Phase I study of pazopanib in combination with weekly paclitaxel in patients with advanced solid tumors.

Abstract

PURPOSE:

To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.

PATIENTS AND METHODS:

Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m(2)) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.

RESULTS:

Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m(2) paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m(2). At the MTR, coadministration of 800 mg pazopanib and 80 mg/m(2) paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.

CONCLUSION:

Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m(2) when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.

• Authors: Antoinette R Tan, Afshin Dowlati, Suzanne F Jones, Jeffrey R Infante, Jennifer Nishioka, Lei Fang, Jeffrey P Hodge, Shelby D Gainer, Thangam Arumugham, A Benjamin Suttle, Mohammed M Dar, Joanne J Lager, Howard A Burris 3rd
• Journal: The oncologist (Oncologist) Vol. 15 Issue 12 Pg. 1253-61 ( 2010) ISSN: 1549-490X [Electronic] England
• PMID: 21147873 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Indazoles
• Pyrimidines
• Sulfonamides
• pazopanib
• Paclitaxel

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Female
• Humans
• Indazoles
• Lymphatic Metastasis
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Paclitaxel (administration & dosage)
• Pyrimidines (administration & dosage)
• Sulfonamides (administration & dosage)
• Survival Rate
• Tissue Distribution
• Treatment Outcome