Phase 1 study of olaratumab plus doxorubicin in Japanese patients with advanced soft-tissue sarcoma.

Abstract

Olaratumab, a monoclonal antibody targeting human platelet-derived growth factor receptor α, plus doxorubicin significantly improved overall survival in patients with advanced soft-tissue sarcoma (STS) in a prior phase 1b/2 randomized trial. Subsequent exposure-response analysis suggested that higher olaratumab exposures earlier might improve outcomes in patients at risk of early disease progression. This phase 1 study (3 treatment cohorts; minimum 6 patients each) investigated the safety, pharmacokinetics and antitumor activity of olaratumab plus doxorubicin in Japanese patients with STS. Patients received olaratumab 15 mg/kg on Days 1 and 8 during each 21-day cycle until disease progression. Patients in Cohort 3 received a 20 mg/kg loading dose of olaratumab in Cycle 1. Doxorubicin was administered for up to 6 cycles. Patients in Cohort 1 received doxorubicin 25 mg/m2 on Days 1, 2 and 3. Patients in Cohorts 2 and 3 received doxorubicin 75 mg/m2 on Day 1. One patient in Cohort 2 experienced a dose-limiting toxicity of Grade 3 febrile neutropenia. Most treatment-emergent adverse events were of mild and moderate severity, and were known doxorubicin toxicities. Olaratumab serum concentrations in Cohort 3 reached a steady-state exceeding the target level in Cycle 1. Partial response was confirmed in 4 patients (2 each in Cohorts 2 and 3). Olaratumab plus doxorubicin had an acceptable safety profile in patients with STS. A loading dose of olaratumab 20 mg/kg was effective for achieving minimum serum concentrations above the target trough level in Cycle 1.

• Authors: Kan Yonemori, Makoto Kodaira, Taroh Satoh, Toshihiro Kudo, Shunji Takahashi, Kenji Nakano, Yuichi Ando, Tomoya Shimokata, Joji Mori, Koichi Inoue, Gerard J Oakley, Sachi Sakaguchi, Kenji Tamura
• Journal: Cancer science (Cancer Sci) Vol. 109 Issue 12 Pg. 3962-3970 (Dec 2018) ISSN: 1349-7006 [Electronic] England
• PMID: 30353601 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study)
• Copyright: © 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Antibodies, Monoclonal
• Doxorubicin
• olaratumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, pharmacokinetics)
• Disease Progression
• Doxorubicin (administration & dosage, adverse effects, pharmacokinetics)
• Drug Administration Schedule
• Female
• Humans
• Japan
• Male
• Middle Aged
• Sarcoma (blood, drug therapy)
• Treatment Outcome