Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).

Study Overview
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Brief Summary
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This was 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, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]) combination therapy or two placebos for 12 months.

Detailed Description
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This was a two-arm, randomized, double-blind, multi-center, international phase III study of dabrafenib in combination with trametinib versus two matching placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or IIIc] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily [BID]) and trametinib (2 mg once daily [QD]). None of the patients had undergone previous systemic anticancer treatment or radiotherapy for melanoma. All the patients had undergone completion lymphadenectomy with no clinical or radiographic evidence of residual regional node disease within 12 weeks before randomization, had recovered from definitive surgery, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. BRAF V600 mutation status was confirmed in primary-tumor or lymph-node tissue by a central reference laboratory. All the patients provided written informed consent. The primary end point was recurrence-free survival, Overall survival, as the key secondary end point, was to be tested in a hierarchical manner only if the primary end point met the criteria for significance. The overall survival analysis used a preplanned three-look Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary, which was used to determine the significance threshold for the first interim overall survival analysis (two-sided P=0.000019). Disease assessments included clinical examination and imaging by means of computed tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months during the first 24 months, then every 6 months until disease recurrence or the completion of the trial. Follow-up for survival began after recurrence and continued through the end of the trial. Adverse events and laboratory values were assessed at screening, on the date of randomization, at least once per month through month 12, and at every visit for disease-recurrence assessment after month 12. Adverse events and laboratory values were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Official Title
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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

Conditions
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Melanoma

Intervention / Treatment
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* Drug: Dabrafenib
* Drug: Trametinib
* Drug: Placebos


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. Surgically rendered free of disease no more than 12 weeks before randomization. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. Adequate hematologic, hepatic, renal and cardiac function. Key Exclusion Criteria: Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases. Evidence of distant metastatic disease. Prior systemic anti-cancer treatment and radiotherapy for melanoma; prior surgery for melanoma is allowed. History of another malignancy or concurrent malignancy including prior malignant melanoma. Exceptions to this include: Patients who have been disease-free for 5 years or patients with a history 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. History or current evidence of cardiovascular risk. History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabrafenib and trametinib<br>Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. | Drug: Dabrafenib<br>* Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)<br>* Other names: GSK2118436;Drug: Trametinib<br>* Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)<br>* Other names: GSK1120212;|
| Placebo Comparator: Dabrafenib and trametinib placebos<br>Subjects received matching placebos orally for 12 months | Drug: Placebos<br>* The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free Survival (RFS) | Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause. | Approximately 3.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo | approximately 3.5 years | 
| Distant Metastasis-free Survival | Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event. | approximately 3.5 years | 
| Freedom From Relapse | Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored. | approximately 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MEK inhibitor, trametinib, Oncology, adjuvant melanoma, dabrafenib, dabrafenib and trametinib combination therapy, BRAF mutation-positive melanoma, BRAF inhibitor