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NCT01597908 · CITED IN SOURCE DOCUMENTS

Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE3
Status at capture
COMPLETED
Registry last update
2021-02-24

This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.

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What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Overall Survival (OS)

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outcome · POSTED

Progression-Free Survival (PFS), as Assessed by the Investigator

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outcome · POSTED

Overall Response Rate (ORR) During Randomized Phase, as Assessed by the Investigator

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outcome · POSTED

Duration of Response (DOR), as Assessed by the Investigator

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outcome · POSTED

All Collected Deaths

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
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)
healthy Volunteers
false
minimum Age
18 Years
sex
ALL
std Ages
  1. ADULT
  2. OLDER_ADULT
Treatment arms and interventions
arm Groups
  1. description
    BRAF inhibitor plus MEK inhibitor
    intervention Names
    1. Drug: Dabrafenib
    2. Drug: Trametinib
    label
    Dabrafenib plus Trametinib
    type
    EXPERIMENTAL
  2. description
    BRAF inhibitor
    intervention Names
    1. Drug: Vemurafenib
    label
    Vemurafenib
    type
    ACTIVE_COMPARATOR
interventions
  1. arm Group Labels
    1. Dabrafenib plus Trametinib
    description
    Dabrafenib 150 mg twice daily orally
    name
    Dabrafenib
    other Names
    1. GSK2118436
    type
    DRUG
  2. arm Group Labels
    1. Vemurafenib
    description
    Vemurafenib 960 mg twice daily orally
    name
    Vemurafenib
    other Names
    1. Monotherapy
    type
    DRUG
  3. arm Group Labels
    1. Dabrafenib plus Trametinib
    description
    Trametinib 2 mg once daily orally
    name
    Trametinib
    other Names
    1. GSK1120212
    type
    DRUG
Study design
allocation
RANDOMIZED
intervention Model
PARALLEL
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
704
type
ACTUAL
Registered outcome plans (not posted results)
primary Outcomes
  1. description
    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.
    measure
    Overall Survival (OS)
    time Frame
    From the date of randomization until date of death due to any cause (up to approximately 6 years)
secondary Outcomes
  1. description
    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.
    measure
    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)
  2. description
    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.
    measure
    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)
  3. description
    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.
    measure
    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)
Full study description
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.
Source references
references
  1. citation
    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.
    pmid
    34225229
    type
    DERIVED
  2. citation
    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.
    pmid
    31166680
    type
    DERIVED
  3. citation
    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.
    pmid
    27864013
    type
    DERIVED
  4. citation
    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.
    pmid
    26433819
    type
    DERIVED
  5. citation
    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.
    pmid
    25399551
    type
    DERIVED
Source notices and limitations
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        and chorioretinopathy.</li></ul></div></li><li><strong> Previously untreated.</strong> An international, open-label, phase III trial (<a href="/clinicaltrials/NCT01597908">COMBI-v</a> [NCT01597908]) included 704 previously untreated patients with metastatic melanoma and <em class="gene-name">BRAF</em> V600 pathogenic variants. P
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        ></ul></div></li><li><strong> Previously untreated.</strong> An international, open-label, phase III trial (<a href="/clinicaltrials/NCT01597908">COMBI-v</a> [NCT01597908]) included 704 previously untreated patients with metastatic melanoma and <em class="gene-name">BRAF</em> V600 pathogenic variants. Patients were randomly assi
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        ="_289" tabindex="-1">The approval was also supported by results from <a href="/clinicaltrials/NCT01072175">COMBI-d</a> (NCT01072175), <a href="/clinicaltrials/NCT01597908">COMBI-v</a> (NCT01597908), and <a href="/clinicaltrials/NCT01336634">BRF113928</a> (NCT01336634).[<a href="#cit/section_5.6">6</a>] </p> <p id="_240" ta
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        approval was also supported by results from <a href="/clinicaltrials/NCT01072175">COMBI-d</a> (NCT01072175), <a href="/clinicaltrials/NCT01597908">COMBI-v</a> (NCT01597908), and <a href="/clinicaltrials/NCT01336634">BRF113928</a> (NCT01336634).[<a href="#cit/section_5.6">6</a>] </p> <p id="_240" tabindex="-1"><strong>Effica
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        n two international, randomized, active-controlled trials: one double-blind trial (the COMBI-d study; NCT01584648) and one open-label trial (the COMBI-v study; NCT01597908). The COMBI-d study compared TAFINLAR plus trametinib to TAFINLAR plus placebo as first-line therapy for patients with unresectable (Stage IIIC) or metastatic
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    Preserved source evidence · Independent clinical review pending · Not medical advice