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A pooled analysis of the final results of the two randomized phase II studies comparing Gemcitabine (G) vs Gemcitabine + Docetaxel (G+D) in patients (pts) with metastatic/relapsed leiomyosarcoma (LMS).

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  1. A pooled analysis of the final results of the two randomized phase II studies comparing Gemcitabine (G) vs Gemcitabine + Docetaxel (G+D) in patients (pts) with metastatic/relapsed leiomyosarcoma (LMS) F.Duffaud, P. Pautier, B. Bui, M.L Hensley, A.Rey, N.Penel, D.Reinke, A. Le Cesne, J.Y Blay, R.G Maki

  2. Disclosure • Consultant for Novartis Pharma, Pfizer

  3. Introduction and Study Rationale • Gemcitabine and Docetaxel have been studied in STS with mixed results • Gemcitabine (G) – limited single agent activity • Phase II studies - 30 min infusion: only low-response rates (RR: 3-18%) Fixed-dose rate (10 mg/m2/min): a pharmacologic advantage* • Docetaxel (D)–limited single agent activity(RR: 0 -18%) • Combination G (fixed-dose-rate infusion) + D • Impressive activity in LMS: • Response Rate 53% (2/5 extra uterine LMS, 16/25 uterine)** • Hypotheses of activity for combination: • prolonged G infusion and synergy between combination of these drugs • 2 randomized trials compared the activity of G versus G+D in metastatic soft tissue sarcomas Patel S 2001*, Hensley 2002**

  4. Introduction and Study Rationale • The SARC002 trial compared G vs G+D as 1st to 4th linetherapy for metastatic soft tissue sarcomas (mSTS) of many subtypes. Maki RG et al. JCO 2007 • “Synergy of G+D accounts for the bulk of the combination’s arm activity, rather than the fixed-dose rate infusion of G” • The French TaxoGem study compared the activity of G vs G+D in LMS exclusively, as 2d-line therapy for metastatic disease after a 1st line anthracycline based regimen, with stratification by primary site (uterus vs extra-uterus) • G+D failed to demonstrate any advantage (OR, PFS) compared to G in uterine OR extra-uterine LMS • Although well tolerated, G+D was more toxic than G alone

  5. Methods • SARC002 study • A Bayesian adaptive randomization procedure was used • based on the estimated probabilities of treatment success (RECIST) • TaxoGem study • Stratification: by primary tumor location (uterine LMS vs. others) • Each stratum considered as an independent phase II study The Simon method was used (ASCO 2008 abstr. 10511, ASCO 2009 abstr 10527) • “Uterus” study, 20 evaluable pts/arm • for a 74% probability of selecting the best arm with a RR of 50%, Baseline RR= 40% • “Extra-uterus” study, 20 evaluable pts/arm • for a 91.8% probability of selecting the best arm with a RR of 40%, Baseline RR = 20% • Pooled analysis • Analysis of theprimary data from all evaluable LMS patients included in both studies

  6. Main eligibility criteria • SARC002 study • Patients with mSTS recurrent/progressive disease, • 0-3 prior chemotherapy regimen(s) • Age > 10 • TaxoGem study • Patients with histologically-proven LMS, metastatic or with unresectable local relapse, • Only one prior doxorubicin based regimen, • Age ≥18 • Both studies • Measurable disease (per RECIST), • ECOG PS ≤ 2, • Adequate organ function

  7. SARC002 and TAXOGEM – study objectives • Primary end-point :Objective Response Rate (RECIST1.0) • SARC002: Tumor response (CR+PR within 24 weeks) and also defined DISEASE CONTROL AS “response” (SD lasting > 24 weeks), tumor evaluation every 2 cycles • TaxoGem: Best response during treatment, tumor evaluation every 2 cycles, • Secondary end-points: PFS, duration of response, toxicity, OS

  8. SARC002 and TaxoGem – treatment • Treatment schedule • G arm: G delivered as a fixed dose rate of 10 mg/m2/min, 1200mg/m2 IV over 120 min (d1+d8) q21 days in the SARC002 study,and 1000 mg/m2 IV over 100 min (d1+d8+d15) q21 days in the TaxoGem study. • G+D arm, both studies: G 900 mg/m2 over 90 min (d1+d8) + D 100 mg/m2 over 60 min d8 + lenograstim (G-CSF) 150 µg/m2/d d9-d15

  9. Pooled analysis- population analysed • 121 evaluable LMS patients from both studies • SARC002 trial: 38 patients • treated between May 2003 – October 2005 • 9 in the G arm, 29 in the G+D arm • TaxoGem trial: 83 patients • treated between April 2006 – March 2009 • 43 in the G arm, 40 in the G+D arm • Previous lines of chemotherapy for metastic disease • 0 for 15 (12%) patients, 1 for 100 (83%) pts,2 for 4 pts and 3 for 2 pts • → 100 pts received G or G+D as second line of chemotherapy

  10. Patient characteristics - Extra uterine LMS

  11. Patient characteristics - Uterine LMS

  12. Pooled analysis – toxicity

  13. Pooled analysis – Progression-free survival

  14. Pooled analysis – Progression-free survival

  15. Responses: Extra - uterine LMS

  16. Responses: Uterine LMS

  17. Pooled analysis – Overall survivalMedian follow-up: 25.2 months[ 0.7 - 37.8 ]

  18. Pooled analysis – Overall survivalMedian follow-up: 28 months [ 2.7 – 37.4 ]

  19. Pooled analysis – conclusions • High rates of progression-free survival-3 months PFS of 67% (G) and 59% (G+D) in extra uterine LMS, and of 55% (G) and 63% (G+D) in uterine LMS - 6 months PFS ≥ 46% in both arms and both groups support the hypothesis that both G alone and G+D are active regimens in uterine and extra uterine LMS according to EORTC STBSG • EORTC EJC 2002, Active agents 2d line in mSTS: 3mo PFR ≥ 40% and 6mo PFR ≥14% • G+D failed to demonstrate any advantage (OR, PFS) compared to G alone in uterine and in extra-uterine LMS • Maki et al.2007: median PFS of 3 and 6.2 mo in G and G+D in all mSTS • TaxoGem median PFS of 5.5 and 4.6 mo in G and G+D for uterine LMS and 5.5 and 3.4 mo in G and G + D in extra-uterine LMS

  20. Pooled analysis – conclusions • Even well tolerated, G+D is more toxic than G • one toxic death in G+D arm; haematotoxicity, asthenia, neurotoxicity,… • It is reasonable to offer G alone as therapy for metastatic LMS • PFS curves do not show differences between G and G+D in metastatic LMS (mLMS) and are superimposable • Although G and G+D are active to some degree in uterine and extra-uterine LMS new agents of greater efficacy are needed for all metastatic LMS

  21. Acknowledgments • Patients and families • French and US Centers and trial investigators • Sponsor : FNCLCC, Paris : M Jimenez, Gosse, V. Bénavent, P. Nezan, C. Delavault, C. Mahier • DM and Statistics, Institut Gustave Roussy, Villejuif : G. Danton, A. Laplanche, A. Mauguen With the support of : Institut National du Cancer (INCa), Ligue Nationale Contre le Cancer Chugai Pharma France, Sanofi-Aventis France

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