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

NCT ID: NCT03551626

Last Updated: 2025-04-29

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 552 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-29
• Study Completion Date: 2021-09-16

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.

Conditions

Malignant Melanoma

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dabrafenib and trametinib combination therapy

Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months.

Group Type: EXPERIMENTAL

Dabrafenib

Intervention Type: DRUG

Supplied as dabrafenib 50 mg and 75 mg capsules for oral administration

Trametinib

Intervention Type: DRUG

Supplied as trametinib 0.5mg, and 2.0mg tablets for oral administration

Interventions

Dabrafenib

Supplied as dabrafenib 50 mg and 75 mg capsules for oral administration

Intervention Type: DRUG

Trametinib

Supplied as trametinib 0.5mg, and 2.0mg tablets for oral administration

Intervention Type: DRUG

Other Intervention Names

DRB436; TMT212

Eligibility Criteria

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

Novartis Investigative Site

Rosario, Sante Fe, Argentina

Novartis Investigative Site

Buenos Aires, , Argentina

Novartis Investigative Site

Córdoba, , Argentina

Novartis Investigative Site

Woolloongabba, Queensland, Australia

Novartis Investigative Site

Cairns, , Australia

Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, Brazil

Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, Brazil

Novartis Investigative Site

São Paulo, São Paulo, Brazil

Novartis Investigative Site

Calgary, Alberta, Canada

Novartis Investigative Site

Edmonton, Alberta, Canada

Novartis Investigative Site

Hamilton, Ontario, Canada

Novartis Investigative Site

London, Ontario, Canada

Novartis Investigative Site

Ottawa, Ontario, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Québec, Quebec, Canada

Novartis Investigative Site

Brno, Czech Republic, Czechia

Novartis Investigative Site

Prague, Czech Republic, Czechia

Novartis Investigative Site

Zlín, Czech Republic, Czechia

Novartis Investigative Site

Hradec Králové, CZE, Czechia

Novartis Investigative Site

Ostrava, Poruba, Czechia

Novartis Investigative Site

Prague, Prague 1, Czechia

Novartis Investigative Site

Olomouc, , Czechia

Novartis Investigative Site

Prague, , Czechia

Novartis Investigative Site

Helsinki, , Finland

Novartis Investigative Site

Tampere, , Finland

Novartis Investigative Site

Turku, , Finland

Novartis Investigative Site

Pierre-Bénite, Cedex 02, France

Novartis Investigative Site

Limoges, Haute Vienne, France

Novartis Investigative Site

Rennes, Ille Et Vilaine, France

Novartis Investigative Site

Besançon, , France

Novartis Investigative Site

Bobigny, , France

Novartis Investigative Site

Bordeaux, , France

Novartis Investigative Site

Boulogne-Billancourt, , France

Novartis Investigative Site

Clermont-Ferrand, , France

Novartis Investigative Site

Dijon, , France

Novartis Investigative Site

Grenoble, , France

Novartis Investigative Site

Lille, , France

Novartis Investigative Site

Lorient, , France

Novartis Investigative Site

Marseille, , France

Novartis Investigative Site

Montpellier, , France

Novartis Investigative Site

Nice, , France

Novartis Investigative Site

Paris, , France

Novartis Investigative Site

Poitiers, , France

Novartis Investigative Site

Reims, , France

Novartis Investigative Site

Toulouse, , France

Novartis Investigative Site

Villejuif, , France

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Athens, , Greece

Novartis Investigative Site

Thessaloniki, , Greece

Novartis Investigative Site

Budapest, , Hungary

Novartis Investigative Site

Pécs, , Hungary

Novartis Investigative Site

Szeged, , Hungary

Novartis Investigative Site

Jerusalem, , Israel

Novartis Investigative Site

Ramat Gan, , Israel

Novartis Investigative Site

Bergamo, BG, Italy

Novartis Investigative Site

Meldola, FC, Italy

Novartis Investigative Site

Antella - Bagno A Ripoli, FI, Italy

Novartis Investigative Site

Genova, GE, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Milan, MI, Italy

Novartis Investigative Site

Modena, MO, Italy

Novartis Investigative Site

Palermo, PA, Italy

Novartis Investigative Site

Padua, PD, Italy

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Roma, RM, Italy

Novartis Investigative Site

Torino, TO, Italy

Novartis Investigative Site

Udine, UD, Italy

Novartis Investigative Site

Napoli, , Italy

Novartis Investigative Site

Sapporo, Hokkaido, Japan

Novartis Investigative Site

Chuo Ku, Tokyo, Japan

Novartis Investigative Site

Riga, , Latvia

Novartis Investigative Site

Vilnius, , Lithuania

Novartis Investigative Site

Ålesund, , Norway

Novartis Investigative Site

Oslo, , Norway

Novartis Investigative Site

Gdansk, , Poland

Novartis Investigative Site

Warsaw, , Poland

Novartis Investigative Site

Wroclaw, , Poland

Novartis Investigative Site

Porto, , Portugal

Novartis Investigative Site

Moscow, , Russia

Novartis Investigative Site

Moscow Region Istra Village, , Russia

Novartis Investigative Site

Omsk, , Russia

Novartis Investigative Site

Saint Petersburg, , Russia

Novartis Investigative Site

Bratislava, , Slovakia

Novartis Investigative Site

Košice, , Slovakia

Novartis Investigative Site

Ljubljana, , Slovenia

Novartis Investigative Site

Gothenburg, , Sweden

Novartis Investigative Site

Örebro, , Sweden

Novartis Investigative Site

Stockholm, , Sweden

Novartis Investigative Site

Umeå, , Sweden

Novartis Investigative Site

Izmir, , Turkey (Türkiye)

Novartis Investigative Site

Bristol, Avon, United Kingdom

Novartis Investigative Site

Northwood, Middlesex, United Kingdom

Novartis Investigative Site

Sheffield, South Yorkshire, United Kingdom

Novartis Investigative Site

Cambridge, , United Kingdom

Novartis Investigative Site

Leeds, , United Kingdom

Novartis Investigative Site

Manchester, , United Kingdom

Novartis Investigative Site

Southampton, , United Kingdom

Countries

Argentina; Australia; Brazil; Canada; Czechia; Finland; France; Greece; Hungary; Israel; Italy; Japan; Latvia; Lithuania; Norway; Poland; Portugal; Russia; Slovakia; Slovenia; Sweden; Turkey (Türkiye); United Kingdom

References

Atkinson V, Robert C, Grob JJ, Gogas H, Dutriaux C, Demidov L, Gupta A, Menzies AM, Ryll B, Miranda F, Banerjee H, Lau M, Del Vecchio M. Improved pyrexia-related outcomes associated with an adapted pyrexia adverse event management algorithm in patients treated with adjuvant dabrafenib plus trametinib: Primary results of COMBI-APlus. Eur J Cancer. 2022 Mar;163:79-87. doi: 10.1016/j.ejca.2021.12.015. Epub 2022 Jan 14.

Reference Type: DERIVED

PMID: 35042070 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.novctrd.com/ctrdweb/patientsummary/patientsummaries?patientSummaryId=1189

A Plain Language Trial Summary is available on www.novctrd.com

Other Identifiers

2018-000168-27

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CDRB436F2410

Identifier Type: -

Identifier Source: org_study_id