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Background This phase I dose-escalation study investigated the safety of the Smoothened inhibitor taladegib in Japanese patients with advanced solid tumors. Methods Patients received taladegib orally once daily for 28-day cycles, using a 3 + 3 dose-escalation method. The primary objective was the safety and tolerability of taladegib at doses up to the global recommended dose (400 mg). Secondary objectives included pharmacokinetics, changes in skin glioma-associated oncogene homolog 1 (Gli1) transcript levels, and antitumor activity. Results Nineteen patients received treatment (100 mg: 3; 200 mg: 3; 400 mg: 13). No dose-limiting toxicities (DLTs) were observed at doses of 100 mg or 200 mg; 3 of the 9 patients evaluable for DLTs at the 400 mg dose level experienced DLTs (thrombocytopenia: 1; decreased appetite: 2). The most commonly reported treatment-related adverse events were dysgeusia (13/19, 68.4%), decreased appetite (12/19, 63.2%), nausea (9/19, 47.4%), fatigue (9/19, 47.4%), and vomiting (6/19, 31.6%). The pharmacokinetic profile suggested that exposure to taladegib was higher in Japanese than non-Japanese patients, possibly related to differences in body weight and/or drug formulation. At all dose levels, a high level of inhibition of skin Gli1 transcript levels was observed after 15 and 30 days of exposure to taladegib. Partial response was achieved by 1 patient (basal cell carcinoma of the skin) and stable disease by 4 patients. Conclusions Taladegib doses of 100 mg and 200 mg, but not the global recommended dose of 400 mg, were well tolerated in this population of Japanese patients with advanced solid tumors.

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF