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Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma (COMBI-v)

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ClinicalTrials.gov Identifier: NCT01597908
Recruitment Status : Completed
First Posted : May 14, 2012
Results First Posted : December 4, 2014
Last Update Posted : February 24, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE May 10, 2012
First Posted Date  ICMJE May 14, 2012
Results First Submitted Date  ICMJE December 1, 2014
Results First Posted Date  ICMJE December 4, 2014
Last Update Posted Date February 24, 2021
Actual Study Start Date  ICMJE June 4, 2012
Actual Primary Completion Date April 17, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 8, 2021)
Overall Survival (OS) [ Time Frame: From the date of randomization until date of death due to any cause (up to approximately 6 years) ]
Overall Survival (OS) was defined as the interval of time between the date of randomization and the date of death due to any cause. For patients who did not die, OS was censored at the date of last contact.
Original Primary Outcome Measures  ICMJE
 (submitted: May 10, 2012)
Overall Survival [ Time Frame: approx. 20 months ]
time from randomisation until death due to any cause
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 8, 2021)
  • Progression-Free Survival (PFS), as Assessed by the Investigator [ Time Frame: From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years) ]
    Progression-free survival (PFS) was defined as the interval of time between the date of randomization and the first documented occurrence of disease progression or death due to any cause. PFS for investigator-assessed response was summarized per Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1, which is a set of published rules defining when cancer patients improve (respond), stay the same (stabilize), or worsen (progress) during treatment. Disease progression was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.
  • Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator [ Time Frame: From randomization until the first documented complete response or partial response (up to approximately 6 years) ]
    Overall response was defined as the percentage of confirmed responders (complete response [CR] + partial response [PR] per RECIST, Version 1.1) as summarized by Investigator assessment. CR was defined as the disappearance of all evidence of target lesions. PR was defined as at least a 30% reduction from Baseline in the sum of the longest diameter (LD) of all target lesions. Data were reported as those participants with measureable disease at Baseline.
  • Duration of Response (DOR), as Assessed by the Investigator [ Time Frame: From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years) ]
    Duration of Response (DOR) was defined as the time from the first documented evidence of a CR (disappearance of all evidence of target lesions) or a PR (at least a 30% reduction from Baseline in the sum of the longest diameter of all target lesions) until disease progression or death due to any cause. PD was defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5 mm or the appearance of at least1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. Data were summarized per RECIST, Version 1.1.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2012)
  • Progression Free Survival [ Time Frame: approx. 10 months ]
    time from randomisation to until the earliest date of disease progression or death due to any cause
  • Overall Response Rate [ Time Frame: approx. 10 months ]
    percentage of subjects with a confirmed or unconfirmed completed response (CR) or partial response (PR) at any time per RECIST 1.1
  • Duration of Response [ Time Frame: approx. 10 months ]
    time from first documented evidence of CR or PR until disease progression or death due to any cause among subjects who achieve an overall response (i.e., confirmed or unconfirmed CR or PR)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma
Official Title  ICMJE A Phase III, Randomised, Open-label Study Comparing the Combination of the BRAF Inhibitor, Dabrafenib and the MEK Inhibitor, Trametinib to the BRAF Inhibitor Vemurafenib in Subjects With Unresectable (Stage IIIc) or Metastatic (Stage IV) BRAF V600E/K Mutation Positive Cutaneous Melanoma
Brief Summary This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.
Detailed Description

Screening/Subject eligibility: Subjects with histologically confirmed cutaneous melanoma that was either unresectable or metastatic (Stages IIIC or IV), were screened for eligibility. Eligible subjects were BRAF V600E or V600K mutation positive. Subjects who had prior systemic anti-cancer treatment in the advanced or metastatic setting were not eligible although prior systemic treatment in the adjuvant setting was allowed.

Randomization: A total of 704 subjects were randomized in a ratio of 1:1 to receive combination therapy (352 subjects) or vemurafenib treatment (352 subjects). Subjects were stratified by LDH level (> the ULN versus =< ULN) and BRAF mutation (V600E versus V600K).

Study treatment: Dabrafenib and trametinib were administered orally at their recommended doses of 150 mg b.i.d. and 2.0 mg once daily, respectively. Subjects randomized in the combination therapy arm received both the agents. Subjects randomized in the vemurafenib arm received vemurafenib at the recommended dose of 960 mg orally b.i.d. Subjects in both the arms continued treatment until disease progression, death, unacceptable toxicity, or withdrawal of consent. The protocol was amended on 07-Aug-2014 which allowed subjects who were still receiving vemurafenib to cross over to the dabrafenib and trametinib combination arm, including those subjects who were still receiving vemurafenib monotherapy treatment after disease progression. A washout period of a minimum of 7 days was considered prior to initiating dabrafenib in combination with trametinib. Subjects who experienced disease progression on the vemurafenib monotherapy arm, discontinued vemurafenib monotherapy, and subsequently received another anticancer therapy were ineligible for cross over to the dabrafenib and trametinib combination arm.

Follow-up/Study closure: After study treatment discontinuation, subjects were followed for survival and disease progression as applicable. This study completed once all the subjects had at least the 5-years of follow-up.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • Drug: Dabrafenib
    Dabrafenib 150 mg twice daily orally
    Other Name: GSK2118436
  • Drug: Vemurafenib
    Vemurafenib 960 mg twice daily orally
    Other Name: Monotherapy
  • Drug: Trametinib
    Trametinib 2 mg once daily orally
    Other Name: GSK1120212
Study Arms  ICMJE
  • Experimental: Dabrafenib plus Trametinib
    BRAF inhibitor plus MEK inhibitor
    Interventions:
    • Drug: Dabrafenib
    • Drug: Trametinib
  • Active Comparator: Vemurafenib
    BRAF inhibitor
    Intervention: Drug: Vemurafenib
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 Completed
Actual Enrollment  ICMJE
 (submitted: May 31, 2017)
704
Original Estimated Enrollment  ICMJE
 (submitted: May 10, 2012)
694
Actual Study Completion Date  ICMJE April 25, 2019
Actual Primary Completion Date April 17, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  • >= 18 years of age
  • Stage IIIc or Stage IV BRAF V600E/K cutaneous melanoma
  • Measurable disease according to RECIST 1.1
  • Women of childbearing potential with negative serum pregnancy test prior to randomisation
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  • Adequate baseline organ function

Key Exclusion Criteria:

  • Any prior use of a BRAF or MEK inhibitor
  • Prior systemic anti-cancer treatment in the advanced or metastatic setting; prior systemic treatment in the adjuvant setting is allowed
  • History of another malignancy (except subjects who have been disease free for 3 years or with a history of completely resected non-melanoma skin cancer)
  • Known HIV, HBV, HCV infection (except chronic or cleared HBV and HCV infection which will be allowed)
  • Brain metastases (except if all known lesions were previously treated with surgery or stereotactic radiosurgery and lesions, if still present, are confirmed stable for >= 12 weeks prior to randomisation or if no longer present are confirmed no evidence of disease for >= 12 weeks, and are asymptomatic with no corticosteroid requirements for >= 4 weeks prior to randomisation, and no enzyme inducing anticonvulsants for >= 4 weeks prior to randomisation
  • History or evidence of cardiovascular risk (LVEF < LLN; QTcB >= 480 msec; blood pressure or systolic >=140 mmHg or diastolic >= 90 mmHg which cannot be controlled by anti-hypertensive therapy)
  • History or current evidence/risk 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,   Finland,   France,   Germany,   Hungary,   Ireland,   Israel,   Italy,   Korea, Republic of,   Netherlands,   New Zealand,   Norway,   Poland,   Russian Federation,   Spain,   Sweden,   Switzerland,   Taiwan,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01597908
Other Study ID Numbers  ICMJE 116513
CDRB436B2302 ( Other Identifier: Novartis )
2011-006088-23 ( EudraCT Number )
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 February 2021

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