INTERGROUP STUDY 0148 BMS CA139223 Effect of TAXOL paclitaxel and Doxorubicin Dose on Disease Free a

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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

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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

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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

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ELIGIBILITY REQUIREMENTS

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

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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
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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

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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

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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

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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)

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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

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PATIENT FOLLOW-UP / STUDY STATUS
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PRETREATMENT CHARACTERISTICS
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COURSES COMPLETED
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DISEASE FREE SURVIVAL AC VS. ACT
p0.0022 (multivariate Cox model)
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DISEASE FREE SURVIVALCOX REGRESSION
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SURVIVAL AC VS. ACT
p 0.0065 (multivariate Cox model)
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SURVIVALCOX REGRESSION
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TAXOL TREATMENT BENEFITS
Reduction in Relative Risk
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DISEASE FREE SURVIVAL DOXORUBICIN 60 VS. 75 VS.
90 MG/M2
pNS
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SURVIVAL DOXORUBICIN 60 VS. 75 VS. 90 MG/M2
pNS
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SUBSET ANALYSES
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DFS HAZARD RATIOS BY RECEPTOR STATUS AC T AC
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OS HAZARD RATIOS BY RECEPTOR STATUSAC T AC
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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

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SAFETY REPORTING REQUIREMENTS
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HEMATOLOGIC TOXICITY GRADE 3 - 4
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SEQUELAE TO HEMATOLOGIC TOXICITY GRADE 3 - 4
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NON-HEMATOLOGIC TOXICITY (I)GRADE 3 - 4
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NON-HEMATOLOGIC TOXICITY (II)GRADE 3 - 4
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OTHER ADVERSE EVENTS
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SECONDARY MALIGNANCIES
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HEMATOLOGIC TOXICITY DURING TAXOL THERAPY
GRADE 3 - 4
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SEQUELAE TO HEMATOLOGIC TOXICITY DURING TAXOL
THERAPY GRADE 3 - 4
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NON-HEMATOLOGIC TOXICITY DURING TAXOL THERAPY
(I) GRADE 3 - 4
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NON-HEMATOLOGIC TOXICITY DURING TAXOL THERAPY
(II) GRADE 3 - 4
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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
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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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