title: 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.affiliation: National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Doi
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Aruna
authors.initials: A
authors.lastname: Dontabhaktuni
authors.forename: Cornelia
authors.initials: C
authors.lastname: Nippgen
authors.forename: Johannes
authors.initials: J
authors.lastname: Nippgen
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ohtsu
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D044466:Asian People; D000077214:Becaplermin; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011507:Proteinuria / Q000139:chemically induced; D020574:Proto-Oncogene Proteins c-sis / Q000097:blood; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C000589393:olaratumab
keywords: IMC-3G3; monoclonal antibody; olaratumab; phase 1; platelet-derived growth factor receptor