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

NCT03551626 | Completed Phase 3 Results DMC

• 2 other identifiers: CDRB436F24102018-000168-27
• Study Type: interventional
• Target: 552
• Locations: 22 countries
• Sites: 99

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.

Conditions

Malignant Melanoma

Keywords

dabrafenib; trametinib; adjuvant; Stage III melanoma; combination treatment; pyrexia

Outcome Measures

Primary Outcomes (1)

• Composite Rate of Pyrexia Related Events

  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)

  Baseline up to 12 months

Secondary Outcomes (5)

• Relapse Free Survival (RFS) Rate

  At 12 and 24 months

• Overall Survival (OS) Rate

  At 12 and 24 months

• Percentage of Participants Who Required Management of Pyrexia

  Baseline up to 12 months

• Percentage of Participants Who Permanently Discontinued Treatment Due to Any Adverse Event (AE)

  Baseline up to 12 months

• 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

Study Arms (1)

Dabrafenib and trametinib combination therapy

EXPERIMENTAL

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

Drug: Dabrafenib; Drug: Trametinib

Interventions

Dabrafenib DRUG

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

Also known as: DRB436

Dabrafenib and trametinib combination therapy

Trametinib DRUG

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

Also known as: TMT212

Dabrafenib and trametinib combination therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma were eligible.
• Subjects who had previously had Stage III melanoma at any time were not eligible.
• 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

You may not qualify if:

• 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
• History or current evidence of cardiovascular risk
• A history or current evidence/risk of retinal vein occlusion (RVO) or central serous retinopathy

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (100)

Novartis Investigative Site

Rosario, Sante Fe, S200KZE, Argentina

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Novartis Investigative Site

Buenos Aires, C1125ABE, Argentina

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Novartis Investigative Site

Córdoba, X5004BAL, Argentina

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Novartis Investigative Site

Woolloongabba, Queensland, 4102, Australia

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Novartis Investigative Site

Cairns, QLD 4870, Australia

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Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 20220410, Brazil

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Novartis Investigative Site

Porto Alegre, Rio Grande do Sul, 90035-003, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 01246 000, Brazil

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Novartis Investigative Site

Calgary, Alberta, T2N 4N2, Canada

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Novartis Investigative Site

Edmonton, Alberta, T6G 1Z2, Canada

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Novartis Investigative Site

Hamilton, Ontario, L8V 5C2, Canada

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Novartis Investigative Site

London, Ontario, N6A 4L6, Canada

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Novartis Investigative Site

Ottawa, Ontario, K1H 8L6, Canada

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Novartis Investigative Site

Toronto, Ontario, M4N 3M5, Canada

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Novartis Investigative Site

Toronto, Ontario, M5G 1Z6, Canada

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Novartis Investigative Site

Montreal, Quebec, H3T 1E2, Canada

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Novartis Investigative Site

Québec, Quebec, G1R 2J6, Canada

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Novartis Investigative Site

Brno, Czech Republic, 656 53, Czechia

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Novartis Investigative Site

Prague, Czech Republic, 180 00, Czechia

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Novartis Investigative Site

Zlín, Czech Republic, 762 75, Czechia

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Novartis Investigative Site

Hradec Králové, CZE, 500 05, Czechia

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Novartis Investigative Site

Ostrava, Poruba, 708 52, Czechia

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Novartis Investigative Site

Prague, Prague 1, 11000, Czechia

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Novartis Investigative Site

Olomouc, 779 00, Czechia

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Novartis Investigative Site

Prague, 12808, Czechia

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Novartis Investigative Site

Helsinki, 9, Finland

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Novartis Investigative Site

Tampere, FIN-33521, Finland

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Novartis Investigative Site

Turku, 20520, Finland

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Novartis Investigative Site

Pierre-Bénite, Cedex 02, 69495, France

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Novartis Investigative Site

Limoges, Haute Vienne, 87000, France

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Novartis Investigative Site

Rennes, Ille Et Vilaine, 35062, France

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Novartis Investigative Site

Besançon, 25030, France

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Novartis Investigative Site

Bobigny, 93009, France

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Novartis Investigative Site

Bordeaux, 33075, France

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Novartis Investigative Site

Boulogne-Billancourt, 92104, France

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Novartis Investigative Site

Clermont-Ferrand, 63003, France

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Novartis Investigative Site

Dijon, 21034, France

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Novartis Investigative Site

Grenoble, 38043, France

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Novartis Investigative Site

Lille, 59037, France

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Novartis Investigative Site

Lorient, 56322, France

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Novartis Investigative Site

Marseille, 13885, France

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Novartis Investigative Site

Montpellier, 34295, France

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Novartis Investigative Site

Nice, 06202, France

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Novartis Investigative Site

Paris, 75475, France

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Novartis Investigative Site

Poitiers, 86021, France

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Novartis Investigative Site

Reims, 51092, France

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Novartis Investigative Site

Toulouse, 31059, France

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Novartis Investigative Site

Villejuif, 94800, France

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Novartis Investigative Site

Athens, 115 27, Greece

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Novartis Investigative Site

Athens, 18547, Greece

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Novartis Investigative Site

Athens, GR 115 22, Greece

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Novartis Investigative Site

Thessaloniki, 54622, Greece

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Novartis Investigative Site

Budapest, H 1122, Hungary

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Novartis Investigative Site

Pécs, 7623, Hungary

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Novartis Investigative Site

Szeged, H 6725, Hungary

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Novartis Investigative Site

Jerusalem, 9112001, Israel

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Novartis Investigative Site

Ramat Gan, 52621, Israel

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Novartis Investigative Site

Bergamo, BG, 24127, Italy

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Novartis Investigative Site

Meldola, FC, 47014, Italy

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Novartis Investigative Site

Antella - Bagno A Ripoli, FI, 50011, Italy

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Novartis Investigative Site

Genova, GE, 16132, Italy

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Novartis Investigative Site

Milan, MI, 20133, Italy

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Novartis Investigative Site

Milan, MI, 20141, Italy

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Novartis Investigative Site

Modena, MO, 41124, Italy

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Novartis Investigative Site

Palermo, PA, 90127, Italy

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Novartis Investigative Site

Padua, PD, 35100, Italy

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Novartis Investigative Site

Roma, RM, 00128, Italy

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Novartis Investigative Site

Roma, RM, 00167, Italy

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Novartis Investigative Site

Torino, TO, 10126, Italy

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Novartis Investigative Site

Udine, UD, 33100, Italy

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Novartis Investigative Site

Napoli, 80131, Italy

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Novartis Investigative Site

Sapporo, Hokkaido, 060-8543, Japan

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Novartis Investigative Site

Chuo Ku, Tokyo, 104 0045, Japan

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Novartis Investigative Site

Riga, LV 1079, Latvia

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Novartis Investigative Site

Vilnius, LT-08660, Lithuania

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Novartis Investigative Site

Ålesund, NO-6026, Norway

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Novartis Investigative Site

Oslo, 0379, Norway

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Novartis Investigative Site

Gdansk, 80 952, Poland

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Novartis Investigative Site

Warsaw, 02 781, Poland

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Novartis Investigative Site

Wroclaw, 53 413, Poland

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Novartis Investigative Site

Porto, 4200-072, Portugal

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Novartis Investigative Site

Moscow, 115478, Russia

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Novartis Investigative Site

Moscow Region Istra Village, 143423, Russia

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Novartis Investigative Site

Omsk, 644013, Russia

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Novartis Investigative Site

Saint Petersburg, 197758, Russia

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Novartis Investigative Site

Bratislava, 812 50, Slovakia

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Novartis Investigative Site

Košice, 04191, Slovakia

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Novartis Investigative Site

Ljubljana, 1000, Slovenia

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Novartis Investigative Site

Gothenburg, SE-413 45, Sweden

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Novartis Investigative Site

Örebro, 701 85, Sweden

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Novartis Investigative Site

Stockholm, SE 171 76, Sweden

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Novartis Investigative Site

Umeå, SE 901 85, Sweden

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Novartis Investigative Site

Izmir, 35040, Turkey (Türkiye)

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Novartis Investigative Site

Bristol, Avon, BS2 8ED, United Kingdom

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Novartis Investigative Site

Northwood, Middlesex, HA6 2RN, United Kingdom

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Novartis Investigative Site

Sheffield, South Yorkshire, S10 2JF, United Kingdom

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Novartis Investigative Site

Cambridge, CB2 2QQ, United Kingdom

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Novartis Investigative Site

Leeds, LS9 7TF, United Kingdom

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Novartis Investigative Site

Manchester, M20 4BX, United Kingdom

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Novartis Investigative Site

Southampton, SO16 6YD, United Kingdom

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Related Publications (1)

• 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.

  PMID: 35042070 DERIVED

Related Links

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

MeSH Terms

Conditions

Melanoma; Fever

Interventions

dabrafenib; trametinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Body Temperature Changes; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Study director
• Organization: Novartis Pharmaceuticals

Novartis.email@novartis.com

862-778-8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2018
• First Posted: June 11, 2018
• Study Start: August 29, 2018
• Primary Completion: October 5, 2020
• Study Completion: September 16, 2021
• Last Updated: April 29, 2025
• Results First Posted: March 18, 2024

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will share

Locations

HU (3); LA (1); LI (1); SL (2); FI (3); CZ (8); GR (4); FR (20); PL (3); CA (9); RU (4); NO (2); PT (1); AU (2); JP (2); SE (4); BR (3); TU (1); GB (7); AR (3); IT (14); IL (2)