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Japanese Journal of Clinical Oncology Advance Access published online on March 4, 2009
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyp006
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© 2009 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Phase I and Pharmacokinetic Study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese Patients with Solid Tumors

Noboru Yamamoto, Yasuhide Yamada, Yutaka Fujiwara, Kazuhiko Yamada, Yasuhito Fujisaka, Toshio Shimizu and Tomohide Tamura

Division of Internal Medicine, National Cancer Center Hospital, Tokyo, Japan

For reprints and all correspondence: Noboru Yamamoto, Division of Internal Medicine, National Cancer Center Hospital, 5-1-1, Tsukiji Chuo-ku, Tokyo 104-0045, Japan. E-mail: nbryamam{at}ncc.go.jp

Received November 7, 2008; accepted January 12, 2009

Objective: rhuMAb 2C4 (pertuzumab, RO4368451), a human epidermal growth factor receptor-2 (HER2) targeted antibody that binds to an epitope distinct from trastuzumab, blocks ligand-associated heterodimerization of HER2 with other HER receptor family members. This study evaluated the toxicity, pharmacokinetics and anti-tumor activities of pertuzumab in Japanese patients with solid tumors.

Methods: Patients with solid tumors refractory to standard therapy were administered pertuzumab 5, 10, 15, 20 and 25 mg/kg intravenously once every 3 weeks. Grade 3 toxicities were considered as dose limiting. The maximum tolerated dose (MTD) was a dose at which two out of six patients had Grade 3 toxicities.

Results: Eighteen patients, aged 38–66 (median 57) years, with solid tumors were enrolled and a total of 32 cycles of pertuzumab were administered. Toxicities were generally acceptable. Grade 3 elevation of gamma-glutamyl transpeptidase was observed in one patient at 25 mg/kg and was considered to be dose limiting. MTD was not reached up to a dose level of 25 mg/kg. The serum concentration of pertuzumab declined slowly (terminal half-life is approximately 3 weeks). The AUC proportionally increased over the dose range tested. There was limited evidence of activity (stable disease 2; progressive disease 13; and not evaluable 3); however, tumor shrinkage and tumor marker decrease were observed in an ovarian cancer and a non-small-cell lung cancer patient, respectively.

Conclusions: Pertuzumab is well tolerated up to 25 mg/kg. Although objective tumor response was not observed, it is worth evaluating as a flat dose and in combination with other cytotoxics and molecular-targeted agents.

Key Words: pertuzumab • Phase I • MTD • pharmacokinetics • solid tumors


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