11

Work in ProgressWork in ProgressWork in ProgressWork in Progress

Scott M. Schuetze, M.D., Ph.D.Scott M. Schuetze, M.D., Ph.D.Associate ProfessorAssociate Professor

University of MichiganUniversity of MichiganAnn ArborAnn Arbor

Scott M. Schuetze, M.D., Ph.D.Scott M. Schuetze, M.D., Ph.D.Associate ProfessorAssociate Professor

University of MichiganUniversity of MichiganAnn ArborAnn Arbor

22

DisclosureDisclosureDisclosureDisclosure

I submitted an abstract, and my I submitted an abstract, and my abstract was selected for poster abstract was selected for poster presentation.presentation.

I will not be discussing my I will not be discussing my poster.poster.

I submitted an abstract, and my I submitted an abstract, and my abstract was selected for poster abstract was selected for poster presentation.presentation.

I will not be discussing my I will not be discussing my poster.poster.

33

Value of abstract presentationValue of abstract presentationValue of abstract presentationValue of abstract presentation Convey results of trial/studyConvey results of trial/study

Disseminate practice-changing informationDisseminate practice-changing information Encourage dialogue for follow-up studyEncourage dialogue for follow-up study

Encourage exchange of ideasEncourage exchange of ideas Identify regional/national/site differencesIdentify regional/national/site differences Educational opportunity for junior membersEducational opportunity for junior members Enhance trial enrollmentEnhance trial enrollment Inform of work to avoid duplicationInform of work to avoid duplication Justify travel to meetingJustify travel to meeting

Convey results of trial/studyConvey results of trial/study Disseminate practice-changing informationDisseminate practice-changing information Encourage dialogue for follow-up studyEncourage dialogue for follow-up study

Encourage exchange of ideasEncourage exchange of ideas Identify regional/national/site differencesIdentify regional/national/site differences Educational opportunity for junior membersEducational opportunity for junior members Enhance trial enrollmentEnhance trial enrollment Inform of work to avoid duplicationInform of work to avoid duplication Justify travel to meetingJustify travel to meeting

44

Disseminate practice-changing Disseminate practice-changing informationinformation

Disseminate practice-changing Disseminate practice-changing informationinformation

Chemotherapy Intensification by Chemotherapy Intensification by Interval Compression in Localized Interval Compression in Localized

ESFT – AEWS0031ESFT – AEWS0031

R. Womer for COGR. Womer for COG

Presented CTOS 2007Presented CTOS 2007

Chemotherapy Intensification by Chemotherapy Intensification by Interval Compression in Localized Interval Compression in Localized

ESFT – AEWS0031ESFT – AEWS0031

R. Womer for COGR. Womer for COG

Presented CTOS 2007Presented CTOS 2007

55

AEWS0031 – CTOS 2007 resultsAEWS0031 – CTOS 2007 resultsAEWS0031 – CTOS 2007 resultsAEWS0031 – CTOS 2007 results

0.00

0.25

0.50

0.75

1.00

Est

imat

ed P

ropo

rtio

n E

vent

-Fre

e

0 2 4 6Years

StandardIntensive

Regimen

By RegimenEFS for All Eligible Patients

““every 2-week chemotherapy is more effective every 2-week chemotherapy is more effective than every 3-week chemotherapy…unless one than every 3-week chemotherapy…unless one is 18 or older”is 18 or older”

66

AEWS0031 – JCO 2009 resultsAEWS0031 – JCO 2009 resultsAEWS0031 – JCO 2009 resultsAEWS0031 – 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

77

Encourage dialogue for follow-Encourage dialogue for follow-up trialup trial

Encourage dialogue for follow-Encourage dialogue for follow-up trialup trial

Phase II trials presented ASCO 1995 Phase II trials presented ASCO 1995 & 1996 (breast, lung, GI, GU & Gyn)& 1996 (breast, lung, GI, GU & Gyn)

100 selected with conclusion of 100 selected with conclusion of “encouraging” or “promising” results“encouraging” or “promising” results

systematic review conducted to systematic review conducted to determine # randomized clinical trials determine # randomized clinical trials conducted based on phase II results.conducted based on phase II results.

Phase II trials presented ASCO 1995 Phase II trials presented ASCO 1995 & 1996 (breast, lung, GI, GU & Gyn)& 1996 (breast, lung, GI, GU & Gyn)

100 selected with conclusion of 100 selected with conclusion of “encouraging” or “promising” results“encouraging” or “promising” results

systematic review conducted to systematic review conducted to determine # randomized clinical trials determine # randomized clinical trials conducted based on phase II results.conducted based on phase II results.

Ian Tannock et al. JCO March 1, 2009

88

Phase II results to phase III trialPhase II results to phase III trialPhase II results to phase III trialPhase II results to phase III trialMedline, proceeding abstracts and Medline, proceeding abstracts and

www.clinicaltrials.gov searched searched10 yrs after presentation of positive results 10 yrs after presentation of positive results

– only 13 of 100 regimens were evaluated– only 13 of 100 regimens were evaluated100 phase II trials positive results ASCO 100 phase II trials positive results ASCO

20062006 15% - final results did not agree15% - final results did not agree 60% - regimen should be evaluated60% - regimen should be evaluated 19% - plan to conduct trial and have resources19% - plan to conduct trial and have resources

Medline, proceeding abstracts and Medline, proceeding abstracts and www.clinicaltrials.gov searched searched

10 yrs after presentation of positive results 10 yrs after presentation of positive results – only 13 of 100 regimens were evaluated– only 13 of 100 regimens were evaluated

100 phase II trials positive results ASCO 100 phase II trials positive results ASCO 20062006 15% - final results did not agree15% - final results did not agree 60% - regimen should be evaluated60% - regimen should be evaluated 19% - plan to conduct trial and have resources19% - plan to conduct trial and have resources

99

Phase II results to phase III Phase II results to phase III resultsresults

Phase II results to phase III Phase II results to phase III resultsresults

Phase II trials designed with low false-Phase II trials designed with low false-negative and higher false-positive ratesnegative and higher false-positive rates

60% of oncology regimens with favorable 60% of oncology regimens with favorable activity in phase II trials lack superiority activity in phase II trials lack superiority in phase III trialsin phase III trials

Transition from phase II abstract to Transition from phase II abstract to favorable outcome in phase III trial is a favorable outcome in phase III trial is a rocky roadrocky road

Phase II trials designed with low false-Phase II trials designed with low false-negative and higher false-positive ratesnegative and higher false-positive rates

60% of oncology regimens with favorable 60% of oncology regimens with favorable activity in phase II trials lack superiority activity in phase II trials lack superiority in phase III trialsin phase III trials

Transition from phase II abstract to Transition from phase II abstract to favorable outcome in phase III trial is a favorable outcome in phase III trial is a rocky roadrocky road

S. Cannistra JCO 2009;27:3073I Kola et al. Nat Rev Drug Discov 2004;3:711

1010

Phase II trial of Reolysin in patients with Phase II trial of Reolysin in patients with sarcoma lung metastasis - M. Mita et alsarcoma lung metastasis - M. Mita et al

Phase II trial of Reolysin in patients with Phase II trial of Reolysin in patients with sarcoma lung metastasis - M. Mita et alsarcoma lung metastasis - M. Mita et al

CTOS 2008 – 35 ptsCTOS 2008 – 35 pts No objective responsesNo objective responses 3 had SD 3 had SD >> 6 months 6 months

CTOS 2009 – 52 pts (completed)CTOS 2009 – 52 pts (completed) No severe side effectsNo severe side effects No objective responsesNo objective responses 6 had SD 6 had SD >> 6 months (met endpoint) 6 months (met endpoint)

Worthy of phase III evaluation or Worthy of phase III evaluation or combination trial?combination trial?

CTOS 2008 – 35 ptsCTOS 2008 – 35 pts No objective responsesNo objective responses 3 had SD 3 had SD >> 6 months 6 months

CTOS 2009 – 52 pts (completed)CTOS 2009 – 52 pts (completed) No severe side effectsNo severe side effects No objective responsesNo objective responses 6 had SD 6 had SD >> 6 months (met endpoint) 6 months (met endpoint)

Worthy of phase III evaluation or Worthy of phase III evaluation or combination trial?combination trial?

1111

Phase II randomized trial of doxorubicin +/- Phase II randomized trial of doxorubicin +/- palifosfamide in STS– C. Vershraegen et alpalifosfamide in STS– C. Vershraegen et alPhase II randomized trial of doxorubicin +/- Phase II randomized trial of doxorubicin +/- palifosfamide in STS– C. Vershraegen et alpalifosfamide 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 toxicityNo CNS toxicity New formulationNew formulation

Up to 6 cycles doxorubicin (75 mg/m2) Up to 6 cycles doxorubicin (75 mg/m2) +/- palifosfamide+/- palifosfamide

Primary end-point: PFSPrimary end-point: PFS

Palifosfamide (ZIO-201)Palifosfamide (ZIO-201) No hemorrhagic cystitis (MESNA not needed)No hemorrhagic cystitis (MESNA not needed) No CNS toxicityNo CNS toxicity New formulationNew formulation

Up to 6 cycles doxorubicin (75 mg/m2) Up to 6 cycles doxorubicin (75 mg/m2) +/- palifosfamide+/- palifosfamide

Primary end-point: PFSPrimary end-point: PFS

1212

Palifosfamide – Palifosfamide – abstractabstract results resultsPalifosfamide – Palifosfamide – abstractabstract results results

38 patients enrolled38 patients enrolledNo difference in toxicity between armsNo difference in toxicity between armsCombination is well-toleratedCombination is well-toleratedEasy to administer on outpatient basisEasy to administer on outpatient basis““Efficacy data is pre-mature”Efficacy data is pre-mature”

38 patients enrolled38 patients enrolledNo difference in toxicity between armsNo difference in toxicity between armsCombination is well-toleratedCombination is well-toleratedEasy to administer on outpatient basisEasy to administer on outpatient basis““Efficacy data is pre-mature”Efficacy data is pre-mature”

1313

Palifosfamide “press release”Palifosfamide “press release”Palifosfamide “press release”Palifosfamide “press release”

Posted October 14, 2009ZIOPHARM 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

1414

Palifosfamide – Palifosfamide – posterposter results resultsPalifosfamide – Palifosfamide – posterposter results results

61 pts evaluated / 67 enrolled61 pts evaluated / 67 enrolledArms balanced for pt age, subtype & Arms balanced for pt age, subtype &

number of prior lines of treatmentnumber of prior lines of treatmentSarcoma assessment at local site & Sarcoma assessment at local site &

confirmed independent radiology reviewconfirmed independent radiology review 14 progressed – doxorubicin arm14 progressed – doxorubicin arm 6 progressed – combination arm6 progressed – combination arm HR=0.62; p=0.026HR=0.62; p=0.026

61 pts evaluated / 67 enrolled61 pts evaluated / 67 enrolledArms balanced for pt age, subtype & Arms balanced for pt age, subtype &

number of prior lines of treatmentnumber of prior lines of treatmentSarcoma assessment at local site & Sarcoma assessment at local site &

confirmed independent radiology reviewconfirmed independent radiology review 14 progressed – doxorubicin arm14 progressed – doxorubicin arm 6 progressed – combination arm6 progressed – combination arm HR=0.62; p=0.026HR=0.62; p=0.026

1515

Progression-free survivalProgression-free survivalProgression-free survivalProgression-free survival

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 1 2 3 4 5 6 7MONTHS

combination

doxorubicin

1616

Interpretation of dataInterpretation of dataInterpretation of dataInterpretation of data

"The hypothesis of the randomized Phase II "The hypothesis of the randomized Phase II trial design for this very difficult to treat trial design for this very difficult to treat cancer population has been validated and cancer population has been validated and the interim results are promising and the interim results are promising and supportive of a pivotal trial" – Dr. Maki, supportive of a pivotal trial" – Dr. Maki, Oct 2009Oct 2009

““These interim results are very promising These interim results are very promising indicating a potentially new drug to indicating a potentially new drug to control this life-threatening disease…” – control this life-threatening disease…” – Dr. Demetri, Nov 2009Dr. Demetri, Nov 2009

"The hypothesis of the randomized Phase II "The hypothesis of the randomized Phase II trial design for this very difficult to treat trial design for this very difficult to treat cancer population has been validated and cancer population has been validated and the interim results are promising and the interim results are promising and supportive of a pivotal trial" – Dr. Maki, supportive of a pivotal trial" – Dr. Maki, Oct 2009Oct 2009

““These interim results are very promising These interim results are very promising indicating a potentially new drug to indicating a potentially new drug to control this life-threatening disease…” – control this life-threatening disease…” – Dr. Demetri, Nov 2009Dr. Demetri, Nov 2009

1717

Palifosfamide follow-up plans?Palifosfamide follow-up plans?Palifosfamide follow-up plans?Palifosfamide follow-up plans?

Doxorubicin + palifosfamide vs Doxorubicin + palifosfamide vs doxorubicin?doxorubicin?

Doxorubicin + palifosfamide vs Doxorubicin + palifosfamide vs doxorubicin + ifosfamide?doxorubicin + ifosfamide?

Doxorubicin + palifosfamide vs Doxorubicin + palifosfamide vs doxorubicin + trabectedin?doxorubicin + trabectedin?

3 or 4-arm trial?3 or 4-arm trial?

Doxorubicin + palifosfamide vs Doxorubicin + palifosfamide vs doxorubicin?doxorubicin?

Doxorubicin + palifosfamide vs Doxorubicin + palifosfamide vs doxorubicin + ifosfamide?doxorubicin + ifosfamide?

Doxorubicin + palifosfamide vs Doxorubicin + palifosfamide vs doxorubicin + trabectedin?doxorubicin + trabectedin?

3 or 4-arm trial?3 or 4-arm trial?

1818

Rexin-G for chemotherapy Rexin-G for chemotherapy resistant sarcomaresistant sarcomaS. Chawla et al.S. Chawla et al.

Rexin-G for chemotherapy Rexin-G for chemotherapy resistant sarcomaresistant sarcomaS. Chawla et al.S. Chawla et al.

Dominant-negative mutant of human Dominant-negative mutant of human cyclin-G1cyclin-G1

Packaged in replication-defective Packaged in replication-defective retroviral coreretroviral core

42 patients – 20 phase I/II, 22 phase II42 patients – 20 phase I/II, 22 phase IIdose 1-2 x 10dose 1-2 x 101111 cfu 2-3x/week for 4 weeks cfu 2-3x/week for 4 weeks

Dominant-negative mutant of human Dominant-negative mutant of human cyclin-G1cyclin-G1

Packaged in replication-defective Packaged in replication-defective retroviral coreretroviral core

42 patients – 20 phase I/II, 22 phase II42 patients – 20 phase I/II, 22 phase IIdose 1-2 x 10dose 1-2 x 101111 cfu 2-3x/week for 4 weeks cfu 2-3x/week for 4 weeks

1919

Rexin-G phase I/II resultsRexin-G phase I/II resultsRexin-G phase I/II resultsRexin-G phase I/II resultsNo objective responses in sarcomaNo objective responses in sarcomaNo grade No grade >>3 toxicity3 toxicityHeterogeneity of sub-types precludes Heterogeneity of sub-types precludes

analysis of dose-response relationshipanalysis of dose-response relationship

No objective responses in sarcomaNo objective responses in sarcomaNo grade No grade >>3 toxicity3 toxicityHeterogeneity of sub-types precludes Heterogeneity of sub-types precludes

analysis of dose-response relationshipanalysis of dose-response relationship

S. Chawla et al. Molecular Therapy 2009;17:1651

2020

Rexin G – phase II resultsRexin G – phase II resultsRexin G – phase II resultsRexin G – phase II results

22 pts chemotherapy resistant 22 pts chemotherapy resistant osteosarcomaosteosarcoma 17 pts evaluable17 pts evaluable No objective responseNo objective response 10 stable disease best response10 stable disease best response Median PFS – 12 weeksMedian PFS – 12 weeks 1 pt with possible histologic response1 pt with possible histologic response

22 pts chemotherapy resistant 22 pts chemotherapy resistant osteosarcomaosteosarcoma 17 pts evaluable17 pts evaluable No objective responseNo objective response 10 stable disease best response10 stable disease best response Median PFS – 12 weeksMedian PFS – 12 weeks 1 pt with possible histologic response1 pt with possible histologic response

S. Chawla et al. Molecular Therapy 2009;17:1651

2121

Rexin GRexin GProgression-free survivalProgression-free survival

Rexin GRexin GProgression-free survivalProgression-free survival

months

2222

Rexin-GRexin-GRexin-GRexin-GShould drug be studied in randomized Should drug be studied in randomized

controlled trial for sarcoma?controlled trial for sarcoma?Approved for second-line use in Approved for second-line use in

Philippines - cost $5,000/infusion Philippines - cost $5,000/infusion (information per internet)(information per internet)

Can one bypass the rocky road of drug Can one bypass the rocky road of drug development by plane?development by plane?

Should drug be studied in randomized Should drug be studied in randomized controlled trial for sarcoma?controlled trial for sarcoma?

Approved for second-line use in Approved for second-line use in Philippines - cost $5,000/infusion Philippines - cost $5,000/infusion (information per internet)(information per internet)

Can one bypass the rocky road of drug Can one bypass the rocky road of drug development by plane?development by plane?

2323

Report observations on Report observations on uncommon sitesuncommon sites

Report observations on Report observations on uncommon sitesuncommon sites

Dermal and subcutaneous Ewing’s – Dermal and subcutaneous Ewing’s – A. Marrari et al.A. Marrari et al. 17 patients – Milano, Italy 1999-200817 patients – Milano, Italy 1999-2008 Surgery & chemotherapy (and XRT in 50%)Surgery & chemotherapy (and XRT in 50%) Median follow-up 5 yrsMedian follow-up 5 yrs Results: 1 relapse - EFS >90%Results: 1 relapse - EFS >90% Dermal and subcut Ewing’s have favorable Dermal and subcut Ewing’s have favorable

prognosisprognosis

Dermal and subcutaneous Ewing’s – Dermal and subcutaneous Ewing’s – A. Marrari et al.A. Marrari et al. 17 patients – Milano, Italy 1999-200817 patients – Milano, Italy 1999-2008 Surgery & chemotherapy (and XRT in 50%)Surgery & chemotherapy (and XRT in 50%) Median follow-up 5 yrsMedian follow-up 5 yrs Results: 1 relapse - EFS >90%Results: 1 relapse - EFS >90% Dermal and subcut Ewing’s have favorable Dermal and subcut Ewing’s have favorable

prognosisprognosis

2424

Report observations on Report observations on uncommon subtypesuncommon subtypes

Report observations on Report observations on uncommon subtypesuncommon subtypes

Chemotherapy in clear cell sarcoma - Chemotherapy in clear cell sarcoma - R. Jones et alR. Jones et al 14 pts treated with doxo or ifos14 pts treated with doxo or ifos 1 partial response1 partial response median TTF - 4 monthsmedian TTF - 4 months Clear cell sarcoma is not chemotherapy Clear cell sarcoma is not chemotherapy

responsiveresponsive

Chemotherapy in clear cell sarcoma - Chemotherapy in clear cell sarcoma - R. Jones et alR. Jones et al 14 pts treated with doxo or ifos14 pts treated with doxo or ifos 1 partial response1 partial response median TTF - 4 monthsmedian TTF - 4 months Clear cell sarcoma is not chemotherapy Clear cell sarcoma is not chemotherapy

responsiveresponsive

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Enhance trial enrollmentEnhance trial enrollmentEnhance trial enrollmentEnhance trial enrollment

Phase I/II study of TH-302 + Phase I/II study of TH-302 + doxorubicin – K. Ganjoo et al.doxorubicin – K. Ganjoo et al. Hypoxia activated IPMHypoxia activated IPM 4 patients enrolled4 patients enrolled DLT encountered at 1DLT encountered at 1stst dose level dose level Treatment was modified to add g-csfTreatment was modified to add g-csf

Phase I/II study of TH-302 + Phase I/II study of TH-302 + doxorubicin – K. Ganjoo et al.doxorubicin – K. Ganjoo et al. Hypoxia activated IPMHypoxia activated IPM 4 patients enrolled4 patients enrolled DLT encountered at 1DLT encountered at 1stst dose level dose level Treatment was modified to add g-csfTreatment was modified to add g-csf

2626

Facilitate exchange of ideasFacilitate exchange of ideasFacilitate exchange of ideasFacilitate exchange of ideasImplementation of a nurse mediated Implementation of a nurse mediated

blog for sarcoma patients – A. Potter blog for sarcoma patients – A. Potter et alet al Website developed by sarcoma nurses to Website developed by sarcoma nurses to

facilitate communication and education of facilitate communication and education of sarcoma patientssarcoma patients

Survey-based feedbackSurvey-based feedback Possible benefit: improved patient’s Possible benefit: improved patient’s

understanding of disease and management, understanding of disease and management, control over decisionscontrol over decisions

Implementation of a nurse mediated Implementation of a nurse mediated blog for sarcoma patients – A. Potter blog for sarcoma patients – A. Potter et alet al Website developed by sarcoma nurses to Website developed by sarcoma nurses to

facilitate communication and education of facilitate communication and education of sarcoma patientssarcoma patients

Survey-based feedbackSurvey-based feedback Possible benefit: improved patient’s Possible benefit: improved patient’s

understanding of disease and management, understanding of disease and management, control over decisionscontrol over decisions

2727

Inform members of work / Inform members of work / general experiencegeneral experience

Inform members of work / Inform members of work / general experiencegeneral experience

A. Yovine et al – European experience with A. Yovine et al – European experience with trabectedin in sarcoma in 214 ptstrabectedin in sarcoma in 214 pts Median dose 1.3 mg/m2 q 3 weeksMedian dose 1.3 mg/m2 q 3 weeks 4% PR rate4% PR rate 10% no progression >6 months10% no progression >6 months

Demetri et al – LMS & liposarcoma 130 ptsDemetri et al – LMS & liposarcoma 130 pts Starting dose 1.5 mg/m2 q 3 weeksStarting dose 1.5 mg/m2 q 3 weeks 5% PR rate5% PR rate 37% no progression >6 months37% no progression >6 months

A. Yovine et al – European experience with A. Yovine et al – European experience with trabectedin in sarcoma in 214 ptstrabectedin in sarcoma in 214 pts Median dose 1.3 mg/m2 q 3 weeksMedian dose 1.3 mg/m2 q 3 weeks 4% PR rate4% PR rate 10% no progression >6 months10% no progression >6 months

Demetri et al – LMS & liposarcoma 130 ptsDemetri et al – LMS & liposarcoma 130 pts Starting dose 1.5 mg/m2 q 3 weeksStarting dose 1.5 mg/m2 q 3 weeks 5% PR rate5% PR rate 37% no progression >6 months37% no progression >6 months

Demetri et al. JCO 2009;27:4188JCO 2009;27:4188

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CTOS abstract processCTOS abstract processCTOS abstract processCTOS abstract process

Does early submission (in June) Does early submission (in June) encourage “placeholder” abstracts?encourage “placeholder” abstracts?

Is the bar for “success” in early phase Is the bar for “success” in early phase trials falling too low?trials falling too low?

Exercise skepticism when Exercise skepticism when interpreting early results.interpreting early results.

Does early submission (in June) Does early submission (in June) encourage “placeholder” abstracts?encourage “placeholder” abstracts?

Is the bar for “success” in early phase Is the bar for “success” in early phase trials falling too low?trials falling too low?

Exercise skepticism when Exercise skepticism when interpreting early results.interpreting early results.

2929

See you in ParisSee you in ParisSee you in ParisSee you in Paris