Phase I/II study of docetaxel combined with resminostat, an oral hydroxamic acid HDAC inhibitor, for advanced non-small cell lung cancer in patients previously treated with platinum-based chemotherapy
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Objectives To determine the recommended dose and efficacy/safety of docetaxel combined with resminostat (DR) in non-small cell lung cancer (NSCLC) patients with previous platinum-based chemotherapy. Materials and Methods A multicenter, open-label, phase I/II study was performed in Japanese patients with stage IIIB/IV or recurrent NSCLC and prior platinum-based chemotherapy. The recommended phase II dose was determined using a standard 3 + 3 dose design in phase I part. Resminostat was escalated from 400 to 600 mg/day and docetaxel fixed at 75 mg/m2. In phase II part, the patients were randomly assigned to docetaxel alone (75 mg/m2) or DR therapy. Docetaxel was administered on day 1 and resminostat on days 1–5 in the DR group. Treatment was repeated every 21 days until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Results A total of 117 patients (phase I part, 9; phase II part, 108) were enrolled. There was no dose-limiting toxicity in phase I part; the recommended dose for resminostat was 600 mg/day with 75 mg/m2 of docetaxel. In phase II part, median PFS (95% confidence interval [CI]) was 4.2 (2.8–5.7) months with docetaxel group and 4.1 (1.5–5.4) months with DR group (hazard ratio [HR]: 1.354, 95% CI: 0.835–2.195; p = 0.209). Grade ≥ 3 adverse events significantly more common with DR group than docetaxel group were leukopenia, febrile neutropenia, thrombocytopenia, and anorexia. Conclusion In Japanese NSCLC patients previously treated with platinum-based chemotherapy, DR therapy did not improve PFS compared with docetaxel alone and increased toxicity.
KeywordsHistone deacetylase inhibitor Non-small cell lung cancer Resminostat Docetaxel Randomized phase II
We would like to thank all patients, clinicians, and support staff who participated in this study. We are grateful to Noriyuki Masuda, Fumitaka Nagamura, and Nobuyuki Yamamoto for their helpful advice as members of the DMC, and Kunihisa Miyakawa for performing an extramural review to assess objective responses and PFS.
Compliance with ethical standards
Role of funding source
This study was supported by Yakult Honsha. The study sponsor contributed to the design of the study, data collection, analysis and interpretation of data, writing of the manuscript, and decision to submit the manuscript for publication. All authors had access to all the data in the study and agreed with the decision to submit for publication.
Conflict of interest
Y. Okamura has stock ownership of Yakult. Y. Okamura and O. Nakamura are employees of Yakult. Y. Hosomi has received personal fees from AstraZeneca, Chugai, Eli Lilly, Ono and Taiho. H. Sakai has received grants from Yakult and personal fees from Bristol-Myers Squibb, Chugai, Eli Lilly, Ono and Taiho. N. Nogami has received grants from Yakult and personal fees from Astellas, AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Ono, Pfizer and Taiho. S. Atagi has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly and Taiho, grants from Merck Serono, Ono, Pfizer and Yakult, and personal fees from Bristol-Myers Squibb. Y. Sasaki has received grants and personal fees from Eisai, Taiho and Yakult, grants from Bristol-Myers Squibb and Novartis, and personal fees from Bayer Yakuhin, Eli Lilly, GlaxoSmithKline, Merck Serono, Nichi-Iko Pharmaceutical, Ono, Sawai and Takeda. T. Kato has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Kyowa Hakko Kirin, Ono, Pfizer and Taiho, grants from Abbvie, Astellas, Bristol-Myers Squibb, Daiichi Sankyo, MSD, Parexel, Quintiles, Takeda and Yakult, and personal fees from Roche. T. Takahashi has received grants and personal fees from AstraZeneca, Chugai, Eli Lilly, Ono and Pfizer, grants from MSD, Takeda and Taiho, and personal fees from Boehringer Ingelheim. T. Seto has received grants and personal fees from AstraZeneca, Chugai, Eisai, Eli Lilly, Boehringer Ingelheim, Novartis, Pfizer, Sanofi and Taiho, grants from Astellas, Bayer Yakuhin, Merck Serono, MSD, Verastem and Yakult, and personal fees from Daiichi Sankyo, Fuji Pharma, Hisamitsu, Kyowa Hakko Kirin, Mochida, Nippon Kayaku, Ono, Roche Diagnostics, Showa Yakuhin Kako, Sumitomo Dainippon Pharma and Takeda. H. Nokihara has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Ono and Taiho, grants from Astellas, Daiichi Sankyo, Eisai, GlaxoSmithKline, Merck Serono, Novartis, Pfizer, Quintiles and Yakult, and personal fees from Bristol-Myers Squibb and Sanofi. K. Nakagawa has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Ono and Pfizer, grants from Eisai, EPS Associate, MSD, Japan Clinical Research Operations, PPD-SNBL, OncoTherapy Science, Quintiles, Takeda, Taiho, and personal fees from Astellas, Eli Lilly, EPS Holdings, Showa Yakuhin Kako and SymBio Pharmaceuticals. M. Nishio has received grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, Ono, Pfizer and Taiho, and grants from Astellas and Novartis. T. Tamura has received personal fees from Astellas, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Ono, Taiho and Yakult. Y. Tambo, M. Maemondo, R. Koyama and T. Kawaguchi have no conflict of interest to disclose.
Statement of human rights
This study was performed in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the institutional review boards of all participating institutions.
All patients provided written informed consent before enrollment in this study.
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