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Byline: Albert J. ten Tije (1), Timothy W. Synold (2), Darcy Spicer (3), Jaap Verweij (1), James H. Doroshow (2), Alex Sparreboom (4) Keywords: valspodar; paclitaxel; disposition; P-glycoprotein; resistance Abstract: The aim of this multicenter study was to determine whether valspodar (Amdray[TM] code designation, SDZ PSC 833), a potent P-glycoprotein (P-gp) inhibitor, affects the pharmacokinetics of unbound paclitaxel (C .sub.u). Data were obtained from 31 patients with advanced breast cancer. Thirteen patients were treated with paclitaxel alone (3-h infusion at 175mg/m.sup.2) and another 18 received paclitaxel (3-h infusion at 70mg/m.sup.2) in combination with a 21-day cycle of oral valspodar (5mg/kg given four times a day) starting 1 day before administration of paclitaxel. Serial blood samples were taken in the first course and C .sub.u in plasma determined using equilibrium dialysis with a [G- 3.sup.H]paclitaxel tracer. The apparent clearance of C .sub.u was not significantly different between the two groups, with mean +- standard deviation (+-SD) values of 230 +- 56.0 and 202 +- 49.9L/h/m.sup.2 in the absence and presence of valspodar, respectively (P = 0.17). The volume of C .sub.u distribution was slightly larger in the presence of valspodar (1160 +- 474 vs. 1620 +- 552L/m.sup.2 P = 0.025), which contributed to a minor difference in the terminal disposition half-life (6.12 +- 3.42 vs. 8.50 +- 2.06h P = 0.028). These data indicate that (i) valspodar lacks the significant interaction with paclitaxel observed previously with other P-gp modulators, (ii) the majority of the increased toxicity of the combination does not appear to be attributable to increased levels of C .sub.u, and (iii) provide further evidence of the conjecture that the plasma concentration of paclitaxel may not be an appropriate measure to monitor the impact of P-gp inhibition. Author Affiliation: (1) Erasmus MC -- Daniel den Hoed Cancer Center, Department of Medical Oncology, Rotterdam, The Netherlands (2) City of Hope Cancer Center, Duarte, CA (3) USC/Norris Comprehensive Cancer Center, Los Angeles, CA (4) Erasmus, Department of Medical Oncology, MC -- Daniel den Hoed Cancer Center, Rotterdam, The Netherlands (5) National Cancer Institute, Bethesda, MD, 20892 Article History: Registration Date: 06/10/2004

Byline: Kim Margolin (1), Jeffrey Longmate (2), Timothy W. Synold (1), David R. Gandara (3), Jeffrey Weber (4), Rene Gonzalez (5), Mary J. Johansen (6), Robert Newman (6), Tracey Baratta (2), James H. Doroshow (1) Keywords: Dolastatin-10; metastatic melanoma; pharmokinetics Abstract: Dolastatin-10 is a novel pentapeptide agentoriginally isolated from the marine molluskDolabella auricularia with amechanism of antitumor activity thatinvolves the inhibition of microtubuleassembly. We performed a Phase II trial ofDolastatin-10, 400 ug/m.sup.2, inpatients with advanced melanoma who hadreceived no prior chemotherapy. Dolastatin-10 pharmokinetics wereevaluated in a subset of patients followingcourses 1 and 2. Twelve patients weretreated with a median of 2 cycles ofDolastatin-10, and no patient experiencedan objective response. The only grade &gt 2toxicities were grade 3 neutropeniauncomplicated by infection, occurring in 4patients following the first treatmentcycle. The total systemic clearance andvolume of distribution at steady-state were2.61 +- 1.9 L/h/m.sup.2 and 28.4 +- 13 L/m.sup.2,respectively. Due toprolonged terminal elimination,Dolastatin-10 plasma concentrations ofgreater than 1 nM were sustained for 24h in all patients studied. Dolastatin-10 is unlikely to havesubstantial activity in the treatment ofmelanoma. Author Affiliation: (1) Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, U.S.A. (2) Department of Biostatistics, City of Hope National Medical Center, Duarte, CA, U.S.A. (3) Department of Medical Oncology, University of California at Davis Medical Center, Sacramento, CA, U.S.A. (4) Department of Medical Oncology, University of Southern California/Kenneth Norris Cancer Center, Los Angeles, CA (5) Department of Medical Oncology, University of Colorado Cancer Center, Denver, CO, U.S.A. (6) Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, TX, U.S.A. Article History: Registration Date: 11/10/2004