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

Abstract

Purpose: 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.

Patients and methods: 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.

Results: 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).

Conclusion: Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Trial registration: ClinicalTrials.gov NCT00929903.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Growth plate expansion in an 11-year-old patient with alveolar parameningeal rhabdomyosarcoma treated with pazopanib for 10 cycles.

Fig 2.

Plasma angiogenesis biomarkers and gene expression. Mean plasma levels (with SE) for (A) vascular endothelial growth factor (VEGF), (B) soluble VEGF receptor-2 (sVEGFR-2), (C) endoglin (ENG), and (D) placental growth factor (PlGF) on days 1 and 15 are displayed for all patients (blue) and those without (yellow) and with (gray) clinical benefit (partial response or stable disease > 6 months). Paired analysis of individual change from baseline to day 15 after pazopanib therapy demonstrated significant decreases in sVEGFR-2 and ENG (n = 41; P < .001 and P = .002, respectively) and significant increases in plasma PlGF (n = 35; P < .001) by two-sided t test. Patients deriving clinical benefit from pazopanib had lower baseline mean VEGF and PlGF (P = .0085 and P = .01, respectively). Statistically significant (E) decreases in relative ENG (β-actin; n = 35; P < .001) and (F) increases in relative PlGF (n = 35; P = .021) gene expression in peripheral-blood mononuclear cells were demonstrated from baseline to day 15.

Fig 2.

Plasma angiogenesis biomarkers and gene expression. Mean plasma levels (with SE) for (A) vascular endothelial growth factor (VEGF), (B) soluble VEGF receptor-2 (sVEGFR-2), (C) endoglin (ENG), and (D) placental growth factor (PlGF) on days 1 and 15 are displayed for all patients (blue) and those without (yellow) and with (gray) clinical benefit (partial response or stable disease > 6 months). Paired analysis of individual change from baseline to day 15 after pazopanib therapy demonstrated significant decreases in sVEGFR-2 and ENG (n = 41; P < .001 and P = .002, respectively) and significant increases in plasma PlGF (n = 35; P < .001) by two-sided t test. Patients deriving clinical benefit from pazopanib had lower baseline mean VEGF and PlGF (P = .0085 and P = .01, respectively). Statistically significant (E) decreases in relative ENG (β-actin; n = 35; P < .001) and (F) increases in relative PlGF (n = 35; P = .021) gene expression in peripheral-blood mononuclear cells were demonstrated from baseline to day 15.

Fig 3.

Dynamic contrast-enhanced T1-weighted acquisition was performed during quiet breathing over 5 to 6 minutes, with repeated imaging before, during, and after bolus administration of a single dose of gadopentetic acid (0.1 mmol/kg), at a rate of 1 cm3/sec, followed by a 20-mL saline flush. Sequence parameters included dynamic, three-dimensional, T1-weighted gradient echo (FLASH, SPGR, VIBE, LAVA, or FFE) with minimum repetition time, minimum echo time, flip angle of 30 degrees, and slice thickness of 4 to 8 mm depending on anatomy. Representative imaging findings at (A, C, E) baseline and (B, D, G) day 15 in a patient with clear cell sarcoma and metastasis surrounding the left iliac bone and involving the left ilacus muscle anteriorly and the gluteus medius muscle posteriorly demonstrate no appreciable change on a standard fat-saturated T2 sequence. (C and D) The same patient shows significant decrease in enhancement on the delta signal intensity curve (graphs represent region of interest time curves for vessel, tumor, and adjacent normal tissue) and (E and F) the blood volume maps from the area of the lesions. All patients experienced a decrease in (G) fractional tumor blood volume (P = .004), (H) vascular permeability (Ki; P = .021), and (I) scaled Ki (P = .006).

Fig 3.

Dynamic contrast-enhanced T1-weighted acquisition was performed during quiet breathing over 5 to 6 minutes, with repeated imaging before, during, and after bolus administration of a single dose of gadopentetic acid (0.1 mmol/kg), at a rate of 1 cm3/sec, followed by a 20-mL saline flush. Sequence parameters included dynamic, three-dimensional, T1-weighted gradient echo (FLASH, SPGR, VIBE, LAVA, or FFE) with minimum repetition time, minimum echo time, flip angle of 30 degrees, and slice thickness of 4 to 8 mm depending on anatomy. Representative imaging findings at (A, C, E) baseline and (B, D, G) day 15 in a patient with clear cell sarcoma and metastasis surrounding the left iliac bone and involving the left ilacus muscle anteriorly and the gluteus medius muscle posteriorly demonstrate no appreciable change on a standard fat-saturated T2 sequence. (C and D) The same patient shows significant decrease in enhancement on the delta signal intensity curve (graphs represent region of interest time curves for vessel, tumor, and adjacent normal tissue) and (E and F) the blood volume maps from the area of the lesions. All patients experienced a decrease in (G) fractional tumor blood volume (P = .004), (H) vascular permeability (Ki; P = .021), and (I) scaled Ki (P = .006).

Fig A1.

Pazopanib pharmacokinetics. (A) Maximum serum concentration (Cmax). (B) Area under the curve from 0 to 24 hours (AUC0-24h). (C) Day 15 trough concentration (Ctrough). Gold circles represent patients who experienced dose-limiting toxicities, and blue circles represent patients who did not.