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Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD). (COMBI-AD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01682083
Recruitment Status : Active, not recruiting
First Posted : September 10, 2012
Results First Posted : September 26, 2018
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE September 6, 2012
First Posted Date  ICMJE September 10, 2012
Results First Submitted Date  ICMJE May 29, 2018
Results First Posted Date  ICMJE September 26, 2018
Last Update Posted Date September 10, 2019
Actual Study Start Date  ICMJE January 8, 2013
Actual Primary Completion Date June 30, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
Relapse-free Survival (RFS) [ Time Frame: Approximately 3.5 years ]
Recurrence-free survival was defined as the time from randomization to disease recurrence (local recurrence, distant recurrence, second primary melanoma), or death from any cause.
Original Primary Outcome Measures  ICMJE
 (submitted: September 7, 2012)
Relapse-free survival (RFS) in subjects [ Time Frame: From date of randomization until the date of first documented recurrence or date of death from any cause, whichever came first, assessed for an average of 24 months ]
The efficacy of dabrafenib and trametinib combination therapy compared to placebo was evaluated by measuring RFS. Relapse Free Survival is defined as the time from randomization to disease recurrence or death from any cause. Recurrence of or death from the same cancer and all deaths from other causes are events. Treatment emergent malignancy(ies) other than second melanomas will not be considered as events, and loss to follow-up is censored. Subjects without RFS events will be censored at the last assessment
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • Overall Survival [ Time Frame: approximately 3.5 years ]
    Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo
  • Distant Metastasis-free Survival [ Time Frame: approximately 3.5 years ]
    Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo. In the DMFS analysis, the first occurrence of distant metastasis or death (if it occurred before documented recurrence) was counted as an event.
  • Freedom From Relapse [ Time Frame: approximately 3.5 years ]
    Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo. In the FFR analysis, local or distant recurrence or a new primary melanoma were counted as events, and patients who died of causes other than melanoma or treatment-related toxicity were censored.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 7, 2012)
  • Overall survival (OS) of dabrafenib and trametinib as a combination therapy versus placebo [ Time Frame: From date of randomization until the date of death, assessed for an average of 24 months ]
    OS is defined as the interval from randomization to the date of death, irrespective of the cause of death; subjects still alive will be censored at the date of the last contact
  • Distant metastasis-free survival (DMFS) of dabrafenib and trametinib as a combination therapy versus placebo [ Time Frame: From date of randomization until the date of first documented distant metastasis or date of death, whichever came first, assessed for an average of 24 months ]
    DMFS is defined as the interval from randomization to the date of first distant metastasis or date of death, whichever occurs first. Subjects alive and without distant metastasis are censored at the date of last assessment
  • Freedom from relapse (FFR) of dabrafenib and trametinib as a combination therapy versus placebo [ Time Frame: From date of randomization until the date of first documented local or distant recurrence, assessed for an average of 24 months ]
    FFR is defined as interval from randomization to local or distant recurrence with censoring of subjects dying from causes other than melanoma or treatment-related toxicity at the date of death. Subjects alive without recurrence or with second primary cancers will be censored at the date of last assessment
  • Safety of dabrafenib and trametinib as a combination therapy in the overall study population [ Time Frame: Duration of the study (upto 24 months) ]
    Safety will be measured by clinical assessments including vital signs and physical examinations, 12-lead electrocardiograms (ECG), echocardiogram (ECHO), eye exams, chemistry and hematology laboratory values, and adverse events (AEs)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dabrafenib With Trametinib in the Adjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma (COMBI-AD).
Official Title  ICMJE 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
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.
Detailed Description

This was a two-arm, randomized, double-blind, multi-center, international phase III study of dabrafenib in combination with trametinib versus two matching 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]). None of the patients had undergone previous systemic anticancer treatment or radiotherapy for melanoma. All the patients had undergone completion lymphadenectomy with no clinical or radiographic evidence of residual regional node disease within 12 weeks before randomization, had recovered from definitive surgery, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. BRAF V600 mutation status was confirmed in primary-tumor or lymph-node tissue by a central reference laboratory. All the patients provided written informed consent.

The primary end point was recurrence-free survival, Overall survival, as the key secondary end point, was to be tested in a hierarchical manner only if the primary end point met the criteria for significance. The overall survival analysis used a preplanned three-look Lan-DeMets group sequential design with an O'Brien-Fleming-type boundary, which was used to determine the significance threshold for the first interim overall survival analysis (two-sided P=0.000019).

Disease assessments included clinical examination and imaging by means of computed tomography, magnetic resonance imaging, or both.) Imaging was performed every 3 months during the first 24 months, then every 6 months until disease recurrence or the completion of the trial. Follow-up for survival began after recurrence and continued through the end of the trial. Adverse events and laboratory values were assessed at screening, on the date of randomization, at least once per month through month 12, and at every visit for disease-recurrence assessment after month 12. Adverse events and laboratory values were graded according to the Common Terminology Criteria for Adverse Events, version 4.0.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • Drug: Dabrafenib
    Each capsule contained 50 mg or 75 mg of free base (present as the mesylate salt)
    Other Name: GSK2118436
  • Drug: Trametinib
    Each tablet contained 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)
    Other Name: GSK1120212
  • Drug: Placebos
    The placebo capsules and tablets contained the same inactive ingredients and film coatings as the dabrafenib and trametinib study treatment
Study Arms  ICMJE
  • Experimental: Dabrafenib and trametinib
    Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for 12 months.
    Interventions:
    • Drug: Dabrafenib
    • Drug: Trametinib
  • Placebo Comparator: Dabrafenib and trametinib placebos
    Subjects received matching placebos orally for 12 months
    Intervention: Drug: Placebos
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: August 28, 2018)
870
Original Estimated Enrollment  ICMJE
 (submitted: September 7, 2012)
1300
Estimated Study Completion Date  ICMJE December 30, 2022
Actual Primary Completion Date June 30, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • 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 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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belgium,   Brazil,   Canada,   Czechia,   Denmark,   France,   Germany,   Greece,   Israel,   Italy,   Japan,   Netherlands,   New Zealand,   Norway,   Poland,   Russian Federation,   Spain,   Sweden,   Switzerland,   Taiwan,   United Kingdom,   United States
Removed Location Countries Czech Republic,   Finland
 
Administrative Information
NCT Number  ICMJE NCT01682083
Other Study ID Numbers  ICMJE 115532
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP