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SARC015: Phase II study of R1507 in wild-type GIST Margaret von Mehren, Fox Chase Cancer Center Katie Janeway, Dana Farber Cancer Institute Background • 10% of GISTs in adults and 85% of GISTs in pediatric patients are wild-type (WT) • TKIs in WT GIST Imatinib Sunitinib Objective RR Median TTP Clinical benefit rate Median PFS KIT 11 72% 25 months 34% 5 months • TKIs in pediatric GIST – No objective responses to imatinib – 1 PR to sunitinib Heinrich et al., JCO 2008 (epub) WT 45% 13 months 56% 19 months Background: IGF1R in GIST Background: IGF1R in GIST • IGF1R expression in pediatric WT GIST 10x that in adult WT GIST* KIT mutant Pediatric wild-type IGF1R Actin *Agaram. Clin Cancer Res, 2008 Background: R1507 • Pediatric phase I – At 9mg/kg weekly dose similar pharmacokinetics and exposure – No DLTs yet reported – Similar AEs Schema Adult and Pediatric cohorts Pediatric: Age at diagnosis ≤ 18 years Adult: Age at diagnosis > 18 years Baseline tumor assessment: CT or MRI of all disease sites PET (optional) as clinically indicated R1507 IV 9 mg/kg weekly Evaluate by CT/MRI: q 9 weeks x 27 weeks then q 12 weeks SD or Response Continue R1507 IV at 9 mg/kg weekly Off treatment criteria: PD intercurrent illness that prevents treatment unacceptable adverse events patient withdraws unacceptable for further treatment in the judgment of investigator Off treatment Off treatment evaluations • Primary: Objectives – Clinical benefit rate (SD>6 mos., PR or CR) in patients with advanced WT GIST treated with R1507 • Secondary: – Response duration, TTP and PFS – Tolerability and adverse event profile • Exploratory – Serum and tumor biomarkers – BMI, glucose, lipid metabolism and linear growth (pediatric only) – PET scans when obtained for clinical care Eligibility • • • • • • • • • Advanced, unresectable GIST KIT and PDGFRA mutation analysis: WT Age > 2 years Performance status Adequate organ function Diabetic patients must have good glucose control No prior therapy targeting IGF1R Off TKI therapy x 7 days Co-existence of paraganglioma and pulmonary chondroma is permitted Overview • Cohorts – Pediatric: Age at diagnosis ≤18. – Adult: Age at diagnosis >18. • R1507 administration – 9 mg/kg IV weekly – Duration: Until progression, intercurrent illness, unacceptable adverse event, delays • Concurrent therapy – No TKI therapy – If response, surgery permitted after 6 months Overview • Response evaluation – CT/MRI q 9 weeks x 27 weeks then q 12 weeks – WHO criteria for the primary outcome – CHOI criteria as a secondary objective • Biological correlates – Blood, paraffin embedded specimens, and when possible, fresh frozen tumor to be obtained Adverse event monitoring • Chemistries, glucose, liver function tests, blood counts weekly • HbA1c start of study, off study • Human anti-human antibodies (HAHA) weeks 1, 4, 12, 18 Timeline • Protocol completed – November 15, 2008 • • • • Statistical input SARC review Submit to Roche for review Goal open date: February 1, 2009