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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)

Primary Purpose

Malignant Melanoma

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Dabrafenib

Trametinib

About this trial

This is an interventional treatment trial for Malignant Melanoma focused on measuring dabrafenib, trametinib, adjuvant, Stage III melanoma, combination treatment, pyrexia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)]
V600E/K mutation positive using a validated local test
Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible.
Subjects who have previously had Stage III melanoma at any time are not eligible.
Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains).
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 have 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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dabrafenib and trametinib combination therapy

Arm Description

Subjects will receive dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

Outcomes

Primary Outcome Measures

Change from baseline in composite rate of pyrexia related events

The composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia by 12 months in overall treated subjects

Secondary Outcome Measures

Relapse free survival (RFS) from the first dose to disease recurrence or death from any cause

RFS is defined as the time from the date of first dose of the study medication to the date of disease recurrence or death due to any cause.

Overall Survival (OS) from the first dose to date of death due to any cause

OS is defined as the time from date of the first dose of study medication to date of death due to any cause.

Percentage of patients who require management of pyrexia

Percentage of patients who experienced pyrexia and required intervention

The percentage of participants who permanently discontinued treatment due to any Adverse event

Participants who permanently discontinued treatment due to any Adverse event during treatment

Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M MS)

QoL assessed using Function Assessment Cancer Therapy-melanoma (FACT-M) assessment tool. This includes the FACT-Melanoma subscale (FACT-M MS) questionnaire -specific subscale consists of 16 questions for Melanoma Subscale (MS) and 8 questions for Melanoma Surgery Scale (MSS).Each of these questions could have a response of Not at all, a little bit, somewhat, quite a bit and very much. The responses were given a value between 0 and 4 with 4 being best response. The FACT-M Total Score (FACT-M TS) ranges from 0 to 172 and is derived as follows: FACT-M TS= PWB Score + SWB Score + EWB Score + FWB Score + MS Score. Higher scores represent a better quality of life.

Full Information

NCT ID

NCT03551626

First Posted

April 30, 2018

Last Updated

October 14, 2021

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT03551626

Brief Title

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

Acronym

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)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2021

Overall Recruitment Status

Completed

Study Start Date

August 29, 2018 (Actual)

Primary Completion Date

October 5, 2020 (Actual)

Study Completion Date

September 16, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection to evaluate the impact on pyrexia related outcomes of an adapted pyrexia AE-management algorithm, as well as safety, efficacy and health-related outcomes. Approximately 600 subjects will be enrolled to receive dabrafenib (150 mg BID) and trametinib (2 mg once daily) combination therapy for 12 months. At enrollment, subjects will be instructed on the pyrexia management algorithm. This study consists of two Periods for Enrolled subjects: Treatment Period - subjects will receive up to 12 months of treatment. Follow-up Period - subjects will be followed through 24 months from their first dose date for relapse, and through end of study for overall survival. Follow-up will start once treatment is complete or is prematurely discontinued and continue through the end of the study, regardless of disease recurrence.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Malignant Melanoma

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

556 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dabrafenib and trametinib combination therapy

Arm Type

Experimental

Arm Description

Subjects will receive dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

Intervention Type

Drug

Intervention Name(s)

Dabrafenib

Intervention Description

Supplied as dabrafenib 50 mg, 75 mg Capsules for oral use

Intervention Type

Drug

Intervention Name(s)

Trametinib

Intervention Description

supplied as trametinib 0.5mg, 2.0mg tablets for oral use

Primary Outcome Measure Information:

Title

Change from baseline in composite rate of pyrexia related events

Description

The composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia by 12 months in overall treated subjects

Time Frame

Baseline up to 12 months

Secondary Outcome Measure Information:

Title

Relapse free survival (RFS) from the first dose to disease recurrence or death from any cause

Description

RFS is defined as the time from the date of first dose of the study medication to the date of disease recurrence or death due to any cause.

Time Frame

Baseline up to approximately 24 months

Title

Overall Survival (OS) from the first dose to date of death due to any cause

Description

OS is defined as the time from date of the first dose of study medication to date of death due to any cause.

Time Frame

Baseline up to approximately 24 months

Title

Percentage of patients who require management of pyrexia

Description

Percentage of patients who experienced pyrexia and required intervention

Time Frame

Baseline up to 12 months

Title

The percentage of participants who permanently discontinued treatment due to any Adverse event

Description

Participants who permanently discontinued treatment due to any Adverse event during treatment

Time Frame

Baseline up to 12 months

Title

Change From Baseline in Subject-reported Quality of Life Assessed by Functional Assessment Cancer Therapy - Melanoma Total Score (FACT-M MS)

Description

Time Frame

Baseline up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)] V600E/K mutation positive using a validated local test Subjects presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible. Subjects who have previously had Stage III melanoma at any time are not eligible. Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains). 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 have 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

Facility Information:

Facility Name

Novartis Investigative Site

City

Rosario

State/Province

Sante Fe

ZIP/Postal Code

S200KZE

Country

Argentina

Facility Name

Novartis Investigative Site

City

Buenos Aires

ZIP/Postal Code

C1125ABE

Country

Argentina

Facility Name

Novartis Investigative Site

City

Cordoba

ZIP/Postal Code

X5004BAL

Country

Argentina

Facility Name

Novartis Investigative Site

City

Woolloongabba

State/Province

Queensland

ZIP/Postal Code

4102

Country

Australia

Facility Name

Novartis Investigative Site

City

Cairns

ZIP/Postal Code

QLD 4870

Country

Australia

Facility Name

Novartis Investigative Site

City

Rio de Janeiro

State/Province

ZIP/Postal Code

20220410

Country

Brazil

Facility Name

Novartis Investigative Site

City

Porto Alegre

State/Province

ZIP/Postal Code

90035-003

Country

Brazil

Facility Name

Novartis Investigative Site

City

Sao Paulo

State/Province

ZIP/Postal Code

01246 000

Country

Brazil

Facility Name

Novartis Investigative Site

City

Calgary

State/Province

Alberta

ZIP/Postal Code

T2N 4N2

Country

Canada

Facility Name

Novartis Investigative Site

City

Edmonton

State/Province

Alberta

ZIP/Postal Code

T6G 1Z2

Country

Canada

Facility Name

Novartis Investigative Site

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8V 5C2

Country

Canada

Facility Name

Novartis Investigative Site

City

London

State/Province

Ontario

ZIP/Postal Code

N6A 4L6

Country

Canada

Facility Name

Novartis Investigative Site

City

Ottawa

State/Province

Ontario

ZIP/Postal Code

K1H 8L6

Country

Canada

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M4N 3M5

Country

Canada

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 1Z6

Country

Canada

Facility Name

Novartis Investigative Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H3T 1E2

Country

Canada

Facility Name

Novartis Investigative Site

City

Quebec

ZIP/Postal Code

G1R 2J6

Country

Canada

Facility Name

Novartis Investigative Site

City

Brno

State/Province

Czech Republic

ZIP/Postal Code

656 53

Country

Czechia

Facility Name

Novartis Investigative Site

City

Ostrava Poruba

State/Province

Czech Republic

ZIP/Postal Code

708 52

Country

Czechia

Facility Name

Novartis Investigative Site

City

Prague 8

State/Province

Czech Republic

ZIP/Postal Code

180 00

Country

Czechia

Facility Name

Novartis Investigative Site

City

Zlin

State/Province

Czech Republic

ZIP/Postal Code

762 75

Country

Czechia

Facility Name

Novartis Investigative Site

City

Hradec Kralove

State/Province

CZE

ZIP/Postal Code

500 05

Country

Czechia

Facility Name

Novartis Investigative Site

City

Prague

State/Province

Prague 1

ZIP/Postal Code

11000

Country

Czechia

Facility Name

Novartis Investigative Site

City

Olomouc

ZIP/Postal Code

775 20

Country

Czechia

Facility Name

Novartis Investigative Site

City

Praha

ZIP/Postal Code

12808

Country

Czechia

Facility Name

Novartis Investigative Site

City

Helsinki

ZIP/Postal Code

Country

Finland

Facility Name

Novartis Investigative Site

City

Tampere

ZIP/Postal Code

FIN-33521

Country

Finland

Facility Name

Novartis Investigative Site

City

Turku

ZIP/Postal Code

20520

Country

Finland

Facility Name

Novartis Investigative Site

City

Pierre Benite Cedex

State/Province

Cedex 02

ZIP/Postal Code

69495

Country

France

Facility Name

Novartis Investigative Site

City

Limoges cedex

State/Province

Haute Vienne

ZIP/Postal Code

87000

Country

France

Facility Name

Novartis Investigative Site

City

Rennes Cedex

State/Province

Ille Et Vilaine

ZIP/Postal Code

35062

Country

France

Facility Name

Novartis Investigative Site

City

Besancon Cedex

ZIP/Postal Code

25030

Country

France

Facility Name

Novartis Investigative Site

City

Bobigny Cedex

ZIP/Postal Code

93009

Country

France

Facility Name

Novartis Investigative Site

City

Bordeaux Cedex

ZIP/Postal Code

33075

Country

France

Facility Name

Novartis Investigative Site

City

Boulogne Billancourt

ZIP/Postal Code

92104

Country

France

Facility Name

Novartis Investigative Site

City

Clermont Ferrand

ZIP/Postal Code

63003

Country

France

Facility Name

Novartis Investigative Site

City

Dijon

ZIP/Postal Code

21034

Country

France

Facility Name

Novartis Investigative Site

City

Grenoble Cedex 9

ZIP/Postal Code

38043

Country

France

Facility Name

Novartis Investigative Site

City

Lille Cedex

ZIP/Postal Code

59037

Country

France

Facility Name

Novartis Investigative Site

City

Lorient Cedex

ZIP/Postal Code

56322

Country

France

Facility Name

Novartis Investigative Site

City

Marseille Cedex 05

ZIP/Postal Code

13885

Country

France

Facility Name

Novartis Investigative Site

City

Montpellier

ZIP/Postal Code

34295

Country

France

Facility Name

Novartis Investigative Site

City

Nice Cedex

ZIP/Postal Code

06202

Country

France

Facility Name

Novartis Investigative Site

City

Paris Cedex 10

ZIP/Postal Code

75475

Country

France

Facility Name

Novartis Investigative Site

City

Poitiers

ZIP/Postal Code

86021

Country

France

Facility Name

Novartis Investigative Site

City

Reims

ZIP/Postal Code

51092

Country

France

Facility Name

Novartis Investigative Site

City

Toulouse Cedex 9

ZIP/Postal Code

31059

Country

France

Facility Name

Novartis Investigative Site

City

Villejuif Cedex

ZIP/Postal Code

94800

Country

France

Facility Name

Novartis Investigative Site

City

Athens

ZIP/Postal Code

115 27

Country

Greece

Facility Name

Novartis Investigative Site

City

Athens

ZIP/Postal Code

18547

Country

Greece

Facility Name

Novartis Investigative Site

City

Athens

ZIP/Postal Code

GR 115 22

Country

Greece

Facility Name

Novartis Investigative Site

City

Thessaloniki

ZIP/Postal Code

54622

Country

Greece

Facility Name

Novartis Investigative Site

City

Budapest

ZIP/Postal Code

H 1122

Country

Hungary

Facility Name

Novartis Investigative Site

City

Pecs

ZIP/Postal Code

7623

Country

Hungary

Facility Name

Novartis Investigative Site

City

Szeged

ZIP/Postal Code

H 6725

Country

Hungary

Facility Name

Novartis Investigative Site

City

Jerusalem

ZIP/Postal Code

9112001

Country

Israel

Facility Name

Novartis Investigative Site

City

Ramat Gan

ZIP/Postal Code

52621

Country

Israel

Facility Name

Novartis Investigative Site

City

Bergamo

State/Province

ZIP/Postal Code

24127

Country

Italy

Facility Name

Novartis Investigative Site

City

Meldola

State/Province

ZIP/Postal Code

47014

Country

Italy

Facility Name

Novartis Investigative Site

City

Antella - Bagno A Ripoli

State/Province

ZIP/Postal Code

50011

Country

Italy

Facility Name

Novartis Investigative Site

City

Genova

State/Province

ZIP/Postal Code

16132

Country

Italy

Facility Name

Novartis Investigative Site

City

Milano

State/Province

ZIP/Postal Code

20133

Country

Italy

Facility Name

Novartis Investigative Site

City

Milano

State/Province

ZIP/Postal Code

20141

Country

Italy

Facility Name

Novartis Investigative Site

City

Modena

State/Province

ZIP/Postal Code

41124

Country

Italy

Facility Name

Novartis Investigative Site

City

Palermo

State/Province

ZIP/Postal Code

90127

Country

Italy

Facility Name

Novartis Investigative Site

City

Padova

State/Province

ZIP/Postal Code

35100

Country

Italy

Facility Name

Novartis Investigative Site

City

Roma

State/Province

ZIP/Postal Code

00128

Country

Italy

Facility Name

Novartis Investigative Site

City

Roma

State/Province

ZIP/Postal Code

00167

Country

Italy

Facility Name

Novartis Investigative Site

City

Torino

State/Province

ZIP/Postal Code

10126

Country

Italy

Facility Name

Novartis Investigative Site

City

Udine

State/Province

ZIP/Postal Code

33100

Country

Italy

Facility Name

Novartis Investigative Site

City

Napoli

ZIP/Postal Code

80131

Country

Italy

Facility Name

Novartis Investigative Site

City

Sapporo-city

State/Province

Hokkaido

ZIP/Postal Code

060-8543

Country

Japan

Facility Name

Novartis Investigative Site

City

Chuo ku

State/Province

Tokyo

ZIP/Postal Code

104 0045

Country

Japan

Facility Name

Novartis Investigative Site

City

Riga

ZIP/Postal Code

LV 1079

Country

Latvia

Facility Name

Novartis Investigative Site

City

Vilnius

ZIP/Postal Code

LT-08660

Country

Lithuania

Facility Name

Novartis Investigative Site

City

Oslo

ZIP/Postal Code

0379

Country

Norway

Facility Name

Novartis Investigative Site

City

Ålesund

ZIP/Postal Code

NO-6026

Country

Norway

Facility Name

Novartis Investigative Site

City

Gdansk

ZIP/Postal Code

80 952

Country

Poland

Facility Name

Novartis Investigative Site

City

Warszawa

ZIP/Postal Code

02 781

Country

Poland

Facility Name

Novartis Investigative Site

City

Wroclaw

ZIP/Postal Code

53 413

Country

Poland

Facility Name

Novartis Investigative Site

City

Porto

ZIP/Postal Code

4200-072

Country

Portugal

Facility Name

Novartis Investigative Site

City

Moscow

ZIP/Postal Code

115478

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Moscow

ZIP/Postal Code

143423

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Omsk

ZIP/Postal Code

644013

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

St Petersburg

ZIP/Postal Code

197758

Country

Russian Federation

Facility Name

Novartis Investigative Site

City

Bratislava

ZIP/Postal Code

812 50

Country

Slovakia

Facility Name

Novartis Investigative Site

City

Kosice

ZIP/Postal Code

04191

Country

Slovakia

Facility Name

Novartis Investigative Site

City

Ljubljana

ZIP/Postal Code

1000

Country

Slovenia

Facility Name

Novartis Investigative Site

City

Goteborg

ZIP/Postal Code

SE-413 45

Country

Sweden

Facility Name

Novartis Investigative Site

City

Orebro

ZIP/Postal Code

701 85

Country

Sweden

Facility Name

Novartis Investigative Site

City

Stockholm

ZIP/Postal Code

SE 171 76

Country

Sweden

Facility Name

Novartis Investigative Site

City

Umea

ZIP/Postal Code

SE 901 85

Country

Sweden

Facility Name

Novartis Investigative Site

City

Izmir

ZIP/Postal Code

35040

Country

Turkey

Facility Name

Novartis Investigative Site

City

Bristol

State/Province

Avon

ZIP/Postal Code

BS2 8ED

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Northwood

State/Province

Middlesex

ZIP/Postal Code

HA6 2RN

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Sheffield

State/Province

South Yorkshire

ZIP/Postal Code

S10 2JF

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Cambridge

ZIP/Postal Code

CB2 2QQ

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Leeds

ZIP/Postal Code

LS9 7TF

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Manchester

ZIP/Postal Code

M20 4BX

Country

United Kingdom

Facility Name

Novartis Investigative Site

City

Southampton

ZIP/Postal Code

SO16 6YD

Country

United Kingdom

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

35042070

Citation

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.

Results Reference

derived

Learn more about this trial

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

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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)

Malignant Melanoma

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial