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, PhDUniversity College London

Rashmi Chugh, MDUniversity of Michigan

ESP1/SARC025

ESP1/SARC025

Ewing Sarcoma PARPi Consortium (ESP) Collaborating

SARC Sponsor and coordinating center

Tesaro Supporter

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

ESP1/SARC025

ESP1/SARC025

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/m2/day, days 2-6)

Anticipated number of patients: 30 - 50

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)

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

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

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

Study Status

Contracting In process Anticipated completion by end of 2013

Activation at limited sites in US and UK Late 2013/early 2014