Phase I study of olaratumab in Japanese patients with advanced solid tumors - PubMed (original) (raw)

Clinical Trial

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

Toshihiko Doi et al. Cancer Sci. 2014 Jul.

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.

Keywords: IMC-3G3; monoclonal antibody; olaratumab; phase 1; platelet-derived growth factor receptor.

© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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Figures

Figure 1

Figure 1

Time on treatment. The duration of treatment for each patient is shown.

Figure 2

Figure 2

Arithmetic mean olaratumab serum concentration versus time profiles following the first dose (a) and multiple (b) doses of olaratumab. Semi-log scales are shown in each plot. h, hour; q2w, every 2 weeks; q3w, every 3 weeks.

Figure 3

Figure 3

Comparison of PK parameters clearance and exposure between non-Asian and Asian patients following multiple infusions of olaratumab. Shown are CLss (circles) and AUCτ (triangles) for the 20 mg/kg-every-2-weeks groups. White circles (○) = CLss, non-Asian patients; black circles (•) = CLss, Asian patients; white triangles (▵) = AUCτ, non-Asian patients; black triangles (▴) = AUCτ Asian patients. AUCτ, area under the concentration versus time curve during one dosing interval; CLss, total body clearance of drug calculated after intravenous administration at steady state.

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References

    1. Heldin CH, Westermark B. Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev. 1999;79:1283–316. - PubMed
    1. Dong J, Grunstein J, Tejada M, et al. VEGF-null cells require PDGFR alpha signaling-mediated stromal fibroblast recruitment for tumorigenesis. EMBO J. 2004;23:2800–10. - PMC - PubMed
    1. Adams SF, Hickson JA, Hutto JY, Montag AG, Lengyel E, Yamada SD. PDGFR-alpha as a potential therapeutic target in uterine sarcomas. Gynecol Oncol. 2007;104:524–8. - PubMed
    1. Fleming TP, Saxena A, Clark WC, et al. Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res. 1992;52:4550–3. - PubMed
    1. Matei D, Emerson RE, Lai YC, et al. Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer. Oncogene. 2006;25:2060–9. - PubMed

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