1. SARC020 – EORTC 62091 TRUSTS – A phase IIb/III multicenter study comparing the efficacy of TRabectedin administered as a 3-hour or 24-hour infusion to doxorubicin in patients with advanced or metastatic Untreated Soft Tissue Sarcoma Study PI: James Butrynski, MD Dana Farber Cancer Institute/SARC Binh Bui, MD Institut Bergonie/EORTC

2. Primary Objective To determine whether trabectedin given as 1 st line chemotherapy for advanced/metastatic soft tissue sarcoma prolongs progression free survival, as compared to doxorubicin. © All Rights Reserved

3. Secondary End Points Overall survival Response rate and response duration Quality of Life Adverse Events/Safety Profile © All Rights Reserved

4. Study design Randomized phase II b / III trial

5. Inclusion Criteria  Histologically proven advanced and/or metastatic malignant soft tissue sarcoma of intermediate/high grade not previously treated (see protocol Appendix B)  Excluded: WD liposarcoma, embryonal rhabdomyosarcoma, Ewing’s, GIST, DFSP  Paraffin blocks or representative H/E slides must be available for histological central review  Confirmed disease progression – investigator judgment  Presence of measureable disease according to RECIST 1.1  No anti-cancer therapy or other investigational agents within 28 days prior to treatment start  Adequate organ function as defined by protocol  WHO performance status 0 or 1  At least 18 years old © All Rights Reserved

6. Exclusion Criteria  History of CNS metastases or leptomeningeal tumor spread  Prior treatment with anthracyclines for advanced or metastatic STS  Women who are pregnant or breastfeeding  Active/uncontrolled infections or medical conditions, including history of chronic alcohol abuse, hepatitis, HIV and cirrhosis  History within past five years of malignancies other than STS (see protocol Section 3 Patient Selection Criteria for exceptions) © All Rights Reserved

7. SARC020 Study Status Total Sites Activated:US – 7 Sites / 10 EU – 19 Sites / 37 TOTAL : 25/47 Total Patients Enrolled:US – 21 Patients EU – 112 Patients Current Status:Accrual for Step 1 completed; enrollment on hold as of 8/6/2012 for interim analysis

8. SARC020 Participating Centers US 7 Open sites in US:  Carolina’s Hematology Oncology Associates  Dana-Farber Cancer Institute  Nebraska Methodist Hospital  Pennsylvania Oncology Hematology Associates  Sarcoma Oncology Center  Stanford  University of Iowa Sites in progress:  Washington University  University of Pittsburgh  Cedars Sinai

9. Recruitment / Country Trabectedin 3 hrsTrabectedin 24 hrsDoxoTotal France16141646 The Netherlands43411 U.S.A26210 Germany3249 Austria2--2 Spain1-12 Total28252780

10. Translational research program  Predictive value of molecular markers Identify / validate biomarkers of sensitivity to trabectedin and doxorubicin Focus on proteins related to the mechanism of action of trabectedin DNA repair proteins Key genes in the development / prognosis of sarcoma subtypes.  FFPE or unstained slides from initial diagnosis Material collected for the confirmation of diagnosis Technique: IHC with guidelines from PharmaMar  Optional (additional IC required) Must be proposed to all patients

11. Recrutment / Center Trabectedi n 3 hrs Trabectedin 24 hrsDoxoTotal 227.Centre Léon Bérard (FR) 1113 228.Institut Bergonie (FR) 45514 229.Centre G.F.Leclerc (FR) 3148 234.Centre Oscar Lambret (FR) 44412 235.Centre R.Gauducheau (FR) 1-12 259.H.Necker-I.Curie (FR) 2-13 287.C.H.U. De La Timone (FR) 13-4 301.N.K.I / A.V.L. A'Dam (NL) 1124 302 Erasmus MC R’Dam (NL) 11-2 310 UMC Leiden (NL) 1--1 3039.Un.C.G.C. Dresden (DE) 1113 335.UMCG (NL) 1124 527.Univ. Mannheim (DE) 1113 906. Med Univ. Vienna (AU) 2--2 8673.Univ Of Iowa Hosp (US) 1326 9178.Sarcoma Onco Cter (US) -2-2 9361.Carolinas MC (US) 11-2 Total28252780

12. RECIST 1.1 (1) Measurable disease: Presence of at least one measurable lesion. If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology

13. SARC020 Participating Centers EU  Austria  Medical University Vienna - General Hospital  France  Centre Leon Berard  Centre Georges-Francois-Leclerc  Institut Bergonie  Centre Oscar Lambret  Institut de Cancerologie de l’Ouest (ICO) – Centre Rene Gauducheau  Institut Curie  Assistance Publique - Hôpitaux de Marseille – Hôpital de La Timone  Germany  Universitaetsklinikum Koeln  UniversitaetsMedizin Mannheim  Universitaetsklinikum Carl Gustav Carus  Klinikum Grosshadern Ludwig-Maximilians Univ. Muenchen  The Netherlands  The Netherlands Cancer Institute – Antoni Van Leeuwenhoekziekenhuis  Erasmus MC - Daniel den Hoed Cancer Center  Leiden University Medical Centre  University Medical Center Groningen  Spain  Hospital General Vall D'Hebron  Switzerland  Centre Hospitalier Universitaire Vaudois  UK  Christie NHS Foundation Trust

14. Accrual on 14/03/2012 Accrual graph for step 1 Institution Number of patients 228.Institut Bergonie (FR)12 234.Centre Oscar Lambret (FR) 11 229.Centre G.F.Leclerc (FR)5 8673.Univ Of Iowa Hosp (US)4 259.H.Necker-I.Curie (FR)3 287.C.H.U. De La Timone (FR) 3 335.UMCG (NL)3 235.Centre R.Gauducheau (FR) 2 527.Univ. Mannheim (DE)2 9178.Sarcoma Onco Cter (US) 2 9361.Carolinas MC (US)2 301.N.K.I / A.V.L. A'Dam (NL)1 3039.Un.C.G.Carus Dresden (DE) 1 371.Hosp. Vall D'Hebron (ES) 1 906.Med Univ Vienna (AT)1 Total53