Date: 2012-05-18
Type of information: Publication of results in a medical journal
phase: 1
Announcement: publication of phase I results in The Lancet, Volume 379, Issue 9829, Pages 1893 - 1901, 19 May 2012
Company: GSK (UK)
Product: dabrafenib
Action
mechanism: Dabrafenib is a selective inhibitor of B-RAF protein kinase carrying V600E mutation. It is currently being developed for the treatment of BRAF mutation-positive tumors.
Disease: melanoma
Therapeutic area: Cancer - Oncology
Country: USA, Australia
Trial
details: The phase I trial - published in the Lancet and funded by GSK- was primarily designed to establish the safe dose of dabrafenib. It involved 184 patients with incurable tumours, 156 of whom had metastatic melanoma. It has been undertaken between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function.
BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. The first dose cohort received 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, the cohorts have been expanded to include up to 20 patients.
Latest
news: Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9—83·7) and confirmed responses in 18 (50%, 32·9—67·1). 21 (78%, 57·7—91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3—74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer.
