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 Goldman, Robert N Raju, Gregory A Gordon, Iman El-Hariry, Florentina Teofilivici, Vojo M Vukovic, Robert Bradley, Michael D Karol, Yu Chen, Wei Guo, Takayo Inoue, Lee S Rosen, Jonathan W Goldman, Robert N Raju, Gregory A Gordon, Iman El-Hariry, Florentina Teofilivici, Vojo M Vukovic, Robert Bradley, Michael D Karol, Yu Chen, Wei Guo, Takayo Inoue, Lee S Rosen

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/m(2). 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/m(2)), one Grade 3 diarrhea and one Grade 3 and one Grade 4 asthenia (259 mg/m(2)). The MTD was 216 mg/m(2) and the recommended phase 2 dose was established at 200 mg/m(2) 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/m(2), and is associated with an acceptable tolerability profile.

Trial registration: NCT00687934.

Figures

Figure 1
Figure 1
Chemical structures of Hsp90 inhibitors and ganetespib concentration vs. time curves. (A) Ganetespib (left) and 17-AAG, a prototypical geldanamycin-derived Hsp90 inhibitor (right); (B) Representative ganetespib concentration vs. time curves for a 216 mg/m2 dose. Red circles represent Day 1, blue squares represent Day 15.
Figure 2
Figure 2
Pharmacokinetic linearity plots. (A) AUC vs. Dose and (B) Cmax vs. Dose. Diamonds represent Day 1, triangles represent Day 15. Solid line represents linear regression of Day 1 and Day 15 data combined. Dotted line is Day 1 only. Dashed and dotted line is Day 15 only. For Days 1 and 15 combined, coefficients of determination for AUC and Cmax were 0.7547 and 0.7637, respectively.
Figure 3
Figure 3
Plasma HSP70 protein concentrations on days 1, 8 and 15 of Cycle 1 for 7–114 mg/m2 and 150–259 mg/m2 dose groups.

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