A phase I/II study of sunitinib in young patients with advanced gastrointestinal stromal tumor.

Abstract:

Background: Gastrointestinal stromal tumor (GIST) in young patients (pts) is a rare disease with distinct features from GIST in adults. Most notably, >85% of adults have tumors arising from receptor tyrosine kinase (RTK) mutations, typically in the KIT and PDGFRA genes, whereas such mutations occur in <15% of young GIST pts, for whom succinate dehydrogenase dysfunction is emerging as a central oncogenic mechanism instead. Sunitinib is an oral multitargeted RTK inhibitor approved for treatment of imatinib-resistant/intolerant GIST. With an IC₅₀ of 245 nmol/L, sunitinib has a high in vitro activity against wild-type KIT compared with imatinib (IC₅₀of 3,132 nmol/L). It is therefore hypothesized that sunitinib will be more active than imatinib in young GIST pts. This is supported by an expanded-access study, but with few pts and some limitations in data collection. A phase I study of sunitinib in pediatric pts with solid tumors, previously treated with multiple regimens of systemic chemotherapy, found that the MTD was half the effective dose in adult pts. It is not known if this will be reflective of the MTD in young GIST pts and/or if sunitinib will be effective at this dose. 

Methods: A single-arm, multinational, multicenter, phase I/II trial evaluating the pharmacokinetics, safety, and preliminary antitumor activity of sunitinib in ptsages 6 to <21 yrs with advanced, unresectable or recurrent GIST is open in North America, Europe, and Asia with 26 sites currently participating. Pts must have a histological diagnosis of GIST, measurable disease by RECIST, and imatinib-resistant/intolerant GIST or the non-mutant KITgenotype of GIST or not have access to imatinib in their country. Pediatric pts (<18 yrs) will receive sunitinib at a starting dose of 15 mg/m²/day on Schedule 4/2 (4 wks on treatment, 2 wks off) in repeated 6-wk cycles, with dose escalation permitted after cycle 1 based on tolerance and real-time pharmacokinetics; young adults will receive sunitinib 50 mg/day on Schedule 4/2. Thirty pts are planned, and 3 have been enrolled to date. This trial is currently enrolling. Contact Pfizer Oncology at 1-800-718-1021. Clinical trial information: NCT01396148.

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Citation:
J Clin Oncol 32:5s, 2014 (suppl; abstr TPS10601)