| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resected BRAF V600E/K stage IIB/C melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stage IIB/C melanoma with mutation in the V600E/K gene after surgery |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 characterize the safety and tolerability. |
|
| E.2.2 | Secondary objectives of the trial |
1.To describe the available RFS data by treatment arm.
2.To describe the available DMFS data by treatment arm.
3.To describe-reported health-related quality of life (HRQoL) by
treatment arm. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 (pT3b-pT4bN0) 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 local assay any time prior to screening (if done routinely in clinical practice) and/or the central laboratory. 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 ≤ 1.5 × ULN; or calculated creatinine clearance ≥ 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 ≤ 1.5 x ULN and < 2 mg/dL
ii.Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 x ULN
11.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
12.Adequate coagulation function, defined as INR ≤1.5× ULN unless the patient is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range;
13.Negative serum β-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.
|
|
| E.4 | Principal 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 ≤ 12 weeks prior to randomization;
i.Note 1: Thromboembolic or cerebrovascular events include stroke, transient ischemic attacks, cerebrovascular accidents, hemodynamically significant 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;
5.Previous or concurrent malignancy for the past 3 years. Except for non-melanoma skin cancer and any in situ cancer;
6.Any condition with a life expectancy of less than 5 years;
7.Participants with a prior cancer associated with RAS mutation;
8.Previous treatment for melanoma beyond complete surgical resection (any prior systemic anticancer therapy; prior radiotherapy);
9.Hypersensitivity to the study drugs or to any of the excipients;
10.Participants with severe lactose intolerance;
11.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 randomization;
ii.Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 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 < 50 copies/mL and CD4 count > 200 cells/mm3, and on stable antiretroviral therapy for at least 6 months, provided that they meet all other study eligibility criteria. Testing for HIV is not mandated for study entry; however, testing must be performed at sites where mandated locally following local clinical practice.;
16.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;
17.Presence of any psychological, familial, sociological or geographical conditions potentially hampering compliance with the study protocol and follow-up schedule according to Investigators’s judgement; those conditions should be assessed with the patient before randomization in the trial;
18.Participant is a family member of the investigator or any associate, colleague and employee assisting in the study conduct (secretary, nurse, technician) or is otherwise in a position likely to represent a conflict of interest, the participant is only eligible if the informed consent has been sought by an appropriately qualified individual who is completely independent of this relationship;
19.Participation in a clinical study with administration of an investigational product within 4 weeks or five times the half-life of the investigational product, whichever is longer, before the first dose of study treatment;
20.Participants who has forfeited his / her freedom by administrative or legal award or is under guardianship. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
•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
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The end of study is planned when all participants have completed their
30-days safety follow-up visit, all statistical analyses will be done at that
time.
|
|
| E.5.2 | Secondary end point(s) |
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
participants 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The end of study is planned when all participants have completed their
30-days safety follow-up visit, all statistical analyses will be done at that
time. |
|
| 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 | No |
| E.6.6 | Pharmacokinetic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| 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 |
| Argentina |
| Switzerland |
| Ukraine |
| Brazil |
| Canada |
| Israel |
| Russian Federation |
| South Africa |
| United Kingdom |
| Belgium |
| Greece |
| Hungary |
| Norway |
| Portugal |
| Sweden |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
End of study is defined as the point when all patients randomized to the
experimental arm (encorafenib 450mg QD in combination with
binimetinib 45mg BID) have had the opportunity to complete their 30-
day safety follow-up visit.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| 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 | 3 |
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