Phase I study of U3-1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors.

Abstract

PURPOSE:

HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor.

EXPERIMENTAL DESIGN:

The study was conducted in 2 parts: part 1--sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2--additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined.

RESULTS:

Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2.

CONCLUSION:

U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.

• Authors: Patricia LoRusso, Pasi A Jänne, Moacyr Oliveira, Naiyer Rizvi, Lisa Malburg, Vicki Keedy, Lorrin Yee, Catherine Copigneaux, Thore Hettmann, Chi-Yuan Wu, Agnes Ang, Abdel-Baset Halim, Robert A Beckman, Darrin Beaupre, Jordan Berlin
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 11 Pg. 3078-87 (Jun 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23591447 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• Antineoplastic Agents
• Biomarkers
• Broadly Neutralizing Antibodies
• patritumab
• Receptor, ErbB-3

Topics

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Antibodies, Neutralizing
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Biomarkers (metabolism)
• Broadly Neutralizing Antibodies
• Female
• Humans
• Male
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, metabolism, pathology)
• Prognosis
• Receptor, ErbB-3 (antagonists & inhibitors)
• Treatment Outcome