Berkenblit, Anna;
Eder, Joseph P.;
Ryan, David P.;
Seiden, Michael V.;
Tatsuta, Noriaki;
Sherman, Matthew L.;
Dahl, Thomas A.;
Dezube, Bruce J.;
Supko, Jeffrey G.
Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors
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Medientyp:
E-Artikel
Titel:
Phase I Clinical Trial of STA-4783 in Combination with Paclitaxel in Patients with Refractory Solid Tumors
Beteiligte:
Berkenblit, Anna;
Eder, Joseph P.;
Ryan, David P.;
Seiden, Michael V.;
Tatsuta, Noriaki;
Sherman, Matthew L.;
Dahl, Thomas A.;
Dezube, Bruce J.;
Supko, Jeffrey G.
Erschienen:
American Association for Cancer Research (AACR), 2007
Erschienen in:Clinical Cancer Research
Sprache:
Englisch
DOI:
10.1158/1078-0432.ccr-06-0964
ISSN:
1078-0432;
1557-3265
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>
<jats:p>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.</jats:p>