Transcript SARC studies: an overview

SARC studies: an overview
Robert Maki, MD PhD
Sarcoma Program
Memorial Sloan-Kettering Cancer Center
Deputy 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
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
SARC
Statistical
Center
SARC
Operations
Office
Institution – Multiple members of CTOS
Board of Directors – Majority from CTOS
CTOS
SARC
Board of Directors
President
Secretary
Officers
Vice President
Treasurer
Executive Committee
Officers
Operations Office
Chairpersons
of standing committees
Statistical Center
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
-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
– 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
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
–
–
–
–
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
ACCRUAL COMPLETE
Imatinib 100-300mg PO BID
based on BSA
Response Assessment
CR, PR Stable
Continue drug
Progression, unacceptable toxicity,
pt. withdraw
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
Opened 5 May 05
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
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
Continue on Study
Progression
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
Continue on Study
Progression
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
Continue on Study
Progression
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
Continue on Study
Progression
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
Patient w/ OS
lung mets resected
Protocol draft written
(Lee Helman, POB NCI;
Su Young Kim, POB NCI)
Randomize
No further Rx
Follow up (to 10 yrs)
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