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

• TKIs in pediatric GIST– No objective responses to imatinib– 1 PR to sunitinib

Heinrich et al., JCO 2008 (epub)

Background: IGF1R in GIST

Background: IGF1R in GIST

• IGF1R expression in pediatric WT GIST 10x that in adult WT GIST*

*Agaram. Clin Cancer Res, 2008

IGF1R

Pediatric wild-typeKIT mutant

Actin

Background: R1507

• Pediatric phase I– At 9mg/kg weekly dose similar

pharmacokinetics and exposure– No DLTs yet reported– Similar AEs

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 yearsAdult: 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 treatmentunacceptable adverse eventspatient withdrawsunacceptable for further treatment in the judgment of investigator

Off treatment evaluations

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

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