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

Publication ,  Journal Article
de Jonge, MJA; Hamberg, P; Verweij, J; Savage, S; Suttle, AB; Hodge, J; Arumugham, T; Pandite, LN; Hurwitz, HI
Published in: Invest New Drugs
June 2013

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.

Duke Scholars

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

June 2013

Volume

31

Issue

3

Start / End Page

751 / 759

Location

United States

Related Subject Headings

  • Young Adult
  • Sulfonamides
  • Quinazolines
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male
 

Citation

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de Jonge, M. J. A., Hamberg, P., Verweij, J., Savage, S., Suttle, A. B., Hodge, J., … Hurwitz, H. I. (2013). Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Invest New Drugs, 31(3), 751–759. https://doi.org/10.1007/s10637-012-9885-8
Jonge, Maja J. A. de, Paul Hamberg, Jaap Verweij, Shawna Savage, A Benjamin Suttle, Jeffrey Hodge, Thangam Arumugham, Lini N. Pandite, and Herbert I. Hurwitz. “Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors.Invest New Drugs 31, no. 3 (June 2013): 751–59. https://doi.org/10.1007/s10637-012-9885-8.
de Jonge MJA, Hamberg P, Verweij J, Savage S, Suttle AB, Hodge J, et al. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Invest New Drugs. 2013 Jun;31(3):751–9.
de Jonge, Maja J. A., et al. “Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors.Invest New Drugs, vol. 31, no. 3, June 2013, pp. 751–59. Pubmed, doi:10.1007/s10637-012-9885-8.
de Jonge MJA, Hamberg P, Verweij J, Savage S, Suttle AB, Hodge J, Arumugham T, Pandite LN, Hurwitz HI. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Invest New Drugs. 2013 Jun;31(3):751–759.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

June 2013

Volume

31

Issue

3

Start / End Page

751 / 759

Location

United States

Related Subject Headings

  • Young Adult
  • Sulfonamides
  • Quinazolines
  • Pyrimidines
  • Protein Kinase Inhibitors
  • Oncology & Carcinogenesis
  • Neoplasms
  • Middle Aged
  • Maximum Tolerated Dose
  • Male