INTERGROUP STUDY 0148 BMS CA 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 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

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

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

STUDY SCHEMA - 3X2 FACTORIAL Every 3 weeks, 4 cycles RANDOMIRANDOMIZEZERANDOMIRANDOMIZEZE mg/m mg/m mg/m 2 + G-CSF TAXOL mg/m 2 over 3 hours Cyclophosphamide 600 mg/m No TAXOL therapy Doxorubicin

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

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

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

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)

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

PATIENT FOLLOW-UP / STUDY STATUS

PRETREATMENT CHARACTERISTICS

COURSES COMPLETED

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

DISEASE FREE SURVIVAL COX REGRESSION

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

SURVIVAL COX REGRESSION

TAXOL TREATMENT BENEFITS Reduction in Relative Risk

DISEASE FREE SURVIVAL: DOXORUBICIN 60 VS. 75 VS. 90 MG/M 2 p=NS

SURVIVAL: DOXORUBICIN 60 VS. 75 VS. 90 MG/M 2 p=NS

SUBSET ANALYSES

DFS HAZARD RATIOS BY RECEPTOR STATUS AC + T : AC

OS HAZARD RATIOS BY RECEPTOR STATUS AC + T : AC

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/m 2 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

SAFETY REPORTING REQUIREMENTS

HEMATOLOGIC TOXICITY GRADE 3 - 4

SEQUELAE TO HEMATOLOGIC TOXICITY GRADE 3 - 4

NON-HEMATOLOGIC TOXICITY (I) GRADE 3 - 4

NON-HEMATOLOGIC TOXICITY (II) GRADE 3 - 4

OTHER ADVERSE EVENTS

SECONDARY MALIGNANCIES

HEMATOLOGIC TOXICITY DURING TAXOL THERAPY GRADE 3 - 4

SEQUELAE TO HEMATOLOGIC TOXICITY DURING TAXOL THERAPY GRADE 3 - 4

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

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

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

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