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 (COMBI-APlus)

Novartis

Status and phase

Completed

Phase 3

Conditions

Malignant Melanoma

Treatments

Drug: Dabrafenib

Drug: Trametinib

Study type

Interventional

Funder types

Industry

Identifiers

NCT03551626

CDRB436F2410

2018-000168-27 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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:

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.
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.

Enrollment

552 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

Key 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