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A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors

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Abstract

Purpose

The platelet-derived growth factor receptor (PDGFR) has an important role in tumorigenesis and tumor progression. Olaratumab (IMC-3G3) is a fully human monoclonal antibody that selectively binds human PDGFRα and blocks ligand binding. This phase I study assessed the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), pharmacokinetics, and preliminary antitumor activity of olaratumab in patients with advanced solid tumors.

Methods

Patients were enrolled into five dose-escalating cohorts of 3–6 patients each. Olaratumab was administered intravenously weekly at 4, 8, or 16 mg/kg (cohorts 1–3) or once every other week at 15 or 20 mg/kg (cohorts 4–5), with 4 weeks/cycle.

Results

Nineteen patients were treated in five cohorts. There were no dose-limiting toxicities; the MTD was not identified with the doses studied. The most common olaratumab-related adverse events (AE) were fatigue and infusion reactions (10.5 % each). With the exception of 1 patient (20 mg/kg) experiencing two grade 3 drug-related AEs after the dose-limiting toxicity assessment period, all drug-related AEs were grade 1 or 2. The trough concentrations (C min) for 16 mg/kg weekly and 20 mg/kg biweekly were higher than 155 μg/mL, and the concentration found to be efficacious in preclinical xenograft models. Twelve patients (63.2 %) had a best response of stable disease [median duration of 3.9 months (95 % CI 2.3–8.7)].

Conclusions

Olaratumab was well tolerated and showed preliminary antitumor activity. RP2Ds are 16 mg/kg weekly and 20 mg/kg biweekly. Phase II studies of olaratumab as monotherapy and in combination are ongoing in several tumor types.

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Acknowledgments

The authors wish to acknowledge the patients, their families, and the study personnel who participated in this clinical trial. We thank Chirag Jani for assistance with figure preparation. The authors thank Lori Kornberg (InVentiv Health Clinical) and Susan Johnson (ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company) for medical writing assistance. This trial was supported by ImClone Systems, LLC, a wholly owned subsidiary of Eli Lilly and Company.

Conflict of interest

Drs. Youssoufian and Nippgen were employees of ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company during the conduct of this trial. Dr. Youssoufian owned ImClone stock at the time of study conduct. Drs.Qin, Dontabhaktuni, and Loizos are employees of ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company and own stock in Eli Lilly and Company. Dr. Loizos is an author on patents in areas related to this manuscript. Drs. Chiorean Sweeney and Amato report no relevant conflict of interest.

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Correspondence to E. Gabriela Chiorean.

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Chiorean, E.G., Sweeney, C., Youssoufian, H. et al. A phase I study of olaratumab, an anti-platelet-derived growth factor receptor alpha (PDGFRα) monoclonal antibody, in patients with advanced solid tumors. Cancer Chemother Pharmacol 73, 595–604 (2014). https://doi.org/10.1007/s00280-014-2389-9

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  • DOI: https://doi.org/10.1007/s00280-014-2389-9

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