A Phase III randomized, open-label study comparing GSK2118436 to DTIC in previously untreated subjects with BRAF mutation positive advanced (Stage III) or metastatic (Stage IV) melanoma (BRF113683)

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. BRAF mutations have been identified at a high frequency in
specific cancers, including approximately 50-60% of melanoma. The frequency of
this activating mutation and the pathway addiction to which it leads makes
mutated BRAF an extremely attractive target. GSK2118436 has demonstrated
suppression of phosphorylated ERK (pERK) in tumor cell lines, demonstrated
anti-proliferative activity against multiple BRAF mutant tumor cell lines, and
achieved biomarker suppression and tumor regression in BRAF mutant xenograft
models. In subjects with mutant BRAF melanomas, 9/15 had an objective tumor
response by RECIST at first restaging (8-9 weeks) at doses of 150 mg BID and
higher.

Primary: superiority of GSK2118436 over DTIC with respect to progression-free
survival for subjects with BRAF mutation positive metastatic melanoma.
Secondary: overall survival, best overall response, duration of response,
non-melanoma skin lesions, second malignancies, further validation of a BRAF
mutation assay, quality of life, safety, tolerability, PK, translational
research.

Open-label, randomized Phase III study comparing intravenous DTIC with the oral
GSK2118436. Subjects will be screened for BRAF mutation V600 E. Only BRAF
mutation positive patients will be eligible. Subjects will receive either
intravenous DTIC 1000mg/m2 every 3 weeks or GSK2118436 150 mg twice daily.
Treatment until disease progression or severe toxicity.
Subjects on the DTIC arm will be allowed to receive GSK2118436 after initial
progression, and will be followed for response, progression, survival, and
further anti-cancer therapy.
Approx. 200 patients.
IDMC.

Treatment with DTIC or GSK2118436.

Risk: adverse events of study treatment.
Burden: Most test/procedures would be performed during regular care as well. No
extra visits.
Extra tests/procedures: approx. 10 ml blood extra per occasion (extra safety
tests, PK, biomarkers), echocardiogram every 6 weeks, ECG every 3-6 weeks,
quality of life questionnaire 5x in 1st 15 weeks, 1x when study ends.
Optional substudies: pharmacogentics (10 ml blood), biomarkers (tumour tissue
(extra biopsy)) after discontinuation of study treatment, biopsy in case of
non-melanoma skin lesions.