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PI: Martee L. Hensley, MD

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 x 4, followed by doxorubicin x 4

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PI: Martee L. Hensley, MD

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  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 x 4, followed by doxorubicin x 4 • 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 (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 -institutions are 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 (neuro, hypersensitivity, pulmonary) • Data monitored by SARC • Some detail for management plan after recurrence • Vital status after recurrence every 6 months

  9. Drug details • Gemcitabine and docetaxel both supplied • Drug distribution from SARC via Biologics to institutions

  10. MSKCC Washington Cancer Institute U Michigan Dana Farber U Chicago Penn Onc/Hem Moffitt St. Vincent’s Mass General MedStar MDACC Open Sites

  11. Results First accrual: 2/13/06 • Accrual to date: 22 patients • Recurrence/Death events = 0 • 9 patients have completed all planned therapy • Progression-free days = 5211 (as of 28 Sep 07)

  12. Results—are we on target? • Target accrual goal 15 patients per year: in 19. months we have 22—seems okay • Treatment is highly unlikely to be futile: up to 7 events could have happened in 2477 days and we have had 0 events in over 5700 days

  13. Results: toxicity Gr 3 G/T heme 4 pts (6 events) Gr 3 Dox heme 6 pts (11 events) Gr 4 Dox heme 3 pts (3 events) Gr 2 G/T hypersensitivity 3 pts (3 events) Gr 3 G/T hypersensitivity 1 patient (1 event) No pulmonary toxicity 1 patient off study treatment for abnl AST/ALT after C3 G/T—proceeded on to doxorubicin. Remains on study for f/u purposes

  14. For discussion: • Clarify in next amendment that patients that must discontinue Gem-Doce for toxicity reasons may remain on study treatment to complete the doxorubicin

  15. Discussion of next steps: • Is a phase III trial with a no-chemotherapy control arm accruable? • Scientifically reasonable control arm options are: • Pelvic RT (would likely appeal to Gyn Onc/GOG) • Observation (could be hard to accrue)

  16. Phase III size considerations: • Home run assumption: 50% PFS at 2 y for “no chemo” group (arm B) and 80% PFS at 2 y for “chemo” group (arm A). -two sided 0.05 level calculation with continuity corrections Type I error    Power   Nfor arm A or arm B   Total N for two arms   0.05    0.80    46      92     0.05    0.85    51      102    0.05    0.90    58      116    

  17. Phase III size considerations: • Chemo improves PFS by 30% assumption: 50% PFS at 2 y for “no chemo” group (arm B) and 65% PFS at 2 y for “chemo” group (arm A). -two sided 0.05 level calculation with continuity corrections Type I error    Power   Nfor arm A or arm B   Total N for two arms   0.05    0.80    183      366    0.05    0.85    297      414   0.05    0.90    240    480    

  18. Are there other options?: • Increase the sample size of SARC 005 in order to narrow the confidence interval? • Open the eligibility to non-uterine LMS (which will of course increase heterogeneity)? • Even if we put our hearts and time behind a phase III, funding for such large trial may be very challenging

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