A Phase III, randomized, double-blinded study comparing the combination of the BRAF inhibitor, dabrafenib and the MEK inhibitor, trametinib to dabrafenib and placebo as first-line therapy in subjects with unresectable (Stage IIIc) or metastatic (Stage IV) BRAF V600E/K mutation-positive cutaneous melanoma (MEK115306)

Cutaneous melanoma is the most aggressive form of skin cancers. The current
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. The need for novel agents for this disease
is therefore evident.
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 explore the effects of the combination in a phase III study.

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

Double-blinded, randomized, Phase III study comparing dabrafenib (150 mg bid)
and trametinib (2 mg once daily) combination therapy to dabrafenib (150 mg bid)
administered with a trametinib placebo (dabrafenib 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.
In case of discontinuation of dabrafenib for safety reasons: option to proceed
with trametinib/placebo.
Approx. 340 patients.
IDMC.

Treatment with dabrafenib plus trametinib or dabrafenib plus a placebo.

Risk: adverse events of study treatment.
Burden: Most tests/procedures would be performed during regular care as well.
Visits every 4 weeks. 3-monthly phone calls.
Extra tests/procedures: approx. 10-20 ml blood extra per occasion (extra safety
tests, PK, biomarkers), echocardiogram and ECG 3 monthly, ophthalmic
examination at screening and after 4 weeks, MRI brain at screening, quality of
life questionnaire 1st year every 8 weeks, thereafter every 12 weeks.
Optional substudies:
- pharmacogentics (10 ml blood)
- biopsy in case of skin lesions
- biopsy after treatment.