SARC022

1. SARC022 A Phase 2 Study of OSI-906 in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors Study PI: Margaret von Mehren, MD Fox Chase Cancer Center

2. Background • WT GIST in adults and children are less responsive to current tyrosine kinase inhibitors compared to tumors with mutations • IGF-1R, a member of the insulin receptor family, has been demonstrated to be expressed on WT GIST tumors • It is hypothesized that growth and proliferation in these tumors may be IGF-1R-dependent, and therefore, targeting IGF-1R will inhibit tumor growth.

3. Primary Objective To determine the response rate (CR and PR) to treatment with OSI-906 (Linsitinib) in patients with advanced wild-type GIST (WT) as determined by RECIST 1.1.

4. Secondary Objectives 1. To determine the clinical benefit rate (SD≥9 months, PR or CR) in patients with advanced WT GIST treated with OSI-906 (Linsitinib). 2. To determine the response duration, progression free survival, and overall survival in patients with advanced WT GIST treated with OSI-906 (Linsitinib). 3. To determine the tolerability and adverse event profile of OSI-906 (Linsitinib) in patients with advanced GIST 4. To explore patterns of protein expression in serum and tumor tissues as predictors of response and progression free survival in advanced wild-type GIST treated with OSI-906 (Linsitinib)

5. Imaging Objectives • To evaluate the metabolic response to OSI-906 (Linsitinib) using FDG-PET. • Determine if tumor metabolic response correlates with anatomic response and clinical benefit. • Measure changes in tumor metabolism by FDG-PET qualitatively and semi-quantitatively with standard uptake value (SUV) and tumor body ratio (TBR) from baseline to first CT-response evaluation and correlate the findings with size changes as defined by conventional cross-sectional imaging scans. • To investigate correlations between glucose, insulin and candidate tumor tissue and blood biomarkers with FDG-PET metabolic response.

6. Key Inclusion Criteria • Measurable GIST with confirmed genotype of wild-type by central pathology review • Age ≥ 18 years • Performance status: ECOG 0-2 • Patients will be stratified into Pediatric and Adult cohorts • Pediatric cohort must have received at least sunitinib and have had progression on or intolerance to sunitinib therapy • Adult cohort must have received at least imatinib and have had progression on or intolerance to imatinib therapy

7. Key Laboratory Inclusion Criteria • Platelet count ≥ 75 x 109/L • Total bilirubin ≤ 1.5 times the upper limit of normal for age • ALT /AST (SGPT/SGOT) ≤ 3x the ULN for the reference lab (≤ 5 x the ULN for the reference lab in the presence of known hepatic metastasis, adjusted for age). • QTc interval <450 msec at baseline, without use of con-meds that prolong the QTc interval • Fasting blood glucose <150 mg/dL at baseline • HbA1c < 7% at screening • Patients with diabetes mellitus should have controlled disease on oral medications, defined as: • no diabetic ketoacidosis within 30 days prior to enrollment • no change in oral medications greater than 10% within 30 days prior to enrollment.

8. Key Exclusion Criteria • ≥ 3 weeks from prior therapy, except TKI therapy: ≥ 7 days. • Patients with insulin requiring diabetes for control of their diabetes. • Patients with known brain metastases • History of allergic reactions to compounds of similar chemical or biologic composition to OSI-906 (Linsitinib) • Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited. • Prior treatment with TKI targeting IGF-1R pathway. • Known HIV-positive patients on combination antiretroviral therapy • Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to randomization. • Patients with a history of solid organ transplant are ineligible because of the potential for pharmacokinetic interactions with OSI-906.

9. Treatment Plan • Within 12weeks from date of enrollment • Pathology samples for confirmation of diagnosis and KIT and PDGFRA genotyping • After confirmation of eligibility, patients will be assessed • Day 1: drug initiation; OSI-906 (Linsitinib) 150 mg po BID • Day 14 • Week 4 and every 4 weeks through week 16 • Week 24 and then every 12 weeks while remaining on study • At each visit: CMP, PO4, CBC, HbA1c • EKG in triplicate on Day 1, 14, week 4, 8, and12 • Pharmacodynamic correlative studies on Days 1, 14, week 4 and 8 • CT/MRI every 8 weeks until week 24; after than imaging will be every 12 weeks • Week 12: HbA1c for all patients; diabetics will have HbA1c every 12 weeks while receiving OSI-906 (Linsitinib) • Week 16: CT/MRI scan including abdomen and pelvis imaging; imaging of lung if clinically indicated

10. Biomarker Assessments

11. Imaging Correlatives • PET Scan will be performed at baseline and at 8 weeks • Will be reviewed along with anatomic imaging at Dana Farber and FCCC • Glucose and IGF ligands and inhibitor levels will also be evaluated

12. Statistical Plan • The probability of early termination if the true response rate = 20% • is 12%. • The null hypothesis will be rejected after the second stage if there • are 5 or more patients with a response out of 40 evaluable patients. • With a sample size of 40 evaluable patients, the power to detect a • 20% clinical benefit rate is 92%, with a significance level (alpha) of • 0.05.

13. Secondary Endpoints • The clinical benefit rate, defined as SD≥9 mos., PR or CR, will be determined. • Safety Analysis: the study will be suspended if the rate of grade 4 toxicities is 20% or greater. • Exploratory Analyses for pharmacodynamic endpoints