Clinical Trial to Assess the Efficacy and Safety of Metirosine in Patients with Pheochromocytoma/Paraganglioma in Compliance with Good Clinical Practice (MCAP-J study)
Presentation Number: SUN 391
Date of Presentation: April 2nd, 2017
Mitsuhide Naruse*1, Fumitoshi Satoh2, Akiyo Tanabe3, Takahiro Okamoto4, Atsuhiro Ichihara4, Mika Tsuiki1, Takuyuki Katabami5, Masatoshi Nomura6, Tomoaki Tanaka7, Tadashi Matsuda8, Tsuneo Imai9, Masanobu Yamada10, Tomohiro Harada11, Nobuyuki Kawata12 and Kazuhiro Takekoshi13
1National Hospital Organization Kyoto Medical Center, Kyoto, Japan, 2Tohoku University Hospital, Sendai, Japan, 3National Center for Global Health and Medicine, Tokyo, Japan, 4Tokyo Women's Medical University, Tokyo, Japan, 5St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama-shi Kanagawa, Japan, 6Kyushu University Hospital, Fukuoka, Japan, 7Chiba University Graduate School of Medicine, Chiba-city, Japan, 8Kansai Medical University Hospital, Hirakata, Japan, 9National Hospital Organization, Higashinagoya National Hospital, Nagoya, Aichi, Japan, 10Gunma University, Graduate School of Medicine, Japan, 11Ono Pharmaceutical Co., Ltd., Osaka, Japan, 12Ono Pharmaceutical Co., Ltd., Osaka-shi, Japan, 13University of Tsukuba, Tsukuba, Japan
Pheochromocytoma/paraganglioma (Pheo/Para) produces catecholamines, which induce a variety of clinical symptoms. Metirosine is a selective inhibitor of tyrosine hydroxylase, a rate-limiting enzyme for catecholamine biosynthesis. Metirosine is a unique agent to ameliorate catecholamine-induced symptoms and has been approved by FDA in 1979. A prospective, multicenter, open-label study in Japanese patients with Pheo/Para (JAPIC CTI-152999) was conducted from July 2015 in compliance with Good Clinical Practice (GCP) to receive regulatory approval of metirosine in Japan. Patients with Pheo/Para aged 12 years or older requiring preoperative treatment or chronic treatment for metastatic or residual diseases were enrolled. The inclusion criteria were as follows: patients with baseline urinary metanephrine (uMN) or normetanephrine (uNM) levels greater than or equal to 3 times the upper limit of normal values, being treated with sympathetic nerve receptor blockers, and with symptoms associated with excess catecholamine. Sixteen patients (3 under preoperative treatment and 13 under chronic treatment) were enrolled. The patient characteristics were 11 males and 5 females, 12 to 86 years of age. After 12-week treatment, the proportion of subjects who achieved at least a 50% reduction of uMN and/or uNM from the baseline, the primary efficacy endpoint, was 31.3% in all patients, 66.7% in patients under preoperative treatment, and 23.1% in patients under chronic treatment at the last evaluation of efficacy. The percent change was –46.8 ± 24.3% (mean ± SD) for uMN, −42.3 ± 17.5% for uNM, and −44.8 ± 17.3% for uMN+uNM. Symptomatic changes due to excess catecholamine were evaluated both by the patient and the physician. By the patient’s evaluations, symptom was relieved in 61.5% and unchanged in 38.5%. By the physician’s evaluations, symptom was relieved in 53.8% and unchanged in 46.2%. None of the patients experienced worsened symptoms. During 24-week treatment, commonly reported adverse events (AEs) related to metirosine were sedation and somnolence in 15 patients (mild in 12, moderate in 2 and severe in 1), mild gain of weight in 2 patients. Serious AEs related to metirosine were sedation, anemia, and death in 1 patient each. Sedation and anemia were resolved after cessation of metirosine. The cause of death was considered by the investigator to be possibly due to the underlying unresectable pheochromocytoma.
This is the first report to reveal the efficacy and safety of metirosine in patients with Pheo/Para in compliance with GCP. In this prospective, multicenter, open-label study, metirosine was shown to be tolerated and effective in relieving symptoms by reducing excess catecholamine in both patients under preoperative and chronic treatment.
Disclosure: MN: Coordinating Investigator, ONO-Pharma, Investigator, ONO-Pharma. FS: Investigator, ONO-Pharma. AT: Protocol review committee, ONO-Pharma, Investigator, ONO-Pharma. TO: Investigator, ONO-Pharma. AI: Investigator, ONO-Pharma. MT: Investigator, ONO-Pharma. TK: Protocol review committee, ONO-Pharma, Investigator, ONO-Pharma. MN: Investigator, ONO-Pharma. TT: Investigator, ONO-Pharma. TM: Investigator, ONO-Pharma, Protocol review committee, ONO-Pharma. TI: Protocol review committee, ONO-Pharma, Investigator, ONO-Pharma. MY: Investigator, ONO-Pharma. KT: Medical expert, ONO-Pharma. Nothing to Disclose: TH, NK