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

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

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

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

SARC

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

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)

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

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

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

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

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)

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

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

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

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

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

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

Completed SARC studies

SARC001: imatinib phase II study for sarcomas ACCRUAL COMPLETE Imatinib 100-300mg 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

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

Open studies

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

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 10-14 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

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!

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 = 34-74 (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

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

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 73-452, depending on results; 28 enrolled; 13 still on study Good accrual to date; toxicity has been significant, requiring dose reduction amendment

Studies in development

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

SARC011: Phase II multi-arm study of R1507 IGF1R mAb in Ewing sarcoma and soft tissue sarcomas Protocol DISTRIBUTED 09/07 R1507 9 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)

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 AZ0530 250 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

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