sarc studies: an overview robert maki, md phd sarcoma program memorial sloan-kettering cancer center...
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SARC studies: an overview
Robert Maki, MD PhDSarcoma Program
Memorial Sloan-Kettering Cancer CenterDeputy Executive Director, SARC
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 Build upon strengths of cancer centers with dedication to sarcoma work dedication to sarcoma work – Collaborative clinical trialsCollaborative clinical trials– Expand the ability to move quickly with efficient Expand the ability to move quickly with efficient
coordinationcoordination– Develop infrastructure between these cancer centers Develop infrastructure between these cancer centers
to facilitate collaborationto 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
Statistical Center
Operations
Office
SARC CTOS
Institution – Multiple members of CTOSBoard of Directors – Majority from CTOS
SARC
SARCBoard of Directors
Executive CommitteeOfficers Chairpersons
of standing committees
Operations Office Statistical Center
Officers President Vice President Secretary Treasurer
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)
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, MDM.D. Anderson Cancer Center
-Robert Maki, MD, PhDMSKCC
-Scott Schuetze, MD, PhDUniversity of Michigan
-Lee Helman, MDNCI-Pediatric Branch
-Gina D’Amato, MDMoffitt Cancer Center
-Michael Fanucchi, MDEmory University
-George Demetri, MDDana Farber Cancer Institute
-David Harmon, MDMassachusetts General Hospital
-Scott Okuno, MDMayo Clinic
-James Whitlock, MDVanderbilt University
-Warren Chow, MDCity of Hope
-David Ettinger, MDJohns Hopkins
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 OfficeAnn 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 collaborationObtain 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– 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– 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
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 treatmentManuscript in preparation
Largest study of imatinib in desmoid tumorsOccasional responses noted in MFH, LMS
ACCRUAL COMPLETE
SARC002: Gem vs Gem/Doce phase III study for sarcomas
n = 122Manuscript: Completed, JCO
Gem Doce > Gem with overall survival advantage
Randomize
Gemcitabine
Response Assessment
Gemcitabine plus Docetaxel
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
ACCRUAL COMPLETE
Open studies
SARC003: Gem/Doce phase II study for Ewing sarcoma, osteosarcoma, chondrosarcoma
Target = (14→40) x 3; 14 x 3 enrolled; 2 still on treatmentOsteosarcoma arm closed; other two pending
Only minor activity seen to date
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
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)
SARC004: Neoadjuvant imatinib before surgery for DFSP
Target = 20; 9 enrolled; 1 on treatmentAddition of two sites helped increase accrual
Opened 21 Apr 05
SARC005: Adjuvant Gem/Doce → Doxorubicin for high risk primary resected uterine LMS
Target = 45; 21 enrolled; at least 9 in follow up after all therapyNo recurrences to date!
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.)
SARC006: Assessment of therapy for Primary MPNST (sporadic or associated with neurofibromatosis type I)
Target = 34-74 (17-37 x 2); 2 enrolled; 0 on studyLooking 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
Opened 1 Dec 05Ifosfamide + 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
SARC007: Phase II perifosine for chemotherapy insensitive sarcomas (EMC, ASPS, chondrosarcoma)
Target ≈ 111 (37 x 3); 56 (13, 10, 29) enrolled; 31 still on studyAccrual surprisingly good for rare diagnoses
These patients will qualify for other SARC studies
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
SARC009: Phase II multi-arm study of dasatinib in soft tissue sarcomas
Target 73-452, depending on results; 28 enrolled; 13 still on studyGood accrual to date; toxicity has been significant, requiring dose reduction amendment
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
Studies in development
SARC010: Phase II multi-arm study of dasatinib in imatinib-, sunitinib- refractory GIST
Target n ~ 30-60“Gleevec Plus” type protocol, looking for activity in imatinib, sunitinib refractory setting
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
SARC011: Phase II multi-arm study of R1507 IGF1R mAb in Ewing sarcoma and soft tissue sarcomas
Target n ~ 245 eligible patients (100 with Ewing sarcoma)Activity already seen in Ewing sarcoma in phase I
Worldwide study, partnership with Hoffman-LaRocheGrant from Hoffman-LaRoche for developmental therapeutics, young investigator
Phase III study as follow up is anticipated (SARC013)
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
SARC012: Phase II 1/2 study of AZ0530 src inhibitor in patients with resected lung metastases from osteosarcoma
Target up to 80 patients, 40 on each armTarget increase in overall survival from 45% to 70% at 3 years
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) Follow up (to 10 yrs)
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