1. Interim Analysis of SARC022, A Phase II study of Linsitinib in Pediatric and Adult Wild Type (WT) Gastrointestinal Stromal Tumors (GIST) M von Mehren, M Heinrich, S Schuetze, K Ganjoo, J Yu, J Yap, AD Van den Abbeele, J Wright, S George

2. Background  WT GIST in adults and children are less responsive to tyrosine kinase inhibitors compared to GIST tumors with KIT/PDGFRA mutations  Insulin-like growth factor-1 receptor (IGF-1R), a member of the insulin receptor family (IR), has been demonstrated to be highly expressed on WT GIST  We hypothesized that growth and proliferation in these tumors may be IGF-1R-dependent, and therefore, linsitinib, a dual inhibitor of IGF-1R and IR, might demonstrate clinical benefit in this patient population

3. Study Schema N=40 Linsitinib (150 mg PO BID on days 1-28, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity) Pediatric WT Eligibility Criteria: Diagnosis ≤18 years of age or diagnosis of Carney Triad or Carney- Stratakis DyadDiagnosis ≤18 years of age or diagnosis of Carney Triad or Carney- Stratakis Dyad Progressed on or intolerant to at least sunitinibProgressed on or intolerant to at least sunitinib Adult WT Eligibility Criteria: Diagnosis >18 years of age and no diagnosis of Carney Triad or Carney- Stratakis DyadDiagnosis >18 years of age and no diagnosis of Carney Triad or Carney- Stratakis Dyad Progressed on or intolerant to at least imatinibProgressed on or intolerant to at least imatinib Primary end point: ORR Secondary end points: SD ≥9 months, PFS, OS, time to progression, metablic responses http://clinicaltrials.gov/ct2/show/NCT01560260

4. Patient Demographics, n=20 Gender Female Male 12 8 Age18-62, average 41 Pediatric type Carney Triad 6262 Performance Status 0/1/212/7/1 Primary Site Stomach (Gastroesophageal) Small bowel Peritoneum 16 (1) 2 1 Metastatic Sites Liver Peritoneum Lymph Nodes 17 11 4 Prior Therapies Imatinib Sunitinib Sorafenib 1-7, median 3 19 7

5. Toxicities  Hyperglycemia:  One grade 2 episode in a patient on steroids for Iodine IV contrast allergy prophylaxis  No increases in HgbA1c levels  No evidence of drug induced:  Hepatotoxicity  QTc prolongation

6. Primary Objective: ORR by RECIST 1.1 Data as of 9/30/13 % Change in Tumor Volume

7. Metabolic Responder Baseline Week-8 Follow-up

8. Metabolic Progressor Baseline Week 8 Follow-up

10. Clinical Benefit Rate Clinical Benefit Rate (CR, PR and SD > 9 months)  As of last data cut off of 9/30/13:  15% (3/20 patients) have remained on study for greater than 9 months  55% (11/20 patients) have had stable disease for at least 6 months, with 10 remaining on study  1 additional patients remains on study for greater than 4 months

11. Time on Study based on Gender Days on Study Lighter color bars are patients off study Female Male

12. Time on Study by Primary Site Time on Study in Days Black boxed patients are off study

13. PFS and OS 6-Month PFS Estimate: 70% Events/N: 6/20 6-Month OS Estimate: 85% Events/N: 3/20

14. Conclusions  Clinical trials in WT GIST are feasible  Linsitinib is well tolerated without any unanticipated toxicities  We have not seen Recist 1.1 ORR to date  55% of patients have had stable disease for six months or longer  Of the patients reviewed, 15% have had EORTC metabolic response by FDG-PET  Additional correlative studies are being completed

15. Acknowledgements The Patients and their families Correlative Science: Funding: Martin Belinsky NCI R21 CA150381 Katherine Janeway NCI R01 CA106588 FCCC Molecular Diagnostics SARC Laboratory SARC Clinical Trials Office: Ann Johnson, Brenda Steltzriede, Denise Reinke CRAB.org: John Crowley, Antje Hoering CTEP: John Wright, MD, PhD