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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01682083




Registration number
NCT01682083
Ethics application status
Date submitted
6/09/2012
Date registered
10/09/2012
Date last updated
30/08/2023

Titles & IDs
Public title
Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).
Scientific title
COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection
Secondary ID [1] 0 0
2012-001266-15
Secondary ID [2] 0 0
115532
Universal Trial Number (UTN)
Trial acronym
COMBI-AD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melanoma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Malignant melanoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Dabrafenib
Treatment: Drugs - Trametinib
Treatment: Drugs - Placebos

Experimental: Dabrafenib and trametinib - Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.

Placebo comparator: Dabrafenib and trametinib placebos - Subjects received matching placebos orally for 12 months


Treatment: Drugs: Dabrafenib
Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)

Treatment: Drugs: Trametinib
Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)

Treatment: Drugs: Placebos
The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Relapse-free Survival (RFS)
Timepoint [1] 0 0
Approximately 3.5 years
Secondary outcome [1] 0 0
Overall Survival
Timepoint [1] 0 0
approximately 3.5 years
Secondary outcome [2] 0 0
Distant Metastasis-free Survival
Timepoint [2] 0 0
approximately 3.5 years
Secondary outcome [3] 0 0
Freedom From Relapse
Timepoint [3] 0 0
approximately 3.5 years

Eligibility
Key inclusion criteria
Key

* Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis more than 1 mm), IIIb or IIIc cutaneous melanoma determined to be V600E/K mutation positive by a central laboratory. Patients presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or II melanoma are eligible.
* Surgically rendered free of disease no more than 12 weeks before randomization.
* Recovered from definitive surgery (e.g. no uncontrolled wound infections or indwelling drains).
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
* Adequate hematologic, hepatic, renal and cardiac function.

Key
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
* Known mucosal or ocular melanoma or the presence of unresectable in-transit metastases.
* Evidence of distant metastatic disease.
* Prior systemic anti-cancer treatment and radiotherapy for melanoma; prior surgery for melanoma is allowed.
* History of another malignancy or concurrent malignancy including prior malignant melanoma. Exceptions to this include: Patients who have been disease-free for 5 years or patients with a history completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible, for example cervical cancer in situ, atypical melanocytic hyperplasia or melanoma in situ, multiple primary melanomas, or other malignancies for which the patient has been disease free for > 5 years.
* History or current evidence of cardiovascular risk.
* History or current evidence of retinal vein occlusion (RVO) or central serous retinopathy (CSR)

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
8/01/2013
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
31/07/2023
Sample size
Target
Accrual to date
Final
870
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
Novartis Investigative Site - Gateshead
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Novartis Investigative Site - North Sydney
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Novartis Investigative Site - Tweed Heads
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Novartis Investigative Site - Westmead
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Novartis Investigative Site - Greenslopes
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Novartis Investigative Site - Milton
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Novartis Investigative Site - Woolloongabba
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Novartis Investigative Site - Adelaide
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Novartis Investigative Site - Box Hill
Recruitment hospital [10] 0 0
Novartis Investigative Site - Heidelberg
Recruitment hospital [11] 0 0
Novartis Investigative Site - Melbourne
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Novartis Investigative Site - Nedlands
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2290 - Gateshead
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2060 - North Sydney
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2485 - Tweed Heads
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2145 - Westmead
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4120 - Greenslopes
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4064 - Milton
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4102 - Woolloongabba
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5000 - Adelaide
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3128 - Box Hill
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3084 - Heidelberg
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3004 - Melbourne
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6009 - Nedlands
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Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
This was a two-arm, randomized, double-blind Phase III study of dabrafenib in combination with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk \[Stage IIIa (lymph node metastasis \>1 mm), IIIb or IIIc\] cutaneous melanoma were screened for eligibility. Subjects were randomized to receive either dabrafenib (150 milligram (mg) twice daily \[BID\]) and trametinib (2 mg once daily \[QD\]) combination therapy or two placebos for 12 months.
Trial website
https://clinicaltrials.gov/study/NCT01682083
Trial related presentations / publications
Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.
Dummer R, Hauschild A, Santinami M, Atkinson V, Mandala M, Kirkwood JM, Chiarion Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Gasal E, Tan M, Long GV, Schadendorf D. Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med. 2020 Sep 17;383(12):1139-1148. doi: 10.1056/NEJMoa2005493. Epub 2020 Sep 2.
Dummer R, Brase JC, Garrett J, Campbell CD, Gasal E, Squires M, Gusenleitner D, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Flaherty K, Larkin J, Robert C, Kefford R, Kirkwood JM, Hauschild A, Schadendorf D, Long GV. Adjuvant dabrafenib plus trametinib versus placebo in patients with resected, BRAFV600-mutant, stage III melanoma (COMBI-AD): exploratory biomarker analyses from a randomised, phase 3 trial. Lancet Oncol. 2020 Mar;21(3):358-372. doi: 10.1016/S1470-2045(20)30062-0. Epub 2020 Jan 30.
Schadendorf D, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Lesimple T, Plummer R, Schachter J, Dasgupta K, Manson S, Koruth R, Mookerjee B, Kefford R, Dummer R, Kirkwood JM, Long GV. Patient-reported outcomes in patients with resected, high-risk melanoma with BRAFV600E or BRAFV600K mutations treated with adjuvant dabrafenib plus trametinib (COMBI-AD): a randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2019 May;20(5):701-710. doi: 10.1016/S1470-2045(18)30940-9. Epub 2019 Mar 27.
Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Lesimple T, Plummer R, Dasgupta K, Haas T, Shilkrut M, Gasal E, Kefford R, Kirkwood JM, Long GV. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma. J Clin Oncol. 2018 Dec 10;36(35):3441-3449. doi: 10.1200/JCO.18.01219. Epub 2018 Oct 22.
Long GV, Hauschild A, Santinami M, Atkinson V, Mandala M, Chiarion-Sileni V, Larkin J, Nyakas M, Dutriaux C, Haydon A, Robert C, Mortier L, Schachter J, Schadendorf D, Lesimple T, Plummer R, Ji R, Zhang P, Mookerjee B, Legos J, Kefford R, Dummer R, Kirkwood JM. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. 2017 Nov 9;377(19):1813-1823. doi: 10.1056/NEJMoa1708539. Epub 2017 Sep 10.
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01682083