Dabrafenib Plus Trametinib vs Vemurafenib Alone in Unresectable or Metastatic BRAF V600E/K Cutaneous Melanoma
This was a two-arm, open-label, randomized, Phase III study comparing dabrafenib (GSK2118436) and trametinib (GSK1120212) combination therapy with vemurafenib.
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)
Additional locations may be listed on ClinicalTrials.gov for NCT01597908.
See trial information on ClinicalTrials.gov for a list of participating sites.
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.
Trial PhasePhase III
Trial Typetreatment
Lead OrganizationNovartis Pharmaceuticals Corporation
- Primary ID116513
- Secondary IDsNCI-2012-01414, 2011-006088-23, CDRB436B2302
- ClinicalTrials.gov IDNCT01597908