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 Program Development Group
John Bryant, PhD
Edward Romond, MD
Elizabeth Tan-Chiu, MD
Sandra Swain, MD

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

4. Operable Breast Cancer Path Positive Axillary Nodes
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*
AC q3wk x 4
Paclitaxel q3wk x 4* or
Paclitaxel qwk x 12*
Trastuzumab qwk x 52
* 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 Paclitaxel
mo. 3
mos. 6
mos. 9
mos. 18
mos.
Arm 2
AC x Trastuzumab + Paclitaxel
mo. 3
mos. 6
mos. 9
mos. 18
mos.

8. NSABP B-31 Criteria 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 Event Primary 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 Patients Real 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)
Majority determination of whether or not protocol criteria for a Cardiac Event were met

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

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

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

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

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

16. Asymptomatic Patients Criteria for Continuing Trastuzumab
Absolute Decrease
of < 10%
Absolute Decrease
of %
Absolute Decrease
of  15%
Relationship of 6 and 9 mo. LVEF to LLN
Within Normal Limits
1- 5% below LLN
 6% below LLN
Cont.
Cont.*
Cont.
Hold *
Hold *
Once the patients start Herceptin, they will be monitored at set intervals by MUGA scan. The above criteria must be followed for continuing or stopping Herceptin in patients who are asymptomatic. If a repeat MUGA scan is indicated, that MUGA scan must fall into one of the categories labeled “continue” (above) before the patient can proceed with further weekly Herceptin doses.
* 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