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Invest New Drugs. 2017 Apr;35(2):217-226. doi: 10.1007/s10637-017-0435-2. Epub 2017 Jan 30.

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.

Author information

1
Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
2
Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
3
Division of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.
4
Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Ehime, Japan.
5
Department of Thoracic Oncology, National Hospital Organization Kinki-chuo Chest Medical Center, Osaka, Japan.
6
Division of Medical Oncology, Showa University School of Medicine, Tokyo, Japan.
7
Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan.
8
Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
9
Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.
10
Department of Respiratory Medicine, Miyagi Cancer Center, Miyagi, Japan.
11
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
12
Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
13
Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
14
Department of Respiratory Medicine, Osaka City University Hospital, Osaka, Japan.
15
Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., Tokyo, Japan.
16
Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan. mnishio@jfcr.or.jp.
17
Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.

Abstract

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.

KEYWORDS:

Docetaxel; Histone deacetylase inhibitor; Non-small cell lung cancer; Randomized phase II; Resminostat

PMID:
28138828
DOI:
10.1007/s10637-017-0435-2
[Indexed for MEDLINE]

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