2. NO OFFENSE INTENDED

3. Why we need investigator-initiated trials

4. “Large” Randomized Sarcoma Trials AuthorRegimenGroupN=Year Pub LeCesneAI v A H IEORTC31400 SantoroA v AIEORTC42495 AntmanAD v ADISWOG33693 NielsenA v E v EEORTC33498 ZalupskiAD b v AD i SWOG27891 BordenA+V v AECOG29890 BakerAd v ADC v ADAd SWOG27287 BenjaminACVD v ACVAd SWOG44576 BordenA 3 v A w v ADECOG28087

5. “Large” Randomized GIST Trials AuthorRegimenGroupN=Year Pub VerweijGleevec 400 v 800 EORTC94604 DemetriGleevec 400 v 800 SWOG750-

6. Is GIST the Exception or the Rule? Drug with spectacular benefit Enrichment design Pent-up demand Prior therapy irrelevant Performance status irrelevant

7. American/European Collaboration United States Canada Denmark The Netherlands Belgium Germany Hungary Switzerland Italy France Spain UK Serbia Norway Sweden Slovakia Poland

8. SARC Meeting ASCO 2006 Yondelis SARC trial Ariad 573 trial …..the next day

9. Search For Data Management Center The applicants All about CRAB John Crowley

10. Non-profit Founded 1997 Seattle, WA John Crowley, CEO > 250 trials –Statistical design –Analysis –Management Services –Electronic data capture –Patient registration and randomization –Protocol development –Statistical support –Site monitoring FDA Validation

11. Meeting at EORTC August 19, 2006 Steering committee Data monitoring committee European participation Role of EORTC Mutual support FDA/EMEA

12. Boston Meeting September 7-8, 2006 Issues of confidentiality Pre-funding agreement Ambitious time line

13. OCTOBER STORM 1234567 891011 A lawyer’s advice 12 A declaration 13 A call from Spain 14 1516 CEO call 17 Call from J/J 1819 A deadline passes 20 SARC, Boston, Madrid 21 2223 Deadline passes SARC proposal 24 Letter filed 252627 J/J calls 28 293031

14. JOHNSON & JOHNSON® PRODUCTS Clear & Clean®, Aveeno®, Shower to Shower®, Stayfree®, o.b. tampons®, Monistat®, Reach®, Band-Aid® bandages, Johnson Baby® Pledge®, Vanish®, Windex®, Shout®, Drano® Oncology drugs: Doxil, Leustatin, Procrit, Velcade

15. GovernmentBusiness University

16. Government Creative semantics is the key to contemporary government; it consists of talking in strange tongues lest the public learn the inevitable inconveniently early …..George Will “If you are going to sin, sin against God, not the bureaucracy. God will forgive you, but the bureaucracy won’t.” …..Hyman Rickover

17. University ACADEME, n. An ancient school where morality and philosophy were taught ACADEMY, n. (from academe). A modern school where football is taught

18. Businessmen “The individual who would not harm you on an individual, face-to-face basis, who is charitable, civic-minded, loving and devout, will wound you or kill behind the corporate veil”. …..Morton Mintz

19. Pharma FDA Cooperative Groups

20. AGENT 86

21. GET SMART SMART: Sarcoma Maintenance Assessed Randomized Trial A randomized, prospective, double-blind, placebo-controlled Phase III trial

22. Oral Tablet AP23573 Clinical Trial – Objectives Primary –Determine safety, tolerability and MTD of multiple dose schedules of oral AP23573 studied in parallel Secondary –Compare blood levels to those in the intravenous program showing anti-tumor activity –Confirm mTOR inhibition by PD assays –Describe anti-tumor activity –Characterize PK parameters

23. Oral AP23573 Trial Status 7 dose schedules studied in parallel –MTD identified Over 125 patients treated Majority of patients with a diagnosis of sarcoma Evidence of mTOR inhibition using pharmacodynamic assay Many patients with prolonged stable disease –On study 4-15+ months Side effect profile consistent with i.v. –Mouth sores main DLT Final dose schedule being optimized for highest cumulative dose and frequency of dosing together with tolerability to allow long-term use

24. SCHEMA Metastatic Sarcoma Stable or Better Following 1 st or 2 nd line chemo RANDOMIZE Oral AP 23573Oral placebo

25. Inclusion Criteria Age 13 or > Documented histologic dx of sarcoma Completed 4-8 cycles of chemotherapy AND Stable or better response (DOCUMENTED) Completed 1 ST OR 2 ND Line PS <2 Adequate organ function NO concomitant CYP3A inhibitors

26. Histopathologic Exclusions Well Diff Lipo or Fibrosarcoma Clear Cell sarcoma Extraskeletal chondrosarcoma Chondrosarcoma Alveolar soft part sarcoma Hemangioendothelioma GIST Embryonal Rhabdomyosarcoma

27. Clinical Benefit Response Rate AP23573 Subtype# ptsCBRRate Bone sarcoma541630 LMS571933 Liposarcoma441330 Other STS571323 Total21229 CBR = CR, PR, SD (4 cycles)

28. Bone/Soft Tissue Sarcoma Rationale Response rate (%) of single agent chemotherapy in sarcoma Osteogenic sarcoma Soft tissue sarcoma Doxorubicin26 Ifosfamide2427 High dose mtx2513 Cisplatin1812 Cyclophosphamide1418 DTIC1418 Act-D 817

29. Response Rate of Combination Chemotherapy in Metastatic Sarcoma Osteosarcoma Soft tissue sarcoma Doxorubicin/DTIC3119 Dox/Ctx/DTIC2435 Dox/Ctx/Act-D2540 Dox/IfosN/A36

30. Clinically Significant Progression-Free Survival Sarcoma relevant history –GISTimatinib –GISTsunitinib –STSGem/Tax Requires validation –Specific frequency of measurement –Independent review

31. Steering Committee Jean-Yves Blay Paolo Casali Martine Van Glabbeke Ian Judson Xavier Garcia del Muro Robert Benjamin John Crowley George Demetri Robert Maki Denise Reinke