Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors.

Abstract

Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

• Authors: Leo Mascarenhas, Chitose Ogawa, Theodore W Laetsch, Brenda J Weigel, Michael W Bishop, Julie Krystal, Scott C Borinstein, Emily K Slotkin, Jodi A Muscal, Pooja Hingorani, Donna E Levy, Gary Mo, Ashwin Shahir, Jennifer Wright, Steven G DuBois
• Journal: Cancer medicine (Cancer Med) Vol. 10 Issue 3 Pg. 843-856 (02 2021) ISSN: 2045-7634 [Electronic] United States
• PMID: 33474828 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal
• Vincristine
• Irinotecan
• Doxorubicin
• olaratumab
• Ifosfamide

Topics

• Adolescent
• Antibodies, Monoclonal (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (pharmacokinetics, therapeutic use)
• Central Nervous System Neoplasms (drug therapy, pathology)
• Child
• Child, Preschool
• Doxorubicin (administration & dosage)
• Drug Resistance, Neoplasm
• Female
• Follow-Up Studies
• Humans
• Ifosfamide (administration & dosage)
• Irinotecan (administration & dosage)
• Male
• Maximum Tolerated Dose
• Neoplasm Recurrence, Local (drug therapy, pathology)
• Neoplasms (drug therapy, pathology)
• Prognosis
• Salvage Therapy
• Tissue Distribution
• Vincristine (administration & dosage)