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

• 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: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: May 10, 2012
• First Posted Date: May 14, 2012
• Results First Submitted Date: December 1, 2014
• Results First Posted Date: December 4, 2014
• Last Update Posted Date: February 24, 2021
• Actual Study Start Date: June 4, 2012
• Actual Primary Completion Date: April 17, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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 (submitted: May 10, 2012)

Overall Survival [ Time Frame: approx. 20 months ]

time from randomisation until death due to any cause

Current Secondary Outcome Measures (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 (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: Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma
• Official Title: 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: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Melanoma

Intervention

• 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

• Experimental: Dabrafenib plus Trametinib
  BRAF inhibitor plus MEK inhibitor
  Interventions:

  • Drug: Dabrafenib
  • Drug: Trametinib
• Active Comparator: Vemurafenib
  BRAF inhibitor
  Intervention: Drug: Vemurafenib

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.
• Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandala M, Haanen JBAG, Lebbe C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.
• Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.
• Grob JJ, Amonkar MM, Karaszewska B, Schachter J, Dummer R, Mackiewicz A, Stroyakovskiy D, Drucis K, Grange F, Chiarion-Sileni V, Rutkowski P, Lichinitser M, Levchenko E, Wolter P, Hauschild A, Long GV, Nathan P, Ribas A, Flaherty K, Sun P, Legos JJ, McDowell DO, Mookerjee B, Schadendorf D, Robert C. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutation-positive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015 Oct;16(13):1389-98. doi: 10.1016/S1470-2045(15)00087-X.
• Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K, Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P, Ribas A, Martin AM, Sun P, Crist W, Legos J, Rubin SD, Little SM, Schadendorf D. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi: 10.1056/NEJMoa1412690. Epub 2014 Nov 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 31, 2017): 704
• Original Estimated Enrollment (submitted: May 10, 2012): 694
• Actual Study Completion Date: April 25, 2019
• Actual Primary Completion Date: April 17, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

• 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, 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: NCT01597908
• Other Study ID Numbers: 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

• 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.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: GlaxoSmithKline
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: GlaxoSmithKline
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: February 2021