CoPrincipal Investigators SARC013/NO21158 SARC Global Collaboration: Phase 3 trial of R1507 in combination with cyclophosphamide/topotecan versus cyclophosphamide/topotecan alone for treatment of first recurrence Ewing sarcoma CoPrincipal Investigators Herbert Juergens Paul Meyers Shreyaskumar Patel

SARC013/NO21158 Open label, randomized, multicenter Phase 3 study Comparing Regimen 1 and Regimen 2 Regimen 1: R1507 in combination with cyclophosphamide/topotecan versus Regimen 2: cyclophosphamide/topotecan alone (crossover to single agent R1507)

SARC013/NO21158 Primary Objective Secondary Objectives Determine overall progression free survival of Regimen 1 versus Regimen 2 Secondary Objectives Determine overall objective response rate, response duration, and overall survival Determine rate of PFS at 12 weeks Define tolerability and adverse event profile Determine response rate and PFS in patients who crossover from Regimen 2 to single agent R1507

SARC013/NO21158 Exploratory Objective Explore patterns of protein expression in serum and tumor tissues as predictors of response, survival, and progression free survival in patients treated with R1507

SARC013/NO21158 Target population Patients age 2 or older First recurrence Ewing sarcoma who have received one prior treatment regimen Accrue 140 evaluable patients per arm

SARC013/NO21158 Eligibility criteria Histologically confirmed Ewing sarcoma (central review) Age > 2 years Performance status Karnofsky or Lansky 70% Measurable disease Adequate organ function HbA1c < 7%

SARC013/NO21158 Exclusion criteria Clinically significant unrelated systemic illness Prior exposure to topotecan or irinotecan Prior treatment with IGF-1R inhibitor Pregnant Active CNS disease

SARC013/NO21158 Early safety review Accrual of 20 patients 10 in each of the treatment groups At least 4 patients per group age > 21 years Data safety monitoring board to review cumulative toxicity data Continue study Modify protocol Terminate study

SARC013/NO21158 Response Evaluation Evaluations every 6 weeks for the first 36 weeks, then every 12 weeks Response and progression by World Health Organization criteria

SARC013/NO21158 Local Therapy Following disease restaging at week 12 patients may receive radiation and/or surgery for local control as appropriate Patients requiring local interventions prior to week 12 will be considered as progressive disease

SARC013/NO21158 Protocol in development Anticipated activation Protocol steering committee Anticipated activation Spring 2009