Phase I study of olaratumab in Japanese patients with advanced solid tumors.

Abstract

Olaratumab (IMC-3G3) is a fully human IgG1 monoclonal antibody that selectively binds the external domain of human platelet-derived growth factor receptor-α with high affinity and blocks ligand binding. This was a single-center, dose-escalation, phase I trial of olaratumab in Japanese patients with advanced/refractory solid malignancies. Three to six patients were enrolled into each of three cohorts: Patients received i.v. olaratumab: 10 mg/kg on days 1 and 8 every 3 weeks (cohort 1); 20 mg/kg every 2 weeks (cohort 2); and 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3). Doses were escalated from cohort 1 through cohort 3. The primary objective was to establish the safety and pharmacokinetic profile of olaratumab. Sixteen patients were treated across three cohorts. There were no dose-limiting toxicities, so the maximum tolerated dose was not reached. The most common olaratumab-related treatment-emergent adverse events (TEAEs) were proteinuria (25.0%) and elevated aspartate transaminase (12.5%). One patient (cohort 2) had two olaratumab-related Grade 3 TEAEs (increased aspartate aminotransferase and tumor hemorrhage); otherwise, olaratumab-related TEAEs were Grade 1/2. Seven patients (43.8%) had a best response of stable disease. Based on the pharmacokinetic concentration profile of olaratumab, the trough concentrations following single and multiple doses at 15 mg/kg on days 1 and 8 every 3 weeks (cohort 3) and multiple doses at 20 mg/kg every 2 weeks (cohort 2) were above the 155 μg/mL target. Thus, these two doses could represent an acceptable schedule for future trials in Japanese patients. Olaratumab had an acceptable safety profile and was well tolerated.

• Authors: Toshihiko Doi, Yan Ma, Aruna Dontabhaktuni, Cornelia Nippgen, Johannes Nippgen, Atsushi Ohtsu
• Journal: Cancer science (Cancer Sci) Vol. 105 Issue 7 Pg. 862-9 (Jul 2014) ISSN: 1349-7006 [Electronic] England
• PMID: 24816152 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Proto-Oncogene Proteins c-sis
• Becaplermin
• olaratumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (adverse effects, pharmacokinetics, therapeutic use)
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Asian People
• Becaplermin
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Proteinuria (chemically induced)
• Proto-Oncogene Proteins c-sis (blood)
• Treatment Outcome