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Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors

Authors' Affiliations: ¹ Beth Israel Deaconess Medical Center; ² Dana-Farber Cancer Institute; ³ Massachusetts General Hospital; ⁴ Dana-Farber/Harvard Cancer Center, Boston, Massachusetts; and ⁵ Synta Pharmaceuticals Corp., Lexington, Massachusetts

Requests for reprints: Jeffrey G. Supko, Massachusetts General Hospital, 55 Fruit Street, Room GRJ1025, Boston, MA 02114. Phone: 617-724-1970; Fax: 617-726-6974; E-mail: jsupko{at}partners.org.

Purpose: STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel.

Experimental Design: Adults with refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and 135 mg/m², respectively. After increasing paclitaxel to 175 mg/m², the STA-4783 dose was escalated as permitted by dose-limiting toxicity during the first 21-day cycle.

Results: Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving 175 mg/m² paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m², and 438 mg/m² was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi's sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06 ± 0.24 h) and a low steady-state apparent volume of distribution (25.1 ± 8.1 L/m²). The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose.

Conclusions: The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in two heavily pretreated patients, both with taxane exposure, have encouraged further clinical evaluation of this regimen.

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