title: 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.
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/m2of 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.
authors.affiliation: 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.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tambo
authors.affiliation: Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hosomi
authors.affiliation: Division of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sakai
authors.affiliation: Department of Thoracic Oncology and Medicine, National Hospital Organization Shikoku Cancer Center, Ehime, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nogami
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Kinki-chuo Chest Medical Center, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Atagi
authors.affiliation: Division of Medical Oncology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yasutsuna
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kato
authors.affiliation: Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
authors.affiliation: Department of Respiratory Medicine, Miyagi Cancer Center, Miyagi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.affiliation: Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nokihara
authors.affiliation: Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Koyama
authors.affiliation: Department of Medical Oncology, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Department of Respiratory Medicine, Osaka City University Hospital, Osaka, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., Tokyo, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Okamura
authors.affiliation: Pharmaceutical Research and Development Department, Yakult Honsha Co., Ltd., Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nakamura
authors.affiliation: 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.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Thoracic Center, St. Luke's International Hospital, Tokyo, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017671:Platinum Compounds / Q000627:therapeutic use; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D043823:Taxoids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D017671:Platinum Compounds; D013449:Sulfonamides; D043823:Taxoids; C550599:resminostat; D000077143:Docetaxel
keywords: Docetaxel; Histone deacetylase inhibitor; Non-small cell lung cancer; Randomized phase II; Resminostat