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

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

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

Eligibility No other cancer within 5 years No prior gem, doce, or dox 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%

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

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%

Minimum total patient-days 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: Number of events Minimum total patient-days 1 2 3 408 4 920 5 1435 6 1955 7 2477 8 3003

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

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

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

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

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

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

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)