1. SARC studies: an overview
Robert Maki, MD PhD
Sarcoma Program
Memorial Sloan-Kettering Cancer Center
Deputy Executive Director, SARC

3. Incorporated November, 2003
SARC
Formerly the North American Consortium of CTOS (Connective Tissue Oncology Society)
501(c)3 organization
Incorporated November, 2003

4. SARC Mission and Vision
Build upon strengths of cancer centers with dedication to sarcoma work
Collaborative clinical trials
Expand the ability to move quickly with efficient coordination
Develop infrastructure between these cancer centers to facilitate collaboration
Further the knowledge regarding diagnosis and treatment of sarcoma
Basic and translational research
Engage all appropriate and necessary resources to cure and prevent sarcomas
EORtc combined studies: amg706 phase III gist; perfosine in chondrosarc; g/t vs a/I
CTOS board action
Minority leader harry reid of nevada
Website: approval from ACS and NCCN

5. SARC SARC CTOS Institution – Multiple members of CTOS
Statistical
Center
CTOS
SARC
Operations
Office
CTOS: INCLUDES ALL 7 SPECIALTIES IN SARCOMA PATIENTS: MULTIDISCIPLINARY CARE IS NECESSARY-10TH ANNIVERSARY
25% ERROR RATE IN PATH OF PTS ENTERED INTO COOP STUDIES
CTOS UNABLE TO PROVIDE LEGAL FRAMEWORK
ONLY STUDY GROUP TIED TO MULTIDISCIPLINARY SOCIETY ON BOTH SIDES OF ATLANTIC
SARC CAME ABOUT BECAUSE WE COULDN’T MATCH SUCCESS OF COOP GROUPS IN EUROPE
BAKER CHAIRED SARCOMA INTERGROUP AND SWOG SARCOMA COMMITTEE; ANTMAN CHAIRED SWOG SARCOMA
Institution – Multiple members of CTOS
Board of Directors – Majority from CTOS

6. SARC

7. SARC Board of Directors
Executive committee members
Charles Nearburg - Dallas
David Marsh - New York
Deborah Buks - Houston
Tim McCormick - Detroit
Piero Picci, MD - Rizzoli Institute
Frits van Coevorden, MD - Netherlands CA Inst
Ad hoc
Denise Reinke (Operations office)
Picci and van Coevorden appointed as CTOS representatives from Europe

8. SARC Executive Committee
L. Baker (U Michigan)
R. Maki (Memorial Sloan-Kettering)
S. Patel (M D Anderson)
G. Demetri (Dana-Farber)
L. Helman (NCI, consultant)
R. Benjamin (M D Anderson, consultant)

9. SARC U.S. Participants Sant Chawla, MD Century City Hospital
Arthur Staddon, MD
Pennsylvania Oncology
Martin Blackstein, MD
University of Toronto
Amir Shahalee, MD
University of Florida
William Tap, MD
UCLA
Dennis Priebat, MD
Washington Cancer Institute
Christopher Ryan, MD
Oregon Health Science Univ
Meg Von Mehren, MD
Fox Chase Cancer Center
Alberto Pappo, MD
Texas Children’s Hospital
Charles Forscher, MD
Cedars Sinai Cancer Center
Charlotte Jacobs, MD
Stanford Cancer Center
-Robert Benjamin, MD
M.D. Anderson Cancer Center
-Robert Maki, MD, PhD
MSKCC
-Scott Schuetze, MD, PhD
University of Michigan
-Lee Helman, MD
NCI-Pediatric Branch
-Gina D’Amato, MD
Moffitt Cancer Center
-Michael Fanucchi, MD
Emory University
-George Demetri, MD
Dana Farber Cancer Institute
-David Harmon, MD
Massachusetts General Hospital
-Scott Okuno, MD
Mayo Clinic
-James Whitlock, MD
Vanderbilt University
-Warren Chow, MD
City of Hope
-David Ettinger, MD
Johns Hopkins
* Initial participation

10. Common features of studies
Multi-center
Pediatric and medical oncology
Rotating leadership for studies
Novel agents and / or novel design
Multiple subtypes of sarcoma permitted
Specific arms for several subtypes
Biological correlates key component of studies
Discussions between lead and collaborating institutions yields final protocol
Strong biostatistical input on all studies
Web-based patient registration and evaluation

11. SARC: Developmental Therapeutics
Committee Chair
Peter Houghton
Preclinical Labs
In vitro
Dafydd Thomas (Michigan)
Gary Schwartz (MSKCC)
In vivo
Peter Houghton (STS)
Richard Gorlick (Osteosarcoma)
Chand Khanna (Dog models)
Clinical Trials
Phase I
Tony Tolcher

12. SARC Operations Office Ann Arbor, MI
L. Baker, Executive Director
R. Maki, Deputy Executive Director
D. Reinke, Administrative Director
K. Marsh, Research Project Manager
Gem-Doce (bone) phase II, perifosine phase II, MPNST “registry” study, dasatinib phase II
J. Reed, PhD, Research Project Manager
IGF1R studies
J. Keene, Project Manager
Developmental therapeutics
C. Bergmans, Administrative Assistant

13. SARC Operations Facilitate research collaboration
Obtain and retain regulatory documents
1572 CV
CLIA documents/lab normals
Consent forms
IRB approval
Human subject training
Federal-wide assurances (SARC)

14. SARC Operations New participants Multidisciplinary membership in CTOS
> 80 new sarcoma patients annually
> 20 if purely a pediatric unit
Commitment to clinical research
Reputation regarding research participation

15. SARC Operations Concept → Protocol Concept approval
Protocol development
Primary PI
Review and letter of intent from participants
IRB approval primary site
Subsequent distribution to other participants
Consent review
Confirmation of IRB prior to site activation

16. SARC Operations Version control Distribution of PDF documents
Amendment driven by primary PI site
Distribution following IRB approval at primary PI site
Posting of protocol at the website

17. SARC Operations Activation/Data capture Data and safety monitoring
Training of CRAs prior to permission to enter
One on one training
Weekly data monitoring conference among staff
Quarterly conference calls
Data and safety monitoring
Monthly conference calls executive committee and PIs
Review accrual, deviations, SAEs
Phase III studies: independent DSMB

18. SARC Operations SAE Reporting Specific requirements per protocol
MedWatch form electronically available at website
Fax coversheet listing all recipients
Submission to supporter/sponsor
Review at Operations office
Distribution to participating sites
Reviewed by Executive Committee

19. SARC Operations Contracting Drug distribution
Template contracts developed with each participating site
Modify as necessary to comply with SARC/supporter or sponsor contract
Drug distribution
3rd party pharmacy
Site visit to ensure practice standards

20. Completed SARC studies

21. SARC001: imatinib phase II study for sarcomas
ACCRUAL COMPLETE
Imatinib mg PO BID based on BSA
Response Assessment
CR, PR Stable
Progression, unacceptable toxicity, pt. withdraw
Continue drug
Off study follow-up for 2 years
n = 241, 9 remain on treatment
Manuscript in preparation
Largest study of imatinib in desmoid tumors
Occasional responses noted in MFH, LMS

22. SARC002: Gem vs Gem/Doce phase III study for sarcomas
ACCRUAL COMPLETE
Randomize
Gemcitabine
Gemcitabine plus Docetaxel
Response Assessment
Patients with response or stabilization of disease remain on treatment until progression, unacceptable toxicity or withdrawal. Follow up continues for 12 months.
Patients who came off study for progression, unacceptable toxicity or by pt / MD request are followed for 12 months
n = 122
Manuscript: Completed, JCO
Gem Doce > Gem with overall survival advantage

23. Open studies

24. SARC003: Gem/Doce phase II study for Ewing sarcoma, osteosarcoma, chondrosarcoma
Eligible pts. with Osteosarcoma, Ewing’s sarcoma or chondrosarcoma
Treatment with gemcitabine / docetaxel
Response Assessment
Patients with stable disease, PR/CR remain on treatment until patient meets off study criteria.
Patient off study for progression, toxicity, patient withdrew or investigator discretion
Follow up after 14 or more cycles, every 3 months for 1 year and then every 6 months for 1 year
Follow up until toxicities resolved, follow up per institutional protocol or until patient is placed on a new protocol
Opened 5 May 05
Target = (14→40) x 3; 14 x 3 enrolled; 2 still on treatment
Osteosarcoma arm closed; other two pending
Only minor activity seen to date

25. SARC004: Neoadjuvant imatinib before surgery for DFSP
Opened 21 Apr 05
Tissue biopsy (w/in 4 wks of Day 1)
Imatinib 400 mg orally bid for days prior to planned resection
Plasma obtained (24 hrs pre-surgery)
Surgical resection
Pt follow-up (3-5 wks)
Target = 20; 9 enrolled; 1 on treatment
Addition of two sites helped increase accrual

26. SARC005: Adjuvant Gem/Doce → Doxorubicin for high risk primary resected uterine LMS
Opened 28 Jan 06
Gemcitabine/Docetaxel tx (4 Cycles)
Response Assessment
Doxorubicin tx (4 Cycles)
Response Assessment
Pt follow-up (every 3 mo for 2 yrs.)
Target = 45; 21 enrolled; at least 9 in follow up after all therapy
No recurrences to date!

27. SARC006: Assessment of therapy for Primary MPNST (sporadic or associated with neurofibromatosis type I)
Opened 1 Dec 05
Ifosfamide + Doxorubicin (IA) (2 cycles)
Evaluate
Ifosfamide + Etoposide (IE) (2 cycles)
Evaluate
Radiation
Surgery
Surgery + Radiation
2 cycles IA or IE
Evaluate
2 cycles IA or IE
Target = (17-37 x 2); 2 enrolled; 0 on study
Looking to open sites that see more NF1 than MPNST as other source for patients
DoD Grant supported—would very much like to increase accrual / complete

28. SARC007: Phase II perifosine for chemotherapy insensitive sarcomas (EMC, ASPS, chondrosarcoma)
Opened 21 Jun 06
Perifosine 100 mg qhs orally daily
Response Assessment q 3 months
SD, PR or CR
Progression
Continue on Study
Remove from Study
Target ≈ 111 (37 x 3); 56 (13, 10, 29) enrolled; 31 still on study
Accrual surprisingly good for rare diagnoses
These patients will qualify for other SARC studies

29. SARC009: Phase II multi-arm study of dasatinib in soft tissue sarcomas
Opened 11 May 07
Dasatinib 100 mg bid
Exam q 4 wks; Imaging q 8 wks
SD, PR or CR
Progression
Continue on Study
Remove from Study
Target , depending on results; 28 enrolled; 13 still on study
Good accrual to date; toxicity has been significant, requiring dose reduction amendment

30. Studies in development

31. SARC010: Phase II multi-arm study of dasatinib in imatinib-, sunitinib- refractory GIST
Protocol draft written
(Jon Trent, MDACC)
Dasatinib 100 mg bid
Exam q 4 wks; Imaging q 8 wks
SD, PR or CR
Progression
Continue on Study
Remove from Study
Target n ~ 30-60
“Gleevec Plus” type protocol, looking for activity in imatinib, sunitinib refractory setting

32. SARC011: Phase II multi-arm study of R1507 IGF1R mAb in Ewing sarcoma and soft tissue sarcomas
Protocol DISTRIBUTED 09/07
R mg/kg weekly
Exam q 1-3 wks; Imaging q 6 wks
SD, PR or CR
Progression
Continue on Study
Remove from Study
Target n ~ 245 eligible patients (100 with Ewing sarcoma)
Activity already seen in Ewing sarcoma in phase I
Worldwide study, partnership with Hoffman-LaRoche
Grant from Hoffman-LaRoche for developmental therapeutics, young investigator
Phase III study as follow up is anticipated (SARC013)

33. SARC012: Phase II 1/2 study of AZ0530 src inhibitor in patients with resected lung metastases from osteosarcoma
Protocol draft written
(Lee Helman, POB NCI;
Su Young Kim, POB NCI)
Patient w/ OS
lung mets resected
Randomize
No further Rx
AZ mg (?)
oral daily
Follow up (to 10 yrs)
Target up to 80 patients, 40 on each arm
Target increase in overall survival from 45% to 70% at 3 years

34. Summary Active US group, based on relationship with CTOS
IITs and industrial studies
Industrial studies allow international cooperation
May be difficult to engage some sites that require NCI input for participation (Canada)
Developmental therapeutics program
Just starting
Young investigator award anticipated to develop next generation of basic science or translational researchers