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Clinical Trial
. 2023 Aug 1;46(8):353-359.
doi: 10.1097/COC.0000000000001014. Epub 2023 Jun 2.

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

Paula M Fracasso  1 , George A Fisher Jr  2 , Sherry A Goodner  1 , Jan H Beumer  3 , Merrill J Egorin  4 , Carole L Fears  1 , Jonathan D Wildi  1 , Gary J Jones  5 , Tillman E Pearce  5 , Branimir I Sikic  2
Affiliations
Clinical Trial

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

Paula M Fracasso et al. Am J Clin Oncol. .

Abstract

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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Conflict of interest statement

P.M.F. reports previous employment with Bristol Myers Squibb from May 2014 to December 2018 and Adaptimmune LLC from December 2018 to September 2020. She then consulted with Adaptimmune LLC until December 2021. Her work on this clinical study was done while she was in academics at Washington University in St. Louis and occurred prior to her work in pharma. No activities in this submitted work have any relationship to her work at Bristol Myers Squibb or Adaptimmune LLC. G.A.F., Jr. reports that he is the Chair, Data safety Monitoring Board for Astra Zeneca and a member of the Data Safety Monitoring Board of Hutchinson Pharma, and an Advisory Board member for Genentech/Roche and Merck Jan H. Beumer reports no conflicts of interest. Sherry A. Goodner reports previous employment with AbbVie from March 2016 to June 2022. Her work on this clinical trial was done while she was employed at Barnes-Jewish Hospital at Washington University in St. Louis prior to her employment at AbbVie. No activities in this submitted work have any relationship to her work at AbbVie. Jonathan D. Wildi reports no conflicts of interest. Carole L. Fears reports no conflicts of interest. Gary J. Jones reports previous employment with Sandoz/Novartis Pharmaceuticals Corporation from August 1990 to December 2000. He consulted with the company from December 2003 to May 2009 and from February 2012 to February 2013. Tillman E. Pearce was an employee for Novartis during the conduct of this study. He has no other conflicts of interest. B.I.S. reports no conflicts of interest.

Figures

Fig. 1
Fig. 1
Mean plasma paclitaxel concentrations after a paclitaxel alone (●) and during administration of valspodar (○) for 9 patients. Paclitaxel was dosed at 175 mg/m2 as a single agent or 40.5 to 87.5 mg/m2 in combination with valspodar 5 mg/kg q6hr. Coadministration of reduced dose of paclitaxel with valspodar resulted in a lower peak concentration of paclitaxel, but otherwise the plasma concentrations of paclitaxel were very similar as compared to full dose of paclitaxel alone.
See this image and copyright information in PMC

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