A study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib compared to two placebos (inactive drugs) in the treatment of BRAF V600E/K mutation-positive melanoma after surgery.

• Register: EUCTR
• Last refreshed on: 31 August 2020
• Main ID: EUCTR2012-001266-15-DE
• Date of registration: 14/11/2012
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A study of the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib compared to two placebos (inactive drugs) in the treatment of BRAF V600E/K mutation-positive melanoma after surgery.
• Scientific title: COMBI-AD: A phase III randomized double blind study of dabrafenib (GSK2118436) in COMBInation with trametinib (GSK1120212) versus two placebos in the ADjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection. - COMBI-AD
• Date of first enrolment: 23/01/2013
• Target sample size: 852
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-001266-15
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Israel, Italy, Netherlands, New Zealand, Norway, Russian Federation, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Contacts

• Name: Medizinischer Infoservice (MCC)
• Affiliation: Novartis Pharma GmbH

• Name: Medizinischer Infoservice (MCC)
• Affiliation: Novartis Pharma GmbH

Key inclusion & exclusion criteria

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) THxID BRAF Assay.
Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. Patients with an unknown primary melanoma are not eligible.
4. Must be surgically rendered free of disease (defined as the date of the most recent surgery) 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.

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 682
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 170

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 anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) including 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).
8. History of another malignancy including melanoma or a concurrent
malignancy except as noted below. Patients who have previously had Stage III melanoma or any malignancy with confirmed activating RAS mutation at any time are not eligible. Note: Prospective RAS testing is not required. However, if the results of previous RAS testing are known, they must be used in
assessing eligibility.
Exceptions:
- Patients with a history of any malignancy that have been disease-free for at least 5 years are eligible except those with confirmed activating RAS mutations.
- Patients with a history of completely resected non-melanoma skin cancer (e.g.
basal cell carcinoma, squamous cell carcinoma) are eligible irrespective of the time since the resection.
- Patients with successfully treated in situ carcinoma are eligible.
- Patients presenting with multiple primary melanomas are eligible only if the lesions are concurrent. Patients who have concurrent multiple primary
melanomas that are “distant” are eligible provided each lesion is considered local disease or resectable regional disease. These cases should be discussed with the Medical Monitor.
09. 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 Hg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy
10. 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 cupp

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

High-risk BRAF V600 mutation-positive melanoma after surgical resection.
MedDRA version: 20.0 Level: HLT Classification code 10027156 Term: Skin melanomas (excl ocular) System Organ Class: 100000004858

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Tafinlar
Product Name: Dabrafenib
Product Code: DRB436
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tafinlar
Current Sponsor code: DRB436
Other descriptive name: dabrafenib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Trade Name: Tafinlar
Product Name: Dabrafenib
Product Code: DRB436
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Tafinlar
CAS Number: 1195765-45-7
Current Sponsor code: DRB436
Other descriptive name: dabrafenib
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Trade Name: Mekinist
Product Name: Trametinib
Product Code: TMT212
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Mekinist
Current Sponsor code: TMT212
Other descriptive name: TRAMETINIB DIMETHYL SULFOXIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 0.5-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Trade Name: Mekinist
Product Name: Trametinib
Product Code: TMT212
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Mekinist
Current Sponsor code: TMT212
Other descriptive name: TRAMETINIB DIMETHYL SULFOXIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 2-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Primary end point(s): Relapse Free Survival (RFS), defined as the time from randomization to disease recurrence or death from any cause.

Secondary Objective: 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

Main Objective: 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

Timepoint(s) of evaluation of this end point: every 3 months

Secondary Outcome(s)

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.

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

Secondary ID(s)

BRF115532

2012-001266-15-BE

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date: 23/01/2013
Contact: