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

• Published in: Journal of clinical oncology Vol. 31; no. 24; pp. 3034 - 3043
• Main Authors: BENDER, Julia L. Glade, LEE, Alice, WEIGEL, Brenda J, BLANEY, Susan M, REID, Joel M, BARUCHEL, Sylvain, ROBERTS, Timothy, VOSS, Stephan D, BING WU, AHERN, Charlotte H, INGLE, Ashish M, HARRIS, Pamela
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Society of Clinical Oncology 20.08.2013
• Subjects: Adolescent; Adult; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Angiogenesis Inhibitors - blood; Angiogenesis Inhibitors - pharmacokinetics; Biological and medical sciences; Child; Child, Preschool; Dermatology; Disease-Free Survival; Female; Humans; Male; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Original Reports; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Sarcoma - blood; Sarcoma - drug therapy; Sarcoma - metabolism; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Young Adult; Human; Antineoplastic agent; Solid tumor; Treatment resistance; Pharmacodynamics; Enzyme; Tyrosine kinase inhibitor; Transferases; Enzyme inhibitor; Soft tissue sarcoma; Malignant tumor; Biological activity; Cancerology; Treatment; S Phase; Cell cycle; Phase I trial; Pharmacokinetics; Protein-tyrosine kinase; Child; Pazopanib; Cancer
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2012.47.0914

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.