PMID- 37264515
OWN - NLM
STAT- MEDLINE
DCOM- 20230929
LR  - 20231003
IS  - 1537-453X (Electronic)
IS  - 0277-3732 (Print)
IS  - 0277-3732 (Linking)
VI  - 46
IP  - 8
DP  - 2023 Aug 1
TI  - A Phase I Trial of the ABCB1 Inhibitor, Oral Valspodar, in Combination With 
      Paclitaxel in Patients With Advanced Solid Tumors.
PG  - 353-359
LID - 10.1097/COC.0000000000001014 [doi]
AB  - 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.
CI  - Copyright (c) 2023 Wolters Kluwer Health, Inc. All rights reserved.
FAU - Fracasso, Paula M
AU  - Fracasso PM
AUID- ORCID: 0000-0003-1211-3304
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine and the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and 
      Washington University School of Medicine, St. Louis, MO.
FAU - Fisher, George A Jr
AU  - Fisher GA Jr
AD  - Department of Medicine (Oncology), Stanford University, Stanford, CA.
FAU - Goodner, Sherry A
AU  - Goodner SA
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine and the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and 
      Washington University School of Medicine, St. Louis, MO.
FAU - Beumer, Jan H
AU  - Beumer JH
AD  - Department of Pharmaceutical Sciences, University of Pittsburgh School of 
      Pharmacy, Pittsburgh, PA.
FAU - Egorin, Merrill J
AU  - Egorin MJ
AD  - Departments of Medicine and Pharmacology, University of Pittsburgh School of 
      Medicine, Pittsburgh, PA.
FAU - Fears, Carole L
AU  - Fears CL
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine and the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and 
      Washington University School of Medicine, St. Louis, MO.
FAU - Wildi, Jonathan D
AU  - Wildi JD
AD  - Division of Oncology, Department of Medicine, Washington University School of 
      Medicine and the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and 
      Washington University School of Medicine, St. Louis, MO.
FAU - Jones, Gary J
AU  - Jones GJ
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ.
FAU - Pearce, Tillman E
AU  - Pearce TE
AD  - Novartis Pharmaceuticals Corporation, East Hanover, NJ.
FAU - Sikic, Branimir I
AU  - Sikic BI
AD  - Department of Medicine (Oncology), Stanford University, Stanford, CA.
LA  - eng
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - P30 CA091842/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase I
PT  - Journal Article
DEP - 20230602
PL  - United States
TA  - Am J Clin Oncol
JT  - American journal of clinical oncology
JID - 8207754
RN  - P88XT4IS4D (Paclitaxel)
RN  - Q7ZP55KF3X (valspodar)
RN  - 0 (Cyclosporins)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (ABCB1 protein, human)
SB  - IM
MH  - Humans
MH  - Paclitaxel
MH  - *Neoplasms/chemically induced
MH  - *Cyclosporins/adverse effects
MH  - ATP Binding Cassette Transporter, Subfamily B/therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects
PMC - PMC10524540
MID - NIHMS1890911
COIS- 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.
EDAT- 2023/06/02 01:07
MHDA- 2023/09/29 06:44
PMCR- 2024/08/01
CRDT- 2023/06/02 00:03
PHST- 2024/08/01 00:00 [pmc-release]
PHST- 2023/09/29 06:44 [medline]
PHST- 2023/06/02 01:07 [pubmed]
PHST- 2023/06/02 00:03 [entrez]
AID - 00000421-990000000-00106 [pii]
AID - 10.1097/COC.0000000000001014 [doi]
PST - ppublish
SO  - Am J Clin Oncol. 2023 Aug 1;46(8):353-359. doi: 10.1097/COC.0000000000001014. 
      Epub 2023 Jun 2.