Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's oncology group phase I consortium report.

Julia L. Glade Bender, Alice Lee, Joel M Reid, Sylvain Baruchel, Timothy Roberts, Stephan D. Voss, Bing Wu, Charlotte H. Ahern, Ashish M. Ingle, Pamela Harris, Brenda J. Weigel, Susan M. Blaney

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Abstract

Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Original languageEnglish (US)
Pages (from-to)3034-3043
Number of pages10
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Volume31
Issue number24
DOIs
StatePublished - Aug 20 2013

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Sarcoma
Pharmacokinetics
Tablets
Maximum Tolerated Dose
Neoplasms
Suspensions
Desmoplastic Small Round Cell Tumor
Magnetic Resonance Imaging
Hepatoblastoma
Vascular Endothelial Growth Factor Receptor-2
Angiogenesis Inhibitors
Intracranial Hemorrhages
Amylases
Blood Volume
Tumor Burden
Lipase
Proteinuria
Powders
Disease-Free Survival
pazopanib

ASJC Scopus subject areas

  • Medicine(all)

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Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors : a children's oncology group phase I consortium report. / Glade Bender, Julia L.; Lee, Alice; Reid, Joel M; Baruchel, Sylvain; Roberts, Timothy; Voss, Stephan D.; Wu, Bing; Ahern, Charlotte H.; Ingle, Ashish M.; Harris, Pamela; Weigel, Brenda J.; Blaney, Susan M.

In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Vol. 31, No. 24, 20.08.2013, p. 3034-3043.

Research output: Contribution to journalArticle

Glade Bender, Julia L. ; Lee, Alice ; Reid, Joel M ; Baruchel, Sylvain ; Roberts, Timothy ; Voss, Stephan D. ; Wu, Bing ; Ahern, Charlotte H. ; Ingle, Ashish M. ; Harris, Pamela ; Weigel, Brenda J. ; Blaney, Susan M. / Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors : a children's oncology group phase I consortium report. In: Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013 ; Vol. 31, No. 24. pp. 3034-3043.
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abstract = "Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors. Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50{\%} of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD. Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41). Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.",
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AU - Lee, Alice

AU - Reid, Joel M

AU - Baruchel, Sylvain

AU - Roberts, Timothy

AU - Voss, Stephan D.

AU - Wu, Bing

AU - Ahern, Charlotte H.

AU - Ingle, Ashish M.

AU - Harris, Pamela

AU - Weigel, Brenda J.

AU - Blaney, Susan M.

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