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 (MEK116513)

Cutaneous melanoma is the most aggressive form of skin cancers. The standard of
care (dacarbazine [DTIC]) is not optimal, since the median progression-free
survival is approximately 2 months, and the median overall survival is
approximately 7 months.
Recently ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte
antigen, and the BRAF-inhibitor vemurafenib, which have demonstrated a
significant survival benefit, have obtained regulatory approval for
unresectable or metastatic melanoma.
Severe toxicities and the lack of a validated biomarker for patient selection
may restrict the use of ipilimumab while the onset of resistance limits the
efficacy of vemurafenib. The RAS/RAF/MEK/ERK pathway is a critical
proliferation pathway in many human cancers. This pathway can be activated by
alterations in specific proteins, including BRAF (via MEK 1-2). BRAF mutations
have been identified at a high frequency in specific cancers, including
approximately up to 60% of melanoma. The frequency of this activating mutation
and the pathway addiction to which it leads makes mutated BRAF an extremely
attractive target. GSK2118436 (dabrafenib) is a potent and selective inhibitor
of BRAF kinase activity and GSK1120212 (trametinib) is a potent and highly
selective inhibitor of MEK1/MEK2 activation and kinase activity. Because both
BRAF and MEK are in the same pathway, and MEK is a substrate of activated BRAF,
inhibiting both proteins simultaneously rather than individually could provide
more effective pathway inhibition. Data generated in animal models with
combinations of BRAF and MEK inhibitors suggest enhanced effects on efficacy
and less potential for proliferative skin lesions as compared to treatment with
a BRAF inhibitor alone. Emerging data from a Phase I/II study suggest that the
combination has an acceptable safety profile and increased activity over
monotherapy. This is the reason to compare the effects of the combination with
those of vemurafenib.

Primary: superiority of dabrafenib and trametinib combination therapy over
vemurafenib monotherapy with respect to overall survival for subjects with
advanced/metastatic BRAF V600E/K mutation-positive cutaneous melanoma.
Secondary: progression free survival, overall response rate, duration of
response, safety, tolerability.

Open label, randomized, Phase III study comparing dabrafenib (150 mg bid) and
trametinib (2 mg once daily) combination therapy to vemurafenib (960 mg bid)
monotherapy. Subjects will be screened for BRAF mutation V600 E/K. Only BRAF
mutation positive patients will be eligible.
Treatment until disease progression or severe toxicity. Follow-up for survival.
Approx. 700 patients.
IDMC.

Treatment with dabrafenib plus trametinib or vemurafenib.

Risk: adverse events of study treatment.
Burden: Most tests/procedures would be performed during regular care as well.
Hardly any extra visits (every 4, thereafter 8-12 weeks).
Extra tests/procedures: approx. 10-20 ml blood extra per occasion (extra safety
tests, biomarkers), echocardiogram week 4 and every 12 weeks (plus screening)
and ECG week 2, 4, 8 and every 12 weeks (plus screening) , ophthalmic
investigation screening and week 4, quality of life questionnaire 1st year week
1 and every 8 weeks, thereafter every 12 weeks.
Optional substudies:
- pharmacogentics (10 ml blood)
- biopsy in case of skin lesions
- remaining (or fresh) tissue for future biomarker research related to the
development of GSK2118436 and/or melanoma)
- Biopsy at progression.