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
This is a two-arm, randomized, double-blind Phase iii study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRaFV600e/K mutation-positive, high-risk [Stage iiia (lymph node metastasis [Greater Than]1 mm), iiib or iiic] cutaneous melanoma will be screened for eligibility.
approximately 852 subjects will be randomized in a 1:1 ratio to receive either dabrafenib (150 mg BiD) and
trametinib (2 mg once daily) combination therapy or two placebos for each for 12 months. Subjects will be stratified by BRaF mutation status (V600e, V600K) and stage of disease (Stage iiia, iiib, iiic).
Doses of study treatment may be modified and/or interrupted for management of toxicities associated with study treatment.
The benefit of the dabrafenib/trametinib combination compared to placebos will be evaluated through the primary endpoint of investigator-assessed RFS. Crossover is not permitted. The treatment effect of dabrafenib and trametinib combination therapy is anticipated to improve relapse free survival (RFS) by 40% over placebos (median RFS of 21 months and 15 months, respectively).
Subjects in both arms will receive treatment for 12 months or until disease recurrence,death, unacceptable toxicity, or withdrawal of consent. Subjects will be followed for disease recurrence and survival during and after the treatment period.
Randomization will be done centrally using a randomization schedule generated by the GSK Biostatistical Department, which will assign subjects in a 1:1 ratio to:
* dabrafenib and trametinib combination therapy;
* dabrafenib and trametinib placebos
Study treatment will be double-blinded. GSK, the site personnel (including the investigator) and the subject will not know the treatment assignment. every effort must be made to maintain the blind until all analyses have been performed.
Relapse Free Survival (RFS), defined as the time from randomization to disease recurrence or death from any cause. Recurrence of or death from the same cancer and all deaths from other causes are events. Treatment emergent malignancy(ies) other than second melanomas will not be considered as events, and loss to follow-up is censored. Patients without RFS events will be censored at the last adequate assessment.
* overall survival (oS) defined as the interval from randomization to the date of death, irrespective of the cause of death; patients still alive will be censored at the date of the last contact.
* Distant Metastasis-free survival (DMFS) defined as the interval from randomization to the date of first distant
metastasis or date of death, whichever occurs first. Patients alive and without distant metastasis are censored at the dateof last assessment.
* Freedom From Relapse (FFR) defined as interval from randomization to local or distant recurrence with censoring
of patients dying from causes other than melanoma or treatment-related toxicity at the date of death. Patients alive without recurrence or with second primary cancers will be censored at the date of last assessment.
* Safety as measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (eCG), echocardiogram (eCHo), eye exams, chemistry and hematology laboratory values, and adverse events (aes).
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Is >=18 years of age.
2. Has signed written informed consent.
3. Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis >1 mm), IIIb or IIIc; refer to Appendix 1 for Staging Guidelines] cutaneous melanoma determined to be V600E/K mutation positive using the bioMerieux (bMX) investigational use only (IUO) THxID BRAF Assay. (IDE: G120011). The testing will be conducted by a central reference laboratory. 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). For minimum surgical requirements see protocol Appendix 2.
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
8. Must have adequate organ function:
System Laboratory Values
ANC >= 1.2 x 109/L
Hemoglobin >= 9 g/dL
Platelet count >= 100 x 109/L
PT/INR and PTT <= 1.5 x ULN
Albumin >= 2.5 g/dL
Total bilirubin <= 1.5 x ULN
AST and ALT <= 2.5 x ULN
Serum creatinine <= 1.5 mg/dL
Left Ventricular Ejection fraction (LVEF) >= LLN by ECHO
a. Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the therapeutic range prior to randomization.
b. If serum creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft-Gault formula. Creatinine clearance must be >= 50 mL/min to be eligible.
c. ECHO scans must be used throughout the study
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 from 14 days prior to randomization, throughout the treatment period and for 4 months after the last dose of study treatment.