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