Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib

Grace K. Dy, Jeffrey R. Infante, S. Gail Eckhardt, Silvia Novello, Wen Wee Ma, Suzanne F. Jones, Anne Huff, Qiong Wang, A. Benjamin Suttle, Lone H. Ottesen, Alex Adjei, Howard A. Burris

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Summary: 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.

Original languageEnglish (US)
Pages (from-to)891-899
Number of pages9
JournalInvestigational New Drugs
Volume31
Issue number4
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

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Angiogenesis Inhibitors
Maximum Tolerated Dose
Exanthema
pazopanib
Erlotinib Hydrochloride
Appetite
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Nausea
Blood Vessels
Diarrhea
Neoplasms
Pharmacokinetics
Liver

Keywords

  • Erlotinib
  • Non-small-cell lung cancer
  • Pazopanib
  • Pharmacokinetics
  • Solid tumors

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

Cite this

Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib. / Dy, Grace K.; Infante, Jeffrey R.; Eckhardt, S. Gail; Novello, Silvia; Ma, Wen Wee; Jones, Suzanne F.; Huff, Anne; Wang, Qiong; Suttle, A. Benjamin; Ottesen, Lone H.; Adjei, Alex; Burris, Howard A.

In: Investigational New Drugs, Vol. 31, No. 4, 01.08.2013, p. 891-899.

Research output: Contribution to journalArticle

Dy, GK, Infante, JR, Eckhardt, SG, Novello, S, Ma, WW, Jones, SF, Huff, A, Wang, Q, Suttle, AB, Ottesen, LH, Adjei, A & Burris, HA 2013, 'Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib', Investigational New Drugs, vol. 31, no. 4, pp. 891-899. https://doi.org/10.1007/s10637-012-9887-6
Dy, Grace K. ; Infante, Jeffrey R. ; Eckhardt, S. Gail ; Novello, Silvia ; Ma, Wen Wee ; Jones, Suzanne F. ; Huff, Anne ; Wang, Qiong ; Suttle, A. Benjamin ; Ottesen, Lone H. ; Adjei, Alex ; Burris, Howard A. / Phase Ib trial of the oral angiogenesis inhibitor pazopanib administered concurrently with erlotinib. In: Investigational New Drugs. 2013 ; Vol. 31, No. 4. pp. 891-899.
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abstract = "Summary: 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.",
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AU - Dy, Grace K.

AU - Infante, Jeffrey R.

AU - Eckhardt, S. Gail

AU - Novello, Silvia

AU - Ma, Wen Wee

AU - Jones, Suzanne F.

AU - Huff, Anne

AU - Wang, Qiong

AU - Suttle, A. Benjamin

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AU - Adjei, Alex

AU - Burris, Howard A.

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N2 - Summary: 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.

AB - Summary: 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.

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