Abstract

Several phase III trials have shown that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the maximum-tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m(2) and carboplatin [dosed at area under the curve (AUC) 5 or 6] given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m(2) and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with breast, small-cell lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at 200 mg increased paclitaxel maximal concentration (C(max)) by 43% and carboplatin (AUC5 or AUC6) C(max) by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen, further studies are underway to determine a clinically tolerable schedule of pazopanib with paclitaxel and carboplatin.

Links

Publisher Full Text

Authors

Burris HA, Dowlati A, Moss RA, Infante JR, Jones SF, Spigel DR, Levinson KT, Lindquist D, Gainer SD, Dar MM, Suttle AB, Ball HA, Tan AR

Institution

Sarah Cannon Research Institute, 250 25th Ave North, Suite 110, Nashville, TN 37203, USA. howard.burris@scresearch.net

Source

Molecular cancer therapeutics 11:8 2012 Aug pg 1820-8

MeSH

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Carboplatin
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasm Staging
Neoplasms
Paclitaxel
Pyrimidines
Sulfonamides
Treatment Outcome

Pub Type(s)

Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22679111