| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-risk BRAF V600 mutation-positive melanoma after surgical resection. |
|
| E.1.1.1 | Medical condition in easily understood language |
| A certain type of skin cancer (after removal by 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 | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10027156 |
| E.1.2 | Term | Skin melanomas (excl ocular) |
| E.1.2 | System Organ Class | 100000004858 |
|
| 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 efficacy of dabrafenib and trametinib combination therapy compared to two placebos with respect to relapse-free survival (RFS) in patients with completely resected, histologically confirmed, BRAF V600E/K high-risk, stage III cutaneous melanoma |
|
| E.2.2 | Secondary objectives of the trial |
To compare overall survival (OS) of dabrafenib and trametinib as a combination therapy versus two placebos.
To compare distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus two placebos.
To compare freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus two placebos.
To evaluate the safety of dabrafenib and trametinib as a combination therapy in the overall study population including incidences of squamous cell carcinoma (SCC), new cancers in other sites, and other proliferative cutaneous lesions |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Is 18 years of age or older.
2. Has signed written informed consent.
3. Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis >1 mm), IIIb or IIIc; cutaneous melanoma determined to be V600E/K mutation positive using the bioMerieux (bMX) investigational use only (IUO) THxID BRAF Assay (IDE: G120011). Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible.
4. Must be surgically rendered free of disease no more than 12 weeks before randomization.
5. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains).
6. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 [Oken, 1982]
8. Must have adequate organ function
9. Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception, as defined in Section 7.3.3 from 14 days prior to randomization, throughout the treatment period and for 4 months after the last dose of study treatment.
10. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category. |
|
| E.4 | Principal exclusion criteria |
1. Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases.
2. Evidence of distant metastatic disease on screening evaluation.
3. Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) and radiotherapy for melanoma. Prior surgery for melanoma is allowed.
4. Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to randomization.
5. Current or expected use of a prohibited medication
6. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
7. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which are allowed).
8. A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency.
9. History of another malignancy or a concurrent malignancy including prior malignant melanoma except as noted below;
Exception: Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas, or other malignancies for which the patient has been disease free for > 5 years except those known to have had a KRAS mutation.
10. A history or evidence of cardiovascular risk including any of the following:
a. A QT interval corrected for heart rate using the Bazett’s formula (QTcB; Appendix 5) ≥ 480 msec;
b. A history or evidence of current clinically significant uncontrolled arrhythmias;
c. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
d. A history or evidence of current > Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines
e. Patients with intra-cardiac defibrillators or permanent pacemakers.
f. Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study). Subjects with moderate valvular thickening should not be entered on study.
g. Treatment refractory hypertension defined as a blood pressure of systolic> 140 mm HgmmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
11. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) including:
a. Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
b. Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as:
i. Evidence of new optic disc cupping;
ii. Evidence of new visual field defects on automated perimetry;
iii. Intraocular pressure >21 mm mmHg as measured by tonography.
13. Interstitial lung disease or pneumonitis.
14. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that, in the opinion of the investigator, could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
15. Pregnant or nursing females. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Relapse Free Survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Overall survival (OS)
Distant metastasis-free survival (DMFS)
Freedom from relapse (FFR)
Safety including incidences of squamous cell carcinoma (SCC), and other proliferative cutaneous lesions
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS: every 3 months, then every 6 months after 2 years
DMFS: every 3 months
FFR: every 3 months
Safety: every month for the first 12 months, then every 3 months until month 24, then every 6 months until relapse. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 125 |
| 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 |
| Australia |
| Brazil |
| Canada |
| Israel |
| New Zealand |
| Taiwan |
| United States |
| Switzerland |
| Russian Federation |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Spain |
| 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
|
| The study will be considered complete, and the final OS analysis will be conducted when approximately 43.5 percent of the initially planned target number of randomized subjects have died or are otherwise lost to follow-up (approximately 260) or at the end of Jul-2023, whichever comes first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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