Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors.

Published

Journal Article

This phase I, open-label, dose-escalation study assessed the maximum-tolerated dose, safety, pharmacokinetics, and preliminary antitumor activity of pazopanib plus lapatinib combination therapy in patients with solid tumors. Patients were to take pazopanib and lapatinib orally once daily in a fasting condition. During the escalation phase, pazopanib and lapatinib doses were escalated in serial patient cohorts, and a limited blood sampling scheme was applied for pharmacokinetic evaluation. In the expansion phase, potential pharmacokinetic interaction between pazopanib and lapatinib was evaluated more extensively. Seventy-five patients were treated. Multiple dosing levels were studied, combining pazopanib up to 800 mg/day with lapatinib up to 1,500 mg/day. Dose-limiting toxicities observed included grade 3 neutropenia, fatigue, asymptomatic decline in left ventricular ejection fraction, diarrhea, and liver enzyme elevations. The most common drug-related adverse events were diarrhea, nausea, anorexia, fatigue, vomiting, rash, hair depigmentation, and hypertension. The dose recommended for further evaluation was pazopanib 800 mg plus lapatinib 1,500 mg (paz-800/lap-1500). No clinically significant drug-drug interaction was observed at the paz-400/lap-1000 level. However, at paz-800/lap-1500, an increase in both the AUC0-t and Cmax of pazopanib was observed. Four partial responses were observed in patients with renal cancer (n=2), giant-cell tumor of the bone (n=1), and thyroid cancer (n=1). Stable disease for ≥ 18 weeks was seen in 12 patients. Pazopanib and lapatinib can be administered in combination at their respective single-agent doses with an acceptable safety profile. Further evaluation of the combination will be pursued, exploring both paz-800/lap-1500 and paz-400/lap-1000.

Full Text

Duke Authors

Cited Authors

  • de Jonge, MJA; Hamberg, P; Verweij, J; Savage, S; Suttle, AB; Hodge, J; Arumugham, T; Pandite, LN; Hurwitz, HI

Published Date

  • June 2013

Published In

Volume / Issue

  • 31 / 3

Start / End Page

  • 751 - 759

PubMed ID

  • 23054212

Pubmed Central ID

  • 23054212

Electronic International Standard Serial Number (EISSN)

  • 1573-0646

International Standard Serial Number (ISSN)

  • 0167-6997

Digital Object Identifier (DOI)

  • 10.1007/s10637-012-9885-8

Language

  • eng