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)

• ClinicalTrials.gov Identifier: NCT03551626
• Recruitment Status: Completed
• First Posted: June 11, 2018
• Last Update Posted: October 15, 2021
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: April 30, 2018
• First Posted Date: June 11, 2018
• Last Update Posted Date: October 15, 2021
• Actual Study Start Date: August 29, 2018
• Actual Primary Completion Date: October 5, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 2, 2020)

Change from baseline in composite rate of pyrexia related events [ Time Frame: Baseline up to 12 months ]

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

Original Primary Outcome Measures (submitted: May 28, 2018)

Change from baseline in composite rate of pyrexia related events [ Time Frame: Baseline up to 12 months ]

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

Current Secondary Outcome Measures (submitted: May 28, 2018)

• Relapse free survival (RFS) from the first dose to disease recurrence or death from any cause [ Time Frame: Baseline up to approximately 24 months ]
  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 [ Time Frame: Baseline up to approximately 24 months ]
  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 [ Time Frame: Baseline up to 12 months ]
  Percentage of patients who experienced pyrexia and required intervention
• The percentage of participants who permanently discontinued treatment due to any Adverse event [ Time Frame: Baseline up to 12 months ]
  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) [ Time Frame: Baseline up to 24 months ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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
• 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)

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.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Malignant Melanoma

Intervention

• Drug: Dabrafenib
  Supplied as dabrafenib 50 mg, 75 mg Capsules for oral use
• Drug: Trametinib
  supplied as trametinib 0.5mg, 2.0mg tablets for oral use

Study Arms

Experimental: Dabrafenib and trametinib combination therapy

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

Interventions:

• Drug: Dabrafenib
• Drug: Trametinib

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 12, 2021): 556
• Original Estimated Enrollment (submitted: May 28, 2018): 600
• Actual Study Completion Date: September 16, 2021
• Actual Primary Completion Date: October 5, 2020 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: 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
• Removed Location Countries: Belgium

Administrative Information

• NCT Number: NCT03551626
• Other Study ID Numbers: CDRB436F2410; 2018-000168-27 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Novartis
• Verification Date: October 2021