1. Phase I Study of Olaparib and Temozolomide, in patients with recurrent and/or metastatic Ewing sarcoma : An Interim Update Edwin Choy, Gregory Cote, James Butrynski, David Harmon, Suzanne George, Andrew Wagner, Jeffrey Morgan, David D’Adamo, George Demetri

2. Olaparib/EWS-FlI1 interaction is one of the strongest associations among 639 cell lines and 130 drugs screened

3. Olaparib prevents EWS-FLI1-positive xenograft growth and metastasis.

4. Single Agent Olaparib is Not Effective in Ewing Sarcoma Choy et al. BMC Cancer. In Press

5. Single Agent Olaparib is Not Effective in Ewing Sarcoma Choy et al. BMC Cancer. In Press

6. Olaparib synergizes with TMZ in EWS-FLI1-positive xenograft mice

7. Objectives of this Phase 1 trial

8. Study Design: Phase I 3+3 dose escalation study of olaparib and temozolomide in patients with recurrent and/or metastatic Ewing’s sarcoma. Treatment regimen: Olaparib is administered orally with temozolomide on an outpatient basis, given for 7 days every 21 days. Imaging: CT/MRI prior to starting study drug, after 6 and 12 weeks from starting study drug, and every 9 weeks thereafter. Additional scans may be performed as clinically indicated. Subjects will continue to be followed until disease progression or death.

9. Inclusion Criteria: Histologically-confirmed Ewing’s sarcoma. Measurable disease on cross sectional imaging of at least 1cm ECOG performance status 0-2 Life expectancy >3 months Age ≥ 18 years. Patients must have received at least one line of chemotherapy, including adjuvant therapy, for the initial treatment of Ewing’s sarcoma. There will be no limits on number of prior regimens using chemotherapy or investigational agents. Allowed for prior treatment with temozolomide

10. Dose Levels

11. Attributable AEs

12. Best Response by RECIST 1.1 * Received prior TMD * * * * ****

13. Dose LevelDLTs 1 0/3 2 3 4 5 2/2 # of DLTs per Dose Level

14. Conclusions We designed and conducted a phase I clinical trial to administer olaparib and temozolomide in patients with Ewing sarcoma progressing after prior chemotherapy 5 dose levels were tested minor responses were seen in 6 of 14 evaluable patients MTD was surpassed at dose level 5 Dose expansion study will be performed using olaparib at 200 mg BID and temozolomide at 75 mg/m2 QD.

15. Acknowledgments Mentorship George Demetri, DFCI Daniel Haber, MGH Jose Baselga, MGH Jane Robertson, Astra Zeneca Clinical Trials Unit at DFCI and MGH Coauthors Kristina Goodman Barbara Anderson David Wells Eleanor Saffian Basyl Stuyvesant Melissa Hohos Mark Morley Julie Field Sarah Solomon Funds Ludwig Center at Dana-Farber / Harvard Cancer Center Jennifer Hunter Yates Sarcoma Foundation Brian MacIsaac Sarcoma Fund