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Open Access Research article

A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies

Jonathan W Goldman1*, Robert N Raju2, Gregory A Gordon2, Iman El-Hariry3, Florentina Teofilivici3, Vojo M Vukovic3, Robert Bradley3, Michael D Karol3, Yu Chen3, Wei Guo3, Takayo Inoue3 and Lee S Rosen1

Author Affiliations

1 UCLA Medical Center, Suite 600, 2020 Santa Monica Blvd, Santa Monica, CA 90404, USA

2 Kettering Health Network Innovation Center, 3535 Southern Blvd, Kettering, OH 45429, USA

3 Synta Pharmaceuticals Corp., 125 Hartwell Ave, Lexington, MA 02421, USA

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BMC Cancer 2013, 13:152  doi:10.1186/1471-2407-13-152

Published: 25 March 2013

Abstract

Background

This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics and antitumor activity of ganetespib in patients with solid malignancies.

Methods

Patients were enrolled in cohorts of escalating ganetespib doses, given as 1 hour IV infusion, once weekly for 3 weeks, followed by a 1-week rest until disease progression or unacceptable toxicity. Endpoints included safety, pharmacokinetic and pharmacodynamic parameters and preliminary clinical activity.

Results

Fifty-three patients were treated at doses escalating from 7 to 259 mg/m2. The most common adverse events were Grade 1 and 2 diarrhea, fatigue, nausea or vomiting. Dose-limiting toxicities (DLT) observed were: one Grade 3 amylase elevation (150 mg/m2), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m2). The MTD was 216 mg/m2 and the recommended phase 2 dose was established at 200 mg/m2 given IV at Days 1, 8, and 15 every 4 weeks. There was a linear relationship between dose and exposure. Plasma HSP70 protein levels remained elevated for over a week post treatment. Disease control rate (objective response and stable disease at ≥ 16 weeks) was 24.4%.

Conclusions

Ganetespib is well tolerated as a weekly infusion for 3 of every 4 weeks cycle. The recommended phase II dose is 200 mg/m2, and is associated with an acceptable tolerability profile.

Trial registration

NCT00687934

Keywords:
Ganetespib; Hsp90 inhibitor; Pharmacokinetics; Phase I study; Solid tumors