Symptomatic LVSD (that is, Grade 3 or greater LVD) Reportable as a SAE, using the term congestive heart failure (CHF) Reportable as a SAE using the term ‘left ventricular systolic dysfunction’ (LVSD) As for TRYPHAENA Reportable as a single diagnosis rather than symptoms or signs and graded according to and NYHA classification As for NEOSPHERE As for NEOSPHERE CHF occurring during the study and up to 24 months after the last dose of study medications was to be reported regardless of causality graded according to and NYHA classification As for NEOSPHERE (except using the term symptomatic LVSD rather than CHF) Symptomatic LVSD occurring during study and up to 36 months after last dose of study medications was to be reported , regardless of causality, and graded according to NCI-CTCAE and NYHA classification Specific and symptoms of LVSD were entered into the comments section of the AE eForm A cardiac questionnaire was completed by investigators prior to each treatment cycle. Cardiac symptom and physical findings of symptomatic LVSD were entered into the cardiac questionnaire eForm Cardiac symptoms and signs were reported on a ‘Symptomatic LVSD’ eCRF page for patients with LVSD
LVEF schedule of assessments Between days 15 and 21 of cycles 2, 4, 8, 11 and 15, and surgery, and < 7 days prior to cycle 5, and after cycle 17 and 21 (Ptz + D arm only) (that is, every 6 weeks during neoadjuvant and adjuvant therapy). Subsequent LVEF assessments every 6 months for 2 years Between days 15 and 21 of Cycles 2, 4 and 6, after surgery and < 7 days prior to cycle 7, and between days 15 and 21 of cycles 10, 12 and 15 and 18 (FEC/Ptz + T + D arm only) (that is, every 6 weeks during the neoadjuvant period and every 6-9 weeks during the adjuvant period), at the post-treatment visit, then every 6 months for 2 years, then annually for 2 years Every 9 weeks during study treatment, at the treatment discontinuation visit, then every 6 months for the first year, then annually for up to 3 years after the treatment discontinuation visit Central review of cardiac data Safety data (in general) reviewed by steering committee Copies of MUGA and ECHO recordings were sent to a central laboratory for independent assessment An independent Cardiac Review Committee (CRC) reviewed data for all potential cardiac events CHF= congestive heart failure; LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic dysfunction; NCI-CTCAE= National Cancer Institute Common Terminology Criteria for Adverse Events; NYHA = New York Heart Association Comment: was some variability in the terminology used to describe significant cardiac dysfunction, with symptomatic left ventricular systolic dysfunction (Grade 3 and above) being used in the TRYPHAENA (BO22280) and CLEOPATRA (WO20698) studies and symptomatic LVSD being classified as congestive heart failure in the NEOSPHERE (WO20697) study. This is considered in reviewing the aggregate data across the studies. Several other parameters were specifically followed as per Table 33. 33: Other events to monitor in the NEOSPHERE (WO20697), TRYPHAENA (BO22280) and CLEOPATRA (WO20698) studies (17, 22, 23) Adverse events to monitor Safety analysis strategy
the CLEOPATRA (WO20698) study is therefore likely to provide an indication of the potential medium-term side effects of pertuzumab given in combination with trastuzumab and docetaxel. Adverse events 40: Key safety data for the NEOSPHERE (WO20697), TRYPHAENA (BO22280) and CLEOPATRA (WO20698) Studies. Data have been reconciled with that found in Module 5 Safety Patients experiencing event Neoadjuvant setting MBC setting NEOSPHERE (WO20697) Neoadjuvant treatment period TRYPHAENA (BO22280) Neoadjuvant treatment period CLEOPATRA (WO20698) Overall treatment period T+D N= 107 Arm A Ptz + T+D Arm B Ptz + T Arm C Ptz + D Arm D Ptz + T + + T+D N=72 Arm A Arm B Ptz +TCH N=76 Arm C Pla +T + D N=396 Ptz + T + D Any AE 100% 98.7% Grade > 3 73.7% 73.5% Related AE 96.2% AE disc 0 5.6% 7.9% 28.8% AE i/m 50.0% 54.3% SAE 35.5% 29.0% AE death 0 0 0 0 0 0 3.0% Death, PD 0 0 0 0 0 0 0 34.3% Death, other 0 0 0 0 0 0 4.0% 0% 6% 2.1 % 2% 2% 9% FEC/ 1.9 0.9 08 07