1. SARC015: Phase II study of R1507 in wild-type GIST Margaret von Mehren, Fox Chase Cancer Center Katie Janeway, Dana Farber Cancer Institute

2. Background 10% of GISTs in adults and 85% of GISTs in pediatric patients are wild-type (WT) TKIs in WT GIST TKIs in pediatric GIST –No objective responses to imatinib –1 PR to sunitinib Heinrich et al., JCO 2008 (epub)

3. Background: IGF1R in GIST

4. IGF1R expression in pediatric WT GIST 10x that in adult WT GIST* *Agaram. Clin Cancer Res, 2008 IGF1R Pediatric wild-typeKIT mutant Actin

5. Background: R1507 Pediatric phase I –At 9mg/kg weekly dose similar pharmacokinetics and exposure –No DLTs yet reported –Similar AEs

6. Schema Evaluate by CT/MRI: q 9 weeks x 27 weeks then q 12 weeks SD or Response PD Off treatment Adult and Pediatric cohorts Pediatric: Age at diagnosis ≤ 18 years Adult: Age at diagnosis > 18 years R1507 IV 9 mg/kg weekly Continue R1507 IV at 9 mg/kg weekly Baseline tumor assessment: CT or MRI of all disease sites PET (optional) as clinically indicated Off treatment criteria:  intercurrent illness that prevents treatment  unacceptable adverse events  patient withdraws  unacceptable for further treatment in the judgment of investigator Off treatment evaluations

7. Objectives Primary: –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

8. 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

9. 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

10. 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

11. 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

12. Timeline Protocol completed –November 15, 2008 Statistical input SARC review Submit to Roche for review Goal open date: February 1, 2009