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

Trial Status: Closed to Accrual

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.

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.

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)

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: CLOSED_TO_ACCRUAL

Arizona

Tucson
Banner University Medical Center - Tucson
Status: CLOSED_TO_ACCRUAL

California

San Francisco
UCSF Medical Center-Mount Zion
Status: CLOSED_TO_ACCRUAL

Colorado

Aurora
University of Colorado Hospital
Status: CLOSED_TO_ACCRUAL
Contact: Karl D. Lewis

Florida

Tampa
Moffitt Cancer Center
Status: CLOSED_TO_ACCRUAL

Georgia

Atlanta
Emory University Hospital / Winship Cancer Institute
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION

Indiana

Indianapolis
Indiana University / Melvin and Bren Simon Cancer Center
Status: COMPLETED

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION
Massachusetts General Hospital Cancer Center
Status: CLOSED_TO_ACCRUAL

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION

North Carolina

Winston-Salem
Wake Forest University Health Sciences
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: CLOSED_TO_ACCRUAL

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: CLOSED_TO_ACCRUAL_AND_INTERVENTION

Tennessee

Nashville
Vanderbilt University / Ingram Cancer Center
Status: ADMINISTRATIVELY_COMPLETE

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: CLOSED_TO_ACCRUAL
Houston
M D Anderson Cancer Center
Status: WITHDRAWN

Washington

Seattle
Fred Hutch / University of Washington Cancer Consortium
Status: COMPLETED

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.

Trial Phase Phase III

Trial Type Treatment

Lead Organization
Novartis Pharmaceuticals Corporation

  • Primary ID 115532
  • Secondary IDs NCI-2013-01043, 2012-001266-15, CDRB436F2301
  • Clinicaltrials.gov ID NCT01682083