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

Phase 3

Completed

Conditions: Malignant Melanoma

Interventions: Drug: Dabrafenib
Drug: Trametinib

Registration Number: NCT03551626

Lead Sponsor: Novartis Pharmaceuticals

Brief Summary: The main purpose of this study was to evaluate the impact on pyrexia-related outcomes of an adapted pyrexia adverse event (AE)-management algorithm, as well as safety, efficacy and health-related outcomes.

Detailed Description: This was an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk cutaneous melanoma were screened for eligibility.

This study consisted of two periods:

1. Treatment Period - patients received up to 12 months of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). In the adapted pyrexia management algorithm, dabrafenib and trametinib were interrupted promptly at the onset of pyrexia (≥38°C) and were restarted upon the improvement of symptoms at the same dose if patients remained symptom free (temperature \<38°C) for at least 24 hours. In addition, dabrafenib and trametinib could be interrupted in the presence of pyrexia syndrome (i.e. chills, rigours, night sweats, or influenza-like symptoms) without documented temperature ≥38°C for cases of suspected recurrent pyrexia, at the investigators' discretion.

2. Follow-up Period - patients were followed for disease relapse through 24 months from first dose date. Moreover, patients were followed for overall survival through withdrawal, lost to follow-up, death, or the end of study, whichever occurs first. The follow-up period started once treatment was completed or treatment was prematurely discontinued.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 552

Inclusion Criteria

Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)] no more than 12 weeks, from last surgery, before Day 1
1. Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma were eligible.
2. Subjects who had previously had Stage III melanoma at any time were not eligible.
3. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains).
V600E/K mutation positive using a validated local test
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1

Key

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 had 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Dabrafenib and trametinib combination therapy	Trametinib	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months.
Dabrafenib and trametinib combination therapy	Dabrafenib	Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months.

Primary Outcome Measures

Name	Time	Method
Composite Rate of Pyrexia Related Events	Baseline up to 12 months	The composite rate of pyrexia related events was calculated as the total number of participants experiencing at least one of the three components of the composite endpoint (i.e., grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), divided by the total number of participants treated in the study and multiplied by 100. Pyrexia is defined as fever ≥ 38 °C. Pyrexia events were graded by the investigator using Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (Life-threatening) and Grade 5 (Death)

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) Rate	At 12 and 24 months	OS is defined as the time from date of the first dose of study medication to date of death due to any cause, whichever comes first. If a patient was not known to have died, then OS rate is the estimated probability that a patient will remain event-free up to the specified time point. OS rate was obtained from the Kaplan-Meier survival estimates. OS was censored at the last contact date when the patient was known to be alive (on or before the cut-off date).
Relapse Free Survival (RFS) Rate	At 12 and 24 months	RFS is defined as the time from the date of first dose of the study treatment to the date of the first documented disease recurrence or death due to any cause whichever comes first. Treatment emergent malignancies other than second melanomas were not considered as events. RFS rate is the estimated percent probability that a patient will remain event-free up to the specified time point. RFS rate was obtained from the Kaplan-Meier survival estimates. RFS was censored if no RFS event was observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a new anti-cancer therapy is started. The censoring date was the date of the last adequate tumor assessment prior to data cut-off date/start of new anti-cancer therapy date.
Change From Baseline in Subject-reported Quality of Life (QoL) Assessed by Functional Assessment Cancer Therapy - Melanoma Subscale Score (FACT-M MS)	Baseline up to 24 months	The FACT-M is a questionnaire that assesses participant health-related quality of life. It includes a melanoma specific (FACT-M MS) subscale that consists in 16 items related to signs, symptoms, physical/social activities most relevant to participants with advanced-stage melanoma. Each item ranges from 0 (not at all) to 4 (very much). FACT-M MS score ranges from 0 to 64, with higher score indicating better quality of life. If a patient discontinued the study treatment at Month 1 or Month 2, then the follow-up assessments started at Month 3 follow-up and continued until Month 24 follow-up or at withdrawal, lost to follow-up, death, or end of study. If a patient discontinued the study treatment from Month 3 through Month 5, the follow-up assessments started at Month 6 follow-up. If a patient discontinued from Month 6 through Month 11, the follow-up assessments started from Month 12 follow-up. For patients who completed treatment, the follow-up assessments started from Month 15 follow-up
Percentage of Participants Who Permanently Discontinued Treatment Due to Any Adverse Event (AE)	Baseline up to 12 months	Percentage of participants who permanently discontinued treatment due to any AE during treatment. An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign, symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study.
Percentage of Participants Who Required Management of Pyrexia	Baseline up to 12 months	Percentage of patients who experienced pyrexia and required intervention including hospitalizations, concomitant medications, and study treatment modifications (dose reductions, permanent discontinuations and/or interruptions) due to pyrexia. Pyrexia is defined as fever ≥ 38 °C