TAS-115 is a novel small-molecule inhibitor of hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor (VEGFR) with antitumor activity in preclinical models. It has also been shown that TAS-115 inhibits Feline McDonough Sarcoma oncogene (FMS) kinase, essential for the differentiation of osteoclasts, and is expected to be effective against bone metastases. In this expansion cohort of phase I trial, the safety and efficacy of TAS-115 were evaluated in CRPC pts with bone metastases.
Eligible CRPC pts with bone metastases who were refractory to standard treatment including docetaxel, abiraterone and/or enzalutamide were enrolled. Two dose levels of TAS-115 (450 and 650 mg/body/day) were administered orally with a 5-days-on/2-days-off schedule for up to 21 days per cycle in this expansion cohort. Efficacy was evaluated based on the RECIST ver 1.1 and bone scan response, deﬁned as 30% decrease in bone scan index (BSI) calculated by quantitative software of BONENAVI®(FUJIFILM RI Pharma, Japan; EXINI bone®, Exini Diagnostics, Sweden). Toxicities were evaluated based on the CTCAE ver 4.03.
As of Apr 2017, a total of 15 pts received TAS-115 (9 pts with 450 mg, and 6 pts with 650 mg). Bone scan response was reported in 4 of 9 pts (44.4%) who had baseline BSI ≥0.5%, which is equivalent to grade≥1 extent of disease. The best overall response per RECIST was stable disease in 7 of 15 pts (46.7%). These efficacies were observed regardless to dose levels. One patient had a long administration period exceeded to 15 months without disease progression, and another one patient experienced remarkable pain relief induced by bone metastases. TAS-115 had no effect on the PSA and ALP. The major (≥30%) adverse drug reactions (ADRs) were anorexia, fatigue, nausea, thrombocytopenia, rash, AST increased, anemia, vomiting and edema. The rate of grade ≥3 to all ADRs was 18.8%. These AEs were recovering by interruption of TAS-115.
Toxicities of TAS-115 were acceptable and manageable in CRPC pts, and preliminary anti-tumor activity, especially against bone metastases was recognized. A phase II trial for CRPC pts with bone metastases is ongoing.
Clinical trial identification
Legal entity responsible for the study
Taiho Phermaceutical CO., LTD.
Taiho Phermaceutical CO., LTD.
N. Matsubara: Honoraria: Taiho Pharmaceutical. Consulting or Advisory role: Janssen, AstraZeneca. Speakers’ bureau: Janssen, AstraZeneca, Sanofi. Research funding: Janssen, Bayer. Y. Naito: Speakers’ bureau: Eisai, Chugai, Taiho, Novartis, Eli Lilly, Meiji Seika, Bayer, Roche. Research Funding: Merck Serono, AstraZeneca, Eli Lilly, Nippon Kayaku. M. Sasaki: Speakers’ bureau: Taiho. Research funding: Eisai, Bayer. N. Yamamoto: Honoraria: AstraZeneca, Pfizer, Chugai, Bristol-Myers, Ono, Eli Lilly. Research funding: Chugai, Taiho, Eisai, Quintiles, Astellas, Novartis, Daiichi Sankyo, Eli Lilly, Boehringer Ingelheim, Takeda, Kyowa Hakko, Bayer, Pfizer. S. Takahashi: Honoraria: Eisai, Astellas, Taiho, Bayer, Daiichi, Pfizer, AstraZeneca, Merck, Sanofi, Novartis, Ono, Bristol, MSD. Consulting or Advisory role: Chugai, Astellas, Bayer, Pfizer. Research funding: Eisai, Chugai, MSD, Lilly, AstraZeneca, Novartis, Taiho, Bayer, Astellas, Ono, Daiichi. H. Uemura: Consulting or Advisory role: Janssen, Takeda. Speakers' bureau: Janssen, Takeda, Astellas, Bayer, Sanofi, AstraZeneca, Fujifilm. Research funding: Astellas. T. Doi: Consulting or Advisory Role: Lilly, Chugai, Kyowa Hakko Kirin, Novartis, MSD, Daiichi Sankyo, Amgen. Research funding: Taiho, Merck, Astellas, Janssen, Takeda, Pfizer, Lilly, Sumitomo Group, Bayer, Chugai, Kyowa Hakko Kirin, Boehringer, Novartis, MSD, Daiichi Sankyo, Celgene.