1. ESP1/SARC025 Global Collaboration: A Phase I Study of a Combination of the PARP inhibitor, Niraparib and Temozolomide in Patients with Previously Treated, incurable Ewing Sarcoma Co-Principal Investigators: Sandra Strauss, MD, PhD University College London Rashmi Chugh, MD University of Michigan ESP1/SARC025

2.  Ewing Sarcoma PARPi Consortium (ESP)  Collaborating  SARC  Sponsor and coordinating center  Tesaro  Supporter

3. Background  Poly(ADP-ribose) (PARP) inhibitors potentiate the activity of cytotoxic agents, particularly DNA damaging agents  Niraparib is a potent and highly selective PARP- 1 and -2 inhibitor  Temozolomide (TMZ) is an alkylating agent that is used as a part of multi-agent therapy for ES  Niraparib and TMZ combination treatment causes in vivo tumor regression in patient- derived Ewing Sarcoma xenografts in mice

4. ESP1/SARC025

5.  Single arm phase I study  Cycle = 28 days  Cohort A - enroll patients at the starting doses of Niraparib (300 mg daily) and TMZ (20, 40, 60, 80, 100 and 120 mg/m 2 /day, days 2-6)  Anticipated number of patients: 30 - 50

6. Primary Objective  To define the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of the PARP inhibitor Niraparib and escalating doses of Temozolomide (TMZ) in patients with pre-treated incurable Ewing sarcoma (ES)

7. Secondary Objectives  To determine the tumor response rate (TRR) of patients with ES treated with Niraparib and TMZ  To determine the progression free survival (PFS), duration of response, 4- and 6- month PFS rate, and overall survival (OS) of patients treated with Niraparib and TMZ

8. Secondary Objectives  To evaluate pharmacodynamic (PD) markers of response to PARP inhibition in combination with TMZ including measurement of PAR and PARP activity and γH2AX induction

9. Inclusion Criteria  Age ≥ 13 years  Histologically confirmed Ewing sarcoma  Recurrent or refractory tumors with no known curative treatment options  ECOG Performance Status 0 – 2  Minimum one prior chemotherapy regimen received with at least 2 of the following agents: doxorubicin, cyclophosphamide, ifosfamide, and etoposide

10. Study Status  Contracting  In process  Anticipated completion by end of 2013  Activation at limited sites in US and UK  Late 2013/early 2014