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Pazopanib shows promise as pediatric sarcoma therapy


 

FROM THE JOURNAL OF CLINICAL ONCOLOGY

Pazopanib was well tolerated and appeared to be of clinical benefit in children with soft tissue sarcoma in a phase I study. Although the findings are preliminary, eight children in the trial achieved stable disease and two achieved a partial response.

"The clinical activity of pazopanib is encouraging in this heavily pretreated pediatric population," said Dr. Julia Glad Bender, of Columbia University Medical Center, New York, and her associates (J. Clin. Oncol. 2013;31:3034-43).

Pazopanib (Votrient) is approved by the Food and Drug Administration as a treatment for adult patients with soft tissue sarcoma and in those with advanced renal cell carcinoma. The drug inhibited cell proliferation, angiogenesis, and possibly tumor growth in pediatric xenografts, prompting the research team to evaluate pazopanib’s therapeutic potential in children.

The multicenter phase I study examined the pharmacokinetic and pharmacodynamic properties of two formulations of pazopanib in children with soft tissue sarcoma or other refractory solid tumors. Overall, 51 children with a median age of 12.9 years and recurrent or refractory solid or primary central nervous system tumors were evaluated in the trial.

For the first component of the trial, the maximum tolerated dose (MTD) of a tablet formulation of pazopanib was determined in 25 children who had a median age of 13.5 years. The starting dose of pazopanib was 275 mg/m2 given every day in 28-day cycles for up to a maximum of 24 cycles. The MTD was found to be 450 mg/m2.

The researchers next determined the MTD of a powder suspension formulation of the drug based on the tablet MTD in 16 children with a median age of 10.5 years. The suspension MTD was found to be 160 mg/m2.

Finally, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used at the start of and after 15 days’ treatment in 10 children with a median age of 17.2 years. All received pazopanib tablets at the MTD of 450 mg/m2. The aim was to see if there was any sign of a change in tumor angiogenesis in response to treatment.

The most common adverse effects seen with pazopanib treatment were gastrointestinal (diarrhea, nausea, and vomiting), fatigue, proteinuria, and hypertension. Grade 3-4 toxicities that limited dosing in the first cycle of treatment included elevations in lipase, amylase and alanine transaminase, proteinuria, and hypertension. There was a single (grade 4) case of intracranial hemorrhage in a child with occult brain metastases.

"Overall toxicity seemed to correlate with exposure rather than dose," the researchers wrote. The bioavailability of pazopanib appeared to be higher with the suspension than with the tablet formulation, so there might be a relationship between higher steady state plasma trough concentrations and the development of hypertension.

"In adults, elevated blood pressure has been suggested as a correlative marker for improved antitumor efficacy of VEGF [vascular endothelial growth factor] pathway inhibitors," the researchers wrote. "Additional studies are warranted to determine whether hypertension can be used to optimize dose or predict clinical benefit in children."

Eight patients in the trial had stable disease for 6 months or more, and seven of those children had soft tissue sarcomas. Partial responses were seen in two children – one with a desmoplastic small round cell tumor and one with a hepatoblastoma. The latter patient had to be removed from the study due to recurrent neutropenia after 12 cycles.

Results of the DCE-MRI analysis showed a decrease in tumor blood volume from a mean of 16% at the start of treatment to 7% at the end of pazopanib treatment (P = .004).

"To our knowledge, this is the first pediatric, multicenter trial to systematically evaluate DCE-MRI in soft tissue sarcoma, demonstrating the feasibility of performing such studies in a clinical trial network," Dr. Bender and team commented.

"Within the imaging stratum, all patients with interpretable studies had a decrease in tumor blood volume and permeability consistent with the antiangiogenic mechanism of pazopanib." Due to the small number of children evaluated, however, it is not possible to correlate the decrease in tumor blood volume with any clinical benefit.

A phase II trial is planned to further determine the pharmacokinetics and pharmacodynamic of pazopanib in children with soft tissue sarcomas and other refractory solid tumors.

The study was supported by grants from the Alex’s Lemonade Stand Foundation, Columbia University, GlaxoSmithKline, and the National Institutes of Health. Dr. Bender has acted as an unpaid advisor to GlaxoSmithKline. The other authors reported no conflicts of interest.

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