1. Phase II Trial of Chemotherapy in Sporadic and Neurofibromatosis Type 1 Associated High Grade Malignant Peripheral Nerve Sheath Tumors Brigitte Widemann, NCI, POB SARC 006

2. SARC006 Study Objectives  Primary Objective  Determine clinical response rate (WHO)  High grade, unresectable, or metastatic, potentially resectable sporadic and NFI associated MPNST for which neoadjuvant chemotherapy is determined to be the best treatment option by institutional PI  Secondary Objectives  Imaging (PET/Volumetric MRI analysis)  Pathology (Percent necrosis; tissue microarray)  Biomarker  Improve knowledge of NF1 epidemiology

3. *Eight chemotherapy courses total MPNST NF1 Sporadic IE x2IA x2 Response Evaluation Local Control Chemotherapy IE x2 PET 3D MRI Surgery XRT MRI PET 3D MRI Trial Schema

4. Patient Eligibility  Sporadic or NF1 associated MPNST  Unresectable; metastatic; potentially resectable but neoadjuvant chemotherapy is determined to be in the best patient interest  Not previously treated with chemotherapy; prior radiation permitted  No upper or lower age limit  ECOG 0-2  Normal organ function  Cardiac (MUGA or Echo)  Renal, liver and bone marrow  Prior treatment with biologic agents or chemotherapy for other NF1 associated tumors permitted  No prior ifosfamide, etoposide or doxorubicin

5. Trial Status  Patients enrolled: 12  NF1 associated MPNST 8 pts; sporadic MPNST 3 pts  Median age 29.5 years (range 21-67 years)  Disease status:  Localized 7 pts; metastatic: 5 pts  On study 7 pts, off study 5 pts  SAEs (possibly, probably, or definitely related):  One pt: Ifosfamide related aphasia (gr. 4), somnolence (gr. 4)  One pt: Anemia, dyspnea, and fatigue (gr. 3), orthostatic hypotension (gr. 2)  One pt: Urinary tract infection (gr. 3)  One pt: Leukopenia (gr. 4) and fever (gr. 1)

6. Response Evaluation NF1 MPNST PT Localized / Metastatic Post cycle 2 (SD, PD, PR) % Change from Baseline Post cycle 4 (SD, PD, PR) % Change from Baseline 1MetastaticSD 0.4  SD 22.3  3MetastaticSD 26  SD 31  4LocalizedPD 26  PD 27  from cy 2 5LocalizedSD 55 44 6LocalizedSD 23  SD 5  8LocalizedNE- - 9MetastaticToo early- - 10LocalizedSD 10  SD 19  12LocalizedToo early- - Nine patients enrolled

7. Response Evaluation Sporadic MPNST PT Localized / Metastatic Post cycle 2 (SD, PD, PR) % Change from Baseline Post cycle 4 (SD, PD, PR) % Change from Baseline 2MetastaticNE- - 7LocalizedPD 40  SD 22  11MetastaticSD 18.4  Too Early- Three patients enrolled

8. SARC 006 Protocol Status  SARC Sites: Open for Enrollment 9 Sites Huntsman Cancer InstituteTexas Children’s Hospital Indiana UniversityUniversity of Iowa MD Anderson Cancer CenterUniversity of Michigan National Cancer InstituteUniversity of Minnesota Pennsylvania Oncology Close to Approval CarolinasJohns Hopkins University of Alabama

9. SARC 006 Protocol Status  SARC Sites: In Review/Consideration Arkansas Children’s HospitalMayo Clinic Cedar SinaiStanford Cancer Center Cleveland ClinicVanderbilt Emory Not participating: City of Hope, Dana-Farber, Fox Chase, Johns Hopkins, Moffitt, MSKCC, Oregon Health and Science University, Sarcoma Oncology Center, Stanford, Seattle Care Alliance, UCLA, University of Florida, Washington Cancer Institute

10. SARC 006 Protocol Status  NF1 Sites: Open for Enrollment 5 Sites Children’s Hospital and Clinics of Minnesota Children’s Memorial Hospital Chicago Children’s Hospital of PhiladelphiaSt. Louis Children’s Wash. Univ. Cincinnati Children’s Hospital Close to Approval University of Alabama In Review/Consideration Children’s Hospital of PittsburgChildren’s National Medical Center

11. SARC 006 Approval Process  Contract with SARC  Institutional protocol review  US Army IRB review:  Informed consent form, assent (ages 13-17 years) form, and information page (ages 7-12 years old), site specific protocol appendices  CV for all investigators  Facility safety plan  PI assurance plan  GCP training for PI  US Army will perform pre-review of documents prior to local IRB submission  All communication with US Army IRB through SARC