 3.Participant still free of disease as evidenced by the required baseline imaging and physical/dermatological assessments performed respectively within 6 weeks and 2 weeks before the randomization (Day 1); 4.Randomization within 12 weeks from full surgical resection including sentinel lymph node biopsy (SLNB); 5.Recovered from definitive surgery (e.g. complete wound healing, no uncontrolled wound infections or indwelling drains); 6.ECOG performance status of 0 or 1; 7.Adequate haematological function: i.Absolute neutrophil count (ANC) >= 1.5 x 1000000000/L ii.Platelets >= 100 x 1000000000/L iii.Hemoglobin >= 9.0 g/dL 8.Adequate renal function: Serum creatinine = 50 mL/min by Cockcroft Gault formula; 9.Adequate electrolytes, defined as serum potassium and magnesium levels within institutional normal limits; 10.Adequate hepatic function: i.Serum total bilirubin = 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
Exclusion criteria
Exclusion criteria: 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.Pregnancy; 3.History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO. 4.History of thromboembolic or cerebrovascular events = 2); iii.Uncontrolled hypertension defined as persistent systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 100 mmHg despite optimal therapy; iv.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); 12.Neuromuscular disorders that are associated with CK > ULN; 13.Non-infectious pneumonitis and Interstitial Lung Disease; 14.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; 15.Participants with active bacterial, fungal, or viral infection, including, but not limited to: HBV, HCV, and known HIV or AIDS-related illness, or an infection requiring systemic therapeutic treatment within 2 weeks prior to randomization. Note: Participants receiving prophylactic antibiotics are exceptions and may participate. Note: Participants with a positive HBsAg (i.e., either acute or chronic active hepatitis) are excluded. Those with positive anti-HBcAb but negative HBsAg and anti-HBsAb profile may be eligible upon review and approval by the sponsor or designee. Note: Participants with positive HCV antibody but undetectable HCV viral load may be eligible upon review and approval by the sponsor or designee. Note: Participants with confirmed stable HIV disease may be eligible if they have viral load 200 cells/mm3, and on stable antire
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| •Severity of adverse events and SAEs on-study graded according to NCI CTCAE Version 5.0 •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 •Incidence of dose interruptions, dose modifications and discontinuation due to AEs and incidence of AEs requiring additional therapy | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Recurrence-free survival (RFS) RFS is defined as the time between the date of randomization and the date of 1) first recurrence (local, regional, or a distant metastasis), 2) new melanoma that is known to be either ulcerated, thick (Breslow thickness>1 mm) or requiring a treatment other than surgery or 3) death (whatever the cause), whichever occurs first (i.e., the date of the earliest of recurrence, ulcerated or thick or requiring a treatment other than surgery new melanoma, and death minus the date of randomization plus one day). For participants who remain alive and whose disease has not recurred, RFS will be censored on the date of last adequate disease assessment. RFS will be based on the disease assessment and date of death provided by the local investigator. A distant metastasis of cutaneous melanoma will always be treated as an event in the RFS analysis, irrespective of the presence of a new melanoma. 2. Distant metastasis-free survival (DMFS) DMFS is defined as the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first (i.e., the date of distant metastasis for participants with a distant metastasis or the date of death for without a distant metastasis minus the date of randomization plus one day). For participants who remain alive and distant metastasis-free, DMFS will be censored on the date of last adequate disease assessment. DMFS will be based on the disease assessment and date of death provided by the local investigator. A distant metastasis of cutaneous melanoma will always be treated as an event in the DMFS analysis, irrespective of the presence of a new melanoma. 3. • The change in the HRQoL from baseline over time and to the average of the scores during the treatment • The change in the HRQoL from baseline for post treatment visits | — |
Countries
Netherlands
Outcome results
None listed