1. 1 Work in Progress Scott M. Schuetze, M.D., Ph.D. Associate Professor University of Michigan Ann Arbor Scott M. Schuetze, M.D., Ph.D. Associate Professor University of Michigan Ann Arbor

2. 2 DisclosureDisclosure I submitted an abstract, and my abstract was selected for poster presentation. I submitted an abstract, and my abstract was selected for poster presentation. I will not be discussing my poster. I will not be discussing my poster. I submitted an abstract, and my abstract was selected for poster presentation. I submitted an abstract, and my abstract was selected for poster presentation. I will not be discussing my poster. I will not be discussing my poster.

3. 3 Value of abstract presentation Convey results of trial/study Convey results of trial/study Disseminate practice-changing information Disseminate practice-changing information Encourage dialogue for follow-up study Encourage dialogue for follow-up study Encourage exchange of ideas Encourage exchange of ideas Identify regional/national/site differences Identify regional/national/site differences Educational opportunity for junior members Educational opportunity for junior members Enhance trial enrollment Enhance trial enrollment Inform of work to avoid duplication Inform of work to avoid duplication Justify travel to meeting Justify travel to meeting Convey results of trial/study Convey results of trial/study Disseminate practice-changing information Disseminate practice-changing information Encourage dialogue for follow-up study Encourage dialogue for follow-up study Encourage exchange of ideas Encourage exchange of ideas Identify regional/national/site differences Identify regional/national/site differences Educational opportunity for junior members Educational opportunity for junior members Enhance trial enrollment Enhance trial enrollment Inform of work to avoid duplication Inform of work to avoid duplication Justify travel to meeting Justify travel to meeting

4. 4 Disseminate practice-changing information Chemotherapy Intensification by Interval Compression in Localized ESFT – AEWS0031 R. Womer for COG Presented CTOS 2007 Chemotherapy Intensification by Interval Compression in Localized ESFT – AEWS0031 R. Womer for COG Presented CTOS 2007

5. 5 AEWS0031 – CTOS 2007 results “every 2-week chemotherapy is more effective than every 3-week chemotherapy…unless one is 18 or older”

6. 6 AEWS0031 – JCO 2009 results “Dose intensification as studied…did not result in an improved outcome for patients with nonmetastatic ESFT.” L. Granowetter et al. JCO 2009;27:2536

7. 7 Encourage dialogue for follow- up trial Phase II trials presented ASCO 1995 & 1996 (breast, lung, GI, GU & Gyn) Phase II trials presented ASCO 1995 & 1996 (breast, lung, GI, GU & Gyn) 100 selected with conclusion of “encouraging” or “promising” results 100 selected with conclusion of “encouraging” or “promising” results systematic review conducted to determine # randomized clinical trials conducted based on phase II results. systematic review conducted to determine # randomized clinical trials conducted based on phase II results. Phase II trials presented ASCO 1995 & 1996 (breast, lung, GI, GU & Gyn) Phase II trials presented ASCO 1995 & 1996 (breast, lung, GI, GU & Gyn) 100 selected with conclusion of “encouraging” or “promising” results 100 selected with conclusion of “encouraging” or “promising” results systematic review conducted to determine # randomized clinical trials conducted based on phase II results. systematic review conducted to determine # randomized clinical trials conducted based on phase II results. Ian Tannock et al. JCO March 1, 2009

8. 8 Phase II results to phase III trial Medline, proceeding abstracts and searched Medline, proceeding abstracts and www.clinicaltrials.gov searched 10 yrs after presentation of positive results – only 13 of 100 regimens were evaluated 10 yrs after presentation of positive results – only 13 of 100 regimens were evaluated 100 phase II trials positive results ASCO 2006 100 phase II trials positive results ASCO 2006 15% - final results did not agree 15% - final results did not agree 60% - regimen should be evaluated 60% - regimen should be evaluated 19% - plan to conduct trial and have resources 19% - plan to conduct trial and have resources Medline, proceeding abstracts and searched Medline, proceeding abstracts and www.clinicaltrials.gov searched 10 yrs after presentation of positive results – only 13 of 100 regimens were evaluated 10 yrs after presentation of positive results – only 13 of 100 regimens were evaluated 100 phase II trials positive results ASCO 2006 100 phase II trials positive results ASCO 2006 15% - final results did not agree 15% - final results did not agree 60% - regimen should be evaluated 60% - regimen should be evaluated 19% - plan to conduct trial and have resources 19% - plan to conduct trial and have resources

9. 9 Phase II results to phase III results Phase II trials designed with low false- negative and higher false-positive rates Phase II trials designed with low false- negative and higher false-positive rates 60% of oncology regimens with favorable activity in phase II trials lack superiority in phase III trials 60% of oncology regimens with favorable activity in phase II trials lack superiority in phase III trials Transition from phase II abstract to favorable outcome in phase III trial is a rocky road Transition from phase II abstract to favorable outcome in phase III trial is a rocky road Phase II trials designed with low false- negative and higher false-positive rates Phase II trials designed with low false- negative and higher false-positive rates 60% of oncology regimens with favorable activity in phase II trials lack superiority in phase III trials 60% of oncology regimens with favorable activity in phase II trials lack superiority in phase III trials Transition from phase II abstract to favorable outcome in phase III trial is a rocky road Transition from phase II abstract to favorable outcome in phase III trial is a rocky road S. Cannistra JCO 2009;27:3073 I Kola et al. Nat Rev Drug Discov 2004;3:711

10. 10 Phase II trial of Reolysin in patients with sarcoma lung metastasis - M. Mita et al CTOS 2008 – 35 pts CTOS 2008 – 35 pts No objective responses No objective responses 3 had SD > 6 months 3 had SD > 6 months CTOS 2009 – 52 pts (completed) CTOS 2009 – 52 pts (completed) No severe side effects No severe side effects No objective responses No objective responses 6 had SD > 6 months (met endpoint) 6 had SD > 6 months (met endpoint) Worthy of phase III evaluation or combination trial? Worthy of phase III evaluation or combination trial? CTOS 2008 – 35 pts CTOS 2008 – 35 pts No objective responses No objective responses 3 had SD > 6 months 3 had SD > 6 months CTOS 2009 – 52 pts (completed) CTOS 2009 – 52 pts (completed) No severe side effects No severe side effects No objective responses No objective responses 6 had SD > 6 months (met endpoint) 6 had SD > 6 months (met endpoint) Worthy of phase III evaluation or combination trial? Worthy of phase III evaluation or combination trial?

11. 11 Phase II randomized trial of doxorubicin +/- palifosfamide in STS– C. Vershraegen et al Palifosfamide (ZIO-201) Palifosfamide (ZIO-201) No hemorrhagic cystitis (MESNA not needed) No hemorrhagic cystitis (MESNA not needed) No CNS toxicity No CNS toxicity New formulation New formulation Up to 6 cycles doxorubicin (75 mg/m2) +/- palifosfamide Up to 6 cycles doxorubicin (75 mg/m2) +/- palifosfamide Primary end-point: PFS Primary end-point: PFS Palifosfamide (ZIO-201) Palifosfamide (ZIO-201) No hemorrhagic cystitis (MESNA not needed) No hemorrhagic cystitis (MESNA not needed) No CNS toxicity No CNS toxicity New formulation New formulation Up to 6 cycles doxorubicin (75 mg/m2) +/- palifosfamide Up to 6 cycles doxorubicin (75 mg/m2) +/- palifosfamide Primary end-point: PFS Primary end-point: PFS

12. 12 Palifosfamide – abstract results 38 patients enrolled 38 patients enrolled No difference in toxicity between arms No difference in toxicity between arms Combination is well-tolerated Combination is well-tolerated Easy to administer on outpatient basis Easy to administer on outpatient basis “Efficacy data is pre-mature” “Efficacy data is pre-mature” 38 patients enrolled 38 patients enrolled No difference in toxicity between arms No difference in toxicity between arms Combination is well-tolerated Combination is well-tolerated Easy to administer on outpatient basis Easy to administer on outpatient basis “Efficacy data is pre-mature” “Efficacy data is pre-mature”

13. 13 Palifosfamide “press release” Posted October 14, 2009 ZIOPHARM Announces Positive Palifosfamide Sarcoma Randomized Phase II Interim Data: Trial Enrollment Stopped Early Ziopharm press release Oct 14, 2009... Ziopharm rallied sharply higher Wednesday on above-average volume after reporting positive data from a trial of its Zymafos drug. www.thestreet.com

14. 14 Palifosfamide – poster results 61 pts evaluated / 67 enrolled 61 pts evaluated / 67 enrolled Arms balanced for pt age, subtype & number of prior lines of treatment Arms balanced for pt age, subtype & number of prior lines of treatment Sarcoma assessment at local site & confirmed independent radiology review Sarcoma assessment at local site & confirmed independent radiology review 14 progressed – doxorubicin arm 14 progressed – doxorubicin arm 6 progressed – combination arm 6 progressed – combination arm HR=0.62; p=0.026 HR=0.62; p=0.026 61 pts evaluated / 67 enrolled 61 pts evaluated / 67 enrolled Arms balanced for pt age, subtype & number of prior lines of treatment Arms balanced for pt age, subtype & number of prior lines of treatment Sarcoma assessment at local site & confirmed independent radiology review Sarcoma assessment at local site & confirmed independent radiology review 14 progressed – doxorubicin arm 14 progressed – doxorubicin arm 6 progressed – combination arm 6 progressed – combination arm HR=0.62; p=0.026 HR=0.62; p=0.026

15. 15 Progression-free survival 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 01234567 MONTHS combination doxorubicin

16. 16 Interpretation of data "The hypothesis of the randomized Phase II trial design for this very difficult to treat cancer population has been validated and the interim results are promising and supportive of a pivotal trial" – Dr. Maki, Oct 2009 “These interim results are very promising indicating a potentially new drug to control this life-threatening disease…” – Dr. Demetri, Nov 2009 "The hypothesis of the randomized Phase II trial design for this very difficult to treat cancer population has been validated and the interim results are promising and supportive of a pivotal trial" – Dr. Maki, Oct 2009 “These interim results are very promising indicating a potentially new drug to control this life-threatening disease…” – Dr. Demetri, Nov 2009

17. 17 Palifosfamide follow-up plans? Doxorubicin + palifosfamide vs doxorubicin? Doxorubicin + palifosfamide vs doxorubicin? Doxorubicin + palifosfamide vs doxorubicin + ifosfamide? Doxorubicin + palifosfamide vs doxorubicin + ifosfamide? Doxorubicin + palifosfamide vs doxorubicin + trabectedin? Doxorubicin + palifosfamide vs doxorubicin + trabectedin? 3 or 4-arm trial? 3 or 4-arm trial? Doxorubicin + palifosfamide vs doxorubicin? Doxorubicin + palifosfamide vs doxorubicin? Doxorubicin + palifosfamide vs doxorubicin + ifosfamide? Doxorubicin + palifosfamide vs doxorubicin + ifosfamide? Doxorubicin + palifosfamide vs doxorubicin + trabectedin? Doxorubicin + palifosfamide vs doxorubicin + trabectedin? 3 or 4-arm trial? 3 or 4-arm trial?

18. 18 Rexin-G for chemotherapy resistant sarcoma S. Chawla et al. Dominant-negative mutant of human cyclin-G1 Dominant-negative mutant of human cyclin-G1 Packaged in replication-defective retroviral core Packaged in replication-defective retroviral core 42 patients – 20 phase I/II, 22 phase II 42 patients – 20 phase I/II, 22 phase II dose 1-2 x 10 11 cfu 2-3x/week for 4 weeks dose 1-2 x 10 11 cfu 2-3x/week for 4 weeks Dominant-negative mutant of human cyclin-G1 Dominant-negative mutant of human cyclin-G1 Packaged in replication-defective retroviral core Packaged in replication-defective retroviral core 42 patients – 20 phase I/II, 22 phase II 42 patients – 20 phase I/II, 22 phase II dose 1-2 x 10 11 cfu 2-3x/week for 4 weeks dose 1-2 x 10 11 cfu 2-3x/week for 4 weeks

19. 19 Rexin-G phase I/II results No objective responses in sarcoma No objective responses in sarcoma No grade >3 toxicity No grade >3 toxicity Heterogeneity of sub-types precludes analysis of dose-response relationship Heterogeneity of sub-types precludes analysis of dose-response relationship No objective responses in sarcoma No objective responses in sarcoma No grade >3 toxicity No grade >3 toxicity Heterogeneity of sub-types precludes analysis of dose-response relationship Heterogeneity of sub-types precludes analysis of dose-response relationship S. Chawla et al. Molecular Therapy 2009;17:1651

20. 20 Rexin G – phase II results 22 pts chemotherapy resistant osteosarcoma 22 pts chemotherapy resistant osteosarcoma 17 pts evaluable 17 pts evaluable No objective response No objective response 10 stable disease best response 10 stable disease best response Median PFS – 12 weeks Median PFS – 12 weeks 1 pt with possible histologic response 1 pt with possible histologic response 22 pts chemotherapy resistant osteosarcoma 22 pts chemotherapy resistant osteosarcoma 17 pts evaluable 17 pts evaluable No objective response No objective response 10 stable disease best response 10 stable disease best response Median PFS – 12 weeks Median PFS – 12 weeks 1 pt with possible histologic response 1 pt with possible histologic response S. Chawla et al. Molecular Therapy 2009;17:1651

21. 21 Rexin G Progression-free survival months

22. 22 Rexin-GRexin-G Should drug be studied in randomized controlled trial for sarcoma? Should drug be studied in randomized controlled trial for sarcoma? Approved for second-line use in Philippines - cost $5,000/infusion (information per internet) Approved for second-line use in Philippines - cost $5,000/infusion (information per internet) Can one bypass the rocky road of drug development by plane? Can one bypass the rocky road of drug development by plane? Should drug be studied in randomized controlled trial for sarcoma? Should drug be studied in randomized controlled trial for sarcoma? Approved for second-line use in Philippines - cost $5,000/infusion (information per internet) Approved for second-line use in Philippines - cost $5,000/infusion (information per internet) Can one bypass the rocky road of drug development by plane? Can one bypass the rocky road of drug development by plane?

23. 23 Report observations on uncommon sites Dermal and subcutaneous Ewing’s – A. Marrari et al. Dermal and subcutaneous Ewing’s – A. Marrari et al. 17 patients – Milano, Italy 1999-2008 17 patients – Milano, Italy 1999-2008 Surgery & chemotherapy (and XRT in 50%) Surgery & chemotherapy (and XRT in 50%) Median follow-up 5 yrs Median follow-up 5 yrs Results: 1 relapse - EFS >90% Results: 1 relapse - EFS >90% Dermal and subcut Ewing’s have favorable prognosis Dermal and subcut Ewing’s have favorable prognosis Dermal and subcutaneous Ewing’s – A. Marrari et al. Dermal and subcutaneous Ewing’s – A. Marrari et al. 17 patients – Milano, Italy 1999-2008 17 patients – Milano, Italy 1999-2008 Surgery & chemotherapy (and XRT in 50%) Surgery & chemotherapy (and XRT in 50%) Median follow-up 5 yrs Median follow-up 5 yrs Results: 1 relapse - EFS >90% Results: 1 relapse - EFS >90% Dermal and subcut Ewing’s have favorable prognosis Dermal and subcut Ewing’s have favorable prognosis

24. 24 Report observations on uncommon subtypes Chemotherapy in clear cell sarcoma - R. Jones et al Chemotherapy in clear cell sarcoma - R. Jones et al 14 pts treated with doxo or ifos 14 pts treated with doxo or ifos 1 partial response 1 partial response median TTF - 4 months median TTF - 4 months Clear cell sarcoma is not chemotherapy responsive Clear cell sarcoma is not chemotherapy responsive Chemotherapy in clear cell sarcoma - R. Jones et al Chemotherapy in clear cell sarcoma - R. Jones et al 14 pts treated with doxo or ifos 14 pts treated with doxo or ifos 1 partial response 1 partial response median TTF - 4 months median TTF - 4 months Clear cell sarcoma is not chemotherapy responsive Clear cell sarcoma is not chemotherapy responsive

25. 25 Enhance trial enrollment Phase I/II study of TH-302 + doxorubicin – K. Ganjoo et al. Phase I/II study of TH-302 + doxorubicin – K. Ganjoo et al. Hypoxia activated IPM Hypoxia activated IPM 4 patients enrolled 4 patients enrolled DLT encountered at 1 st dose level DLT encountered at 1 st dose level Treatment was modified to add g-csf Treatment was modified to add g-csf Phase I/II study of TH-302 + doxorubicin – K. Ganjoo et al. Phase I/II study of TH-302 + doxorubicin – K. Ganjoo et al. Hypoxia activated IPM Hypoxia activated IPM 4 patients enrolled 4 patients enrolled DLT encountered at 1 st dose level DLT encountered at 1 st dose level Treatment was modified to add g-csf Treatment was modified to add g-csf

26. 26 Facilitate exchange of ideas Implementation of a nurse mediated blog for sarcoma patients – A. Potter et al Implementation of a nurse mediated blog for sarcoma patients – A. Potter et al Website developed by sarcoma nurses to facilitate communication and education of sarcoma patients Website developed by sarcoma nurses to facilitate communication and education of sarcoma patients Survey-based feedback Survey-based feedback Possible benefit: improved patient’s understanding of disease and management, control over decisions Possible benefit: improved patient’s understanding of disease and management, control over decisions Implementation of a nurse mediated blog for sarcoma patients – A. Potter et al Implementation of a nurse mediated blog for sarcoma patients – A. Potter et al Website developed by sarcoma nurses to facilitate communication and education of sarcoma patients Website developed by sarcoma nurses to facilitate communication and education of sarcoma patients Survey-based feedback Survey-based feedback Possible benefit: improved patient’s understanding of disease and management, control over decisions Possible benefit: improved patient’s understanding of disease and management, control over decisions

27. 27 Inform members of work / general experience A. Yovine et al – European experience with trabectedin in sarcoma in 214 pts A. Yovine et al – European experience with trabectedin in sarcoma in 214 pts Median dose 1.3 mg/m2 q 3 weeks Median dose 1.3 mg/m2 q 3 weeks 4% PR rate 4% PR rate 10% no progression >6 months 10% no progression >6 months Demetri et al – LMS & liposarcoma 130 pts Demetri et al – LMS & liposarcoma 130 pts Starting dose 1.5 mg/m2 q 3 weeks Starting dose 1.5 mg/m2 q 3 weeks 5% PR rate 5% PR rate 37% no progression >6 months 37% no progression >6 months A. Yovine et al – European experience with trabectedin in sarcoma in 214 pts A. Yovine et al – European experience with trabectedin in sarcoma in 214 pts Median dose 1.3 mg/m2 q 3 weeks Median dose 1.3 mg/m2 q 3 weeks 4% PR rate 4% PR rate 10% no progression >6 months 10% no progression >6 months Demetri et al – LMS & liposarcoma 130 pts Demetri et al – LMS & liposarcoma 130 pts Starting dose 1.5 mg/m2 q 3 weeks Starting dose 1.5 mg/m2 q 3 weeks 5% PR rate 5% PR rate 37% no progression >6 months 37% no progression >6 months JCO 2009;27:4188 Demetri et al. JCO 2009;27:4188

28. 28 CTOS abstract process Does early submission (in June) encourage “placeholder” abstracts? Does early submission (in June) encourage “placeholder” abstracts? Is the bar for “success” in early phase trials falling too low? Is the bar for “success” in early phase trials falling too low? Exercise skepticism when interpreting early results. Exercise skepticism when interpreting early results. Does early submission (in June) encourage “placeholder” abstracts? Does early submission (in June) encourage “placeholder” abstracts? Is the bar for “success” in early phase trials falling too low? Is the bar for “success” in early phase trials falling too low? Exercise skepticism when interpreting early results. Exercise skepticism when interpreting early results.

29. 29 See you in Paris