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Cardiac Toxicity on NSABP B-31

Cardiac Toxicity on NSABP B-31. Charles E. Geyer, Jr. MD Director of Medical Affairs NSABP Pittsburgh, PA September 17, 2005. B-31 Cardiac Monitoring Program Development Group. John Bryant, PhD Edward Romond, MD Elizabeth Tan-Chiu, MD Sandra Swain, MD .

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Cardiac Toxicity on NSABP B-31

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  1. Cardiac Toxicity on NSABP B-31 Charles E. Geyer, Jr. MD Director of Medical Affairs NSABP Pittsburgh, PA September 17, 2005

  2. B-31 Cardiac Monitoring ProgramDevelopment Group • John Bryant, PhD • Edward Romond, MD • Elizabeth Tan-Chiu, MD • Sandra Swain, MD

  3. B-31 Cardiac Monitoring ProgramData Management • Priya Rastogi, MD • Greg Yothers, PhD • Ann Brown, ScD • Cheryl Butch, RN, BA • Carole Donnelly • Steve Zieger

  4. NSABP B-31 Operable Breast Cancer HER-2 Positive Tumor Path Positive Axillary Nodes Randomization AC q3wk x 4 Paclitaxel q3wk x 4* or Paclitaxel qwk x 12* + Trastuzumab qwk x 52 AC q3wk x 4 Paclitaxel q3wk x 4* or Paclitaxel qwk x 12* * Choice of Taxol schedule and hormonal therapy at discretion of investigator – stratification factors

  5. B-31 Design Assumptions • A potential 4% incidence of CHF was anticipated with concurrent trastuzumab and paclitaxel following AC • This would be acceptable if ≥25% relative risk reduction for death were demonstrated, particularly if cardiac effects were largely reversible • 10 year OS improvement projection 62-70%

  6. B-31 Cardiac Eligibility Criteria • Normal left ventricular ejection fraction • No past or active cardiac disease including: • History of myocardial infarction • History of congestive heart failure • Angina pectoris requiring medication • Arrhythmia requiring medication • Clinically significant valvular disease • Uncontrolled hypertension • Left ventricular hypertrophy • Cardiomegaly on CXR

  7. B-31 LVEF Evaluation Schedule Arm 1 AC x 4 Paclitaxel 0 mo. 3 mos. 18 mos. 6 mos. 9 mos. Arm 2 AC x 4 Trastuzumab+Paclitaxel 0 mo. 3 mos. 18 mos. 6 mos. 9 mos.

  8. NSABP B-31Criteria for Trastuzumab Initiation • Trastuzumab only initiated if • Patient remained free of cardiac symptoms AND • Post AC LVEF ≥ LLN AND • Absolute decline was ≤ 15 percentage points from pre-entry value • Patients not meeting post AC criteria • Trastuzumab arm - 66/974 (6.8%) • Control arm - 82/962 (8.5%) • Combined arms - 148/1936 (7.6%)

  9. B-31 Cardiac EventPrimary Endpoint for Cardiac Safety If either of the following occurred • Definite or probable Cardiac Death • Symptomatic CHF confirmed by MUGA or Echo • Dyspnea with normal activity or at rest AND • Documented absolute drops in LVEF of: • Greater than 10% to below 55%, or • Greater than 5% to below institution’s LLN Absolute difference of ≤ 4% in CE between arms in patients with good post AC LVEFs considered acceptable .

  10. Symptomatic PatientsReal Time Blinded Evaluation • Symptoms of possible CHF reported within 14 days regardless of severity (Form CR) • Source documents blinded centrally in regards to trastuzumab therapy • Reviewed by each member of external Cardiac Advisory Panel (CAP) • Majoritydetermination of whether or not protocol criteria for a Cardiac Event were met

  11. NSABP B-31Cardiac Event Rates Romond et al. ASCO 2005

  12. Trastuzumab Associated CHF Risk Factors 3 Year cumulative incidence of CHF: Arm 2 evaluable cohort 9/48 20.0% 3-Yr Cum Inc of CHF (%) 3/48 11/196 1/160 2/160 5/229 6.8% 6.1% 2.5% 1.1% 1.5 % Age ≤49 ≥50 ≤49 ≥50≤49 ≥50 Post AC50-54 55-6465+ LVEF

  13. Recovery of Patients Reporting Symptoms of Possible CHF ACPTX AC PTX+H Confirmed CHF (n) 4 31 Followed ≥ 6 months from CHF 1 27 Symptoms during last 6 months 1/1 1/27On meds during last 6 months 1/1 18/27 Not confirmed with CHF (n) 8 43 Followed ≥ 6 months from symptoms 6 39 Symptoms during last 6 months 0/6 1/39 On meds during last 6 months 0/6 8/39

  14. Histograms of Left Ventricular Ejection Fraction Arm 2 patients with symptoms meeting criteria for CHF (a) (N=25) (N=30) (b) Arm 2 patients with symptoms not meeting criteria for CHF (N=35) (N=44) (c) (d) Proportion Arm 2 patients discontinuing H due to asymptomatic decline in LVEF (e) (f) (N=80) (N=56) 70+ 70+ < 30 < 30 30-34 30-34 50-54 65-69 60-64 65-69 35-39 40-44 45-49 55-59 60-64 35-39 40-44 45-49 50-54 55-59 Current LVEF, 18+ Months Nadir LVEF

  15. B-31 LVEF Evaluation Schedule Arm 1 AC x 4 Paclitaxel 0 mo. 3 mos. 18 mos. 6 mos. 9 mos. Arm 2 AC x 4 Trastuzumab + Paclitaxel 0 mo. 3 mos. 18 mos. 6 mos. 9 mos.

  16. Asymptomatic PatientsCriteria for Continuing Trastuzumab Within Normal Limits 1- 5% below LLN  6% below LLN Absolute Decrease of < 10% Absolute Decrease of 10 - 15% Absolute Decrease of 15% Relationship of 6 and 9 mo. LVEF to LLN Cont. Cont. Cont.* Cont. Hold * Hold * Hold * Hold * Hold * * Repeat LVEF assessment after 4 weeks - If criteria for continuation met – resume trastuzumab - If 2 consecutive holds, or total of 3 holds occur – discontinue trastuzumab

  17. NSABP B-31 Trastuzumab Discontinuation Due to Asymptomatic or Symptomatic Cardiac Dysfunction by Quarter

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