Phase I clinical trial of STA-4783 in combination with paclitaxel in patients with refractory solid tumors.

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Berkenblit A, Eder JP Jr, Ryan DP, Seiden MV, Tatsuta N, Sherman ML, Dahl TA, Dezube BJ, Supko JG

Phase I clinical trial of STA-4783 in combination with paclitaxel in patients with refractory solid tumors.

Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):584-90.

PubMed ID
17255281 [ View in PubMed
]
Abstract

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/m(2), respectively. After increasing paclitaxel to 175 mg/m(2), 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/m(2) paclitaxel, the incidence of severe toxicity increased with escalation of the STA-4783 dose above 263 mg/m(2), and 438 mg/m(2) 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/m(2)). 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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