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

Phase 3CompletedNCT01682083

Novartis Pharmaceuticals870 enrolled

Overview

This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus 2 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. Approximately 852 patients were planned to be randomized in a 1:1 ratio, stratified by BRAF mutation status (V600E, V600K) and stage of disease (Stage IIIa, IIIb, IIIc). Patients received either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]) combination therapy or 2 matching placebos (one each for dabrafenib and trametinib) for 12 months or until disease recurrence, death, unacceptable toxicity, or withdrawal of consent. Patients were followed for disease recurrence and survival during and after the treatment period. The study did not permit crossover. Doses of study treatment could be modified and/or interrupted for management of toxicities associated with study treatment.

The study periods were follows: 1. Screening: Assessments were to be completed within 28 days of randomization. 2. Treatment: The treatment period was 12 months. Discontinuation of study treatment could occur earlier than 12 months for disease recurrence, death, unacceptable toxicity or withdrawal of consent. 3. Post treatment follow-up (before recurrence): Patients were to be followed for disease recurrence every 3 months after the end of treatment until Month 24, every 6 months after Month 24 and annually after Month 60 (365 days +/- 14 days from last visit). 4. Post treatment follow-up (after recurrence): After disease recurrence patients remained on study for follow-up assessments every 3 months until Month 24, every 6 months after Month 24, and annually after Month 60 (365 days +/- 14 days from last visit).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Key Inclusion Criteria: * At least 18 years of age * Completely resected histologically confirmed high-risk (Stage IIIa \[lymph node metastasis \> 1 mm\], IIIb or IIIc) cutaneous melanoma determined to be V600E/K mutation positive using the bioMerieux (bMX) THxID BRAF Assay by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma were eligible * Must be surgically rendered free of disease (defined as the date of the most recent surgery) no more than 12 weeks before randomization * Recovered from definitive surgery (e.g., no uncontrolled wound infections or indwelling drains) * ECOG Performance Status of 0-1 * Had 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 on Screening evaluation * Prior anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) including radiotherapy for melanoma. Prior surgery for melanoma was allowed * History of another malignancy including melanoma or a concurrent malignancy. Patients who previously had Stage III melanoma or any malignancy with confirmed activating RAS mutation at any time were not eligible. Exceptions to this include: * Patients with a history of any malignancy that had been disease-free for at least 5 years were 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) were eligible irrespective of the time since the resection * Patients with successfully treated in situ carcinoma were eligible * Patients presenting with multiple primary melanomas were eligible only if the lesions were concurrent. Patients who had concurrent multiple primary melanomas that were "distant" were eligible provided each lesion was considered local disease or resectable regional disease.

Locations (168)

Novartis Investigative Site

Birmingham, Alabama, United States

Novartis Investigative Site

Tucson, Arizona, United States

Novartis Investigative Site

San Francisco, California, United States

Novartis Investigative Site

San Francisco, California, United States

Novartis Investigative Site

Aurora, Colorado, United States

Outcomes

Primary Outcomes

Percentage of Participants With Relapse-free Survival (RFS) Events

Relapse-Free Survival (RFS) was defined as the time from randomization to disease recurrence or death from any cause. RFS events included loco-regional recurrence, distant metastases, new primary melanoma, and death without prior documented recurrence; such deaths were counted as events and not censored. Patients without an event at the analysis cut-off (30-Jun-2017) were censored at the date of the last radiological or non-radiological efficacy assessment. Patients lost to follow-up before recurrence or who initiated subsequent anti-cancer therapy prior to recurrence were censored at the last efficacy assessment before loss to follow-up or therapy initiation. Events after prolonged loss to follow-up were handled per the analysis plan. Malignancies other than new primary melanoma were not considered RFS events and, except for basal cell carcinoma, were reported as serious adverse events. Tumor tissue from any new primary cancer was collected for biomarker analyses.

Time frame: Approximately 4 years

Relapse-free Survival (RFS)

Time frame: Approximately 4 years

Secondary Outcomes

Percentage of Participants With Overall Survival (OS) Events

Censoring was performed using the date of last known contact for those who were alive at the time of analysis.

Time frame: Approximately 10 years

Overall Survival (OS)

Overall Survival (OS) was defined as the interval from randomization to the date of death, irrespective of the cause of death. Censoring was performed using the date of last known contact for those who were alive at the time of analysis.

Time frame: Approximately 10 years

Percentage of Participants With Distant Metastasis-free Survival (DMFS) Events

Distant metastasis-free survival (DMFS) was defined as the time from randomization to the first occurrence of distant metastasis or death, whichever occurred first, if death preceded documented recurrence. Patients who remained alive and free of distant metastasis were censored at the date of their last assessment.

Time frame: Approximately 4 years

Distant Metastasis-free Survival (DMFS)

Time frame: Approximately 4 years

Percentage of Participants With Freedom From Relapse (FFR) Events

The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death.

Time frame: Approximately 4 years

Freedom From Relapse (FFR)

Freedom from relapse (FFR) was defined as the 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. The first appearance of local/distant metastasis or mortality due to disease recurrence or toxicity were used as events. Censoring was performed using the date of last assessment for those who were alive without local/distant metastasis or new primary melanoma at the time of analysis. FFR was censored if patients died from causes other than melanoma or treatment-related toxicity at the date of death.

Time frame: Approximately 4 years

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

Overview

Conditions

Interventions

Eligibility

Locations (168)

Outcomes

Primary Outcomes

Secondary Outcomes