Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib
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Introduction As angiogenic pathways have become important targets for inhibition of tumor growth, we examined the concept of dual pathway blockade by small-molecule tyrosine kinase inhibitors targeting vascular endothelial and epidermal growth factor receptors. Methods Escalating doses of pazopanib (400–800 mg once daily [QD]) plus erlotinib (100–150 mg QD) doses were evaluated in cohorts of 3–6 adults with advanced solid tumors. Twelve additional patients were enrolled in an expansion cohort to confirm the maximum tolerated dose (MTD). Results The MTD, defined during assessment of 20 patients, was pazopanib 600 mg plus erlotinib 150 mg. Two dose-limiting toxicities, rash and elevated liver enzymes, occurred at pazopanib 800 mg and erlotinib 150 mg. Overall, 30 % and 27 % of patients required dose interruption of pazopanib or erlotinib, respectively; 15 % of patients required a dose reduction of erlotinib to manage toxicities. The most common adverse events in patients treated with any dose regimen of pazopanib plus erlotinib (N = 33) were diarrhea, rash, nausea, and decreased appetite. The adverse-event profile of the combination did not appear to differ from that of each compound administered alone. Coadministration of pazopanib 600 mg QD and erlotinib 150 mg QD did not consistently affect the pharmacokinetics of either compound relative to that observed for either compound administered alone. Of 26 patients evaluated for efficacy, 3 (12 %; all non-small-cell lung cancer) had partial response and 10 (38 %) had stable disease. Conclusions Concomitant administration of pazopanib 600 mg and erlotinib 150 mg is feasible, with a manageable toxicity profile. These results support further clinical development of the pazopanib-erlotinib combination.
KeywordsPazopanib Erlotinib Pharmacokinetics Solid tumors Non-small-cell lung cancer
We thank Jane Saiers, PhD, The WriteMedicine, Inc., and Jerome F. Sah, PhD, ProEd Communications, Inc., for their medical editorial assistance with this manuscript. Financial support for this study and medical editorial assistance was provided by GlaxoSmithKline Pharmaceuticals, Philadelphia, Pennsylvania.
This study complied with the laws of the countries in which it was conducted (United States and Italy), and the study was approved by the respective institutional ethics committees.
Conflicts of interest
AH, QW, ABS, and LHO are employees of GlaxoSmithKline and hold company stock. JRI has been an uncompensated consultant for GlaxoSmithKline and his organization has received grants for research and consultant/advisor roles. All other authors report no financial conflicts of interest.
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