Phase I and pharmacokinetic study of HER2-targeted rhuMAb 2C4 (Pertuzumab, RO4368451) in Japanese patients with solid tumors.

Abstract

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.

• Authors: Noboru Yamamoto, Yasuhide Yamada, Yutaka Fujiwara, Kazuhiko Yamada, Yasuhito Fujisaka, Toshio Shimizu, Tomohide Tamura
• Journal: Japanese journal of clinical oncology (Jpn J Clin Oncol) Vol. 39 Issue 4 Pg. 260-6 (Apr 2009) ISSN: 1465-3621 [Electronic] England
• PMID: 19261664 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Natriuretic Peptide, Brain
• Receptor, ErbB-2
• pertuzumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (pharmacokinetics, therapeutic use, toxicity)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents (pharmacokinetics, therapeutic use, toxicity)
• Area Under Curve
• Breast Neoplasms (drug therapy, surgery)
• Carcinoma, Non-Small-Cell Lung (drug therapy, surgery)
• Chemotherapy, Adjuvant
• Diarrhea (chemically induced)
• Digestive System Neoplasms (drug therapy, surgery)
• Drug Eruptions (etiology)
• Female
• Humans
• Hypersensitivity (diagnosis, etiology)
• Lung Neoplasms (drug therapy, surgery)
• Lymphopenia (chemically induced)
• Male
• Middle Aged
• Natriuretic Peptide, Brain (drug effects, metabolism)
• Neoplasms (drug therapy, surgery)
• Neoplasms, Germ Cell and Embryonal (drug therapy, surgery)
• Neoplasms, Unknown Primary (drug therapy, surgery)
• Ovarian Neoplasms (drug therapy, surgery)
• Radiotherapy, Adjuvant
• Receptor, ErbB-2 (drug effects)