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

Malignant Melanoma Clinical Trial

— COMBI-APlus  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03551626
• Other study ID #: CDRB436F2410
• Secondary ID: 2018-000168-27
• Status: Completed
• Phase: Phase 3
• Start date: August 29, 2018
• Est. completion date: September 16, 2021

Study information

• Verified date: September 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 552
• Est. completion date: September 16, 2021
• Est. primary completion date: October 5, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Fever
• Hyperthermia
• Malignant Melanoma
• Melanoma

Intervention

Drug:
• Dabrafenib
Supplied as dabrafenib 50 mg and 75 mg capsules for oral administration
• Trametinib
Supplied as trametinib 0.5mg, and 2.0mg tablets for oral administration

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Rosario	Sante Fe
Australia	Novartis Investigative Site	Cairns
Australia	Novartis Investigative Site	Woolloongabba	Queensland
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Canada	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	Montreal	Quebec
Canada	Novartis Investigative Site	Ottawa	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Czechia	Novartis Investigative Site	Brno	Czech Republic
Czechia	Novartis Investigative Site	Hradec Kralove	CZE
Czechia	Novartis Investigative Site	Olomouc
Czechia	Novartis Investigative Site	Ostrava	Poruba
Czechia	Novartis Investigative Site	Prague	Prague 1
Czechia	Novartis Investigative Site	Prague 8	Czech Republic
Czechia	Novartis Investigative Site	Praha
Czechia	Novartis Investigative Site	Zlin	Czech Republic
Finland	Novartis Investigative Site	Helsinki
Finland	Novartis Investigative Site	Tampere
Finland	Novartis Investigative Site	Turku
France	Novartis Investigative Site	Besancon Cedex
France	Novartis Investigative Site	Bobigny Cedex
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Boulogne Billancourt
France	Novartis Investigative Site	Clermont Ferrand
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Grenoble Cedex 9
France	Novartis Investigative Site	Lille Cedex
France	Novartis Investigative Site	Limoges	Haute Vienne
France	Novartis Investigative Site	Lorient
France	Novartis Investigative Site	Marseille Cedex 05
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Nice
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Pierre Benite	Cedex 02
France	Novartis Investigative Site	Poitiers
France	Novartis Investigative Site	Reims
France	Novartis Investigative Site	Rennes Cedex	Ille Et Vilaine
France	Novartis Investigative Site	Toulouse
France	Novartis Investigative Site	Villejuif
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Thessaloniki
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Pecs
Hungary	Novartis Investigative Site	Szeged
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Antella - Bagno A Ripoli	FI
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Meldola	FC
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Padova	PD
Italy	Novartis Investigative Site	Palermo	PA
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Udine	UD
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Latvia	Novartis Investigative Site	Riga
Lithuania	Novartis Investigative Site	Vilnius
Norway	Novartis Investigative Site	Alesund
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Gdansk
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Portugal	Novartis Investigative Site	Porto
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow Region Istra Village
Russian Federation	Novartis Investigative Site	Omsk
Russian Federation	Novartis Investigative Site	St Petersburg
Slovakia	Novartis Investigative Site	Bratislava
Slovakia	Novartis Investigative Site	Kosice
Slovenia	Novartis Investigative Site	Ljubljana
Sweden	Novartis Investigative Site	Goteborg
Sweden	Novartis Investigative Site	Orebro
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Umea
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Bristol	Avon
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	Manchester
United Kingdom	Novartis Investigative Site	Northwood	Middlesex
United Kingdom	Novartis Investigative Site	Sheffield	South Yorkshire
United Kingdom	Novartis Investigative Site	Southampton

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Argentina,  Australia,  Brazil,  Canada,  Czechia,  Finland,  France,  Greece,  Hungary,  Israel,  Italy,  Japan,  Latvia,  Lithuania,  Norway,  Poland,  Portugal,  Russian Federation,  Slovakia,  Slovenia,  Sweden,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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