COMBI-AD: A phase III randomized double blind study of dabrafenib (GSK2118436) in COMBInation with trametinib (GSK1120212) versus two placebos in the ADjuvant treatment of high-risk BRAF V600 mutation-positive melanoma after surgical resection (BRF115532)

Cutaneous melanoma is the most aggressive form of all skin cancers. Its
incidence is continuing to rise. Surgical resection is the treatment of choice
for localized melanoma and frequently results in cures for early stage (I and
II) disease, with a 90% 10-year survival rate for stage I disease. However,
patients with lymph node involvement >=1mm are at high risk of both relapse
after definitive surgery. Approximately half of these patients will ultimately
die of metastatic. Although high-dose interferon is currently the only approved
therapy for the adjuvant treatment of melanoma it is not widely accepted as the
standard of care due to a questionable survival benefit and a high incidence of
serious toxicities. Thus there is a need for effective adjuvant therapy for
these high-risk patients.
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.
Although the role of the MAP kinase pathway has not yet been studied in early
melanoma, there is adequate scientific rationale and data to expect that the
combination of dabrafenib and trametinib will provide similar responses on V600
mutant cells in the adjuvant setting as for more advanced disease. BRAF
mutations are present in primary lesions, and are preserved in corresponding
metastatic lesions. The combination of dabrafenib with trametinib in the
adjuvant setting is further supported by in vitro and in vivo preclinical data.
This phase III study is designed to evaluate the efficacy of dabrafenib and
trametinib combination therapy compared to two placebos with respect to
relapse-free survival in patients with completely resected, histologically
confirmed, BRAF V600E/K high risk, stage III cutaneous melanoma.

Primary: efficacy of dabrafenib and trametinib combination therapy compared to
placebo with respect to relapse-free survival in patients with completely
resected, histologically confirmed, BRAF V600E/K high risk, stage III cutaneous
melanoma.
Secondary: overall survival, distant metastasis-free survival, freedom from
relapse, safety, tolerability.

Double-blind, randomized phase III study comparing (1:1) dabrafenib (150 mg
bid) and trametinib (2 mg once daily) combination therapy to placebo (placebos
to dabrafenib and trametinib. Subjects will be screened for BRAF mutation V600
E/K. Only BRAF mutation positive patients will be eligible.
Treatment for 12 months or until disease progression or severe toxicity (which
ever comes first). Follow-up until progression and thereafter for survival.
Planned study duration (incl. survival follow-up) approx. 5 years.
Approx. 850 patients.

Treatment with dabrafenib plus trametinib or placebo.

Risk: adverse events of study treatment.
Burden: Monthly visits in 1st, every 3 months in 2nd year and every 6 months
thereafter until progression. After progression follow-up for survival (may be
by phone).
Tests etc. until progression:
Physical examination every visit (3x incl. rectal examination), eye examination
5x.
Blood tests 13x (approx. 15 ml/occasion plus 5x 15 ml extra for biomarkers).
CT/MRI scan 1st year 5x, 2nd year every 3 months, thereafter every 6 months.
ECG 6x.
Echocardiography 6x.
Tumor biopsy at recurrence.
Questionnaire quality of life 1st year 5x, thereafter every visit/contact (also
during survival follow-up).
Only females: PAP-smear 3x, pregnancy test 5x.
Optional substudies:
- pharmacogentic (6 ml blood).
- biopsy in case of skin lesions or new tumor.