Phase I study of pazopanib in combination with paclitaxel and carboplatin given every 21 days in patients with advanced solid tumors.
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.
Sarah Cannon Research Institute, 250 25th Ave North, Suite 110, Nashville, TN 37203, USA. howard.burris@scresearch.net
Howard A
HA
Burris
Afshin
A
Dowlati
Rebecca A
RA
Moss
Jeffrey R
JR
Infante
Suzanne F
SF
Jones
David R
DR
Spigel
Kelly T
KT
Levinson
Diana
D
Lindquist
Shelby D
SD
Gainer
Mohammed M
MM
Dar
A Benjamin
AB
Suttle
Howard A
HA
Ball
Antoinette R
AR
Tan
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007191:Indazoles; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D017239:Paclitaxel / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome
D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D016190:Carboplatin; D017239:Paclitaxel