Transcript CTOS 2002 Meeting

Work in Progress
Scott M. Schuetze, M.D., Ph.D.
Associate Professor
University of Michigan
Ann Arbor
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Disclosure
I submitted an abstract, and my
abstract was selected for poster
presentation.
 I will not be discussing my
poster.

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Value of abstract presentation
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Convey results of trial/study
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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
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Disseminate practice-changing
information
Chemotherapy Intensification by
Interval Compression in Localized
ESFT – AEWS0031
R. Womer for COG
Presented CTOS 2007
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AEWS0031 – CTOS 2007 results
EFS for All Eligible Patients
0.75
1.00
By Regimen
0.50
Regimen
0.00
0.25
Standard
Intensive
0
2
4
6
Years
“every 2-week chemotherapy is more effective
than every 3-week chemotherapy…unless one
is 18 or older”
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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
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Encourage dialogue for followup 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
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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
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15% - final results did not agree
60% - regimen should be evaluated
19% - plan to conduct trial and have resources
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Phase II results to phase III
results
Phase II trials designed with low falsenegative 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
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S. Cannistra JCO 2009;27:3073
I Kola et al. Nat Rev Drug Discov 2004;3:711
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Phase II trial of Reolysin in patients with
sarcoma lung metastasis - M. Mita et al
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CTOS 2008 – 35 pts
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CTOS 2009 – 52 pts (completed)
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No objective responses
3 had SD > 6 months
No severe side effects
No objective responses
6 had SD > 6 months (met endpoint)
Worthy of phase III evaluation or
combination trial?
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Phase II randomized trial of doxorubicin +/palifosfamide in STS– C. Vershraegen et al
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Palifosfamide (ZIO-201)
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No hemorrhagic cystitis (MESNA not needed)
No CNS toxicity
New formulation
Up to 6 cycles doxorubicin (75 mg/m2)
+/- palifosfamide
 Primary end-point: PFS
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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”
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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
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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
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14 progressed – doxorubicin arm
6 progressed – combination arm
HR=0.62; p=0.026
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Progression-free survival
1.0
0.9
combination
0.8
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
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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
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Palifosfamide follow-up plans?
Doxorubicin + palifosfamide vs
doxorubicin?
 Doxorubicin + palifosfamide vs
doxorubicin + ifosfamide?
 Doxorubicin + palifosfamide vs
doxorubicin + trabectedin?
 3 or 4-arm trial?
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Rexin-G for chemotherapy
resistant sarcoma
S. Chawla et al.
Dominant-negative mutant of human
cyclin-G1
 Packaged in replication-defective
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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
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S. Chawla et al. Molecular Therapy 2009;17:1651
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Rexin G – phase II results
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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
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S. Chawla et al. Molecular Therapy 2009;17:1651
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Rexin G
Progression-free survival
months
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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?
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Report observations on
uncommon sites
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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
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Report observations on
uncommon subtypes
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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
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Enhance trial enrollment
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Phase I/II study of TH-302 +
doxorubicin – K. Ganjoo et al.
Hypoxia activated IPM
 4 patients enrolled
st
 DLT encountered at 1 dose level
 Treatment was modified to add g-csf
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Facilitate exchange of ideas
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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
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Inform members of work /
general experience
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A. Yovine et al – European experience with
trabectedin in sarcoma in 214 pts
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Median dose 1.3 mg/m2 q 3 weeks
4% PR rate
10% no progression >6 months
Demetri et al – LMS & liposarcoma 130 pts
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Starting dose 1.5 mg/m2 q 3 weeks
5% PR rate
37% no progression >6 months
Demetri et al. JCO 2009;27:4188
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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.
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See you in Paris
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