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Phase III Study of Gemcitabine ± Docetaxel in Metastatic Soft Tissue Sarcoma

This study evaluates gemcitabine with or without docetaxel in soft tissue sarcoma. Utilizes Bayesian design and dynamic randomization to assess treatment effectiveness and toxicity. Initial results show gemcitabine + docetaxel may be superior for leiomyosarcoma patients. Low platelet count was the most common toxicity, with minimal febrile neutropenia. Dynamic randomization helped optimize therapy. Further data presentation is awaited.

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Phase III Study of Gemcitabine ± Docetaxel in Metastatic Soft Tissue Sarcoma

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  1. A phase III study of gemcitabine ± docetaxel for metastatic soft tissue sarcoma Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno S, Samuels B, Harmon DC, Fanucchi M, Hensley ML, Reinke D, Thall PF, Benjamin RS, Baker LH CTOS 2005, Boca Raton, FL

  2. Rationale for phase III study • Gemcitabine alone has at least activity in some sarcomas (LMS, osteosarcoma, angiosarcoma) • Two phase II studies show activity of gemcitabine + docetaxel in soft tissue sarcoma (STS) • There appears to be synergy in sarcoma cell lines between the two drugs when given in the sequence gem→doc Merimsky O et al. Cancer Chemother Pharmacol 2000; 45:177 Patel SR et al. J Clin Oncol 2001;19:3483. Svankarova L et al. Eur J Cancer 2002; 38:556 Okuno S et al. Cancer 2003; 97:1969 Hensley ME et al. JCO 2002; 20:2824 Leu KM et al. JCO 2004; 22: 1706

  3. Purpose • Execute a phase III study of gemcitabine +/- docetaxel in patients with up to 3 prior lines of therapy for metastatic disease • Is it the controlled rate infusion of gemcitabine that yields the activity in this combination? • In which subtypes is combination active? Is the combination better, or more toxic, or both? • Utilize a novel Bayesian design, dynamic randomization, to minimize the number of patients necessary to determine a statistically significant difference between arms

  4. Entry Criteria • Soft tissue sarcoma, no GIST, KS, meso • Age ≥ 10 • Measurable disease • No more than 3 prior regimens for metastatic disease • Good organ function; T Bili ≤ ULN, Cr ≤ 2 • Not pregnant • No neuropathy > G1 • No uncontrolled CNS metastases

  5. Phase III regimens ● Dynamic randomization: Bayesian model ● 120 patient enrollment target ● Restage after cycles 2, 4, 6, 8, then ~Q 3 months

  6. Definition of response • RECIST used for classic response criteria • For purposes of the dynamic randomization model, a different definition of success was defined: • Any PR or better after 2, 4, 6, 8 cycles = success • Any RECIST progression = failure • Stability recorded as SD for any of the 1st four time points • We arbitrarily decided that lowering the failure rate is 1.3 times as important as increasing the response rate • This weighs stable disease as more important in the model than frank response

  7. Dose adjustments • Recover to ANC > 1K, PLT > 100K each cycle • Sliding scale dose on d8 • ANC > 1000: full dose day 8 • ANC 500-999 or PLT 50-99: 75% dose G, (Doc) • ANC < 500 or PLT < 50: Hold Rx • Febrile neutropenia, G 3-4 non heme toxicity → 25% dose reduction • May reduce dose up to twice before stopping

  8. Status as of 3 October 2005 120 patients are enrolled; 118 are assessable for use in the dynamic randomization model U Michigan 30 MDACC 27 Washington Hosp Center 17 MSKCC 16 Mayo 14 Lutheran General, Chicago 10 Emory 5 MGH/Partners 2

  9. Tumor histology

  10. All events: toxicity data for 120 patients As of 02 Nov 2005, NCI-CTC 2.0. G2 allergic reaction = Rash, Urticaria, Drug Fever

  11. Cumulative toxicity by patient, n=120

  12. Other toxicity (all events) *Other G3 includes: lymphopenia (4), GI bleed (2), abdominal pain, diarrhea, mucositis, cough, pleural effusion, hiccups, bone pain, back spasm/pain, rash, nail changes, hypokalemia; data as of 02 Nov 2005

  13. Interim statistical model results • Dynamic randomization model includes 100 of 110 patients accrued as of June, 2005 • p < 0.01 boundary stopping rule was not crossed for either leiomyosarcoma nor non-leiomyosarcoma groups

  14. Randomization probability (after n=100 patients) Prior Irradiation

  15. Conclusions • In analysis of the randomization of patients, gemcitabine + docetaxel appears superior to higher dose single agent gemcitabine for patients with leiomyosarcoma. • There is a trend toward improved response rate with the combination of therapy for patients with other types of soft tissue sarcomas • Low platelet count most common toxicity • Nearly no febrile neutropenia using (peg)-filgrastim • Fatigue, edema, myalgias occasionally dose limiting • Dynamic randomization is an effective study design to minimize the number of patients receiving the less active therapy • More data will be presented tomorrow!

  16. Acknowledgements • Patients and families who participated in this study • Lilly and Sanofi-Aventis for their participation and support • Staff at SARC and the multiple centers responsible for the execution of this study

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