Abstract C108: An expanded imaging cohort of pazopanib in children and adolescents with relapsed or refractory soft tissue sarcoma (ADVL0815): A Children's Oncology Group phase I consortium trial.

Abstract

Abstract Background: Pazopanib (NCT00929903) is an orally available small molecule inhibitor of VEGFR 1–3, PDGFR α/β, and c-kit, which has been shown to prolong progression free survival in adults with soft tissue sarcoma (STS). Following a standard phase I dose escalation trial to determine the pediatric maximum tolerated dose (MTD), an expanded cohort of children and adolescents with relapsed and refractory STS and at least one lesion amenable to dynamic contrast enhanced MRI (DCE-MRI) was studied to explore changes in tumor blood volume and vascular permeability following initiation of pazopanib, and to correlate these changes with clinical outcome. Methods: Oral pazopanib was administered at 450mg/m2 once daily in 28 day cycles, for up to 24 cycles. DCE-MRI scans were obtained at baseline and within 15 × 2 days after initiation of pazopanib. DCE-MRI data sets were analyzed using a two compartment kinetic model yielding estimates of fractional blood volume and the permeability transfer constant (Ki). Results: 10 subjects were enrolled [5 male; median age 17 yrs (range, 8–23)], of whom 8 had paired DCE-MRI scans of sufficient quality to be evaluable. Subjects received a median of 4 cycles (range 1–7; 3 remain on study receiving courses 6, 7 and 8). One subject had a dose limiting toxicity of Gr3 back and extremity pain with Gr3 sensory neuropathy. Other non-dose limiting toxicities occurring in >10% of subjects (n=10) during the first cycle included mild myelosuppression, sinus bradycardia, fatigue, diarrhea, nausea, vomiting, anorexia, dehydration, dizziness, headache, liver transaminase elevation and hyperglycemia. All subjects with evaluable DCE-MRI (n=8) experienced a decrease in tumor blood volume following initiation of pazopanib, with a mean pre-treatment level of 16% (range 1–29%) versus 7% (0–15%) post-treatment (p<0.01). Similarly all subjects had a decrease in Ki with mean pretreatment values of 7.74 (range 2.31–20.38) ml/100g/min, decreasing post-treatment to 4.28 (range 0.19–12.60) ml/100g/min (p<0.01). Although limited by the small sample size, there is a suggestion that patients with best response of stable disease appear to have lower tumor blood volume at baseline than those with progressive disease. Conclusions: DCE-MRI changes in tumor blood volume and Ki in pediatric and adolescent patients with soft tissue sarcoma are supportive of physiological activity and the antiangiogenic mechanism of pazopanib. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C108.