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Work in Progress

Work in Progress. Scott M. Schuetze, M.D., Ph.D. Associate Professor University of Michigan Ann Arbor. Disclosure. I submitted an abstract, and my abstract was selected for poster presentation. I will not be discussing my poster. Value of abstract presentation.

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Work in Progress

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

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

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

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

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

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

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

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

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

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

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

  15. 1.0 0.9 0.8 combination 0.7 0.6 0.5 0.4 doxorubicin 0.3 0.2 0.1 0.0 0 1 2 3 4 5 6 7 MONTHS Progression-free survival

  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

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

  18. Rexin-G for chemotherapy resistant sarcomaS. Chawla et al. • Dominant-negative mutant of human cyclin-G1 • Packaged in replication-defective retroviral core • 42 patients – 20 phase I/II, 22 phase II • dose 1-2 x 1011 cfu 2-3x/week for 4 weeks

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

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

  21. Rexin GProgression-free survival months

  22. Rexin-G • Should drug be studied in randomized controlled trial for sarcoma? • 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?

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

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

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

  26. Facilitate exchange of ideas • 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 • Survey-based feedback • Possible benefit: improved patient’s understanding of disease and management, control over decisions

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

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

  29. See you in Paris

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