Study of Dabrafenib+Trametinib in the Adjuvant Treatment of Stage III BRAF V600+ Melanoma After Complete Resection to Evaluate the Impact on Pyrexia Related Outcomes

Study Overview
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Brief Summary
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This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection to evaluate the impact on pyrexia related outcomes of an adapted pyrexia AE-management algorithm, as well as safety, efficacy and health-related outcomes. Approximately 600 subjects will be enrolled to receive dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination therapy for 12 months. At enrollment, subjects will be instructed on the pyrexia management algorithm. This study consists of two Periods for Enrolled subjects: Treatment Period - subjects will receive up to 12 months of treatment. Follow-up Period - subjects will be followed through 24 months from their first dose date for relapse, and through end of study for overall survival. Follow-up will start once treatment is complete or is prematurely discontinued and continue through the end of the study, regardless of disease recurrence.

Official Title
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COMBI-APlus: Open-label, Phase IIIb Study of Dabrafenib in COMBInation With Trametinib in the Adjuvant Treatment of Stage III BRAF V600 Mutation-positive Melanoma After Complete Resection to Evaluate the Impact on Pyrexia Related Outcomes of an Adapted Pyrexia AE-management Algorithm (Plus)

Conditions
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Malignant Melanoma

Intervention / Treatment
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* Drug: Dabrafenib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)] V600E/K mutation positive using a validated local test Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. Subjects who have previously had Stage III melanoma at any time are not eligible. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 Exclusion Criteria: Uveal or mucosal melanoma Evidence of metastatic disease including unresectable in-transit metastasis Received any prior adjuvant or neoadjuvant treatment, including but not limited to chemotherapy, checkpoint inhibitors, targeted therapy [e.g., BRAF and/or MEK inhibitors], biologic therapy, vaccine therapy, investigational treatment, or radiotherapy for melanoma Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to study treatment; completely resected basal cell and squamous cell skin cancers and any completely resected carcinoma in situ History or current evidence of cardiovascular risk A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dabrafenib and trametinib combination therapy<br>Subjects will receive dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months. | Drug: Dabrafenib<br>* Supplied as dabrafenib 50 mg, 75 mg Capsules for oral use<br>Drug: Trametinib<br>* supplied as trametinib 0.5mg, 2.0mg tablets for oral use<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in composite rate of pyrexia related events | The composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia by 12 months in overall treated subjects | Baseline up to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse free survival (RFS) from the first dose to disease recurrence or death from any cause | RFS is defined as the time from the date of first dose of the study medication to the date of disease recurrence or death due to any cause. | Baseline up to approximately 24 months | 
| Overall Survival (OS) from the first dose to date of death due to any cause | OS is defined as the time from date of the first dose of study medication to date of death due to any cause. | Baseline up to approximately 24 months | 
| Percentage of patients who require management of pyrexia | Percentage of patients who experienced pyrexia and required intervention | Baseline up to 12 months | 
| The percentage of participants who permanently discontinued treatment due to any Adverse event | Participants who permanently discontinued treatment due to any Adverse event during treatment | Baseline up to 12 months | 
| Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M MS) | QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes the FACT-Melanoma subscale (FACT-M MS) questionnaire -specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life. | Baseline up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adjuvant, Stage III melanoma, combination treatment, pyrexia, dabrafenib, trametinib