1. Phase II Trial of Neoadjuvant Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Unresectable Malignant Peripheral Nerve Sheath Tumors A collaborative effort of:A collaborative effort of: –SARC: Trial coordination –NCI: Principal investigators –SARC institutions –Selected NF1 centers Funded through a Clinical Trial Award by the US Army DoDFunded through a Clinical Trial Award by the US Army DoD

2. MPNST Trial Objectives Primary objective:Primary objective: –Response rate (CR/PR, WHO criteria) after 4 cycles of neoadjuvant chemotherapy in NF1 and sporadic MPNST Secondary objectives:Secondary objectives: –Response evaluation with 18 FDG-PET and volumetric MRI –Correlate response by imaging studies with pathologic response –Molecular biology of MPNSTs, tissue microarray –Serum proteomics (compared to sera from pts with NF1 and plexiform neurofibromas) –Epidemiology of MPNSTs in NF1

3. Trial Design Eligibility: High grade unresectable MPNSTEligibility: High grade unresectable MPNST MPNST NF1 Sporadic IE x2 IA x2 ResponseEvaluation LocalControl Chemotherapy IE x2 PET 3D MRI SurgeryXRT  Statistical plan:  Simon optimal two-stage design (0.1 alpha/beta)  First stage 17 patients, go to second stage if 4+/17 respond  Chemotherapy active in strata if 11+/37 patients respond MRI PET 3D MRI

4. Treatment Schema

5. Data Collection on Trial Patient registration and Data submission SARC Website Tumor tissue from diagnosis and at time of surgery (if applicable): Washington University, St. Louis, MO Serum samples for proteomics: Pre treatment, pre and post local control NCI, Pediatric Oncology Branch MRI for central response evaluation and comparison 3D, 2D, 1D 18 FDG-PET pre treatment and after 4 cycles of chemotherapy (not mandatory) Phenotypic analysis for NF1 at baseline(questionnaire) NNFF Database Vancouver, Canada

6. Protocol Status NCI IRB and DoD approval obtainedNCI IRB and DoD approval obtained Data forms developed by SARCData forms developed by SARC Informed consent has to receive institutional and US Army IRB approval prior to patient entryInformed consent has to receive institutional and US Army IRB approval prior to patient entry –Model informed consent with US Army requested elements was provided by SARC –SARC and NCI will assist in development and review of institutional informed consent

7. Site / PI information required by DoD: PI Assurance formPI Assurance form Facility Safety PlanFacility Safety Plan MPA or FWA numberMPA or FWA number PI most recent GCP trainingPI most recent GCP training Planned reimbursement to sites: IRB review/approvalIRB review/approval $ 3500 / patient entered$ 3500 / patient entered $ 15 serum sample, $ 400 tumor processing/shipment$ 15 serum sample, $ 400 tumor processing/shipment $ 100 CT/MRI, $ 200 PET ( to ensure compliance with protocol)$ 100 CT/MRI, $ 200 PET ( to ensure compliance with protocol) DoD Requirements and Reimbursement

8. DoD Funded NF1 Consortium Operations Center Award: University of Alabama at BirminghamUniversity of Alabama at Birmingham Site Award recipients: University of Alabama at BirminghamUniversity of Alabama at Birmingham Children’s Hospital BostonChildren’s Hospital Boston Children’s Hospital of PhiladelphiaChildren’s Hospital of Philadelphia Children’s National Medical Center, Washington, DCChildren’s National Medical Center, Washington, DC Cincinnati Children’s Hospital Medical CenterCincinnati Children’s Hospital Medical Center National Cancer Institute, Bethesda, MDNational Cancer Institute, Bethesda, MD University of ChicagoUniversity of Chicago University of UtahUniversity of Utah Washington University, St. Louis, MOWashington University, St. Louis, MO