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)

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)

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.

Study Overview

• Status: Completed
• Conditions: Malignant Melanoma
• Intervention / Treatment: Drug: Dabrafenib; Drug: Trametinib

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.

• Study Type: Interventional
• Enrollment (Actual): 552
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1125ABE
    • Novartis Investigative Site
  • Cordoba, Argentina, X5004BAL
    • Novartis Investigative Site
  • Sante Fe
    • Rosario, Sante Fe, Argentina, S200KZE
      • Novartis Investigative Site
• Australia
  • Cairns, Australia, QLD 4870
    • Novartis Investigative Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Novartis Investigative Site
• Brazil
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20220410
      • Novartis Investigative Site
  • RS
    • Porto Alegre, RS, Brazil, 90035-003
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 01246 000
      • Novartis Investigative Site
• Canada
  • Quebec, Canada, G1R 2J6
    • Novartis Investigative Site
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Novartis Investigative Site
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Novartis Investigative Site
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Novartis Investigative Site
    • London, Ontario, Canada, N6A 4L6
      • Novartis Investigative Site
    • Ottawa, Ontario, Canada, K1H 8L6
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M4N 3M5
      • Novartis Investigative Site
    • Toronto, Ontario, Canada, M5G 1Z6
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Novartis Investigative Site
• Czechia
  • Olomouc, Czechia, 779 00
    • Novartis Investigative Site
  • Praha, Czechia, 12808
    • Novartis Investigative Site
  • CZE
    • Hradec Kralove, CZE, Czechia, 500 05
      • Novartis Investigative Site
  • Czech Republic
    • Brno, Czech Republic, Czechia, 656 53
      • Novartis Investigative Site
    • Prague 8, Czech Republic, Czechia, 180 00
      • Novartis Investigative Site
    • Zlin, Czech Republic, Czechia, 762 75
      • Novartis Investigative Site
  • Poruba
    • Ostrava, Poruba, Czechia, 708 52
      • Novartis Investigative Site
  • Prague 1
    • Prague, Prague 1, Czechia, 11000
      • Novartis Investigative Site
• Finland
  • Helsinki, Finland, 9
    • Novartis Investigative Site
  • Tampere, Finland, FIN-33521
    • Novartis Investigative Site
  • Turku, Finland, 20520
    • Novartis Investigative Site
• France
  • Besancon Cedex, France, 25030
    • Novartis Investigative Site
  • Bobigny Cedex, France, 93009
    • Novartis Investigative Site
  • Bordeaux Cedex, France, 33075
    • Novartis Investigative Site
  • Boulogne Billancourt, France, 92104
    • Novartis Investigative Site
  • Clermont Ferrand, France, 63003
    • Novartis Investigative Site
  • Dijon, France, 21034
    • Novartis Investigative Site
  • Grenoble Cedex 9, France, 38043
    • Novartis Investigative Site
  • Lille Cedex, France, 59037
    • Novartis Investigative Site
  • Lorient, France, 56322
    • Novartis Investigative Site
  • Marseille Cedex 05, France, 13885
    • Novartis Investigative Site
  • Montpellier, France, 34295
    • Novartis Investigative Site
  • Nice, France, 06202
    • Novartis Investigative Site
  • Paris 10, France, 75475
    • Novartis Investigative Site
  • Poitiers, France, 86021
    • Novartis Investigative Site
  • Reims, France, 51092
    • Novartis Investigative Site
  • Toulouse, France, 31059
    • Novartis Investigative Site
  • Villejuif, France, 94800
    • Novartis Investigative Site
  • Cedex 02
    • Pierre Benite, Cedex 02, France, 69495
      • Novartis Investigative Site
  • Haute Vienne
    • Limoges, Haute Vienne, France, 87000
      • Novartis Investigative Site
  • Ille Et Vilaine
    • Rennes Cedex, Ille Et Vilaine, France, 35062
      • Novartis Investigative Site
• Greece
  • Athens, Greece, 115 27
    • Novartis Investigative Site
  • Athens, Greece, 18547
    • Novartis Investigative Site
  • Athens, Greece, GR 115 22
    • Novartis Investigative Site
  • Thessaloniki, Greece, 54622
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H 1122
    • Novartis Investigative Site
  • Pecs, Hungary, 7623
    • Novartis Investigative Site
  • Szeged, Hungary, H 6725
    • Novartis Investigative Site
• Israel
  • Jerusalem, Israel, 9112001
    • Novartis Investigative Site
  • Ramat Gan, Israel, 52621
    • Novartis Investigative Site
• Italy
  • Napoli, Italy, 80131
    • Novartis Investigative Site
  • BG
    • Bergamo, BG, Italy, 24127
      • Novartis Investigative Site
  • FC
    • Meldola, FC, Italy, 47014
      • Novartis Investigative Site
  • FI
    • Antella - Bagno A Ripoli, FI, Italy, 50011
      • Novartis Investigative Site
  • GE
    • Genova, GE, Italy, 16132
      • Novartis Investigative Site
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
  • MO
    • Modena, MO, Italy, 41124
      • Novartis Investigative Site
  • PA
    • Palermo, PA, Italy, 90127
      • Novartis Investigative Site
  • PD
    • Padova, PD, Italy, 35100
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00128
      • Novartis Investigative Site
    • Roma, RM, Italy, 00167
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
  • UD
    • Udine, UD, Italy, 33100
      • Novartis Investigative Site
• Japan
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8543
      • Novartis Investigative Site
  • Tokyo
    • Chuo ku, Tokyo, Japan, 104 0045
      • Novartis Investigative Site
• Latvia
  • Riga, Latvia, LV 1079
    • Novartis Investigative Site
• Lithuania
  • Vilnius, Lithuania, LT-08660
    • Novartis Investigative Site
• Norway
  • Alesund, Norway, NO-6026
    • Novartis Investigative Site
  • Oslo, Norway, 0379
    • Novartis Investigative Site
• Poland
  • Gdansk, Poland, 80 952
    • Novartis Investigative Site
  • Warszawa, Poland, 02 781
    • Novartis Investigative Site
  • Wroclaw, Poland, 53 413
    • Novartis Investigative Site
• Portugal
  • Porto, Portugal, 4200-072
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • Moscow Region Istra Village, Russian Federation, 143423
    • Novartis Investigative Site
  • Omsk, Russian Federation, 644013
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 197758
    • Novartis Investigative Site
• Slovakia
  • Bratislava, Slovakia, 812 50
    • Novartis Investigative Site
  • Kosice, Slovakia, 04191
    • Novartis Investigative Site
• Slovenia
  • Ljubljana, Slovenia, 1000
    • Novartis Investigative Site
• Sweden
  • Goteborg, Sweden, SE-413 45
    • Novartis Investigative Site
  • Orebro, Sweden, 701 85
    • Novartis Investigative Site
  • Stockholm, Sweden, SE 171 76
    • Novartis Investigative Site
  • Umea, Sweden, SE 901 85
    • Novartis Investigative Site
• Turkey
  • Izmir, Turkey, 35040
    • Novartis Investigative Site
• United Kingdom
  • Cambridge, United Kingdom, CB2 2QQ
    • Novartis Investigative Site
  • Leeds, United Kingdom, LS9 7TF
    • Novartis Investigative Site
  • Manchester, United Kingdom, M20 4BX
    • Novartis Investigative Site
  • Southampton, United Kingdom, SO16 6YD
    • Novartis Investigative Site
  • Avon
    • Bristol, Avon, United Kingdom, BS2 8ED
      • Novartis Investigative Site
  • Middlesex
    • Northwood, Middlesex, United Kingdom, HA6 2RN
      • Novartis Investigative Site
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S10 2JF
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dabrafenib and trametinib combination therapy; Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months.	Drug: Dabrafenib; Supplied as dabrafenib 50 mg and 75 mg capsules for oral administration; Other Names: DRB436; Drug: Trametinib; Supplied as trametinib 0.5mg, and 2.0mg tablets for oral administration; Other Names: TMT212

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse Free Survival (RFS) Rate	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.	At 12 and 24 months
Overall Survival (OS) Rate	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).	At 12 and 24 months
Percentage of Participants Who Required Management of Pyrexia	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	Baseline up to 12 months
Percentage of Participants Who Permanently Discontinued Treatment Due to Any Adverse Event (AE)	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.	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)	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	Baseline up to 24 months

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 29, 2018
• Primary Completion (Actual): October 5, 2020
• Study Completion (Actual): September 16, 2021

Study Registration Dates

• First Submitted: April 30, 2018
• First Submitted That Met QC Criteria: May 28, 2018
• First Posted (Actual): June 11, 2018

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: September 7, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: adjuvant; trametinib; dabrafenib; combination treatment; Stage III melanoma; pyrexia
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Wounds and Injuries; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Body Temperature Changes; Heat Stress Disorders; Skin Neoplasms; Melanoma; Hyperthermia; Fever; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib; Dabrafenib
• Other Study ID Numbers: CDRB436F2410; 2018-000168-27 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No