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

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Summary

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.

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Acknowledgments

We thank the patients and their families who made this study possible. We thank Mohammed Dar, MD, of GlaxoSmithKline for providing input in the analysis of data and authoring the CSR. We thank Tamalette Loh, PhD, of ProEd Communications, Inc., for her editorial assistance in preparation of this manuscript. Financial support for this study and medical editorial assistance was provided by GlaxoSmithKline Pharmaceuticals, Research Triangle Park, NC.

Ethical standards

This study complied with the laws of the countries in which it was conducted (United States and The Netherlands), and the study was approved by the respective institutional ethics committees.

Conflict of interest

M.J.A. de Jonge, P. Hamberg, and S. Savage report no potential conflict of interest. J. Verweij reports honoraria from and a consultant/advisor role with GlaxoSmithKline. H.I. Hurwitz has received research funding from GlaxoSmithKline. A.B. Suttle, J. Hodge, T. Arumugham, and L.N. Pandite are GlaxoSmithKline employees and stockholders.

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Authors and Affiliations

  1. Department of Medical Oncology, Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands

    Maja J. A. de Jonge

  2. GlaxoSmithKline, Five Moore Drive, PO Box 13398, Research Triangle Park, NC, 27709, USA

    A. Benjamin Suttle, Jeffrey Hodge, Thangam Arumugham & Lini N. Pandite

  3. Erasmus University Medical Center/Daniel den Hoed Cancer Center, Groene Hilledijk 301, 3075 EA, Rotterdam, The Netherlands

    Paul Hamberg & Jaap Verweij

  4. Duke Medical Center, 2100 Erwin Road, Durham, NC, 27705, USA

    Shawna Savage & Herbert I. Hurwitz

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  1. Maja J. A. de Jonge
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  2. Paul Hamberg
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  8. Lini N. Pandite
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  9. Herbert I. Hurwitz
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Correspondence to Maja J. A. de Jonge.

Additional information

Previous publication

Portions of these data were presented at the 2006 ASCO Annual Meeting and published in J Clin Oncol 2006;24:18s(suppl; abstr 3088).

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de Jonge, M.J.A., Hamberg, P., Verweij, J. et al. Phase I and pharmacokinetic study of pazopanib and lapatinib combination therapy in patients with advanced solid tumors. Invest New Drugs 31, 751–759 (2013). https://doi.org/10.1007/s10637-012-9885-8

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  • DOI: https://doi.org/10.1007/s10637-012-9885-8

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