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Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced cutaneous melanoma
Author(s) -
Yamazaki Naoya,
Tsutsumida Arata,
Takahashi Akira,
Namikawa Kenjiro,
Yoshikawa Shusuke,
Fujiwara Yutaka,
Kondo Shunsuke,
Mukaiyama Akihira,
Zhang Fanghong,
Kiyohara Yoshio
Publication year - 2018
Publication title -
the journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.9
H-Index - 65
eISSN - 1346-8138
pISSN - 0385-2407
DOI - 10.1111/1346-8138.14210
Subject(s) - dabrafenib , trametinib , tolerability , medicine , adverse effect , melanoma , clinical endpoint , combination therapy , oncology , pharmacology , vemurafenib , clinical trial , cancer research , mapk/erk pathway , biology , metastatic melanoma , kinase , microbiology and biotechnology
The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics ( PK ) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events ( AE ), and the primary end‐point in phase 2 was to assess confirmed overall response rate ( ORR ). The secondary end‐points in phase 1 included PK , confirmed/unconfirmed ORR and duration of response ( DOR ). The secondary end‐points in phase 2 were PK , unconfirmed ORR , DOR , safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator‐assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9–99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.