PI: Martee L. Hensley, MD

1. SARC 005: Adjuvant treatment of high risk uterine LMS with gemcitabine/docetaxel followed by doxorubicin: a phase II multi-center trial PI: Martee L. Hensley, MD

2. Objectives: • Determine 2-year PFS among women with uterine LMS treated with gem-doce, followed by doxorubicin • Determine tolerability/toxicity • Explore predictors of PFS: age, tumor size, grade, serosal involvement, STS stage v. FIGO stage, mitotic rate, ER, PR, menopausal status at dx

3. Schema Gemcitabine 900 mg/m2 over 90 minutes days 1, 8 Docetaxel 75 mg/m2 day 8 q 3 wk x 4 cycles Repeat CT scan Doxorubicin 60 mg/m2 q 3 w x 4 Repeat CT scan within 6 weeks after CT c/a/p every 3 mo for 2 y, then every 6 mo

4. > 18 years FIGO stage I or II, high grade LMS s/p hysterectomy (uterine-limited disease with pathology showing serosal involvement IS eligible even though this is FIGO IIIA) <12 weeks from surgery NED by CT within 3 weeks of enrollment Good marrow, kidneys, liver No other cancer within 5 years No prior gem, doce, or dox No prior pelvic RT No current HRT or anti-hormone therapy EF > 50% Eligibility

5. Correlative studies • Provide tumor details: size, serosal disease, mitotic rate • Provide patient details: age, menopausal status at dx and at start of adjuvant therapy • Send unstained slides to MSKCC - ER and PR - Site paid $75 when slides are received

6. Statistical issues • Target accrual 45 patients • Bayesian model for continuous assessment of PFS and safety • Accrue at least 15 patients per year • Stop early if data suggest 2 year PFS will be no better than 30%

7. Calculating futility • Event: death or evidence of progression • Stop if number of events is too many for the total patient-disease-free-days-on study:

8. Data capture and management • On line SARC registration • On line data entry • On line CRFs—easy to use - All grade 3 and 4 - Selected grade 2 (neurological, hypersensitivity, pulmonary) • Data monitored by SARC • Some detail for management plan after recurrence • Vital status after recurrence every 6 months

9. Milestones • Full protocol written, reviewed, approved by SARC, industry sponsors • Contracts between SARC and Lilly, SARC and Sanofi-Aventis are completed • Gemcitabine and docetaxel both supplied • Drug distribution from SARC via Biologics to institutions

10. Milestones • Protocol IRB-approved, contracts, etc: MSKCC, WCI, DFCI • Several recent IRB approvals, contracts pending: U Mich, Penn, Moffitt

11. Results First accrual: 13 February 2006 • Accrual to date: 7 - MSKCC 5 - Univ Wash 2 • Events = 0 • 3 patients have completed all planned therapy • Progression-free days = 1063

12. Results: toxicity Grade 3 heme tox: 1 patient Grade 4 heme tox: 1 patient No pulmonary toxicity No patients off study for toxicity

13. For discussion: • Any barriers to opening study? • Any accrual difficulties? • Any unexpected treatment difficulties?

14. Next steps: • Treatment likely to be safe, deliverable as adjuvant, sequential therapy • Assuming the 2-year PFS is as targeted, SARC should start to design the phase III trial • Major issue: “Control” arm that is reasonable and accruable • Pelvic RT? (would likely appeal to Gyn Onc/GOG) • Observation? (would be hard to accrue) • Short-term biologic? (no good rationale) • Short-term single agent chemo? (not a real control, and might wash out any difference)