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NDA 50-772 TLC D-99 Doxorubicin HCL Liposome The Liposome Company, Inc.

NDA 50-772 TLC D-99 Doxorubicin HCL Liposome The Liposome Company, Inc. Proposed Indication: “First line treatment of metastatic breast cancer in combination with cyclophosphamide”. TLC D-99 Review Team. Administrative History. 11/24/87 IND # 30,894 submitted

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NDA 50-772 TLC D-99 Doxorubicin HCL Liposome The Liposome Company, Inc.

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  1. NDA 50-772TLC D-99Doxorubicin HCL LiposomeThe Liposome Company, Inc. Proposed Indication: “First line treatment of metastatic breast cancer in combination with cyclophosphamide”

  2. TLC D-99 Review Team

  3. Administrative History 11/24/87 IND # 30,894 submitted 2/4/94 End of Phase II meeting 6/30/98 Guidance meeting (Study 2 closed) 11/3/98 Study 3 included as a supportive trial 12/14/98 NDA submitted

  4. In 1994 the Agency agreed to: • Utilize response rate as the primary basis of efficacy comparison. • Utilize proportional analyses rather than absolute increments (15%). • Evaluate response rates using 95% C.I. of the odds ratio. • Utilize 1-sided C.I. for this response comparison. • Utilize a lower bound of this C.I. (R = 0.75)

  5. Administrative History • June 30,1998 Guidance meeting (Study 2 closed) • Nov 3, 1998 Study 3 included as a supportive trial • Dec 14, 1998 NDA submitted

  6. Study Design and Endpoints

  7. The dose of epirubicin used in study 3 has not been established equivalent to doxorubicin for the following reasons: • Doses of 100 to 120 mg/m2 have been used in combination therapy and were more effective than the lower doses. • Epirubicin may be not equivalent to doxorubicin on a mg per mg basis. • Epirubicin at 75 mg/m2has not been demonstrated to be a standard treatment for first line metastatic breast cancer.

  8. Survival CurveEpirubicin Study

  9. Efficacy ResultsStudies 1 and 2

  10. SurvivalStudies 1 and 2

  11. Study 1Survival

  12. Study 2Survival

  13. Study 2Multivariate analysis • Prognostic factors for covariate adjustment : (J Clin Oncol 16:2401-2408, 1998) • Disease Free Interval • AST level • Liver metastases • Previous adjuvant chemotherapy • Treatment effect with covariates: Risk Ratio:0.70p-value :0.034 • Covariates adjustment for progesterone and estrogen receptors:p-value 0.05

  14. Time to ProgressionStudies 1 and 2

  15. Efficacy ResultsStudy 3

  16. SurvivalStudy 3

  17. Time to ProgressionStudy 3

  18. SummaryStudy 3 • Similar response rates and survival • Trend toward longer TTP for TLC arm • Relatively low dose of Epirubicin • Small study stopped prematurely

  19. Cardiotoxicity

  20. Summary of Toxicities

  21. Regulatory issues • Studies 1 and 2 showed less cardiotoxicity TLC arm • Non-inferiority (Ratio of Response Rates): • Study 1: 0.78 • Study 2: 0.62

  22. Regulatory issues Overall survival: Study 1: HR: 1.01 95% CI: 0.71 Study 2: p= 0.07 HR: 0.75 95% CI: 0.54 The comparator arm on Study 3 is not adequate

  23. Reviewer Conclusions • Insufficient evidence to support TLC D-99 for first line treatment of metastatic breast cancer • Non-inferior R.R in Study 1 • Negative Survival trend Study 2 • Study 3 inadequate comparator • TLC D-99 less cardiotoxic, but this endpoint alone does not support the proposed indication

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