# Presentation: 692341

## 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

- 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

- Every 3 weeks, 4 cycles

- RANDOMI
- ZE

- TAXOL
- 175 mg/m2
- over 3 hours

- Cyclophosphamide 600 mg/m2

- +

- 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

**COURSES COMPLETED**

## DISEASE FREE SURVIVAL: AC VS. AC+T

**DISEASE FREE SURVIVAL: AC VS. AC+T**

**p=0.0022 (multivariate Cox model)**

## DISEASE FREE SURVIVALCOX REGRESSION

## SURVIVAL: AC VS. AC+T

**p = 0.0065 (multivariate Cox model)**

## SURVIVALCOX REGRESSION

## TAXOL TREATMENT BENEFITS

*Reduction in Relative Risk*

## DISEASE FREE SURVIVAL: DOXORUBICIN 60 VS. 75 VS. 90 MG/M2

**p=NS**

## SURVIVAL: DOXORUBICIN 60 VS. 75 VS. 90 MG/M2

**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/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

## 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