4.2 Article

A Phase I Trial of the ABCB1 Inhibitor, Oral Valspodar, in Combination With Paclitaxel in Patients With Advanced Solid Tumors

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LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/COC.0000000000001014

Keywords

P-glycoprotein; multidrug resistance; ABC transporters; valspodar; PSC 833; paclitaxel

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This phase 1 trial aimed to determine the safety of paclitaxel with valspodar in patients with advanced solid tumors. The combination therapy resulted in manageable hematologic and non-hematologic adverse events. However, the efficacy was limited, leading to discontinuation of its clinical development.
Objectives:Multidrug resistance mediated by P-glycoprotein is a potential obstacle to cancer treatment. This phase 1 trial determined the safety of paclitaxel with valspodar, a P-glycoprotein inhibitor, in patients with advanced solid tumors. Methods:Patients were treated with single-agent paclitaxel Q3W 175 mg/m(2) (or 135 mg/m(2) if heavily pretreated) as a 3-hour infusion. If their disease was stable (SD) or progressive (PD), paclitaxel at 30% (52.5 mg/m(2)), 40% (70 mg/m(2)), or 50% (87.5 mg/m(2)) of 175 mg/m(2) (full dose) was administered with valspodar 5 mg/kg orally 4 times daily for 12 doses. Pharmacokinetic sampling (PK) for paclitaxel and valspodar was performed during single-agent and combination therapy. Results:Sixteen patients had SD/PD after one cycle of paclitaxel and then received paclitaxel at 30% (n=3), 40% (n=3), and 50% (n=10) with valspodar. Hematologic adverse events (AEs) including myelosuppression at paclitaxel 40% were comparable to those of full-dose paclitaxel. Non-hematologic AEs consisted of reversible hepatic (hyperbilirubinemia and transaminitis) and neurologic AEs (ataxia and paresthesias). Eleven patients experienced SD with a median of 12.7 weeks (range, 5.4 to 36.0), 4 patients progressed, and 1 was inevaluable. Reduced dose paclitaxel with valspodar resulted in lower plasma peak concentrations of paclitaxel; otherwise, concentrations were similar to single-agent paclitaxel. Conclusion:Paclitaxel at 70 mg/m(2) was administered safely with valspodar. Limited efficacy in hematologic and solid tumors resulted in discontinuation of its clinical development and other transporter inhibitors. Recently, the development of ATP-binding cassette transporter inhibitors has been reconsidered to mitigate resistance to antibody-drug conjugates.

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