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Dr. I. Craig Henderson University of California at San Francisco

INTERGROUP STUDY 0148 BMS CA139-223 Effect of TAXOL® ( paclitaxel ) and Doxorubicin Dose on Disease Free and Overall Survival of Patients with Node Positive Breast Cancer CALGB, ECOG, SWOG, NCCTG. Dr. I. Craig Henderson University of California at San Francisco. STUDY RATIONALE.

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Dr. I. Craig Henderson University of California at San Francisco

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  1. INTERGROUP STUDY 0148BMS CA139-223Effect of TAXOL® (paclitaxel) and Doxorubicin Dose on Disease Free and Overall Survival of Patients with Node Positive Breast CancerCALGB, ECOG, SWOG, NCCTG Dr. I. Craig Henderson University of California at San Francisco

  2. STUDY RATIONALE • Dose response curve for doxorubicin may be steep • TAXOL and doxorubicin are not cross resistant • Sequential use of AC and TAXOL allows evaluation of both doxorubicin dose and a promising new drug

  3. STUDY OBJECTIVES • To assess the effects of three doxorubicin doses (60, 75, 90 mg/m²) in combination with a fixed dose of cyclophosphamide • To assess the effects of the sequential addition of TAXOL following cyclophosphamide and doxorubicin combination therapy

  4. ELIGIBILITY REQUIREMENTS • Operable breast cancer, clear margins • Node positive • < 84 days from last surgery • No non-surgical treatment • Normal organ function

  5. 60 mg/m2 75 mg/m2 90 mg/m2 + G-CSF STUDY SCHEMA - 3X2 FACTORIAL Cyclophosphamide 600 mg/m2 + Doxorubicin RANDOMI ZE No TAXOL therapy TAXOL 175 mg/m2 over 3 hours Every 3 weeks, 4 cycles Every 3 weeks, 4 cycles

  6. STUDY DESIGN • Stratification 1-3, 4-9, and 10+ nodes • Tamoxifen for five years beginning at week 24 for all ER+ and/or PgR+ • Radiation therapy immediately after completion of all study chemotherapy for patients who had undergone segmental mastectomy

  7. SAMPLE SIZE • Powered to detect TAXOL, doxorubicin dose, and interaction effects on DFS • Median disease free survival without TAXOL assumed to be six years • 95% power to detect 25% decrease in hazard rate from the addition of TAXOL • Planned accrual of 3000 patients over three years, and 1800 recurrences expected after an additional four years follow up

  8. STUDY CONDUCT • Central randomization / data management - CALGB • Independent DSMB planned reviews • - Interim safety analyses every six months • - Interim DFS analyses after 450, 900, 1350 events

  9. STUDY CHRONOLOGY • 3170 patients accrued (3121 treated) from May 1, 1994 to April 15, 1997 • Based on pre-planned interim analysis at 453 events, DSMB decided in March 1998 to release results • In May 1998, study results presented at ASCO showed a 22% reduction in risk of recurrence and 26% reduction in risk of mortality (median follow up 20.4 months)

  10. sNDA CHRONOLOGY • June 1998 BMS and CALGB collaboration • for regulatory submission • October 1998 Pre-sNDA meeting with FDA • December 1998 Study database update • (median follow-up 30.1 months) • April 1999 sNDA submission

  11. PATIENT FOLLOW-UP / STUDY STATUS

  12. PRETREATMENT CHARACTERISTICS

  13. COURSES COMPLETED

  14. DISEASE FREE SURVIVAL: AC VS. AC+T p=0.0022 (multivariate Cox model)

  15. DISEASE FREE SURVIVALCOX REGRESSION

  16. SURVIVAL: AC VS. AC+T p = 0.0065 (multivariate Cox model)

  17. SURVIVALCOX REGRESSION

  18. TAXOL TREATMENT BENEFITS Reduction in Relative Risk

  19. DISEASE FREE SURVIVAL: DOXORUBICIN 60 VS. 75 VS. 90 MG/M2 p=NS

  20. SURVIVAL: DOXORUBICIN 60 VS. 75 VS. 90 MG/M2 p=NS

  21. SUBSET ANALYSES

  22. DFS HAZARD RATIOS BY RECEPTOR STATUS AC + T : AC

  23. OS HAZARD RATIOS BY RECEPTOR STATUSAC + T : AC

  24. SUMMARY OF EFFICACY • The addition of TAXOL following standard combination therapy in patients with node positive breast cancer reduces the risk of recurrence by 22% and the risk of mortality by 26% compared to no further treatment • No evidence exists of a dose response to doxorubicin for dosages above 60 mg/m2 • No evidence exists of an interaction between doxorubicin dose and the use of TAXOL • The benefit of TAXOL in various subsets (including receptor subsets) is consistent with the effect of chemotherapy in the worldwide Overview

  25. SAFETY REPORTING REQUIREMENTS

  26. HEMATOLOGIC TOXICITY GRADE 3 - 4

  27. SEQUELAE TO HEMATOLOGIC TOXICITY GRADE 3 - 4

  28. NON-HEMATOLOGIC TOXICITY (I)GRADE 3 - 4

  29. NON-HEMATOLOGIC TOXICITY (II)GRADE 3 - 4

  30. OTHER ADVERSE EVENTS

  31. SECONDARY MALIGNANCIES

  32. HEMATOLOGIC TOXICITY DURING TAXOL THERAPY GRADE 3 - 4

  33. SEQUELAE TO HEMATOLOGIC TOXICITY DURING TAXOL THERAPY GRADE 3 - 4

  34. NON-HEMATOLOGIC TOXICITY DURING TAXOL THERAPY (I) GRADE 3 - 4

  35. NON-HEMATOLOGIC TOXICITY DURING TAXOL THERAPY (II) GRADE 3 - 4

  36. REASONS OFF TREATMENT Percent of Patients (1) One patient with respiratory/cardiac failure secondary to neoplastic process (2) One patient HSR, one patient brain infarction subsequent to sepsis

  37. CONCLUSIONS • The benefit of adding TAXOL to standard anthracycline-containing therapy is similar in magnitude to adding chemotherapy to surgery • The robustness of the results of this large study is supported by the consistency of the treatment effects between the ASCO and sNDA analyses • The addition of single agent TAXOL to standard combination therapy is well tolerated

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