Conditions: Locally Advanced Breast Cancer
Keywords: Neoadjuvant chemotherapy locally advanced breast cancer Her2neu
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
Primary Objective:

• Determination of pathologic complete response (pCR) rates

Secondary Objective:

* Determination of cardiac toxicity as measured by: composite of LVEF, longitudinal strain and troponin.
* Breast conservation rates
* Overall survival

Study Design

* Approximately 34-74 patients with Her2 positive, Stage II-regional IV breast cancer will be enrolled.
* Patients will be stratified by ER/PR status.
* They will be randomized to ddACTHP vs TCHP.

  * Initially, 17 patients will be randomly assigned to each treatment arm.
  * If 3 or fewer patients have a pCR, then that arm will be terminated and no further patients will be entered on that treatment arm.
  * If 4 or more patients obtain a pCR, 20 additional patients (total of 37 patients) will be randomized to that treatment arm.
  * If 11 or more patients out of 37 have a pCR, the treatment will be of interest for further study.

Detailed description:

Arms:
arm 1: Doxorubicin 60 mg/m2 IV day 1 Cyclophosphamide 600 mg/m2 IV day 1 Pegfilgrastim 6mg SC, day 2 of AC

Cycled every 14 days for 4 cycles, followed by, Paclitaxel 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15 Trastuzumab 8 mg/kg IV day 1, followed by 6mg/kg Pertuzumab loading dose 840 mg IV followed by 420 mg IV every 3 weeks

Cycled every 21 days for 4 cycles, followed by, Trastuzumab 6mg/kg every 21 days to complete 1 year arm 2: TCHP (Docetaxel, Carboplatin, Trastuzumab, Pertuzumab, Pegfilgrastim ) institutional practice is to titrate the infusion rate on the initial Paclitaxel dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 ml/hr). Subsequent Paclitaxel doses are given over 1 hour.

Interventions: intervention 1: Docetaxel intervention 2: Carboplatin intervention 3: Trastuzumab intervention 4: Pertuzumab intervention 5: Pegfilgrastim intervention 6: Trastuzumab intervention 7: Paclitaxel intervention 8: Doxorubicin intervention 9: Cyclophosphamide intervention 10: Paclitaxel
Intervention descriptions: intervention 1: Docetaxel 75mg/m2 IV, day 1 intervention 2: Carboplatin AUC 6 IV, day 1 intervention 3: Trastuzumab 8mg/kg IV initial dose, followed by 6mg/kg IV , day 1 intervention 4: Pertuzumab 840 mg IV initial dose followed by 420 mg IV, day 1 intervention 5: Pegfilgrastim 6mg SC, day 2 Cycled as per arm intervention 6: Trastuzumab 6mg/kg every 21 days to complete 1 year intervention 7: Titrate the infusion rate on the initial Paclitaxel dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 ml/hr). Subsequent Paclitaxel doses are given over 1 hour. intervention 8: Doxorubicin 60 mg/m2 IV day 1 intervention 9: Cyclophosphamide 600 mg/m2 IV day 1 intervention 10: 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15

Protocol document:
Prot_SAP_000.pdf: 
A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense Doxorubicin/
Cyclophosphamide Followed by Paclitaxel/Trastuzumab/Pertuzumab (AC THP) and 
Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early Her2Neu Positive 
Breast Cancer 
PI: Dr. Aarti S. Bhardwaj
NCT03329378
Docuement Date: 8-23-2019


1 
Local Protocol#: GCO# 17-1585 
Revised 8/23/2019 
Title: A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense 
Doxorubicin/Cyclophosphamide followed by Paclitaxel/Trastuzumab/Pertuzumab (AC 
THP) and  Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early Her2Neu 
Positive Breast Cancer 
Coordinating Center: 
    Mount Sinai Medical Center, North Division 
Principal Investigators:          Aarti S Bhardwaj MD 
   One Gustave L Levy Place, Box 1079 
         New York, NY 10029 
         Phone 212-824-8585/Fax 646-537-9639 
E-mail: aarti.bhardwaj@mountsinai.org
Co-Investigators: 
Breast Medical Oncology: 
Amy Tiersten MD 
Hanna Yoko Irie MD, PhD. 
Julie Fasano MD 
Charles Shapiro MD 
Paula Klein MD: BIW 
Steve Malamud MD: BIW 
Theresa Shao MD: BIW 
Anupma Goel MD:SLR 
Breast Surgical Oncology 
Elisa Port MD 
Christina Weltz MD 
Hank Schmidt MD 
Susan Boolbol MD 
Radiation Oncology: 
Sheryl Green MD 
Richard Bakst MD 
Cardiology: 
Gagan Sahni MD 
Partho Sengupta MD 
Jagat Narula MD 
Dennis Finkielstein MD 
Edgar Argulian MD 
Pathology Department 
Shabnam Jaffer MD 
Statistics 
John Mandeli PhD 


2 
 
1. SYNOPSIS 
 
A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense 
Doxorubicin/Cyclophosphamide followed by Paclitaxel/Trastuzumab/Pertuzumab 
(ACTHP) and  Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early 
Her2Neu Positive Breast Cancer 
                                                      (34-74 patients) 
 
Objectives 
Primary Objective: 
• 
Determination of pathologic complete response (pCR) rates, (i.e., ypT0 ypN0 in the 
current AJCC system).  
 
Secondary Objective:  
• 
Determination of cardiac toxicity as measured by:  composite of LVEF, longitudinal 
strain and troponin.  
• 
Breast conservation rates 
• 
Overall survival  
 
 
Patient Population (Accrual 34 -74): 
 
Inclusion criteria: 
• 
ECOG performance status of 0 or 1 
• 
Eligible tumors must meet one of the following criteria:  
o Operable (T1c, T2-3, N0-1, M0) 
o Locally advanced (T1c or greater or any N) 
o Inflammatory breast cancer (T4d, any N, M0)  
• 
Breast cancer determined to be: 
o Confirmed HER2-positive (IHC 3+ or 2+ and ISH positive)  
o any ER or PR receptor status 
• 
LVEF assessment by echocardiogram within 30 days of initiation; EF of ≥55% considered 
normal. 
• 
Normal troponin I level at baseline 
Exclusion criteria: 
1. Patients with a history of decompensated congestive heart failure or an EF < 55% will be 
excluded 
2. Active or history of cardiac disease that would preclude the use of the drugs  
3. Definitive clinical or radiologic evidence of metastatic disease or bilateral breast cancer 
• 
Previous therapy with anthracylines, taxanes, or trastuzumab for any malignancy 
 
 
Study Design 
• Approximately 34-74 patients with Her2 positive, Stage I-regional IV breast cancer will 
be enrolled.  
• Patients will be stratified by ER status.  
• They will be randomized to ddACTHP vs TCHP. 
o Initially, 17 patients will be randomly assigned to each treatment arm.  


3 
 
o If 3 or fewer patients have a pCR, then that arm will be terminated and no further 
patients will be entered on that treatment arm. 
o If 4 or more patients obtain a pCR, 20 additional patients (total of 37 patients) will 
be randomized to that treatment arm.  
o If 11 or more patients out of 37 have a pCR, the treatment will be of interest for 
further study.   
• After completion of neoadjuvant therapy, each patient will be evaluated for definitive 
treatment by their breast surgeons. Surgical management and radiation oncology 
management as per institutional guidelines.   
• After completion of chemotherapy and surgical and/or radiation therapy, patients with 
estrogen receptor (ER) –positive and/or progesterone receptor–positive tumors will be 
offered adjuvant endocrine therapy.  
 
 
Evaluations 
• Physical examination of breasts and regional lymph node basins will be performed 
before each cycle of chemotherapy.  
• Cardiac: Echocardiograms to evaluate for EF, longitudinal strain will be performed 
every 3 months. 
• Blood Sample: Troponin measurements will be performed as per protocol at regular 
intervals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


4 
 
 
 
TABLE OF CONTENTS 
Section 
 
 
 
 
 
 
 
 
Page 
 
 
 
 
 
 
 
 
 
 
 
1.0 Summary  
 
 
 
 
 
 
 
5 
 
2.0 Background and Rationale 
 
 
 
 
 
5 
     2.1 Rationale for Neoadjuvant Chemotherapy  
 
 
5 
     2.2 Defining pCR as an Endpoint 
 
 
 
 
6 
     2.3 Trastuzumab  
 
 
 
 
 
 
6 
     2.4 Dual Her2Neu Blockade 
 
 
 
 
 
7 
     2.5 Neoadjuvant Pertuzumab 
 
 
 
 
 
7 
     2.6 Investigating Cardiac Toxicity 
 
 
 
 
8 
     2.7 Our Study 
 
 
 
 
 
 
 
9 
   
3.0 Hypothesis 
 
 
 
 
 
 
 
10 
 
4.0 Objectives 
 
 
 
 
 
 
 
10 
      4.1 Primary Objective  
 
 
 
 
 
10 
      4.2 Secondary Objectives 
 
 
 
 
 
10 
 
5.0 Patient Selection  
 
 
 
 
 
 
11 
      5.1 Inclusion Criteria 
 
 
 
 
 
 
11 
      5.2 Exclusion Criteria   
 
 
 
 
 
12 
 
6.0 Treatment Plan  
 
 
 
 
 
 
13 
      6.1 ACTHP and TCHP Regimens 
 
 
 
 
13 
      6.2 Randomization 
 
 
 
 
 
 
14 
      6.3 Dose Determination  
 
 
 
 
 
14 
      6.4 Treatment Course 
 
 
 
 
 
 
14 
 
7.0 Dose Modifications and Management of Toxicity 
 
 
15 
      7.1 Management of Anemia 
 
 
 
 
 
15 
      7.2 Adverse Event Management during AC THP  
 
16 
      7.3 Adverse Event Management during TCHP 
 
 
26 
      7.4 Management of Trastuzumab Monotherapy 
 
 
29 


5 
 
      7.5 Management of Infusion Reactions 
 
 
 
33 
      7.6 Extravasation Management  
 
 
 
            34 
 
8.0 Adverse Events Reporting 
 
 
 
 
 
35 
      8.1 Adverse Events List and Reporting Requirements 
 
35 
      8.2 Common Terminology Criteria For Adverse Events 
 
38 
      8.3 Reporting Requirements 
 
 
 
 
 
39 
      8.4 Reporting to the IRB 
 
 
 
 
 
40 
      8.5 Monitoring of Adverse Events and Period of Observation 
40 
      8.6 Secondary Malignancy  
 
 
 
 
 
41 
 
9.0 Data Reporting/Regulatory Requirements 
 
 
 
41 
     9.1 Data Collection 
 
 
 
 
 
 
41 
     9.2 Data Reporting 
 
 
 
 
 
 
41 
 
10.0 Data Safety and Monitoring Committee 
 
 
 
41 
 
11.0 Provisions to Protect the Privacy Interests of Subjects 
 
42 
 
12.0 Statistical Data Management and Analysis  
 
 
42 
    12.1 Primary Outcome 
 
 
 
 
 
 
42 
    12.2 Interim Analysis 
 
 
 
 
 
 
42 
    12.3 Secondary Outcome  
 
 
 
 
 
42 
    12.4 Stopping Rule for Cardiac Toxicity 
 
 
 
43 
 
13.0 Study Calendar  
 
 
 
 
 
 
44 
     13.1 AC  THP  
 
 
 
 
 
 
45 
     13.2 TCHP  
 
 
 
 
 
 
 
47 
 
14.0 References 
 
 
 
 
 
 
 
50 
 
15.0 Appendices 
 
 
 
 
 
 
 
53 
 Appendix A Protocol Schema 
 
 
 
 
53 
 Appendix B Notification to Cardiology 
 
 
 
54 
 Appendix C Blood Serum Troponin Collection Protocol 
55 
 Appendix D Pathology Form, Determination of pCR status      56 
 Appendix E Serious A/E Reporting Form  
 
 
57 


6 
 
      
 
 
    
1.0 Summary 
 
Breast cancer is the second leading cause of death amongst women in the western world.1 For 
those patients with localized disease who could become surgical candidates, the standard of 
care is to offer neoadjuvant systemic chemotherapy as part of multimodality therapy. It has 
been shown that adding trastuzumab and more recently pertuzumab to chemotherapy improves 
outcomes in the neoadjuvant setting for Her2neu positive cancers, yet it is not known which 
chemotherapy regimen is best to combine with these two biologic agents. The NOAH trial has 
confirmed adding trastuzumab to chemotherapy in the neoadjuvant setting prolonged 3yr DFS 
by 15% and doubles the rate of pCR. 2Dose dense doxorubicin (A), cyclophosphamide (C) 
followed by paclitaxel (T) with trastuzumab (H) (ddACTH) has been widely accepted as the 
standard regimen which is an extrapolation from the adjuvant literature. More recently it has 
been shown that the addition of pertuzumab (P) to chemotherapy significantly increases the 
pCR rate thus making the case for dual blockade of Her2Neu in the neoadjuvant setting 3,4 
which lead to the recent FDA approval of pertuzumab in the neoadjuvant setting. Both studies 
of dual Her2Neu blockade used to support the FDA’s decision: TRYPHAENA 3 and 
NEOSPHERE 4 lack long-term cardiotoxicity data so more studies are needed to investigate 
cardiotoxicity using novel measurements.  We aim to determine which of two regimens 
(anthracycline containing and anthracycline-free) will provide both a high pCR rate and less 
cardiotoxicity. Via a prospective Phase II randomized trial, we aim to compare an FDA 
approved regimen (with the addition of carboplatin) (TCHP) with a commonly used 
doxorubicin based regimen with the addition of pertuzumab (ddACTHP), not previously 
explored for locally advanced Her2neu positive breast cancer. The primary objective will be to 
evaluate efficacy as measured by pCR rates and the secondary objective will be to evaluate 
cardiac toxicities using a definition that includes changes in LVEF, longitudinal strain and 
troponin values.  
 
2.0 Background and Rationale 
 
Over 200,000 new cases of invasive breast cancer are expected to be diagnosed in the United 
States each year and 40,000 will die from disease.1,5  Locally advanced breast cancer has not 
always been consistently defined but usually includes tumors that are inoperable/large and/or 
have extensive lymph node involvement.6  
 
       2.1 Rationale for Neoadjuvant Chemotherapy 
Neoadjuvant chemotherapy is used for locally advanced breast cancer to increase the 
likelihood of breast conservation outcomes. A benefit of preoperative chemotherapy is 
that it allows the oncologist to evaluate tumor response in vivo6 and is therefore a model 


7 
 
for more efficient drug development strategies. Studies have shown that when 
neoadjuvant chemotherapy is administered to operable breast cancer patients, that there 
is no difference in survival as compared to giving the same chemotherapy adjuvantly.7 
Previous RCTs have shown that pCR may predict DFS and OS. In the NSABP-18 trial 
which compared preoperative versus postoperative delivery of 4 cycles of doxorubicin 
plus cyclophosphamide (AC), patients in the preoperative AC arm who attained pCR 
had a markedly reduced risk of death (hazard ratio (HR) 0.32, p<0.0001) at 16 years of 
follow-up compared with those who did not.7 A Cochrane meta-analysis of 14 trials of 
preoperative versus postoperative chemotherapy enrolling 5,500 patients with a median 
follow-up of 18 to 124 months reported that the risk of death in patients who attained 
pCR was reduced by almost half compared with patients who had residual tumor 
present at the time of surgery (HR 0.48; 95 percent CI 0.33, 0.69).8 The NSABP-B27 
was a phase III, randomized trial designed to evaluate whether adding preoperative 
docetaxel to neoadjuvant doxorubicin/cyclophosphamide, and noted a strong, 
statistically significant correlation between pCR and DFS and OS. 9 
 
      2.2 Defining pCR as a an endpoint 
Based on the above studies, the FDA recognized pCR as a surrogate endpoint for DFS 
and OS and created in May, 2012 a guidance for industry regarding using pathologic 
CR as an endpoint for neoadjuvant trials to support accelerated approval of novel 
therapeutics.10  There has not always been a uniform definition of pCR making 
reporting and interpretation of these trials difficult.10 The FDA proposed the following 
definition: the absence of any residual invasive cancer on hematoxylin and eosin 
evaluation of the resected breast specimen and all sampled ipsilateral lymph nodes 
following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 in the current 
AJCC system).10As per these guidelines presence of residual DCIS should not be used 
to judge the effectiveness of systemic neoadjuvant chemotherapy. 10 
 
      2.3 Trastuzumab 
Historically, women with breast cancers that overexpress Her2neu were at greater risk 
for disease progression and death than women whose tumors do not overexpress 
Her2neu prior to the development of Trastuzumab.11 Trastuzumab, a recombinant 
humanized monoclonal antibody against the extracellular domain of the Her2neu 
protein blocks downstream signaling of Her2neu and substantially improves the 
efficacy of chemotherapy in women with metastatic and early-stage Her2neu-positive 
breast cancers. Neoadjuvant therapy may be most appropriate for patients likely to have 
good locoregional response such as patients with Her2neu-positive or triple negative 
disease (ER-/PR-/Her2-). 12 The addition of trastuzumab for Her2neu positive locally 
advanced breast cancer in the neoadjuvant setting further increased pCR rates. The 
NOAH (Neoadjuvant Trastuzumab) trial compared 1 year of treatment with 


8 
 
trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no 
trastuzumab (n=118), in women with HER2-positive locally advanced or inflammatory 
breast cancer treated with a neoadjuvant chemotherapy regimen consisting of 
doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil and found 
pCR doubled from 19 to 38% (p=0.001)  and 3 year DFS increased from 56 to 71% 
(p=.0013)with the addition of trastuzumab.2  The GeparQuattro (epirubicin and 
cyclophosphamide followed by capecitabine and docetaxel with trastuzumab) showed 
a pCR rate of 31.7%  compared to 15.7% with the addition of trastuzumab. 13 
Preliminary results from the NSABP-41 (which will complete accrual in 2015) of 
neoadjuvant ACT (paclitaxel) H showed a pCR rate of 49.1%.14 The results of the 
trial have not been published, yet this regimen is used routinely in the clinical setting.    
       2.4 Dual Her2Neu Blockade 
Dual Her2Neu blockade was the next logical step of exploration. The CLEOPATRA 
trial was a randomized, double-blind, placebo-controlled, phase 3 trial involving 
patients with HER2-positive metastatic breast cancer who had not received 
chemotherapy or biologic therapy for their metastatic disease. Pertuzumab is a 
humanized anti-HER-2 monoclonal antibody that binds to the extracellular 
dimerization subdomain of the HER-2 receptor thereby preventing herterodimer 
formation most notably with HER3 and reduces intracellular signaling. Pertuzumab 
and trastuzumab bind to different sites on the HER-2 receptor and have complementary 
anti-tumor activities. 2, 3 Patients were randomized to trastuzumab plus docetaxel plus 
pertuzumab or placebo. 15 Pertuzumab prolonged PFS by 6 months and OS by more 
than 15 months at 3 yrs. HR of 0.66, resulting in a 34% reduction in risk of death. 
Median overall survival was 37.6 months (95% CI 34·3—NE [not estimable]) in the 
placebo group but had not been reached (95% CI 42·4—NE) in the pertuzumab group 
(hazard ratio 0·66, 95% CI 0·52- 0·84; p=0·0008). 15 
      2.5. Neoadjuvant Pertuzumab 
Studies using pertuzumab in the neoadjuvant setting such as TRYPHAENA and 
NEOSPHERE both have shown significant increases in pCR rates secondary to the 
addition of pertuzumab to various trastuzumab based regimens. NeoSphere is a 
multicentre, open-label, phase 2 study, of treatment-naive women with HER2-positive 
operable, locally advanced or inflammatory breast cancer randomly assigned to receive 
four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg 
every 3 weeks) plus docetaxel (75 mg/m², escalating, if tolerated, to 100 mg/m² every 
3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 
weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab 
(group C) or pertuzumab plus docetaxel (group D). All patients went on to definitive 
treatment and adjuvant F (5-flourouracil) E (epirubicin) C (cyclophosphamide) 


9 
 
chemotherapy. The primary endpoint was pCR in the breast. This study showed that 
treatment with pertuzumab, trastuzumab and docetaxel chemotherapy significantly 
improved the rate of total pCR by 17.8% compared to trastuzumab and docetaxel alone 
(39.3 vs. 21.5%, p=0.0063). 4 However in this study the most recent definition of pCR 
including no evidence of disease in sampled lymph nodes was not used but was 
described. The TRYPHAENA study was a multicenter, open-label phase II study, of 
patients with operable, locally advanced, or inflammatory breast cancer who were 
randomized to receive six neoadjuvant cycles every 3 weeks of Arm A: 5-fluorouracil, 
epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: 
FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6). pCR was assessed 
at surgery and adjuvant therapy given to complete 1 year of H.  The primary endpoint 
was cardiotoxicity and the secondary endpoint was pCR. It showed a pCR of 63.6% in 
the anthracycline-free arm which contained pertuzumab, trastuzumab, docetaxel and 
carboplatin chemotherapy vs. a pCR of 54.7% in the anthracycline based arm which 
contained pertuzumab, trastuzumab and docetaxel. 3 However it is important to note 
that this study was not powered to compare the pCR rates across arms because it was a 
secondary endpoint.   
       2.6 Investigating Cardiac Toxicity 
However neither of these studies explored doxorubicin-containing regimens and more 
investigation regarding long-term cardiotoxicity is needed. Cardiac toxicity is an 
important side effect of trastuzumab. Although no added cardiac toxicity with 
pertuzumab has been observed in the metastatic setting, more long-term data is needed 
in the neoadjuvant setting. The NeoSphere trial which contained non-anthracycline 
based regimens was not powered to detect cardiotoxicity but was positive in showing 
no appreciable difference was detected when pertuzumab was added to trastuzumab. 4 
The mean maximum decrease in LVEF was low (4-5%) and was balanced across 
treatment groups. 4  The TRYPHAENA study which was powered for cardiotoxicity 
and included anthracyclines showed that the combination of pertuzumab with 
trastuzumab resulted in low rates of symptomatic LVSD and low rates of significant 
declines in LVEF (≥ 10% points from baseline to < 50%). A slightly higher percentage 
of patients  (yet statistically insignificant) experienced asymptomatic declines in LVEF 
in the anthracycline arms compared to the  anthracycline free arm (5.6% and 5.3% 
compared to 3.9%) and the only 2 patients that experienced symptomatic LVSD were 
in the anthracycline based arm.   
It has been shown that other cardiac measures may be useful for predicting 
development of cardiotoxicity. Myocardial deformation indices have been shown to 
identify subclinical dysfunction in a variety of diseases.16,17 In recent studies, 
longitudinal strain (deformation of the left ventricle along the long axis)  is a parameter 
which is most predictive of development of cardiotoxicity.18 In a recent clinical study, 


10 
 
longitudinal strain has been shown to be an independent and incremental early predictor 
of later reduction in EF in patients at risk for trastuzumab-induced cardiotoxicity.18 In 
a study of 43 patients with breast cancer treated with anthracyclines followed by 
trastuzumab and paclitaxel a drop of more than  10% in peak global longitudinal strain 
from baseline to 3 month could predict later development of cardiotoxicity at 6 months 
while LVEF and parameters  of diastolic dysfunction did not. 19 A change in 
longitudinal strain was the strongest predictor of subsequent decrease in EF (GLS 
(global longitudinal peak systolic strain): AUC, 0.84, P < .001). 20 Additionally 
circulating blood markers such as troponins and others may be predictive of identifying 
clinically relevant cardiotoxicity.19 As the myocardium undergoes volume of pressure 
stress, cardiac myocytes release measurable substances that may or may not correlate 
with patient characteristics, echocardiographic findings, and clinical signs and 
symptoms. Troponin measurements have been used to measure myocardial injury and 
predict incident LV dysfunction in patients receiving high doses of anthracyclines but 
their role in patients receiving low to moderate doses of anthracyclines is not well 
established.21 In a study of patients with breast cancer treated with dose-dense 
chemotherapy incorporating trastuzumab and lapatinib cardiac troponin I (cTnI) were 
commonly detected and these elevations may precede changes in LVEF but do not 
predict LVEF. 21 Longitudinal strain and troponin I warrant further study in the 
neoadjuvant setting. 
 
      2.7 Our Study 
There is no standard neoadjuvant regimen for Her2Neu positive breast cancer. Often 
we extrapolate from the adjuvant setting and use regimens like ACTH and TCH in the 
neoadjuvant setting.  Based primarily on data from NeoSphere and secondarily from 
TRYPHAENA, the FDA approved of pertuzumab and trastuzumab and docetaxel for 
the neoadjuvant treatment of patients with Her2Neu-positive, locally advanced, 
inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node 
positive) as part of a complete treatment regimen for early breast cancer on Sept 30th 
2013. This was the first neoadjuvant regimen approved in breast cancer and the first 
treatment approved based on pCR. 23 The addition of pertuzumab to trastuzumab and 
docetaxel and carboplatin chemotherapy results in a pCR of 63.6% with minimal 
cardiac toxicity. 3 Thus, TCHP has amongst the highest reported pCRs with no reported 
significant cardiotoxicity so further study of the TCHP regimen is warranted. BCIRG 
006 compared TCH (docetaxel, carboplatin, trastuzumab) with ACTH (doxorubicin, 
cyclophosphamide, docetaxel, trastuzumab)  in the adjuvant setting and showed that 
there was no statistical advantage of ACTH over TCH but a slight improvement in DFS 
in the ACTH treatment arm. This numeric advantage comes at the cost of 21 CHFs (5X 
more than in TCH 2% vs. 0.4%).24  This study compared ACTH and TCH,  but used 
docetaxel not paclitaxel for the “T” in ACTH and therefore did not use a dose dense 


11 
 
regimen, which is not our current standard of care. Dose dense ACTH with paclitaxel 
has the most evidence for improved outcomes in the adjuvant setting and it is widely 
accepted.25 There is lingering doubt that TCH may not be as effective in comparison. 
Perhaps the additional benefit of pertuzumab may obviate the need for anthracycline 
based chemotherapy.  ACTH with P has not been investigated in the neoadjuvant 
setting and TCHP has not yet been compared with a doxorubicin-containing regimen. 
Also the cardiac safety of pertuzumab as part of a doxorubicin-containing regimen has 
not yet been established. Moreover, since we do not yet have data for pertuzumab in 
the adjuvant setting, providing pertuzumab in the neoadjuvant setting to operable 
tumors may be the only chance to give these patients the added benefit of pertuzumab.  
We propose a randomized Phase 2 study to evaluate neoadjuvant  ddACTHP and 
TCHP in patients with Stage II-IIIA, (including T1c tumors) breast cancer with Her2 
positive breast cancer. The primary outcome will be efficacy as measured by pCR rates 
and the secondary outcome will be cardiac toxicity, as defined by changes in LVEF, 
longitudinal strain, and biomarkers of cardiac injury (troponin) as described above. We 
propose to measure longitudinal strain and Troponin I as a preclinical marker of 
cardiotoxicity and determine if they are predictive of cardiotoxicity in addition to 
measuring LVEF. 
 
3.0 Hypothesis:  
We aim to determine which of 2 treatments TCHP or ACTHP shows adequate efficacy 
and expect TCHP to be less cardiotoxic than ACTHP because of the lack of anthracyline-based 
chemotherapy. 
 
4.0. Objectives: 
4.1 Primary Objective: 
• 
Determination of pathologic complete response (pCR) rates, defined by the absence of 
any residual invasive cancer on hematoxylin and eosin evaluation of the resected breast 
specimen and all sampled ipsilateral lymph nodes following completion of neoadjuvant 
systemic therapy (i.e., ypT0 ypN0 in the current AJCC system).  
4.2 Secondary Objectives:  
4.2.1 Determination of cardiac toxicity as measured by:  composite of LVEF,  
         longitudinal strain and troponin.  
o 
Changes in LVEF from regularly scheduled echocardiograms, every 3 
months 
o 
A change in longitudinal strain combined with an abnormally elevated 
value of troponin should provide about a 90% sensitivity to predict early 
cardiotoxicity. Peak systolic longitudinal strain is calculated by averaging 
the values of peak systolic strain in the basal, mid and apical segments of 


12 
 
the LV in 4-, 3- and 2-chamber views on echocardiograms. A value of <-
18% or a >15% decline in strain from patient’s baseline value will be used 
as a cut-off value. Similarly a value of troponin I > 0.08 ng/ml 21, 30,31 will 
be considered elevated.  
o 
Determination of non-cardiac toxicities as measured by frequencies of 
adverse events categorized using CTCAE v4.03.  
4.2.2     Breast Conservation Rates 
Breast conservation rates: rate of breast-conserving surgery for patients for 
whom mastectomy was planned before treatment. It would be based on surgical 
opinion at time of surgery if the tumor was appropriately “downstaged” to 
perform breast conserving surgery on patients previously recommended to 
have a mastectomy 
            4.2.3 Overall survival  
5.0. Patient Selection:   
5.1. Inclusion criteria: 
• 
The patient must have signed and dated an IRB-approved consent form that conforms 
to federal and institutional guidelines. 
• 
Female 
• 
18 years or older 
• 
ECOG performance status of 0 or 1 
• 
Eligible tumors must meet one of the following criteria:  
o 
Operable (T1c, T2-3, N0-1, M0) 
o Locally advanced (T1c or greater or any N)Inflammatory breast cancer 
(T4d, any N, M0)  
• 
Staging evaluation:  
o 
History and physical exam, cbc, chemistry profile 
o 
CT Chest/Abdomen/Pelvis and a bone scan or PET/CT as needed  
• 
Diagnosis of invasive adenocarcinoma made by core needle biopsy 
• 
Breast cancer determined to be: 
• 
Confirmed HER2-positive : (ASCO CAP guidelines, 10/7/2013) 
o IHC 3+ based on circumferential membrane staining  that is 
complete, intense 
o ISH positive based on: 
o Single probe average HER2 copy number  ≥ 6 signals/cell 


13 
 
o Dual probe HER2/CEP 17 ratio ≥ 2.0 with an average HER2 
copy number ≥ 4.0 signals/cell 
o Dual probe HER2/CEP 17 ratio ≥ 2.0, with an average HER2 
copy number of < 4.0 signals/cell 
o Dual probe HER2/CEP17 ratio <2.0 with the average HER2 copy 
number of ≥6.0 signals/cell 
• 
 any ER or PR receptor status 
• 
LVEF assessment by echocardiogram within 30 days of initiation; EF of ≥ 55% 
considered normal. 
• 
Normal troponin I level at baseline 
• 
Blood counts must meet the following criteria: 
o 
ANC greater than or equal to 1500/mm3 
o 
Platelet count greater than or equal to 100,000/mm3 
o 
Hemoglobin greater than or equal to 10 g/dL 
• 
Serum creatinine less than or equal 2.5 mg/100ml  
• 
Adequate hepatic function by these criteria: total bilirubin must be less than or equal to 
1.5 x the ULN for the lab unless the patient has a bilirubin elevation great than the ULN 
to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation 
of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the 
lab; and AST must be less than or equal to 1.5 x ULN for the lab. Both alkaline 
phosphatase and AST may not both be greater than the ULN.  
• 
Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study 
if liver imaging (CT, MRI, PET-CT or PET scan) performed within 90 days prior to 
randomization does not demonstrate metastatic disease and the requirements are met 
as above 
• 
Patients with alkaline phosphatase that is > ULN but less than or equal to  2.5 x ULN 
or unexplained bone pain are eligible for inclusion in the study if a bone scan, PET-CT 
scan, or PET scan performed within 90 days prior to randomization does not 
demonstrate metastatic disease.  
5.2. Exclusion criteria: 
• 
Patients with a history of decompensated congestive heart failure or an EF < 55% will 
be excluded 
• 
Cardiac disease that would preclude the use of the drugs included in the above regimens 
This includes but is not confined to: 
o Active cardiac disease: 
 
angina pectoris requiring the use of anti-anginal medication; 


14 
 
 
ventricular arrhythmias except for benign premature ventricular 
contractions controlled by medication; 
 
conduction abnormality requiring a pacemaker; 
 
supraventricular and nodal arrhythmias requiring a pacemaker or not 
controlled with medication; and 
 
clinically significant valvular disease 
 
symptomatic pericarditis 
 
pulmonary hypertension 
o History of cardiac disease: 
 
myocardial infarction; 
 
congestive heart failure; or 
 
cardiomyopathy 
• 
Definitive clinical or radiologic evidence of metastatic disease or bilateral breast 
cancer (excluding  DCIS (Ductal Carcinoma In Situ) 
• 
History of non-breast malignancies (except for in-situ cancer treated only by local 
excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior 
to randomization 
• 
Previous therapy with anthracylines, taxanes, or trastuzumab for any malignancy 
• 
Pregnant or refusing to use contraception 
6.0. Treatment Plan (Please see Appendix A: schema) 
6.1. Treatment Regimens 
Approximately 54-74 patients with Her2 positive, Stage II-regional IV breast cancer will 
be enrolled. Patients will be stratified by ER status. They will be randomized to:  
      6.1.1. Dose Dense AC  THP22 
• 
Doxorubicin 60 mg/m2 IV day 1 
• 
Cyclophosphamide 600 mg/m2 IV day 1  
• 
Pegfilgastrim 6mg SC, day 2 of AC  
Cycled every 14 days for 4 cycles, followed by, 
 
• 
Paclitaxel 80 mg/m2 IV x 1 hour infusion on days 1, 8, and 15* 
• 
Trastuzumab  8 mg/kg IV day 1, followed by 6mg/kg   
• 
Pertuzumab loading dose 840 mg IV followed by 420 mg IV every 3 weeks  
Cycled every 21 days for 4 cycles, or 


15 
 
       
6.1.2. TCHP (regimen as per references 3, 4 and NCCN guidelines) 22 
• 
Docetaxel 75mg/m2  IV, day 1 
• 
Carboplatin AUC 6 IV, day 1  
• 
Trastuzumab 8mg/kg IV initial dose, followed by 6mg/kg  IV , day 1 
• 
Pertuzumab 840 mg IV initial dose followed by 420 mg  IV, day 1 
• 
Pegfilgastrim 6mg SC, day 2 
• 
Cycled every 21 days for 6 cycles 
 * Our institutional practice is to titrate the infusion rate on the initial Paclitaxel 
dose (40 ml/hr x 5 min, then 80 ml/hr x 5 min, then 120 ml/hr x 10 min, then 200 
ml/hr).  Subsequent Paclitaxel doses are given over 1 hour. 
• 
Supportive care (including antiemetics, premedications and anaphylactic 
medications) as per institutional guidelines at each site. 
     6.2. Randomization 
Each site (Mount Sinai, Beth Israel/ and St Lukes/Roosevelt) will randomize treatment 
groups 
1:1 
stratifying 
by 
ER 
status 
(<1% 
and ≥ 1% of tumor cell nuclei are immunoreactive.%). The ER category will be 
provided on the patient registration form in order for the pharmacy personnel or 
coordinator—depending on location to randomize patients appropriately. At Mount 
Sinai Hospital the research pharmacist will implement randomization. At Beth Israel 
and St Luke’s/Roosevelt, the clinical research coordinator will implement 
randomization to each arm. The stratification by site will ensure that we have balanced 
numbers in the two arms for each site. 
     6.3. Dose Determinations:  
Recalculation of BSA and drug doses is required if the patient has a 10% of greater 
change in weight from baseline or, if the dose has already been adjusted due to weight 
change, from the weight at the time of the most recent dose adjustment.  
    6.4. Treatment Course 
6.4.1. Physical examination of breasts and regional lymph node basins will be 
performed before each cycle of chemotherapy.  
Bidimensional tumor measurements of breast and/or axilla if clinically involved are to 
be performed at every medical oncology visit. If the Product of the lesion dimensions 
increase by >25% would defer to managing medical oncologist and surgical oncologist 
to determine if interim imaging is recommended to verify progression vs stability vs 
response and if chemotherapy must be altered for progression of disease or if patient 
will be recommended to go to surgery directly and thus be removed from the trial.  


16 
 
6.4.2. Bloodwork: CBCs, differential counts, and platelet counts will be done weekly 
to monitor the myelotoxicity of chemotherapy in the first cycle, and subsequently, 
blood counts will be performed on day 1 of each cycle. (CBC weekly for weekly 
paclitaxel). Comprehensive panel to be ordered as per standard EPIC Beacon 
chemotherapy protocols.  
6.4.3. Cardiac evaluation: 
• 
via echocardiograms to detect LVEF and longitudinal strain at baseline and every 3 
months. See LVEF requirements for initiation of trastuzumab after AC above.  10 (see 
Appendix B regarding cardiologist’s documentation of longitudinal strain). 
• 
Troponin I serum measurements will be performed at screening for baseline (within 7 
days of first infusion), right before chemotherapy is administered (time “0”), 24 hours 
after start of chemotherapy, within 1 month of time “0”  and within 3 months of time 
“0”  for duration of both  regimens until surgery. Most of these 
scheduled troponin  measurements will be performed within 24 hours of chemotherapy 
administration (see Study Calendar and  Appendix C regarding  appropriate collection 
of specimen for troponin measurement). 
6.4.4 Definitive Treatment:  
After completion of neoadjuvant therapy, each patient will be evaluated for definitive 
treatment by their breast surgeon. As per standard of care, this will include breast 
specific imaging as determined by their surgeon as well as any systemic imaging that 
may be required to follow up any prior equivocal findings.  Surgical management and 
radiation oncology management as per institutional guidelines. pCR will be determined 
by the pathologist. (See Appendix D for pathologist’s documentation of pCR). 
      
6.4.5. Eligibility for Adjuvant Treatment: 
• 
Adjuvant therapy including continuation of Trastuzumab 6mg/kg  every 21 
days  to complete 1 year  vs other anti-Her2 based adjuvant treatment 
options will be at the discretion of the treating MD given evolving treatment 
strategies/evidence. 
• 
After completion of chemotherapy and surgical and/or radiation therapy, patients 
with estrogen receptor (ER) –positive and/or progesterone receptor–positive 
tumors will be offered adjuvant endocrine therapy.  
6.4.6. Surveillance Phase 


17 
 
• 
Patients will be evaluated at 3-month intervals during the initial year and then at 6-
month intervals thereafter for total of 2 years 
• 
Follow up echocardiograms will be performed annually for 2 years or earlier if 
there is a change in patient’s symptom status. 
7.0 Dose Modifications and Management of Toxicity 
• 
The CTCAE v4.03 must be used to grade the severity of AEs. Refer to 
            http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
• 
All doses must be based on the AE requiring the greatest modification. 
• 
Chemotherapy doses that have been reduced may not be escalated. 
unless specified otherwise in the treatment management sections/tables. 
             
      7.1. Management of anemia for ACTHP and TCHP  
Chemotherapy should not proceed with greater than or equal to grade 4 anemia.  
Chemotherapy can resume when anemia less than or equal to grade 2. Transfusion is 
acceptable for improving the hemoglobin value to allow therapy to continue without 
delay. The patient should be assessed to rule out other causes of anemia. Use of 
erythropoiesis-stimulating agents is prohibited. 
 
       7.2. Adverse Event Management during ACTHP   
  
 7.2.1 Cardiac AEs during AC THP 
• 
If the patient develops any of the following cardiac AEs during AC (please see table 1 
below), study therapy should be discontinued and further therapy is at the investigator's 
discretion. 
 
Table 1. Cardiac A/E 


18 
 
 
• 
Any greater than or equal to grade 3 AE listed in the Cardiac Disorders section of the 
CTCAE v.4.03 
 
 
7.2.2 Non-cardiac AEs during AC 
• 
If AC is discontinued due to non-cardiac toxicity, paclitaxel, trastuzumab and 
pertuzumab should be initiated. 
• 
If AEs occurring during dose-dense AC have resulted in treatment delays, the AC 
therapy should be converted to the every-3-week treatment schedule. If in three weeks 
toxicity has not resolved or is not less than grade 1 (except ANC  ≥ 1200 mm3  and 
bilirubin ≤ the baseline grade or anemia ≤  grade 2) then discontinue AC and move on 
to THP.  
• 
All dose modifications defined below:  (see Table 2) 
Table 2: Treatment Management of Non-Cardiac A/E for AC  
Dose modification must be based on AEs that occurred during the cycle (column 2) AND AEs present 
on the scheduled Day 1 of Cycles 2-4 (column 3) 
All dose modifications apply to both AC 
Dose modification must be based on the AE requiring the greatest modification 
CTCAE 
v4.03  
Adverse Event/Grade 
Modifications for AEs that 
occurred during a cycle but 
RESOLVE PRIOR TO THE 
NEXT 
TREATMENT 
CYCLE 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION 
OF 
THE 
TREATMENT 
CYCLE 
(See footnote b) 
Hematologic 
Neutrophil count decreased 
Maintain dose 
ANC: Hold until ≥ 1200 mm3. 
If recovery takes: 1 week: 
3


19 
 
Grade 2 (<1500-1000/mm3) 
maintain dose; 2-3 weeks- 
decrease 
one 
dose 
level(footnote c) 
Grade 3,4 
Platelet count decreased 
Maintain dose 
Hold until ≥ 75,000 mm3.If 
recovery takes: 
Grades 2,3 
1 week: maintain dose; 2-3 
weeks: decrease one dose 
level 
Grade 4 
Decrease dose one level 
Hold until ≥ 75,000 mm3. 
Decrease one dose level 
Anemia 
Grade 2  
Maintain Dose 
Maintain Dose 
Grade 3 
Maintain Dose 
Maintain Dose 
Grade 4 
Hold 
Hold, Resume when Grade ≤ 2 
GI (if related to chemotherapy) 
  
Diarrhea 
Grade 2 
Maintain dose 
Maintain dose or decrease one 
level 
Grade 3 
Decrease dose one level 
Decrease dose one level 
Grade 4 
Decrease dose one level or D/C D/C 
Mucositis-oral 
Grade 2 
Maintain dose 
Maintain dose or decrease one 
level 
Grade 3 
Decrease dose one level 
Decrease dose one level 
Grade 4 
Decrease dose one level or D/C D/C 
Vomiting (despite antiemetics) 
Grade 2 
Maintain dose or decrease one 
level 
Maintain dose or decrease one 
level 
Grade 3, 4 
Decrease dose one level or D/C D/C 
Hepatic (Bilirubin, AST, alk phos) 
  
Grade 2 
Decrease dose one level 
Hold until bilirubin returns to 
the baseline grade and AST 
and alk phos have returned to 
≤ grade 1; decrease one dose 
level 
Grade 3 
Decrease dose one level or D/C 
Hold until bilirubin returns to 
the baseline grade and AST 
and alk phos have returned to 
≤ grade 1; decrease one dose 
level or D/C 
Grade 4 
D/C 
D/C 
Infection or febrile neutropenia 
Grade 2 (N/A) 
Decrease dose one level 
  
Grade 3 
Decrease dose one level 
  
Grade 4 
Decrease dose one level or D/C   
Other clinically significant AEs (footnote d)   
Grade 2 
Maintain dose or decrease one 
level 
  
Grade 3 
Decrease dose one level 
 Decrease dose one level 
Grade 4 
Decrease dose one level or D/C D/C 
a. Resolved means that all clinically significant AEs are ≤ grade 1 (except ANC  ≥ 1200 mm3  and 
bilirubin ≤ the baseline grade or anemia ≤  grade 2) on Day 1 of the next scheduled cycle (i.e. treatment 
can be given without delay)  
b. Hold and check weekly. With exception of neutrophils and bilirubin and anemia resume treatment 
when toxicity is ≤ grade 1. If toxicity has not resolved after 3 weeks of delay D/C AC and proceed to 
THP 
c. Doxorubicin Dose Levels: 0:60mg/m2; 1:50mg/m2; 2:40 mg/m2; 3: D/C 


20 
 
   Cyclophosphamide Dose Levels: 0: 600mg/m2;1:500mg/m2;2:400 mg/m2; 3: D/C 
d. Determination of clinically significant AEs is at the discretion of the investigator 
 Adapted from NSABP-47 protocol 
 
7.2.3 Treatment Management of Trastuzumab for  ACTHP  
• 
Use the CTCAE v4.03 to grade the severity of AEs 
• 
Treatment decisions should be based on the AE requiring the greatest modification 
• 
There are no reductions in the trastuzumab dose. If trastuzumab is held, the loading 
dose followed by the maintenance dose for the remaining doses may be administered, 
at the investigator’s discretion, when resuming therapy. 
• 
Trastuzumab must end 1 year (52 weeks) following the first trastuzumab dose 
regardless of any missed doses 
• 
When weekly paclitaxel is delayed for reasons not requiring a delay in 
trastuzumab/pertuzumab, 
investigators 
are 
encouraged 
to 
continue 
trastuzumab/pertuzumab. 
However, 
at 
the 
discretion 
of 
the 
investigator, 
trastuzumab/pertuzumab may also be held.  
• 
With the exception of cardiac toxicity, pulmonary toxicity, or severe allergic or 
anaphylactic reaction (related to trastuzumab), trastuzumab/pertuzumab therapy should 
continue even if chemotherapy has been discontinued before completion of all 
chemotherapy cycles.  
7.2.4 Cardiac Safety criteria for initiation of Trastuzumab therapy following AC: 
Please see table 3 below regarding LVEF requirements for initiation of trastuzumab 
following AC. If the patient develops any of the following cardiac AEs during AC 
(Table 1), protocol therapy should be discontinued and further therapy will be 
personalized per investigators discretion. Initiation of trastuzumab is prohibited 
 
Table 3: LVEF for initiation of trastuzumab therapy after AC 
LVEF assessed 10-
21 days after last AC 
dose 
Change in LVEF percentage points from baseline a 
Increase 
or 
no 
change 
Decrease of < 10 
percentage points 
Decrease of ≥ 10 
percentage points 
≥55% 
Initiate trastuzumab therapy 
50-54% 
N/A 
Initiate trastuzumab 
therapy 
Initiate trastuzumab 
therapy and repeat 
echo in 6 weeks b 
≤ 49% 
N/A 
Do NOT initiate trastuzumab therapy; Initiate 
paclitaxel as per protocol c 
a. The baseline LVEF is the LVEF measured prior to randomization. 


21 
 
b. If repeat echo/MUGA was required, the LVEF value for the 2nd assessment must meet 
criteria as stated above for initiation of trastuzumab. 
c. Cardiac follow-up as per protocol. 
d. Adapted from NSABP-47 protocol 
 
-Any grade 2 AE 
-Any grade 3 AE listed in cardiac disorders of CTCAE 4.03 
7.2.5 Cardiac AEs during Trastuzumab treatment 
Any greater than or equal to grade 2 cardiac AE listed below (table 4):  
Trastuzumab will not be continued following any grade 2 cardiac AE listed in table 4. 
(Trastuzumab should be administered following any of the other grade 2 AEs listed in 
the Cardiac Disorders section of the CTCAE v4.03 but not listed below.  
 
 
 
 
 
 
Table 4: Cardiac Disorders CTCAE criteria 
 
• 
Any greater than or equal to grade 3 AE listed in the Cardiac Disorders section of the 
CTCAE v.4.0. 
B. Heart Failure and Left Ventricular Systolic Dysfunction 
• 
Symptomatic decrease in LVEF: 
o Grade 2, 3, or 4 heart failure: Discontinue trastuzumab 
o Grade 3 or 4 left ventricular systolic dysfunction: Discontinue trastuzumab 
o The protocol-specified schedule for obtaining LVEF assessments should 
continue to be followed even after the discontinuation of study therapy or 
occurrence of a cardiac event. 
• 
Asymptomatic Decrease in LVEF: 
o Patients in both arms will undergo sophisticated echocardiograms every 3 
months following randomization. 
o The results of the LVEF assessments during trastuzumab therapy will be used 
to determine if trastuzumab can be continued. (See table below) 
7.2.6 Trastuzumab management based on LVEF assessments: Patients with asymptomatic 
decrease in LVEF: For patients who do not develop symptoms related to LV dysfunction or 
3


22 
 
other cardiac AEs as stated above will depend on the absolute LVEF value and absolute change 
in percentage points between the baseline LVEF and LVEF serial measurements. 32,33 (Table 
5) 
Table 5: Trastuzumab Management Based on LVEF assessments 
Relationship of LVEF 
to LLN 
Asymptomatic Decrease in LVEF from baseline 
< 10 Percentage 
points 
10-15 
Percentage 
Points 
> 
15 
Percentage 
Points 
Within Normal Limits 
Continue 
trastuzumab 
Continue 
trastuzumab 
Hold 
Trastuzumab 
and repeat ECHO 
after 4 weeks 
1-5 Percentage Points 
below LLN 
Continue 
trastuzumab b 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks b, c 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks c,d 
≥ 6 percentage points 
below LLN 
Continue 
trastuzumab and 
repeat ECHO after 
4 weeksd 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks c,d 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks c 
< Normal 
Symptomatic: HOLD TRASTUZUMAB 
a Based on NSABP-31 protocol 32; Modified to include recommendations for cardiology 
consultation or treatment of cardiac dysfunction (or both) when appropriate 
b Consider cardiac assessment and initiation of angiotensin converting-enzyme inhibitor 
therapy. 
c After 2 holds (> 8 weeks), consider permanent discontinuation of trastuzumab or for >3 
incidents of treatment interruptions for cardiomyopathy 
d Initiate angiotensin converting-enzyme inhibitor therapy and refer to cardiologist 
LLN: lower limit of normal; ECHO: echocardiography 
7.2.7 Table 6. All AEs during trastuzumab treatment 
Treatment Management for Trastuzumab (H) related adverse events 
Dose modification must be based on the AE requiring the greatest modification 
CTCAE 
v4.03  
Adverse Event/Grade 
CTCAE 
Grade v4.03 
Action to be Taken 
Cardiac AEs as listed in 
CTACE v4.03 
1 
Continue 
trastuzumab 
at 
investigator’s 
discretion 
2 
Hold 
trastuzumab 
and 
conduct 
cardiac 
evaluation. See above (under initiation of 
trastuzumab after AC) regarding which grade 2 
AEs require trastuzumab discontinuation. For 
other cardiac grade 2 AEs, trastuzumab should 
be held during evaluation of AE and until ≤ grade 
1; continue or discontinue at investigator’s 
discretion. 
3, 4 
Discontinue trastuzumab 
Gastrointestinal Disorders 


23 
 
Diarrhea 
2 
Maintain dose without delay or hold until 
resolved to ≤ grade 1 and resume 
3 
Hold trastuzumab until resolved to ≤ grade 1, 
then resume 
4 
D/C trastuzumab 
Immune System Disorders 
Allergic reaction  
1 
Slow the infusion and assess the patient; 
management is at the investigator’s discretion 
2 
Stop 
infusion 
and 
administer 
support 
medications per investigator’s discretion. When 
symptoms resolve to ≤ grade 1, infusion may be 
resumed later that day at a slower rate or on the 
next day at a slower rate with pre-meds. Pre-
meds should be used for all subsequent 
treatments. 
3 
Follow instructions for grade 2; trastuzumab 
may be discontinued at the investigator’s 
discretion. 
4 
D/C trastuzumab 
Anaphylaxis 
3 
Follow instructions for grade 3 allergic reactions 
or, at investigator’s discretion, discontinue 
trastuzumab 
 
4 
D/C trastuzumab 
Respiratory, Thoracic and Mediastinal Disorders 
ARDS 
3,4 
D/C trastuzumab 
Cough 
2,3 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
Dyspnea 
1,2,3 
Hold trastuzumab; rule out heart failure and non-
infectious lung disease. Unless prohibited based 
on instructions for other clinical diagnoses (i.e. 
other AEs), resume trastuzumab when grade 0 if 
secondary to dyspnea AE or when AE ≤ grade 1. 
4 
D/C trastuzumab 
Hypoxia 
2,3 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
4 
D/C trastuzumab 
Pneumonitis 
2 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
3,4 
D/C trastuzumab 
Pulmonary Edema 
2,3 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
4 
D/C trastuzumab 
Pulmonary Fibrosis 
1 
If fibrosis was present at baseline, trastuzumab 
may be continued at the investigator’s discretion. 
If new or worsening fibrosis, D/C trastuzumab 
2,3,4 
D/C trastuzumab 


24 
 
Pulmonary 
Hypertension 
2,3,4 
D/C trastuzumab 
Other 
Clinically 
Significant 
AE’s as 
determined 
by 
the 
investigator 
2 
Hold trastuzumab until ≤ grade 1 or D/C 
trastuzumab 
3,4 
D/C trastuzumab 
7.2.8 Management of Pertuzumab during AC THP Regimen 
7.2.8.1 Cardiac A/E 
The only guidelines for management of pertuzumab cardiotoxicity are derived from 
CLEOPATRA 15 a randomized controlled trial for Stage IV breast cancer that included 
a pertuzumab containing regimen. Currently there are insufficient data available to 
determine cardiac toxicity risk factors for the combination of pertuzumab and 
trastuzumab. Because current preliminary data suggest that the incidence of clinical 
cardiac toxicity in patients receiving combination pertuzumab/trastuzumab-based 
treatments is similar to that reported for trastuzumab-based treatments, this study will 
include regular cardiac LVEF monitoring of all patients, and will implement the 
treatment delay/stopping algorithm for LVEF decline as is the standard for patients 
receiving trastuzumab-based chemotherapy as described above. Specifically there are 
inadequate data available to assess the prognostic significance of asymptomatic drops 
of LVEF for pertuzumab containing regimens. Please refer to 7.2.3-7.2.7 for guidelines 
for trastuzumab management which we will follow for pertuzumab management. 
Similar to trastuzumab there are no dose modifications for pertuzumab. Pertuzumab 
therapy finishes when chemotherapy completes as per regimens described above (See 
section 6.1) and does not continue onwards with trastuzumab monotherapy. 
Pertuzumab and trastuzumab will be discontinued in any patient who develops clinical 
signs and symptoms suggesting congestive heart failure, with the diagnosis confirmed 
by a suggestive chest X-ray and a drop in LVEF by ECHO or MUGA. Congestive heart 
failure should be treated and monitored according to standard medical practice 
7.2.8.2 Non-Cardiac A/E 
The most common adverse events observed when pertuzumab is given with 
trastuzumab include diarrhea, nail changes, allergic reactions, anemia, and 
thrombocytopenia. 
Loperamide recommended for Grade 2 diarrhea. Management at discretion of treating 
physician.  
7.2.9 Management of Paclitaxel (T) of ACTHP Regimen 
7.2.9.1 Treatment Guidelines 


25 
 
Paclitaxel should be completed in 12 weeks. If delays for medical or non-medical 
reasons occur, every effort should be made  to administer all 12 doses of paclitaxel 
within 15 weeks after initiation of  paclitaxel. No dose of paclitaxel may be given 
beyond the 15th week from the start of paclitaxel therapy as per NSABP-31 32.  
 
7.2.9.2 Initiation of Paclitaxel Therapy 
Since AC and paclitaxel are substantially different in toxicity and mechanism of action, 
any toxicity that occurs during AC administration and resolves prior to paclitaxel 
administration does not require dose reduction or delay during paclitaxel therapy. In 
addition, a patient who discontinues AC therapy due to toxicity should still proceed 
with paclitaxel according to the protocol.  
 
7.2.9.3 Paclitaxel Administration when Trastuzumab is Delayed or Discontinued 
When trastuzumab is delayed because of conditions related to LVEF, cardiac ischemia, 
or arrhythmia, paclitaxel administration may also be delayed at the investigator's 
discretion. If trastuzumab is delayed for reasons other than those cited above, paclitaxel 
administration should continue.  
When trastuzumab is permanently discontinued because of conditions related to LVEF, 
cardiac ischemia, arrhythmia, or severe allergic reactions, Paclitaxel administration 
may also be permanently discontinued at the investigator's discretion. If trastuzumab is 
permanently discontinued for reasons other than those cited above, paclitaxel 
administration should continue.  
 
7.2.9.4 Table 7 A/E Management of Weekly Paclitaxel 
 Unless otherwise specified, paclitaxel that is held due to toxicity will not resume until the 
toxicity has resolved to ≤ grade 1. 
 
Treatment Management for Weekly Paclitaxel 
Dose modification must be based on AEs that occurred between treatments (column 2) AND AEs present 
on the scheduled treatment day (column 3) 
Dose modification must be based on the AE requiring the greatest modification 
CTCAE 
v4.03  
Adverse Event/Grade 
Modifications for AEs that 
occurred between treatments 
BUT DID NOT REQUIRE A 
DELAY IN TREATMENT 
(See footnote a) 
Modifications for AEs that 
REQUIRE A DELAY IN 
ADMINISTRATION 
OF 
THE NEXT TREATMENT 
(See footnote b) 
Hematologic 
 
 
Neutrophil count decreased 
Maintain dose 
ANC: Hold until ≥ 1000 mm3.  
Decrease one dose level 
Grade 3,4 
Platelet count decreased 
Maintain dose 
Hold until ≥ 75,000 mm3.If 
recovery takes: 
1 wk: maintain dose; 2-3 
weeks: decrease one dose 
level 
Grades 2,3 


26 
 
Grade 4 
Decrease one dose level 
Hold until ≥ 75,000 mm3. 
Decrease one dose level 
Hemoglobin Decreased 
Maintain Dose 
Maintain Dose 
Grade 2  
Grade 3 
Maintain Dose 
Maintain Dose 
Grade 4 
Hold 
Hold, Resume when Grade 2 
GI (if related to chemotherapy) 
 
Diarrhea 
 
Maintain dose 
 
Maintain dose or decrease 
one level 
Grade 2 
Grade 3 
Decrease dose one level 
Decrease dose one level 
Grade 4 
Decrease dose one level or 
D/C 
Decrease dose one level or 
D/C 
Mucositis-oral 
 
Maintain dose 
Maintain dose or decrease 
one level 
Grade 2 
Grade 3 
Decrease dose one level 
Decrease dose one level 
Grade 4 
D/C 
D/C 
Vomiting (despite antiemetics) 
 
Maintain dose or decrease one 
level 
Maintain dose or decrease 
one level 
Grade 2 
Grade 3, 4 
Decrease dose one level or 
D/C 
D/C 
Hepatic (Bilirubin, AST, alk phos) 
 
Grade 2 
Decrease dose one level 
Hold until bilirubin returns to 
the baseline grade and AST 
and alk phos have returned to 
≤ grade 1; decrease one dose 
level 
Grade 3 
Decrease dose one level 
Hold until bilirubin returns to 
the baseline grade and AST 
and alk phos have returned to 
≤ grade 1; decrease one dose 
level or D/C 
Grade 4 
D/C 
D/C 
Infection or febrile neutropenia 
 
Grade 2 (N/A) 
Decrease dose one level 
Decrease dose one level 
Decrease dose one level or D/C 
Grade 3 
Grade 4 
Other clinically significant AEs (footnote d) 
   
Grade 2 
Maintain dose or decrease one 
level 
 
Grade 3 
Decrease dose one level 
 Decrease dose one level 
Grade 4 
Decrease dose one level or 
D/C 
D/C 
a. Treatment may not proceed until clinically significant AEs are ≤ grade 1 (except ANC  ≥ 1000 mm3  
and bilirubin ≤ the baseline grade or anemia ≤  grade 2) on Day 1 of the next scheduled cycle (i.e. 
treatment can be given without delay)  
b. Hold and check weekly. With exception of neutrophils and bilirubin and anemia resume treatment 
when toxicity is ≤ grade 1. If toxicity has not resolved after 3 weeks of delay D/C paclitaxel, see 
specific  instructions for continuing trastuzumab (VII-6C) 
c. Paclitaxel Dose Levels: 0:80mg/m2; 1:60mg/m2; 2:45 mg/m2; 3: D/C 
d. Determination of clinically significant AEs is at the discretion of the investigator 
(Adapted from NSABP-47 protocol) 
 


27 
 
Table 8.Treatment management for paclitaxel-related neuropathy 
Nervous System Disorders • 
Paresthesias 
 • Peripheral sensory 
neuropathy 
1 – 7 Days Duration 
Persistent for > 7 Days or 
Caused the Next Treatment 
to be Delayed 
Grade 1 
Maintain dose 
Grade 2 
Maintain dosea 
Decrease dose one level b 
Grade 3 
First episode: 
Decrease paclitaxel one dose 
level a 
Second episode 
D/C Paclitaxel 
D/C paclitaxel 
Grade 4 
D/C paclitaxel 
a Must be resolved to ≤ grade 1 on the next treatment day.  
b Hold paclitaxel for persistent grade 2 neuropathy. When ≤ grade 1, resume treatment with 
dose modification for paclitaxel. If grade 2 toxicity persists after 3 weeks of delay, 
discontinue paclitaxel 
(Adapted from NSABP-47 protocol) 
Table 9.Treatment management for paclitaxel-related musculoskeletal pain  
Note: The following treatment management instructions apply to patients with 
musculoskeletal pain not controlled by analgesics. Use of narcotics and NSAIDs is 
encouraged to maintain the paclitaxel dose if possible 
Musculoskeletal and 
Connective Tissue Disorders 
 • Arthralgia  
• Myalgia 
1 – 7 Days Duration 
 
 
Persistent for > 7 Days or 
Caused the Next Treatment 
to be Delayed 
Grade 1 (despite analgesics) 
Maintain dose 
Grade 2 (despite analgesics) 
Maintain dose 
Maintain paclitaxel dose or 
Decrease paclitaxel one 
dose level* 
Grade 3 (despite analgesics) 
First episode: Decrease 
paclitaxel one dose level  
Second episode: 
Discontinue paclitaxel 
First episode: Decrease 
paclitaxel one dose level* or 
Discontinue paclitaxel  
Second episode: 
Discontinue paclitaxel 
* Hold paclitaxel for persistent grade 2 or 3 musculoskeletal pain. 
(Trastuzumab/Pertuzumab should be continued while paclitaxel is held.) When ≤ grade 1, 
resume treatment with dose modification. If grade 2 or grade 3 toxicity persists after 3 
weeks of delay, discontinue paclitaxel.  
(Adapted from NSABP-47 protocol) 
 


28 
 
7.3 Adverse Event Management during TCHP 
      7.3.1 Treatment Management of Non-Cardiac A/E of TC of TCHP Regimen 
Table 10. Treatment Management of Non-Cardiac A/E of TC of TCHP Regimen 
Adverse Event  
CTACE 
v4.03 
Grade 
Docetaxel 
Carboplatin 
 
Hematologic 
ANC 
Grade 3,4 
ANC: Defer dose if ANC< 1000 mm3 
Delay one week and repeat cbc for recovery to ANC 
1000 
If despite GCSF, febrile neutropenia occurs or dose 
delay is required, consider dose reduction by 25% for 
docetaxel and reduce to AUC 5 mg/mL/min for 
carboplatin 
Platelet count 
decreased 
Grade 2,3,4 
Defer dose if platelets < 100,000 mm3 and repeat cbc 
for recovery of platelets ≥ 100,000 
If dose delay is required, consider dose reduction by 
25% for docetaxel and reduce to AUC 5 mg/mL/min 
for carboplatin 
 
Anemia 
Grade  ≥ 2 
Consider blood transfusion, administer for Hg > 10 
g/dL 
Grade ≥ 3,4 
Consider blood transfusion and docetaxel should be 
reduced to 60mg/m2 and carboplatin to AUC 5 
mg/mL/min 
Non-Hematologic Toxicities 
Renal Impairment: Adjust Carboplatin dose using Calvert formula. Dose = AUC 
(25+GFR) 
 
Cr Cl <20 ml/min 
 
No dose 
adjustment 
required 
CONTRAINDICATED 
Hepatic Impairment: patients who have both elevations of transaminase (ALT and/or 
AST) greater than 1.5X ULN AND alkaline phosphatase greater than 2.5X the ULN, the 
recommended  docetaxel dose is 60mg/m2 
Bilirubin 
 
 
 
> ULN 
 
Not recommended 
No dose reduction necessary 
Nausea (despite 
optimal antiemetics) 
Grade 4 
D/C therapy 
D/C therapy 
Diarrhea 
Grade 2 
Loperamide recommended 
Grade ≥ 3 
Optimally treat 
with antidiarrheals 
and Reduce 
docetaxel dose to 
60mg/m2. If 
continues despite 
dose reduction, 
consider D/C 
docetaxel 
 
Stomatitis 
Grade 3 
Reduce to 60 
mg/m2. If despite 
dose reduction, it 
persists, further 
 


29 
 
reduce to 
50mg/m2 
 
Other Toxicities 
Grade 0-2 
Delay treatment by one or more weeks until 
recovery to grade 0 or 1 
Grade 3,4 
Reduce to 60 
mg/m2 
Reduce to AUC 5 
 
Infection or Febrile 
Neutropenia 
(neutrophil < 
500cells/mm3 for 
more than one week) 
Grade 3,4 
Reduce to 60 
mg/m2 
Reduce to AUC 5 
 
Neuropathy 
Grade 2 
 Delay carboplatin and docetaxel by maximum of 2 
weeks 
As soon as patient recovers to Grade 1, decrease 
docetaxel to 60mg/m2 
If grade ≥ 2 persists for  ≥  2 weeks, patient can 
continue on carboplatin and trastuzumab alone or 
come off therapy 
In case of second episode, reduce docetaxel dose 
from 60 to 50 mg/m2 
 
Cutaneous Reactions 
Grade 1 
No change 
Grade 2 
Consider dose reduction to 60mg/m2 
Grade 3 
Delay maxiumum 2 weeks until ≤  Grade 1 and then 
for subsequent cycles Reduce docetaxel to 60 
mg/m2 and if occurs again, second reduction 
allowed of 50 mg/m2 
(Adapted from BCIRG 006 protocol 24) 
  
      7.3.2 Management of docetaxel-related edema  
Suggested interventions include: 
• Hydrochlorothiazide/triamterene (Dyazide®) 1 capsule by mouth daily; dose can be 
increased to twice daily.  
• Furosemide (Lasix®) 40 mg by mouth daily if edema progresses despite Dyazide (or 
equivalent) therapy. Potassium supplementation should be given as needed 
 
7.3.3: Management of Trastuzumab  for the TCHP Regimen  
• 
Use the CTCAE v4.03 to grade the severity of AEs 
• 
Treatment decisions should be based on the AE requiring the greatest modification 
• 
There are no reductions in the trastuzumab dose. If trastuzumab is held, the loading 
dose followed by the maintenance dose for the remaining doses may be administered, 
at the investigator’s discretion, when resuming therapy. 
• 
Trastuzumab must end 1 year (52 weeks) following the first trastuzumab dose 
regardless of any missed doses 
• When docetaxel + carboplatin is delayed, investigators are encouraged to continue 
trastuzumab/pertuzumab  
• With the exception of cardiac toxicity, pulmonary toxicity, or severe allergic or 
anaphylactic reaction (related to trastuzumab), trastuzumab therapy should continue 


30 
 
even if chemotherapy has been discontinued before completion of all chemotherapy 
cycles. 
Please see 7.2.5-7.2.7 for management of cardiac and non-cardiac A/E related to 
trastuzumab 
7.3.4 Management of Pertuzumab for the TCHP Regimen 
7.3.4.1 Cardiac A/E 
The only guidelines for management of pertuzumab cardiotoxicity are derived from 
CLEOPATRA 15 a randomized controlled trial for Stage IV breast cancer that included 
a pertuzumab containing regimen. Currently there are insufficient data available to 
determine cardiac toxicity risk factors for the combination of pertuzumab and 
trastuzumab. Because current preliminary data suggest that the incidence of clinical 
cardiac toxicity in patients receiving combination pertuzumab/trastuzumab-based 
treatments is similar to that reported for trastuzumab-based treatments, this study will 
include regular cardiac LVEF monitoring of all patients, and will implement the 
treatment delay/stopping algorithm for LVEF decline as is the standard for patients 
receiving trastuzumab-based chemotherapy as described above. Specifically there are 
inadequate data available to assess the prognostic significance of asymptomatic drops 
of LVEF for pertuzumab containing regimens. Please refer to 7.2.3-7.2.7 for guidelines 
for trastuzumab management which we will follow for pertuzumab management. 
Similar to trastuzumab there are no dose modifications for pertuzumab. Pertuzumab 
therapy finishes when chemotherapy completes as per regimens described above (See 
section 6.1) and does not continue onwards with trastuzumab monotherapy. 
Pertuzumab and trastuzumab will be discontinued in any patient who develops clinical 
signs and symptoms suggesting congestive heart failure, with the diagnosis confirmed 
by a suggestive chest X-ray and a drop in LVEF by ECHO or MUGA. Congestive heart 
failure should be treated and monitored according to standard medical practice 
      7.3.4.2 Non-Cardiac A/E 
The most common adverse events observed when pertuzumab is given with 
trastuzumab include diarrhea, nail changes, allergic reactions, anemia, and 
thrombocytopenia. 
Loperamide recommended for Grade 2 diarrhea. Management at discretion of treating 
physician. 
7.4  Management of Trastuzumab Monotherapy following completion of chemotherapy          
ACTHP and TCHP 
7.4.1 Treatment Management of Trastuzumab Monotherapy  


31 
 
• 
Use the CTCAE v4.03 to grade the severity of AEs 
• 
Treatment decisions should be based on the AE requiring the greatest modification 
• 
There are no reductions in the trastuzumab dose. If trastuzumab is held, the loading 
dose followed by the maintenance dose for the remaining doses may be administered, 
at the investigator’s discretion, when resuming therapy. 
• 
Trastuzumab must end 1 year (52 weeks) following the first trastuzumab dose 
regardless of any missed doses 
• 
With the exception of cardiac toxicity, pulmonary toxicity, or severe allergic or 
anaphylactic reaction (related to trastuzumab), trastuzumab therapy should continue 
even if chemotherapy has been discontinued before completion of all chemotherapy 
cycles.  
7.4.2 Cardiac AEs during Trastuzumab treatment 
Any greater than or equal to grade 2 cardiac AE listed below (table 4):  
Trastuzumab will not be continued following any grade 2 cardiac AE listed in table 4. 
(Trastuzumab should be administered following any of the other grade 2 AEs listed in 
the Cardiac Disorders section of the CTCAE v4.03 but not listed below. 
 
Table 4: Cardiac Disorders CTCAE criteria 
 
• 
Any greater than or equal to grade 3 AE listed in the Cardiac Disorders section of the 
CTCAE v.4.0. 
B. Heart Failure and Left Ventricular Systolic Dysfunction 
• 
Symptomatic decrease in LVEF: 
o Grade 2, 3, or 4 heart failure: Discontinue trastuzumab 
o Grade 3 or 4 left ventricular systolic dysfunction: Discontinue trastuzumab 
o The protocol-specified schedule for obtaining LVEF assessments should 
continue to be followed even after the discontinuation of study therapy or 
occurrence of a cardiac event. 
• 
Asymptomatic Decrease in LVEF: 
o Patients in both arms will undergo sophisticated echocardiograms every 3 
months following randomization. 
o The results of the LVEF assessments during trastuzumab therapy will be used 
to determine if trastuzumab can be continued. (See table below) 
7.4.3 Trastuzumab management based on LVEF assessments: Patients with 
asymptomatic decrease in LVEF: For patients who do not develop symptoms related to LV 
dysfunction or other cardiac AEs as stated above will depend on the absolute LVEF value 
3 


32 
 
and absolute change in percentage points between the baseline LVEF and LVEF serial 
measurements. 32,33 (Table 5) 
Table 5: Trastuzumab Management Based on LVEF assessments 
Relationship of LVEF 
to LLN 
Asymptomatic Decrease in LVEF from baseline 
< 10 Percentage 
points 
10-15 
Percentage 
Points 
>15 
Percentage 
Points 
Within Normal Limits 
Continue 
trastuzumab 
Continue 
trastuzumab 
Hold 
Trastuzumab 
and repeat ECHO 
after 4 weeks 
1-5 Percentage Points 
below LLN 
Continue 
trastuzumab b 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks b, c 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks c,d 
≥ 6 percentage points 
below LLN 
Continue 
trastuzumab and 
repeat ECHO after 
4 weeksd 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks c,d 
Hold 
trastuzumab 
and repeat ECHO 
after 4 weeks c 
< Normal 
Symptomatic: HOLD TRASTUZUMAB 
a Based on NSABP-31 protocol 32; Modified to include recommendations for cardiology 
consultation or treatment of cardiac dysfunction (or both) when appropriate 
b Consider cardiac assessment and initiation of angiotensin converting-enzyme inhibitor 
therapy. 
c After 2 holds (> 8 weeks), consider permanent discontinuation of trastuzumab or for >3 
incidents of treatment interruptions for cardiomyopathy 
d Initiate angiotensin converting-enzyme inhibitor therapy and refer to cardiologist 
LLN: lower limit of normal; ECHO: echocardiography 
 
 
7.4.4 Table 6. All AEs during trastuzumab treatment 
Treatment Management for Trastuzumab (H) related adverse events 
Dose modification must be based on the AE requiring the greatest modification 
CTCAE 
v4.03  
Adverse Event/Grade 
CTCAE 
Grade v4.03 
Action to be Taken 
Cardiac AEs as listed in 
CTACE v4.03 
1 
Continue 
trastuzumab 
at 
investigator’s 
discretion 
2 
Hold 
trastuzumab 
and 
conduct 
cardiac 
evaluation. See above (under initiation of 
trastuzumab after AC) regarding which grade 2 
AEs require trastuzumab discontinuation. For 
other cardiac grade 2 AEs, trastuzumab should 
be held during evaluation of AE and until ≤ grade 
1; continue or discontinue at investigator’s 
discretion. 
3, 4 
Discontinue trastuzumab 
Gastrointestinal Disorders 


33 
 
Diarrhea 
2 
Maintain dose without delay or hold until 
resolved to ≤ grade 1 and resume 
3 
Hold trastuzumab until resolved to ≤ grade 1, 
then resume 
4 
D/C trastuzumab 
Immune System Disorders 
Allergic reaction  
1 
Slow the infusion and assess the patient; 
management is at the investigator’s discretion 
2 
Stop 
infusion 
and 
administer 
support 
medications per investigator’s discretion. When 
symptoms resolve to ≤ grade 1, infusion may be 
resumed later that day at a slower rate or on the 
next day at a slower rate with pre-meds. Pre-
meds should be used for all subsequent 
treatments. 
3 
Follow instructions for grade 2; trastuzumab 
may be discontinued at the investigator’s 
discretion. 
4 
D/C trastuzumab 
Anaphylaxis 
3 
Follow instructions for grade 3 allergic reactions 
or, at investigator’s discretion, discontinue 
trastuzumab 
 
4 
D/C trastuzumab 
Respiratory, Thoracic and Mediastinal Disorders 
ARDS 
3,4 
D/C trastuzumab 
Cough 
2,3 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
Dyspnea 
1,2,3 
Hold trastuzumab; rule out heart failure and non-
infectious lung disease. Unless prohibited based 
on instructions for other clinical diagnoses (i.e. 
other AEs), resume trastuzumab when grade 0 if 
secondary to dyspnea AE or when AE ≤ grade 1. 
4 
D/C trastuzumab 
Hypoxia 
2,3 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
4 
D/C trastuzumab 
Pneumonitis 
2 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
3,4 
D/C trastuzumab 
Pulmonary Edema 
2,3 
Hold trastuzumab and determine etiology. Unless 
prohibited based on instructions for other clinical 
diagnoses (i.e. other AEs), resume trastuzumab 
when grade 0 if secondary to dyspnea AE or when 
AE ≤ grade 1. 
4 
D/C trastuzumab 
Pulmonary Fibrosis 
1 
If fibrosis was present at baseline, trastuzumab 
may be continued at the investigator’s discretion. 
If new or worsening fibrosis, D/C trastuzumab 
2,3,4 
D/C trastuzumab 


34 
 
Pulmonary 
Hypertension 
2,3,4 
D/C trastuzumab 
Other 
Clinically 
Significant 
AE’s as 
determined 
by 
the 
investigator 
2 
Hold trastuzumab until ≤ grade 1 or D/C 
trastuzumab 
3,4 
D/C trastuzumab 
 
7.5 Management of Infusion Reactions 
      7.5.1 Management of Trastuzumab Infusion Reaction 
Infusion reactions consist of a symptom complex, such as fever and chills, and on 
occasion nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, 
dyspnea, hypotension, rash, and asthenia. Infusion reactions should be managed by 
standard clinical practice. Stop infusion and give antipyretics if fever occurs within 24 
hours of trastuzumab infusion. Once the temperature is < 38°C, resume infusion at a 
slower rate and monitor the patient according to institutional standard practice. Chills 
triggered by trastuzumab infusion can be treated with acetaminophen and/or 
diphenhydramine hydrochloride. Meperidine may be given at the investigator’s 
discretion. 
Pulmonary toxicity including dyspnea, interstitial pneumonitis, pulmonary infiltrates, 
pleural effusions, non-cardiogenic pulmonary edema, pulmonary insufficiency and 
hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis can occur as 
sequelae of infusion reactions. Management of pulmonary toxicity should follow 
clinical standard practice. 
Trastuzumab should be discontinued for anaphylaxis or angioedema. 
7.5.2 Management of Pertuzumab Infusion Reaction 
Infusion reactions (either during or on the day of infusion) have been associated with 
pertuzumab; commonly described as fever, chills, fatigue, headache, weakness, 
myalgia, hypersensitivity, abnormal taste or vomiting. The incidence of 
hypersensitivity/anaphylaxis was slightly higher in the group receiving pertuzumab 
(compared to placebo) in combination with trastuzumab and docetaxel. Monitor for 1 
hour after the first infusion and for 30 minutes after subsequent infusions. For 
significant infusion reactions, interrupt or slow infusion rate; for severe infusion 
reactions, consider permanently discontinuing. Medications and equipment for the 
treatment of hypersensitivity should be available for immediate use during infusion. 
       7.5.3. Management of Paclitaxel Infusion Reaction 
Hypersensitivity reactions with Paclitaxel. There will be no dose modifications for 
hypersensitivity reactions. Management of mild  
to moderate hypersensitivity reactions is at the discretion of the  


35 
 
investigator. Severe reactions (Grade 3 or 4), such as hypotension requiring treatment, 
dyspnea requiring bronchodilators, angioedema, or generalized urticaria, require 
immediate and permanent discontinuation of Taxol and aggressive symptom 
management. If a grade 3 or 4 hypersensitivity reaction occurs during or after 
trastuzumab administration, following  paclitaxel, both trastuzumab and paclitaxel 
mustbe permanently discontinued.  
 
       7.5.4 Management of Docetaxel Infusion Reaction 
Patients should be observed closely for hypersensitivity reactions, especially during the 
first and second docetaxel infusions. Hypersensitivity reactions may occur within a few 
minutes following the initiation of the infusion of docetaxel; thus, facilities for the 
treatment of hypotension and bronchospasm should be available. Severe 
hypersensitivity reactions characterized by generalized rash/erythema, hypotension 
and/or bronchospasm, or very rarely fatal anaphylaxis, have been reported in patients 
who received the recommended 3-day dexamethasone premedication. Hypersensitivity 
reactions require immediate discontinuation of the docetaxel infusion and 
administration of appropriate therapy. These patients should not be re-challenged with 
the docetaxel. Docetaxel must not be given to patients who have a history of severe 
hypersensitivity reactions to docetaxel or to other drugs formulated with polysorbate 
80. Minor symptoms such as flushing or localized cutaneous reactions generally do not 
require interruption of therapy. 
7.6 Extravasation Management 
      7.6.1 Doxorubicin 
 
Extravasation of doxorubicin can result in severe local tissue injury and necrosis 
requiring wide excision of the affected area and skin grafting. Immediately terminate 
the drug and apply ice to the affected area. Doxorubicin must not be given by the 
intramuscular (IM) or subcutaneous route. If extravasation occurs, stop infusion 
immediately and disconnect (leave cannula/needle in place); gently aspirate 
extravasated solution (do NOT flush the line); remove needle/cannula; elevate 
extremity. Initiate antidote (dexrazoxane or dimethyl sulfate [DMSO]). Apply dry cold 
compresses for 20 minutes 4 times daily for 1 to 2 days ; withhold cooling beginning 
15 minutes before dexrazoxane infusion; continue withholding cooling until 15 minutes 
after infusion is completed. Topical DMSO should not be administered in combination 
with dexrazoxane; may lessen dexrazoxane efficacy. See institutional guidelines 
regarding use of dexrazoxane and DMSO 
 
      7.6.2 Paclitaxel  
 


36 
 
Paclitaxel is an irritant with vesicant-like properties; ensure proper needle or catheter 
placement prior to and during infusion; avoid extravasation. Injection-site reactions are 
generally mild (skin discoloration, tenderness, erythema, or swelling) and occur more 
commonly with an extended infusion duration (eg, 24 hours); injection-site reactions 
may be delayed (7 to 10 days). More severe reactions (phlebitis, cellulitis, skin 
exfoliation, necrosis, fibrosis, and induration) have also been reported. Recall skin 
reactions may occur despite administering through a different IV site. 
     7.6.3 Docetaxel 
 
If extravasation occurs, stop infusion immediately and disconnect (leave 
cannula/needle in place); gently aspirate extravasated solution (do NOT flush the line); 
remove needle/cannula; elevate extremity. Information conflicts regarding the use of 
warm or cold compresses 
 
8.0 Adverse Events Reporting 
      8.1 Adverse Events: List and Reporting Requirements  (See Appendix E) 
An Adverse Event (AE) is any undesirable sign, symptom or medical condition or 
experience that develops or worsens in severity after starting the first dose of study 
treatment or any procedure specified in the protocol, even if the event is not considered 
to be related to the study. 
Abnormal laboratory values or diagnostic test results constitute adverse events only if 
they induce clinical signs or symptoms or require treatment or further diagnostic tests. 
Adverse events will be monitored from the time the subject signs informed consent. 
Subjects will be instructed to report all AEs during the study and subjects will be 
assessed for the occurrence of AEs throughout the study. All AEs (serious and 
nonserious) must be recorded on the source documents and case report forms regardless 
of the assumption of a causal relationship with the study drug. 
Adverse Events that begin or worsen after informed consent should be recorded in the 
Adverse Events section of the case report form (CRF). Conditions that were already 
present at the time of informed consent should be recorded in the baseline symptoms 
section of the CRF. Adverse Event monitoring should be continued for at least 30 days 
following the last dose of study treatment. Adverse Events (including lab abnormalities 
that constitute AEs) should be described using a diagnosis whenever possible, rather 
than individual underlying signs and symptoms. When a clear diagnosis cannot be 
identified, each sign or symptom should be reported as a separate AE. 
 
8.1.1 


37 
 
The following list of AEs (Table 10) and the characteristics of an observed AE will 
determine whether the event requires expedited reporting in addition to routine 
reporting. 
Comprehensive Adverse Events and Potential Risks List 
Table 11: Adverse Event List for Trastuzumab and Pertuzumab 
Adverse Events with Possible Relationship to Trastuzumab or 
Pertuzumab  
(CTCAE 4.03 Term)  
 
Likely 
(> 
20%)  
Less Likely (≤e20%)  
Rare but Serious (<3%)  
BLOOD AND LYMPHATIC SYSTEM DISORDERS  
 
 
1. Anemia  
 
2. 
Febrile 
neutropenia2  
 
CARDIAC DISORDERS 
 
1. Cardiomyopathy  
2. 
Left 
ventricular 
systolic dysfunction  
 
3. Pericardial effusion  
4. Pericarditis  
5. Sinus tachycardia  
 
6. 
Supraventricular 
tachycardia  
 
GASTROINTESTINAL 
DISORDERS  
 
1. 
Abdominal 
pain  
2. Diarrhea  
3. Mucositis oral  
4. Nausea  
5. Vomiting  
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS  
 
1. Chills  
 
2. Fatigue  
 
3. Fever  
 
4. Flu like symptoms  
 
5. 
Infusion 
related 
reaction  
6. Non-cardiac chest 
pain  
 
7. Pain  
 
IMMUNE SYSTEM DISORDERS  
 
1. Allergic reaction3  
2. Anaphylaxis  
 
INFECTIONS AND INFESTATIONS  
 
   1. Infection4  
 
INVESTIGATIONS  
 
1. Alkaline phosphatase 
increased  
2. 
Aspartate 
aminotransferase 
increased  
3. GGT increased  
 


38 
 
4. 
Neutrophil 
count 
decreased2  
METABOLISM AND NUTRITION DISORDERS  
 
1. Anorexia  
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS  
 
1. Arthralgia  
2. Back pain  
3. Bone pain  
4. Myalgia  
 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS)  
 
1. Tumor pain  
 
NERVOUS SYSTEM DISORDERS  
 
1. 
Headache  
 
2. Peripheral sensory 
 neuropathy  
 
RESPIRATORY, 
THORACIC 
AND 
MEDIASTINAL 
DISORDERS  
 
1. 
Allergic 
rhinitis  
 
2. Cough  
 
3. Dyspnea3  
 
4. Hypoxia3  
 
5. Pneumonitis3  
6. Pulmonary edema  
7. Pulmonary fibrosis  
  1. Adult respiratory   distress syndrome3 
  2. Bronchospasm3 
3. Pneumonitis3  
4. Pulmonary edema  
5. Pulmonary fibrosis  
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS  
 
1. Rash acneiform  
Rash acneiform (Gr. 3)  
2. Rash maculo-papular  
Rash maculo-papular (Gr. 3)  
3. Urticaria  
Urticaria (Gr. 3)  
 
VASCULAR DISORDERS  
 
1. Hypertension5  
2. Hypotension5  
 
1This table will be updated as the toxicity profile of the agent is revised.  
2Fatal event when given in combination with Xeloda® (capecitabine) and Taxotere® (docetaxel).  
3Severe hypersensitivity reactions including angioedema and pulmonary adverse events (e.g., 
hypoxia, dyspnea, pulmonary infiltrates, pleural effusion, and acute respiratory distress syndrome) 
have been reported.  
4Infection may include any of the 75 sites of infection under the INFECTIONS AND 
INFESTATIONS SOC.  
5Associated with infusion reactions.  
 
  
8.1.2 Additional adverse events:  
The following are adverse events which have been reported on trastuzumab and 
pertuzumab trials; however, the relationship to trastuzumab is currently 
undetermined.  
Cardiac Disorders – acute coronary syndrome, atrial fibrillation, cardiac arrest, 
myocardial infarction; ventricular arrhythmia; ventricular fibrillation; ventricular 
tachycardia  
Ear and Labyrinth Disorders - hearing impaired  
Endocrine Disorders – hypothyroidism  
Eye Disorders - blurred vision; extraocular muscle paresis  
Gastrointestinal Disorders - colitis; dyspepsia; enterocolitis; esophageal ulcer; 
gastritis; pancreatitis; upper gastrointestinal hemorrhage  
General Disorders and Administration Site Conditions - sudden death NOS  
Immune System Disorders - immune system disorders - Other (autoimmune thyroiditis)  


39 
 
Investigations - alanine aminotransferase increased; blood bilirubin increased; cardiac 
troponin-I; creatinine increased; platelet count decreased  
Metabolism and Nutrition Disorders - hypomagnesemia; hyponatremia  
Musculoskeletal and Connective Tissue Disorders - avascular necrosis; generalized 
muscle weakness; muscle weakness left-sided; muscle weakness lower limb; muscle 
weakness right-sided; muscle weakness trunk; muscle weakness upper limb; 
musculoskeletal and connective tissue disorder - Other (myopathy)  
Nervous System Disorders - ataxia; cognitive disturbance; depressed level of 
consciousness; dizziness; hydrocephalus; ischemia cerebrovascular; neuralgia; seizure; 
syncope  
Psychiatric Disorders - anxiety; confusion; depression; psychosis  
Renal and Urinary Disorders - acute kidney injury; hematuria; proteinuria; urinary 
tract obstruction  
Reproductive System and Breast Disorders - fallopian tube obstruction; prostatic 
obstruction; spermatic cord obstruction; uterine obstruction; vaginal obstruction  
Respiratory, Thoracic and Mediastinal Disorders - apnea; laryngeal edema; 
pharyngolaryngeal pain; pleural effusion; pneumothorax; pulmonary hypertension; 
voice alteration  
Skin and Subcutaneous Tissue Disorders - nail loss; pruritus; skin ulceration  
Vascular Disorders - thromboembolic event 
 
Note: Trastuzumab in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination 
may result in events never previously associated with either agent.  
8.1.3. Additional adverse events from the FDA-approved October 2010 
Prescribing Information for Herceptin® (Trastuzumab)  
General Disorders – edema limbs, edema trunk  
Infections and Infestations – pharyngitis  
Nervous System Disorders – dizziness  
Psychiatric Disorders – depression, insomnia  
Renal and Urinary Disorders – other (glomerulopathy) 
 
  8.2. Common Terminology Criteria for Adverse Events (CTCAE) version 
          Adverse events should be reported according to CTCAE version 4.03 
     8.2.1 Adverse Event Definitions 
     
8.2.1.1 Adverse events  
 An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who 
received a pharmaceutical product. The event does not necessarily have to have a causal 
relationship with this treatment. 
     
8.2.1.2 Serious Adverse Events 
A serious adverse event (SAE) is defined as any AE which results in death, is 
immediately life-threatening, results in persistent or significant disability / incapacity, 
requires or prolongs patient hospitalization, is a congenital anomaly / birth defect, or is 
to be deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardize the patient and may require 


40 
 
medical or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. 
 
 
     
8.2.1.3 Intensity of Event 
Intensity of the events will be graded according to the CTCAE version 4.03 and 
reported in the CRF/eCRF. 
   
8.2.1.4 Causal Relationship 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-
challenge, confounding factors such as concomitant medication, concomitant diseases 
and relevant history. Assessment of causal relationship should be recorded in the case 
report forms: 
• 
Yes: There is a reasonable causal relationship between the investigational  drug 
administered and the AE. 
• 
No: There is no reasonable causal relationship between the investigational drug 
administered and the AE. 
 
       8.3. Reporting Requirements 
The study must be conducted in compliance with FDA regulations and local safety 
reporting requirements. 
All adverse events, serious and non-serious, will be fully documented on the 
appropriate case report form (CRF)/electronic case report form (eCRF). For each 
adverse event, an investigator will provide the onset, end, intensity, treatment required, 
outcome, seriousness and action taken with the investigational drug. The investigator 
will determine the relationship of the investigational drug to all AEs. Worsening of the 
underlying disease or of other pre-existing conditions will be recorded as an AE in the 
CRF/eCRF. Changes in vital signs, ECG, physical examination and laboratory test 
results will be recorded as an AE in the CRF/eCRF, if they are judged clinically relevant 
by the investigator. 
The investigator has the obligation to report AEs during the specified observational 
phase. If defined in the personalized treatment plan, the investigator also has the 
responsibility to report AEs occurring in a certain period after a patient completes the 
trial. Any AEs reported by the investigator during this phase must be documented in 
the appropriate CRF/eCRF. 


41 
 
Documentation of SAEs must include a causal relationship assessment and provide as 
much detail regarding the SAE as possible. With receipt of follow-up information, the 
SAE documentation and CRF/eCRF must be updated accordingly. 
      8.4. Reporting to the Institutional Review Board (IRB) 
Investigators will report SAEs according to IRB policies and procedures. Expedited 
reporting to the IRB of serious adverse events, e.g. suspected unexpected serious 
adverse reactions (SUSARs), will be done according to local regulatory requirements.  
     8.5. Monitoring of Adverse Events and Period of Observation 
All adverse events, both serious and non-serious, and deaths that are encountered from 
initiation of study intervention, throughout the study, and within 30 days of the last 
study intervention should be followed to their resolution, or until the investigator 
assesses them as stable, or the investigator determines the event to be irreversible, or 
the participant is lost to follow-up. The presence and resolution of AEs and SAEs (with 
dates) should be documented on the appropriate case report form as required and 
recorded in the participant’s medical record to facilitate source data verification. 
For some SAEs, the study sponsor or designee may follow-up by telephone, fax, and/or 
monitoring visit to obtain additional case details deemed necessary to appropriately 
evaluate the SAE report (e.g., hospital discharge summary, consultant report, or 
autopsy report). Participants should be instructed to report any serious post-study 
event(s) that might reasonably be related to participation in this study. Investigators 
should notify the IRB of any unanticipated death or adverse event occurring after a 
participant has discontinued or terminated study participation that may reasonably be 
related to the study. 
8.6. Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm.   Second 
malignancies require ONLY routine reporting unless otherwise specified.  
9.0. Data Reporting/Regulatory Requirements 
      9.1 Data Collection: 
Demographic data, ascertained either directly from the    patient or from the subject’s 
medical chart, will be entered into eRAP, a secure, password-protected, computerized 
research database.  Health information reported by the subject will be corroborated by 
the subject’s medical records 


42 
 
       9.2 Data Reporting 
 
Investigators must record the information required by the protocol. Case Report Forms 
will be completed for each subject enrolled into the clinical study. It is the investigator’s 
responsibility for ensuring that all clinical and laboratory data entered on the 
corresponding CRFs are complete, accurate and authentic. 
 
10.0 Data Safety and Monitoring Board 
The Data Safety and Monitoring Board (DSMB) of Tisch Cancer Institute at Mount 
Sinai (TCI) will monitor the trial at periodic intervals to ensure the safety of subjects 
enrolled in the trial as determined by the DSMB charter. The TCI DSMB is composed 
of clinical specialists from oncology and hematology, nursing, pharmacy and 
biostatistics with experience in oncology and who have no direct relationship with the 
study. The PI will submit data and safety monitoring reports to the DSMB at a 
frequency (every three to six months) to be determined by the TCI DSMB based on 
accrual rate and risks to the subjects. At the time of renewal, the study team will submit 
the most recent DSMB approval for safety review to the MSMC IRB. All protocol 
deviations, violations, and eligibility waivers will be reported to the DSMB and  IRB.  
The Coordinating Site will assure that there is a mechanism in place to distribute the 
report to all participating investigators for submission to their local IRB.  The report 
will document that a review of data and outcomes across all centers took place on a 
given date.  It will summarize the the cumulative toxicities reported from all 
participating sites without specific disclosure by treatment arm.  It will also inform site 
investigators of the study the DSMB’s conclusion with respect to progress or need for 
modification of the protocol.   
11.0      Provisions to Protect the Privacy Interests of Subjects 
Written Informed consent will be obtained in the Investigators’ private offices in order 
to maintain confidentiality.  If patients find any procedures, tests or questionnaires 
uncomfortable they may speak with the investigator and can decline to get the test done. 
Patients will be informed about health information and confidentiality. Subjects will be 
informed that certain parties will have access to confidential health information 
including the treating team, research team and also possibly IRB, governmental 
regulatory agencies and the sponsor. Patients will be made aware that participation in 
the study is purely voluntary and should they wish to withdraw their consent at any 
point, the subjects will not be penalized at any point. 
All members who will have access to subjects’ private information will have HIPPAA 
training. The study team will ask permission and obtain authorization from each 
participant regarding access to personal health information including demographics, 


43 
 
past and present medical records, research records, records about phone calls made as 
part of the study and records about study visits.  
12.0  Statistical Data management and analysis 
        12.1 Primary Outcome:  
 
The primary objective of the study is to evaluate pCR rates in the two arms.  A Simon 
two-stage design will be used for each of the two treatment arms. In each treatment arm 
the null hypothesis will be H0: p< 0.20 (treatment uninteresting) and the alternative 
hypothesis will be HA: p> 0.40 (treatment interesting), where p is the pCR rate. 
Initially, 17 patients will be randomly assigned to each treatment arm. If 3 or fewer 
patients have a pCR, then that arm will be terminated and no further patients will be 
entered on that treatment arm. If 4 or more patients obtain a pCR, 20 additional patients 
(total of 37 patients) will be randomized to that treatment arm. If 11 or more patients 
out of 37 have a pCR, the treatment will be of interest for further study. This design 
has a type I and type II error rate of 0.10.  Efficacy will be analyzed by an intent to treat 
analysis. All patients who stop chemotherapy early due to progressive disease would 
count as treatment failures and would be included in both efficacy and safety analyses. 
          12.2 Interim Analysis 
One interim analysis for efficacy is planned after accrual and follow-up of 17 patients 
in each treatment arm as described above.  
           12.3 Secondary Outcome: Cardiac Toxicity 
Cardiac toxicity rates will be compared between the two treatment arms. The 
proportion of patients experiencing a >10% decline in peak systolic longitudinal strain 
from baseline will be compared between the treatment arms by the chi-square test or 
Fisher’s exact test. The proportion of patients having an elevated value of troponin I 
(defined as >0.08 ng/ml) will be compared between treatment arms by the chi-square 
test or Fisher’s exact test. Echocardiograms will measure LVEF at baseline and every 
3 months. These measures over time will be compared between treatment arms by a 
mixed effects model for longitudinal data. Assumptions underlying mixed models will 
be investigated and checked before use of an appropriate model. Safety data will be 
analyzed for all patients having at least one dose of a study drug.  
The TRYPHAENA study discussed in section 2 showed that the combination of 
pertuzumab with trastuzumab resulted in low rates of asymptomatic decline in LVEF. 
Only 3.9%-5.6% of patients had asymptomatic declines in LVEF for the three treatment 
arms studied and only 2 patients experienced symptomatic LVSD. However, the 


44 
 
cardiac safety of pertuzumab as part of a doxorubicin-containing regimen has not yet 
been established and is a focus of the present study. Our study of 37 patients in each 
arm will allow detection of a difference between a 4% and a 25% proportion of patients 
with >10% declines in LVEF with 75% power for a two-sided test at the 0.10 level.  
       12.4 Stopping Rule for Safety/Toxicity 
A treatment arm will be suspended pending further review due to safety if there is 
sufficient evidence to suggest that the true probability of a Grade 2 or more cardiac 
adverse event or a Grade 3 or worse non-cardiac adverse event exceeds 10%. Sufficient 
evidence will be taken to be an observed toxicity rate whose lower one-sided 90% 
confidence limit exceeds 10%. The observed toxicity rates will be examined after every 
10th enrolled patient in a treatment arm becomes evaluable. Operationally this limit will 
be met if the following is observed, Grade 2 or worse cardiac or Grade 3 or worse non-
cardiac AE: If 3 of first 10 patients develop cardiac toxicity grade 2 or above or non-
cardiac toxicity grade 3 or above then suspend or if 5 of the first 20 patients develop 
grade 2 or above cardiac toxicity or grade 3 or above non-cardiac toxicity then suspend 
or if 6 of the first 30 patients develop grade 2 cardiac toxicity or above or grade 3 or 
above non-cardiac toxicity then suspend the trial and re-evaluate 
 
13.0 STUDY CALENDAR 
Scans, including CT scans and/or PET, ECHO, and x-rays must be done < 30 days prior 
to the start of therapy. 


45 
 
13.1 Arm 1 ddAC THP 
  
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5  
Surgery 
 
End of 
Study 
(Adjuvant 
anti-Her2 
therapy 
and 
endocrine 
therapy as 
per 
protocol) 
Follow-up  
Visit Day 
  
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1, 8, 15, 22, 29, 36, 43, 
50, 57, 64, 71, 78 
  
 
  
 Q 3 months 
for first year 
and q 6 
months for 
second year 
Medication Administration 
Doxorubicin 
  
X 
  
X 
  
X 
  
X 
  
  
  
 
  
  
Cyclophosphamide 
  
X 
  
X 
  
X 
  
X 
  
  
  
 
  
  
Pegfilgastrim 
  
  
X 
  
X 
  
X 
  
X 
  
  
 
  
  
Paclitaxel 
  
  
  
  
  
  
  
  
  
X 
  
 
  
  
Trastuzumab 
  
  
  
  
  
  
  
  
  
X (day 1,22,43, 64) 
  
 
  
  
Pertuzumab 
  
  
  
  
  
  
  
  
  
X(day 1,22,43, 64) 
  
 
  
  
LABS 
cbc 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X  (SOC) 
  
  
 
  
  
Comprehensive 
panel 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X  (SOC) 
  
  
 
  
  
Imaging 
Staging: CT C/A/P 
and bone scan or 
PET scan  
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
 
  
  


46 
 
Echo (q 3 months) 
X  (SOC) 
  
  
  
  
  
  
  
  
X (Around Day 29) (SOC) 
  
  
 
  
 X (for 1st year) 
Echo annually 
 
 
 
 
 
 
 
 
 
 
 
 
 
X For 2 years 
Pathology Assessments 
Pre-chemotherapy 
biopsy, Her2 status 
confirmed 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Assessment of pCR 
by pathologists 
  
  
  
  
  
  
  
  
  
  
  
X (SOC) 
 
  
  
Visit Assessments 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Inclusion/Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Demographics 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
 
  
 X (SOC) 
Medical history 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
 
  
 X (SOC) 
Concurrent meds 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
 
  
 X (SOC) 
History and 
Physical exam 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X (SOC) 
  
  
 
  
 X (SOC) 
Vital signs 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X (SOC) 
  
  
 
  
 X (SOC) 
Height 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X (SOC) 
  
  
 
  
 X (SOC) 
Weight 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X (SOC) 
  
  
 
  
 X (SOC) 
BSA 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X (SOC) 
  
  
 
  
X (SOC)  
Performance 
status 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X (SOC) 
  
  
 
  
 X (SOC) 
Adverse event 
evaluation 
X 
X 
  
X  
  
X   
  
X 
  
X 
  
  
 
  
  
Study Assessments 


47 
 
Troponin I 
X 
 X 
(time 
“0”) 
X 
  
  
X 
  
 X (Day 29) 
 
  
 
  
  
 
13.2 Arm 2: TCHP 
 
  
Pre 
Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5  
Cycle 6  
Surgery 
 
End of 
Study 
Follow-up 
Visit Day 
  
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1 
Day 
2 
Day 1 
Day 
2 
  
 
  
  Q 3 months 
for first year 
and q 6 
months for 
second year 
Medication Administration 
Docetaxel 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
 
  
  
Carboplatin 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
 
  
  
Trastuzumab 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
 
  
  
Pertuzumab 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
  
 
  
  
Pegfilgastrim 
  
  
X 
  
X 
  
X 
  
X 
  
 X 
  
X 
  
 
  
  
Labs 
cbc 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X  
(SOC) 
  
  
 
  
  
Comprehensive panel 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X  
(SOC) 
  
  
 
  
  
Imaging 
Staging: CT C/A/P and 
bone scan or PET scan  
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  


48 
 
Echo (q 3 months) 
X  (SOC) 
  
  
  
  
  
  
  
  
X 
(SOC) 
  
  
  
  
 
  
 X (for 1st year) 
Echo annually 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For 2 years 
Pathology Assessments 
Pre-chemotherapy 
biopsy, Her2 status 
confirmed 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Assessment of pCR by 
pathologists 
  
  
  
  
  
  
  
  
  
  
  
  
  
X (SOC) 
 
  
  
Visit Assessments 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Inclusion/Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
Demographics 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X  (SOC) 
Medical history 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X  (SOC) 
Concurrent meds 
X  (SOC) 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X  (SOC) 
History and Physical 
exam 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
  
 
  
X  (SOC) 
Vital signs 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
  
 
  
X  (SOC) 
Height 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
  
 
  
X  (SOC) 
Weight 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
  
 
  
X  (SOC) 
BSA 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
  
 
  
X  (SOC) 
Performance status 
X  (SOC) 
X 
(SOC) 
  
X 
(SOC) 
  
X  
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
X 
(SOC) 
  
  
 
  
X  (SOC) 
Adverse event 
evaluation 
X 
X 
  
X  
  
X   
  
X 
  
X 
  
X 
  
  
 
  
  
Study Assessments 
Troponin I 
X 
 X 
X 
  
X 
  
  
  
X 
  
  
 
  
  


49 
 


50 
 
14.0 References 
1.U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2009 
Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and 
Human Services, Centers for Disease Control and Prevention, and National Cancer 
Institute; 2013. Available at: http://www.cdc.gov/uscs. 
2. Gianni L et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant 
trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive 
locally advanced breast cancer (the NOAH trial): a randomised controlled superiority 
trial with a parallel HER2-negative cohort. Lancet. 2010;375(9712):377-84. 
3. Schneeweiss, A et al. Pertuzumab plus trastuzumab in combination with standard 
neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens 
in patients with HER2-positive early breast cancer: a randomized phase II cardiac 
safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-84.  
4. Gianni, L et al. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in 
women with locally advanced, inflammatory, or early HER2-positive breast cancer 
(NeoSphere): a randomised multicentre, open-label, phase 2 trial. The  Lancet  Oncol. 
2012; 13 (1): 25 – 32.  
5. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Altekruse SF, 
Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen 
HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2009 (Vintage 
2009 Populations), National Cancer Institute. Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data 
submission, posted to the SEER web site, 2012. 
6. McArthur, H et al. Neoadjuvant trial design: time for a brave new world? Nature 
Reviews. 2010; 7: 359-360. 
7.Rastogi, P et al. Preoperative Chemotherapy: Updates of National Surgical 
Adjuvant Breast and Bowel Project Protocols B-18 and B-27, J Clin Oncol. 2008; 
26:778-785. 
8. van der Hage, J et al.Preoperative Chemotherapy for Women With Operable Breast 
Cancer, Cochrane Database of Systematic Reviews. 2007, 2, Art. No: CD005002. 
9. Bear et al. Sequential Preoperative or Postoperative Docetaxel Added to 
Preoperative Doxorubicin Plus Cyclophosphamide for Operable Breast Cancer: 
National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 
2006; 24(13): 2019-2027. 
 
10. Guidance for Industry Pathologic Complete Response in Neoadjuvant Treatment 
of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated 
Approval. U.S. Department of Health and Human Services.Food and Drug 
Administration. Center for Drug Evaluation and Research (CDER). May 2012. 
 
11. Dawood S. et al. Prognosis of Women With Metastatic Breast Cancer by HER2 
Status and Trastuzumab Treatment: An Institutional-Based Review.. J Clin Oncol. 
2010; 28 (1) 92-98. 


51 
 
12.von Minkwitz, G, Untch M, Blohmer JU, et al. Definition and impact of pathologic 
complete response on prognosis after neoadjuvant chemotherapy in various intrinsic 
breast cancer subtypes. J Clin Oncol.2012; 30: 1796- 1804. 
13. Untch M. et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast 
cancer: results from the GeparQuattro study. J Clin Oncol. 2010;28(12):2024-2031. 
14.  Robidoux et al. Evaluation of lapatinib as a component of neoadjuvant therapy 
for HER2+ operable breast cancer: NSABP protocol B-41. J Clin Oncol. 2012; suppl; 
abstr LBA506.  
15. Swain et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic 
breast cancer (CLEOPATRA study): overall survival results from a randomised, 
double-blind, placebo-controlled, phase 3 study. The Lancet Oncology.2013; 14 (6): 
461 – 471. 
16. Geyer H et al. Assessment of myocardial mechanics using speckle tracking 
echocardiography: fundamentals and clinical applications. J Am Soc 
Echocardiogr.2010; 23(4):351-369. 
17.Sengupta PP, Narula J. Reclassifying heart failure. Heart Fail Clin. 2008;4(3):379-
82. 
18. Sawaya H et al. Assessment of Echocardiography and Biomarkers for the 
Extended Prediction of Cardiotoxicity in Patients Treated with Anthracyclines, 
Taxanes, and Trastuzumab. Circ Cardiovasc Imaging. 2012; 5: 596-603. 
19. Sawaya et al. Early detection and prediction of cardiotoxicity in chemotherapy-
treated patients. Am J Cardiol. 201;107(9):1375-1380. 
20. Negishi K et al. Independent and Incremental Value of Deformation Indices for 
Prediction of Trastuzumab-Induced Cardiotoxicity.J Am Soc Echocardiogr. 2013; 3: 
S0894-7317. 
21. Morris et al. Troponin I and C-Reactive Protein Are Commonly Detected in 
Patients with Breast Cancer Treated with Dose-Dense Chemotherapy Incorporating 
Trastuzumab and Lapatinib. Clin Cancer Res. 2011; 17 (10): 3490-3499. 
22. NCCN Guidelines 
23. http://www.asco.org/advocacy/fda-approves-pertuzumab-neoadjuvant-breast-
cancer 
24. Slamon et al, Adjuvant Trastuzumab in HER2-Positive Breast Cancer (BCIRG 
006). N Engl J Med 2011; 365:1273-1283. 
25. Citron ML et al. Randomized trial of dose-dense versus conventionally scheduled 
and sequential versus concurrent combination chemotherapy as postoperative 
adjuvant treatment of node-positive primary breast cancer: first report of Intergroup 
Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003; 
21(8):1431-1439. 
 
26. Capelan et al. Pertuzumab: new hope for patients with HER2-positive breast 
cancer. Annals of Oncology. 2012; 0: 1–10.  


52 
 
 
27. Rexer et al. Direct inhibition of PI3K in combination with dual HER2 inhibitors is 
required for optimal antitumor activity in HER2+ breast cancer cells Breast Cancer 
Research.2014; 16 (1):1-14. 
28. Carracedo et al. The PTEN–PI3K pathway: of feedbacks and cross-talks. 
Oncogene. 2008; 27: 5527–5541 
 
29.Yamaguchi et al. Signaling cross-talk in the resistance to HER family receptor 
targeted therapy. Oncogene. 2014; 33: 1073–1081. 
 
30. Cardinale D, Sandri MT, Martinoni A et al. Myocardial injury revealed by plasma 
troponin I in breast cancer treated with high-dose chemotherapy. Ann Oncol 2002; 13: 
710–715. 
 
31. Cardinale D et al. Prognostic value of troponin I in cardiac risk stratification of 
cancer patients undergoing high dose chemotherapy. Circulation. 2004; 109:2749-
2754. 
32. Tan-Chiu E. et al. Assessment of Cardiac Dysfunction in a Randomized Trial 
Comparing Doxorubicin and Cyclophosphamide Followed by Paclitaxel, With or 
Without Trastuzumab As Adjuvant Therapy in Node-Positive, Human Epidermal 
Growth Factor Receptor 2–Overexpressing Breast Cancer: NSABP B-31. J Clin 
Oncol. 2005; 23 (31) 7811-7819. 
33. Mackey JR et al. Cardiac management during adjuvant trastuzumab therapy: 
recommendations of the Canadian Trastuzumab Working Group. Curr Oncol. 2008; 
15(1): 24–35. 
 
 
 
 
 
 
 
 
 
 
 
 


53 
 
 
Appendix A: Protocol Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                                                                                                                                                                                            
If 3 or fewer patients have a pCR, then that arm will be terminated and no further patients 
will be entered on that treatment arm. If 4 or more patients obtain a pCR, 20 additional 
patients (total of 37 patients) will be randomized to that treatment arm. 
 
 
 
 
 
Randomize 
17 receive dd AC THP 
- Doxorubicin 60 mg/m2 IV day 1   
- Cyclophosphamide 600 mg/m2 IV day 1  
   q 14 days X cycles 1-4 
-Pegfilgastrim 6mg SC on day 2 of chemotherapy 
Followed by: 
- Paclitaxel 80 mg/m2 IV x 3hr infusion day 1 q    
  weekly x 12 cycles 
-Trastuzumab: first dose:  
  8mg/kg IV, subsequent doses: 6 mg/kg IV weekly 
beginning on day 1 of the first paclitaxel cycle  
-Pertuzumab 840 mg initial dose followed by 420 mg 
every 3 weeks  for 6 cycles 
 
17 receive TCHP 
-Docetaxel 75mg/m2, day 1, every 3 weeks for 6 
cycles 
-Carboplatin AUC 6, day 1 every 3 weeks for 6 cycles 
-Trastuzumab 8mg/kg initial dose, followed by 
6mg/kg every 3 weeks, Day 1 for 6 cycles-
Pertuzumab 840 mg initial dose followed by 420 mg 
every 3 weeks for 6 cycles 
-Pegfilgastrim 6mg SC on day 2 of chemotherapy for 
6 cycles 
 
- Q 3 months echocardiograms (check LVEF and LV strain 
-Troponin measured at baseline within 24 hrs of chemo and 
at 1 month and then 3 month intervals 
-Physical Exams prior to each cycle of chemotherapy 
- Definitive treatment: lumpectomy or mastectomy or RT 
   to determine pCR 
 
 
34 women with Her2neu positive      
    LABC stratified by: 
• 
ER status: positive or negative by IHC 
 
 
 
 


54 
 
 
Appendix B: Notification to Cardiology to Calculate Longitudinal Strain with 
Echocardiograms 
To Cardiologist: 
Please note: this patient is on a study as above. Please calculate patient’s Ejection 
Fraction (EF) as well as longitudinal strain and document it here and in the report. 
Patient Name: 
Patient MRN: 
Local Protocol ID#  
(A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense 
Doxorubicin/Cyclophosphamide followed by Paclitaxel/Trastuzumab/Pertuzumab 
Compared with Docetaxel/Carboplatin/Trastuzumab/Pertuzumab For Early Her2Neu 
Positive Breast Cancer) 
Documentation: : (or attach report)Patient’s EF: 
Patient’s calculated  longitudinal strain: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*please return completed form to Dr. Aarti Bhardwaj MD via email with subject “protocol EF 
and longitudinal strain” 
 


55 
 
 
 
Appendix C: Blood Serum Troponin Collection 
o Samples should be obtained at protocol specified time points 1 using 
supplies available onsite, specifically a green top tube.  
o The minimum amount of sample required is 0.15cc of blood.  
o All specimens should be sent to the institution’s central lab immediately 
for processing as per their standard of practice. 
 
1. Troponin I serum measurements will be performed at screening for  baseline, right before 
chemotherapy is administered (time “0”), 24 hrs after start of chemotherapy, within 1 month of time 
“0”  and within 3 months of time “0”  for duration of both regimens until surgery. Most of these 
scheduled  troponin  measurements will be done within 24 hours of chemotherapy administration  
See Study calendar. 
 
 
 
 
 
 
 
 
 
 
 
 
 


56 
 
 
Appendix D: Pathology Form: Determination of pCR status 
Patient Name: 
Patient MRN: 
Local Protocol ID#: 
(A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense 
Doxorubicin/Cyclophosphamide followed by Paclitaxel/Trastuzumab/Pertuzumab 
Compared with Docetaxel/Carboplatin/Trastuzumab/Pertuzumab For Early Her2Neu 
Positive Breast Cancer) 
Documentation: 
1.Please circle one 
    Total pCR            or        Residual disease 
 
 
 


57 
 
 
Appendix E. Serious Adverse Event Reporting Form 
SERIOUS ADVERSE EVENT REPORTING FORM  
 
1 – Trial Information  
SPONSOR  
 
OVERALL PRINICPAL INVESTIGATOR  
 
LOCAL PRINCIPAL INVESTIGATOR  
 
IRB NUMBER 
 
STUDY TITLE 
 
 
2 –  About the event  
Are you reporting a UP? (Unanticipated Problem) 
Yes 
 
No 
 
 
3 – SAE report type  
Report type 
Initial notification  
 
Follow up 
 
 
4 –  About the time of the event 
Date Investigator informed 
 
Date of report 
 
Date of Onset 
 
Date Resolved 
 
 
 
 
5 – Participant information  
SUBJECT ID NUMBER 
 
Age 
 
Gender 
Male 
 
Female 
 
 
6 – Description of Event  
Seriousness 
Causality 
Expectedness 
Death 
 
Not related 
 
Expected 
 
Life threatening 
 
Unlikely 
 
Not expected 
 
Hospitalization or prolongation of hospital stay 
 
Possibly 
 
 
Persistent or significant disability or incapacity 
 
Probably 
 
 


58 
 
Congenital abnormality or birth defect 
 
Definitely 
 
 
Otherwise considered serious 
 
 
Brief description of event  
[] Check if Cardiac Event 
 
 
Diagnosis 
 
 
 
Outcome 
Fatal 
 
On-going 
 
Recovered with sequelae 
 
Recovered 
 
If recovered (or recovered with sequelae) selected, enter date of recovery 
 
If fatal enter date of death 
 
Cause of death:  


59 
 
7 – Medication details 
Information about the CHEMOTHERAPY/ STUDY DRUG 
Drug (please specify action taken next to the agent) Legend is in the last column 
Dose 
Route 
Start date 
Stop date 
Action Taken 
 
 
 
 
 
1- Dose stopped 
2- Dose reduced 
3- Dose unchanged 
4- Dose increased 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant Concomitant Medication 
Drug (please specify action taken) 
Indication 
Dose 
Route 
Start date 
Stop date 
Action Taken 
 
 
 
 
 
 
1- Dose stopped 
2- Dose reduced 
3- Dose unchanged 
4- Dose increased 
5- N/A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Other clinical information, including relevant tests (laboratory, CT, ECG etc.) **Please include relevant redacted source documentation. 
 
 


60 
 


61 
 
 

ICF_001.pdf: 
A Phase II Randomized Trial Evaluating Neoadjuvant Dose-Dense Doxorubicin/
Cyclophosphamide Followed by Paclitaxel/Trastuzumab/Pertuzumab (AC THP) and
Docetaxel/Carboplatin/Trastuzumab/Pertuzumab (TCHP) For Early Her2Neu Positive
Breast Cancer
PI: Dr. Aarti S. Bhardwaj
NCT03329378
Docuement Date: 6-29-2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 1 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
TITLE OF RESEARCH STUDY:
Title: 
A 
Phase 
II 
Randomized 
Trial 
Evaluating 
Neoadjuvant 
Dose-Dense 
Doxorubicin/Cyclophosphamide 
followed 
by 
Paclitaxel/Trastuzumab/Pertuzumab 
and  
Docetaxel/Carboplatin/Trastuzumab/Pertuzumab For Early Her2Neu Positive Breast Cancer
PRINCIPAL INVESTIGATOR (HEAD RESEARCHER) NAME AND CONTACT INFORMATION:
Name:
 Aarti S Bhardwaj, MD
Physical Address: 
      
               
Mailing Address: 
One Gustave L Levy Place, Box 1079, New York, NY 10029                        
Phone: 
212-824-8578
Name:
Paula Klein, MD
Physical Address:
Mailing Address: 
325 West 15th Street, New York, NY 10011
Phone: 
212-604-6021
Name:
Anupama Goel, MD
Physical Address:
Mailing Address:
1000 10th Avenue, Suite 11C02, New York, NY 10019
Phone:
212-523-6769
WHAT IS A RESEARCH STUDY?
A research study is when scientists try to answer a question about something that we don’t know 
enough about.  Participating may not help you or others.  
People volunteer to be in a research study.  The decision about whether or not to take part is totally 
up to you. You can also agree to take part now and later change your mind. Whatever you decide is 
okay.  It will not affect your ability to get medical care within the Mount Sinai Health System.  
Someone will explain this research study to you. Feel free to ask all the questions you want before 
you decide.  Any new information that develops during this research study that might make you 
change your mind about participating will be given to you promptly.
Basic information about this study will appear on the website http://www.ClinicalTrials.gov.  There are 
a few reasons for this:  the National Institutes of Health (NIH) encourages all researchers to post their 
research; some medical journals only accept articles if the research was posted on the website; and, 
for research studies the U.S. Food and Drug Administration (FDA) calls "applicable clinical trials” a 
description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time.
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 2 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
PURPOSE OF THIS RESEARCH STUDY:
The purpose of this study is to determine if one chemotherapy regimen administered before surgery 
works better than another regimen to treat early stage Her2+ breast cancer and to determine how 
harmful each regimen is to the function of the heart.
Her2 positive breast cancer is a type of breast cancer that tests positive for a protein called human 
epidermal growth factor receptor 2 (HER2).  This protein promotes the growth of cancer cells. One 
option for the treatment of Her2 positive breast cancer is the use of chemotherapy to shrink the breast 
tumor before surgery. This is called neoadjuvant chemotherapy
We will be measuring how much tumor may or may not be present at the time of surgery after 1 or 2 
different regimens of chemotherapy has been given to shrink the tumor. When there is no cancer left 
at the time of surgery this is called a pathologic complete response (pCR). We are measuring the 
rates of pathologic complete response for each chemotherapy regimen.  
The two chemotherapy regimens to which patients may be randomized (like the flip of a coin) are: 

Dose Dense AC  THP which contains doxorubicin (A), cyclophosphamide (C) every 2 
weeks for 4 cycles followed by paclitaxel (T), trastuzumab (H) and pertuzumab (P) for a total of 
12 weeks and 

TCHP which contains Docetaxel (T), Carboplatin (C), Trastuzumab (H), Pertuzumab (P) every 
3 weeks for 6 cycles for total of 18 weeks. 
Doxorubicin, 
cyclophosphamide, 
paclitaxel, 
docetaxel 
and 
carboplatin 
are 
standard 
chemotherapeutics. Trastuzumab and Pertuzumab are monoclonal antibodies which are specific 
proteins or antibodies directed against the Her2 protein or receptor on breast cancer cells. 
Trastuzumab and Pertuzumab are FDA approved in the treatment of Her2 positive breast cancer. 
Pertuzumab is a newer agent and is believed to contribute to higher rates of pCR.
You may qualify to take part in this research study because you have early stage breast cancer or 
inflammatory breast cancer that is Her2+ and have baseline normal heart function.
After completion of the neoadjuvant chemotherapy, Anti-Her2 therapy will be continued on a 
specified schedule as per standard of care for a total of a year for BOTH regimens.
After completion of the neoadjuvant chemotherapy you will be evaluated for surgical treatment by your 
breast surgeon. You will be offered surgery and radiation as determined by your breast surgeon and 
radiation oncologist.  
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 3 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
After completion of surgical and/or radiation therapy, patients with estrogen receptor (ER)–positive 
and/or progesterone receptor (PR)–positive tumors will be offered an antiestrogen pill for further 
treatment of their breast cancer which is standard treatment. 
 
Funds for conducting this research are provided by Mount Sinai.
LENGTH OF TIME AND NUMBER OF PEOPLE EXPECTED TO PARTICIPATE
Your participation in this research study is expected to last 3 years (1 year on study, 2 years of 
cardiac follow-up).
The study will take place in the Dubin Breast Center at Mount Sinai Hospital, Mount Sinai Beth Israel 
Comprehensive Cancer Center West, and Mount Sinai West.
The number of people expected to take part in this research study at MSH (Mount Sinai Hospital) is 
45 patients, 18 patients at MSBI (Mount Sinai Beth Israel), and 12 patients at MSW (Mount Sinai 
West). The total number of people expected to take part in this research study is 75.
DESCRIPTION OF WHAT’S INVOLVED:
Research activities will take place at Mount Sinai Hospital, Mount Sinai Beth Israel and Mount Sinai 
West.
Screening:
After signing this consent form, you will enter the screening phase of the study during which you will 
have various tests and procedures to determine if you are eligible to participate in this study. 

Your medical history, height, weight, and vital signs ( heart rate, blood pressure, breathing rate 
and temperature) will be taken. You will have a physical exam and screening echocardiogram 
(ultrasound of the heart) to assess the function of your heart
Depending on the extent of lymph node involvement or abnormal lab values, imaging may be 
required to rule out metastatic breast cancer (cancer that has spread from the primary site 
[place where it started] to other places in the body) so you may also have a CT of your chest, 
abdomen and pelvis and bone scan or a PET/CT scan to assess the extent of disease.  Your 
breast biopsy will confirm your cancer is Her2+ to be eligible for the study.  All of this is 
considered standard of care. 

Approximately 3 teaspoons of blood will be taken for blood analysis. The blood will be used for 
a complete blood count, chemistry profile (routine lab tests looking at electrolytes and 
chemicals in your blood), and liver function tests. If you are a woman of child bearing age, a 
urine pregnancy test will be performed to ensure you are not pregnant. If you are pregnant you 
will be excluded from the study. All of this is standard of care.

For Research Purposes only the following tests will be done: 
1.
Performing an extra measurement on your baseline echocardiogram called longitudinal 
strain which is a number we will follow during the study to assess cardiac (heart) toxicity.  
This is done after the processing of the echocardiogram and is non-invasive. This extra 
measurement will not be billed to you or to your insurance. 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 4 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
2. Checking a baseline blood test as a marker of heart function, called troponin I 
(approximately a teaspoon of blood). This test will not be billed to you or to your insurance. 
Once it is determined that you are eligible for the study, you will enter the treatment phase.
Study Treatment: 
The study treatment you get will be chosen by chance, like flipping a coin (randomization). Neither 
you nor the study doctor will choose what study treatment you get. You will have an equal chance of 
being given each study treatment. 
Arm A is for the chemotherapy treatment plan AC THP where A stands for doxorubicin and C 
stands for cyclophosphamide.  This treatment is given once every 2 weeks for 4 cycles (a cycle for 
this regimen is 14 days). Pegfilgastrim will be administered on the second day of each cycle to boost 
the white blood cells to prevent infection from the chemotherapy during the AC portion. Thereafter you 
will receive 4 cycles (a cycle is 21 days for this portion of the treatment) of T (taxol) once weekly along 
with Trastuzumab and Pertuzumab (2 antibodies that target the Her2Neu receptor), given on the first 
day of the first week of every cycle for a total of 4 treatments. The duration of chemotherapy is 
approximately 20 weeks.    Please see the table below.
Arm A AC THP
 
Cycle 1
14 days
Cycle 2
14 days
Cycle 3
14 days
Cycle 4
14 days
Cycle 
5 
21 
days
Cycle 
6
21 
days
Cycle 
7
21 
days
Cycle 
8
21 
days
Surg
ery
Visit Day
Day 
1
Day 
2
Day 
1
Day 
2
Day 
1
Day 
2
Day 
1
Day 
2
Days
1, 8, 
15
 Days 
1, 8, 
15
Days
1, 8, 
15
Days
1, 8, 
15
Doxorubicin
X
 
X
 
X
 
X
 
 
 
Cyclophosphamide
X
 
X
 
X
 
X
 
 
 
Pegfilgastrim
 
X
 
X
 
X
 
X
 
 
Paclitaxel
 
 
 
 
 
 
 
 
X
X
X
X
Trastuzumab
 
 
 
 
 
 
 
 
Day 1 
only
Day 1 
only
Day 1 
only
Day 1 
only
 
Pertuzumab
 
 
 
 
 
 
 
 
Day 1 
only
Day 1 
only
Day 1 
only
Day 1 
only
AC takes approximately 3 hours to administer by infusion (a method of putting drugs into the 
bloodstream through a needle or catheter) 
THP takes approx. 3-4 hours to administer by infusion.
Pegfilgastrim is an injection given subcutaneously (a needle applied just under the skin).
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 5 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Arm B is the TCHP chemotherapy arm. Docetaxel, Carboplatin, Trastuzumab and Pertuzumab will be 
given on Day 1 of every 3 week cycle for 6 cycles (18 weeks). Pegfilgastrim which is administered by 
a subcutaneous injection will be given on the day after chemotherapy to boost the white blood cells 
and to prevent infections. Each administration of chemotherapy will take place at your doctor’s 
infusion center/clinic. Please see the table below.
Arm B: TCHP
 
Cycle 1
21 days
Cycle 2
21 days
Cycle 3
21 days
Cycle 4
21 days
Cycle 5 
21 days
Cycle 6 
21 days
Surgery
Visit Day
Day 
1
Day 
2
Day 
1
Day 
2
Day 
1
Day 
2
Day 
1
Day 
2
Day 
1
Day 
2
Day 
1
Day 
2
 
Docetaxel
X
 
X
 
X
 
X
 
X
 
X
 
 
Carboplatin
X
 
X
 
X
 
X
 
X
 
X
 
 
Trastuzumab
X
 
X
 
X
 
X
 
X
 
X
 
 
 
Pertuzumab
X
 
X
 
X
 
X
 
X
 
X
 
 
Pegfilgastrim
 
X
 
X
 
X
 
X
 
 
 
X
 
TCHP takes approximately 5-6 hours to administer by infusion.
Pegfilgastrim is an injection given subcutaneously (a needle applied just under the skin)

 During each of these visits for chemotherapy, you will have a physical exam and your weight 
and vital signs will be taken. You will be asked about any side effects you may be 
experiencing, or medications you may be taking. For the duration of chemotherapy, you will be 
monitored via standard of care blood tests, such as hematology and, comprehensive 
chemistry panels (approximately 3 teaspoons of blood). 

To monitor your heart function while receiving doxorubicin or trastuzumab or pertuzumab, you 
will have an echocardiogram every 3 months as standard of care. And we will measure 
longitudinal strain which is a non-invasive mathematical measurement and is and is done post-
processing as part of the experimental portion of the protocol.

You will also have a blood test called troponin measured right before chemotherapy is 
administered, 24 hours after start of chemotherapy, within 1 month and 3 months of first 
troponin. This is part of the experimental portion of the protocol, and we will be tracking it to 
evaluate cardiac toxicity. The amount of blood taken for this test will be less than 1/20 of 
teaspoon (0.15 mL) each time.
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 6 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16

After completion of chemotherapy, your breast surgeon will determine the type of surgery 
(lumpectomy or mastectomy) or additional treatment you will undergo. 

pCR will be determine by the pathologist on the final removed tumor specimen.

After completion of the neoadjuvant chemotherapy, Anti-Her2 therapy will be continued on 
a specified schedule as per standard of care for a total of a year for BOTH regimens

After surgery, you may require a consultation with a radiation oncologist.  

After completion of chemotherapy and surgical and/or radiation therapy, if you are   estrogen 
receptor (ER) positive and/or progesterone receptor (PR)positive  you will be offered standard 
of care endocrine therapy. Tumors that are ER/PR-positive are much more likely to respond to 
hormone therapy which can help prevent a return of the disease by blocking the effects of 
estrogen.
Follow up: 
-
Cardiac: annual ultrasound of the heart will be performed for 2 years or it will be performed 
earlier if there is a change in symptoms.
Contraception
 For Women:
Since you are participating in a study that involves drugs or investigational treatment with potential 
risks to a developing fetus, it is recommended, for your protection, that you not become pregnant for 
the duration of the study. Also, you should not participate if you are breastfeeding. Therefore, 
practicing effective contraception is important. No individual contraceptive is 100% effective. 
Recommended methods of birth control are:

The consistent use of an approved hormonal contraception (birth control pill/patches, rings), 

An intrauterine device (IUD), 

Contraceptive injection (Depo-Provera), 

Double barrier methods (Diaphragm with spermicidal gel or condoms with contraceptive foam), 

Sexual abstinence (no sexual intercourse) or 

Sterilization.

If Estrogen or Progesterone receptor positive we recommend against estrogen containing oral 
contraceptive pills or intrauterine devices
Hormonal contraceptives, implants, and injections are only considered effective if used properly and 
started at least one month before you begin the study, continuing throughout the study and for one 
month after the end of the study. You should ask your study doctor if you should continue birth control 
for longer than 30 days after the end of the study. If you are unsure whether the method of birth 
control you use is acceptable to use while participating in this study, you should ask your study doctor 
before you begin the study. If you are less than one year post-menopausal, there is the potential that 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 7 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
you could become pregnant. If you or your partner becomes pregnant or thinks either of you may be 
pregnant at any time during the trial, it is important that you tell your study doctor immediately. The 
trial drug may be stopped and a referral will be made to an obstetrician/gynecologist for follow-up. If 
you plan to become pregnant in the year following a clinical trial, speak with your study doctor. 
If you have any questions about birth control, your study coordinator or study doctor will be able to 
answer your questions and give you advice.
Should you become pregnant, regardless of the outcome, the sponsor may ask for information on 
your pregnancy, even if you are withdrawn from the study. Your written consent will be obtained 
separately in the case that this happens.
For Men:
Since you are participating in a study that involves drugs or treatment with potential risks to a 
developing fetus, it is recommended that you use a condom and not father a child or donate sperm 
while you are taking the study drug. Also, it is recommended that you use a condom and not father a 
child and/or donate sperm for 90 days after you stop taking the study drug. This is because levels of 
the study drug may be present in the sperm and/or seminal fluid even after you stop taking the study 
drug. Continuing to use a condom and not donating sperm during this 90 day period may allow time 
for any study drug that is still present in sperm and/or seminal fluid to be eliminated from your body 
before you attempt to father a child or donate sperm. You are encouraged to tell your female 
partner(s) and/or their doctor(s) that you are participating in a clinical trial.
A urine pregnancy test will be done before you begin the study. 
YOUR RESPONSIBILITIES IF YOU TAKE PART IN THIS RESEARCH:
If you decide to take part in this research study you will be responsible for the following things: 

Attending study visits as specified

Following the instructions of the study team

Using effective birth control

Informing the study team of new medications prescribed by any of your health providers before 
starting chemotherapy Informing the study team of any side effects you may experience.
COSTS OR PAYMENTS THAT MAY RESULT FROM PARTICIPATION:
Taking part in this research study may lead to added costs to you. You or your insurance company 
will be responsible for the costs of all items and services during the research study that you would 
have received for your condition if you were not enrolled in this research study. You or your insurance 
company will also be responsible for the costs of all services that occur during the research study that 
your physician believes are medically necessary to treat you.
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 8 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
You or your insurance company will not be responsible for the costs of the items and services 
associated with this research study which are provided to you only for research purposes and not to 
treat your condition.
You will not be paid for taking part in this study.
POSSIBLE BENEFITS:
It is important to know that you may not get any benefit from taking part in this research.  Others may 
not benefit either.  However, possible benefits may be the potential benefits of neoadjuvant 
chemotherapy such as shrinkage of the tumor and therefore potentially breast conserving surgery vs 
mastectomy as your surgical option after chemotherapy. 
There is no way to predict whether a response to the study treatment will improve your quality of life 
or prolong survival. The results of this study may or may not help future breast cancer patients.
REASONABLY FORESEEABLE RISKS AND DISCOMFORTS:
Trastuzumab and Pertuzumab 
Less Likely < 20% 

Cardiomyopathy: heart muscle becomes abnormally enlarged or thickened, decreased left 
ventricle ejection fraction (LVEF), fluid in the sac around the heart (pericardial effusion), 
inflammation/swelling of the sac around the heart (pericarditis), fast heartbeat with regular 
rhythm (sinus tachycardia), and fast heartbeat usually in an area above the heart’s chambers 
(supraventricular tachycardia). We will monitor your heart function by echocardiogram every 
three months as standard of care. 
Diarrhea

Fever associated with low white blood cell count

Abdominal pain

Mouth sores

Nausea

Vomiting

Body aches

Decreased red blood cells and increased liver proteins, these levels will be monitored during 
the study

Headaches or numbness in the hands and feet can occur

Lung inflammation (pneumonitis)

Runny, stuff nose, sneezing or cough

Acne

Skin rash

Hives
Very Unlikely < 1%
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 9 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16

Anaphylaxis (allergic reaction which is an abnormal reaction of the body to substances called 
allergens). Can cause life threatening low blood pressure, shortness of breath and death. 

Rare risk of pulmonary edema (fluid buildup in the lungs)

Lung scarring (pulmonary fibrosis)

This drug should not be given to anyone who has a known allergy or sensitivity to benzyl 
alcohol
Carboplatin:
More Likely >10% 

Peripheral Neuropathy: Tingling, numbness or pain in fingers or toes that may progress

Electrolyte imbalances (Low Potassium or sodium for example)

Vomiting

Abdominal pain 

Nausea (without vomiting)

Bone marrow depression or cytopenias of red blood cells or white blood cells or platelets 
thereby potentially increasing your risks of anemia, infection or bleeding

Increased serum alkaline phosphatase, increased serum AST, these are levels of liver function

Hypersensitivity to the medication

Weakness 

Acute Kidney Injury
Less Likely 1% to 10% 
Hair loss
Constipation 
Diarrhea
Loss of taste
Mouth sores or inflammation
Increased serum bilirubin (one measurement of liver function)
Very Unlikely<1% 

Severe allergic reaction which is an abnormal reaction of the body to substances called 
allergens. Can cause life threatening low blood pressure, shortness of breath, and death.  

Loss of appetite

Stroke

Cardiac Failure

Dehydration 

Redness of the skin

Febrile neutropenia (fever in the setting of low white blood cell counts)

High or low blood pressure

Injection site reaction (pain, redness, swelling)

Fatigue
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 10 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16

Skin rash
Doxorubicin
More Likely >10% 

Cardiomyopathy (heart muscle becomes abnormally enlarged or thickened, decreased left 
ventricle ejection fraction (LVEF) which is the output of blood from the heart.

Cardiotoxicity 

Chest tightness 

Fatigue

Headache 

Palmar-plantar erythrodysesthesia: rash that can start as redness of palms of hands and 
plantar aspects of feet and progress to pain and skin peeling of these areas

Skin rash 

Kaposi sarcoma (a rare type of cancer)

Hair Loss

Facial swelling 

Nausea

Constipation 

Diarrhea 

Loss of appetite

Thrombocytopenia (low platelets)

Neutropenia (low white blood cell count)

Leukopenia (low white blood cell count)

Anemia (low red blood cell count)

Weakness 

Back pain 

Pharyngitis (throat pain or irritation)

Dyspnea  (shortness of breath)
Less Likely 1% to 10%

Cardiac arrest 

Chest pain 

Tachycardia- accelerated heart rate

Dizziness 

Drowsiness 

Acne vulgaris

Weight loss 

Dehydration 

Elevated blood sugar

Difficulty swallowing
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 11 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16

Inflammation or irritation of the esophagus 

Oral candidiasis (thrush or fungal infection of the mouth) 

Hematuria (blood in the urine)

Hemorrhagic cystitis (bladder irritation resulting in blood in the urine)

Hypersensitivity reaction 

Nose bleeds
Very unlikely < 1%

Anxiety

Muscle aches

Electrolyte imbalances

Skin rash

Flatulence (gas)
Cyclophosphamide
More likely > 10%

Alopecia (hair loss which may be reversible; onset: 3-6 weeks after start of treatment)

Loss of periods

Sterility (loss of fertility)

Cytopenias: low red blood cell counts, low white blood cell counts that may increase risk for 
infection or bleeding
Less Likely: 1% to 10% 
Abdominal pain
Anorexia (an eating disorder characterized by an abnormally low body weight)
Diarrhea
Mucositis (painful inflammation of the mucous membranes lining the digestive tract)
Nausea/vomiting 
Mouth sores
Hemorrhagic cystitis
Very unlikely < 1%

Acute respiratory distress syndrome: accumulation of fluid in the lungs which can be severe

High blood pressure

Pneumonia

Secondary malignancy

Kidney infections

Sepsis or systemic infections
Paclitaxel
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 12 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
More Likely >10%

Flushing 

Swelling in the lower limbs

Low blood pressure

Hair loss

Rash 

Nausea/vomiting 

Diarrhea 

Mouth sores or inflammation 

Neutropenia (low white blood cells) 

Anemia (low red blood cells)

Thrombocytopenia (low platelets)

Alkaline phosphatase increased/AST increased (measures of liver function)

Peripheral neuropathy (tingling or numbness in fingers and toes)

Muscle or joint aches or pains

Weakness 

Allergic reaction

Infection
Less Likely 1% to 10%

Abnormal heart rhythms

Nail changes or weakening or breaking

Febrile neutropenia (fevers associated with a low white blood cell count)

Bilirubin increased (a measure of liver function) 
Very Unlikely <1% 

Abnormal heart rhythms

Skin infections

Severe allergic reaction

Skin Rash

Blood clots

Pancreatitis
Docetaxel
More Likely >10%

Flushing 

Lower limb swelling

Low blood pressure

Hair loss

Rash 

Nausea/vomiting 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 13 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16

Diarrhea 

Mouth sores or inflammation

Neutropenia (low white blood cells) 

Anemia (low red blood cells)

Thrombocytopenia (low platelets)

Alkaline phosphatase increased, AST increased (measures of liver function, require 
surveillance)
1% to 10%:  Less Likely

Abnormal heart rates

Nail changes

Febrile neutropenia (fevers associated with low white blood cells)

Bilirubin increased (a measure of liver function) 
Pegfilgastrim
More Likely > 10%

Muscle and skeletal pain 

Limb pain 
Less Likely 1-10%

Acute respiratory distress syndrome (ARDS)

Severe allergic reaction

Swelling of the body

Chest pain

Fever

Injection site reactions

Rash
Other Risks

Risk of loss of private information; this risk always exists, but there are procedures in place to 
minimize the risk.  
Blood Draw Risks
The risks of a blood draw include pain, bruising, and the slight possibility of infection at the place 
where the needle goes in.  Some people feel dizzy or may faint during or after a blood draw.
Fertility/Pregnancy Risks
If you are or become pregnant, this research may hurt your baby or your pregnancy in ways that are 
unknown. The unknown risks might be minor or might be major (death). You should not become 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 14 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
pregnant or father a baby while on this research study. Please read the acceptable methods of birth 
control found under the Description of What’s Involved section of this document.  
 
OTHER POSSIBLE OPTIONS TO CONSIDER:
You may decide not to take part in this research study without any penalty.  The choice is totally up to 
you.
If you choose not to participate in this research study, you will continue to receive treatments and 
diagnostic procedures including radiographic imaging, and blood tests for your cancer that are 
standard of care and appropriate as determined by your medical oncologist and could potentially 
include either one of these treatment regimens. 
IN CASE OF INJURY DURING THIS RESEARCH STUDY:
If you are injured or made sick from taking part in this research study, medical care will be provided. 
Generally, this care will be billed to you or your insurance in the ordinary manner and you will be 
responsible for all treatment costs not covered by your insurance, including deductibles, co-payments 
and coinsurance.  This does not prevent you from seeking payment for injury related to malpractice or 
negligence. Contact the investigator for more information.
You are not waiving any legal right to seek additional compensation through the courts by signing this 
form.
ENDING PARTICIPATION IN THE RESEARCH STUDY:
You may stop taking part in this research study at any time without any penalty. This will not affect 
your ability to receive medical care at any of the Mount Sinai Health System hospitals or to receive 
any benefits to which you are otherwise entitled.
If you decide to stop being in the research study please contact the Principal Investigator or the 
research staff.   
If you decide to stop being in the research study, the following may occur: If you were getting benefit 
from the study drug(s) you may experience progression off the drug and need to discuss alternative 
therapies with your provider.
If you stop being in the research study, already collected information may not be removed from the 
research study database and will continue to be used to complete the research analysis.  You may be 
asked whether the investigator can collect information from your routine medical care. If you agree, 
this data will be handled the same as research data. 
You may also withdraw your permission for the use and disclosure of any of your protected 
information for research, but you must do so in writing to the Principal Investigator at the address on 
the first page. Even if you withdraw your permission, the Principal Investigator for the research study 
may still use the information that was already collected if that information is necessary to complete the 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 15 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
research study. Your health information may still be used or shared after you withdraw your 
authorization if you have an adverse event (a bad effect) from participating in the research study.
Withdrawal without your consent: The study doctor, the sponsor or the institution may stop your 
involvement in this research study at any time without your consent. This may be because the 
research study is being stopped, the instructions of the study team have not been followed, the 
investigator believes it is in your best interest, or for any other reason. If specimens or data have been 
stored as part of the research study, they too can be destroyed without your consent.  More possible 
reasons for removal from the study include: subjects will be removed from the research study if they 
become pregnant, potentially if they have tumor progression, or experience certain adverse events 
such as cardiac events.
CONTACT PERSON(S):
If you have any questions, concerns, or complaints at any time about this research, or you think the 
research has hurt you, please contact the office of the research team and/or the Principal Investigator 
at phone number
Icahn School of Medicine at Mount Sinai - Dr. Aarti Bhardwaj at phone number 212-824-8578
Mount Sinai Beth Israel - Dr. Paula Klein at phone number 212-604-6021
Mount Sinai West - Dr. Anupama Goel at phone number 212-523-6769
If you experience an emergency during your participation in this research, call 911 or go to the 
emergency room.
This research has been reviewed and approved by an Institutional Review Board. You may reach a 
representative of the Program for Protection of Human Subjects at the Icahn School of Medicine at 
Mount Sinai at telephone number (212) 824-8200 during standard work hours for any of the reasons 
listed below. This office will direct your call to the right person within the Mount Sinai Health System:

Your questions, concerns, or complaints are not being answered by the research team.

You cannot reach the research team.

You are not comfortable talking to the research team.

You have questions about your rights as a research subject.

You want to get information or provide input about this research.
DISCLOSURE OF FINANCIAL INTERESTS:
Sometimes, physicians/researchers receive payments for consulting or similar work performed for 
industry.  Effective September 2014 Mount Sinai reviews only payments to an individual totaling more 
than $5,000 a year per entity when determining potential conflicts of interest.  If you have questions 
regarding industry relationships, we encourage you to talk your physician/researcher or visit our 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 16 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
website at http://icahn.mssm.edu/ where Mount Sinai publicly discloses the industry relationships of 
our faculty.
MAINTAINING CONFIDENTIALITY – HIPAA AUTHORIZATION:
As you take part in this research project it will be necessary for the research team and others to use 
and share some of your private protected health information. Consistent with the federal Health 
Insurance Portability and Accountability Act (HIPAA), we are asking your permission to receive, use 
and share that information.
What protected health information is collected and used in this study, and might also be disclosed 
(shared) with others?
As part of this research project, the research team at the hospital(s) involved in the research will 
collect your: name, address, telephone, dates directly related to the individual (birth, admission, 
discharge, etc.), social security number, medical records number, health plan numbers, , and other 
unique numbers]
The researchers will also get information from your medical record at the Mount Sinai Health System 
and your private doctor. 
During the study the researchers will gather information by: 

taking a medical history (includes current and past medications or therapies, illnesses, 
conditions or symptoms, family medical history, allergies, etc.)

doing a physical examination that generally also includes blood pressure reading, heart rate, 
breathing rate and temperature

completing the tests, procedures, questionnaires and interviews explained in the description 
section of this consent.
Why is your protected health information being used?
Your personal contact information is important to be able to contact you during the study. Your health 
information and the results of any tests and procedures being collected as part of this research study 
will be used for the purpose of this study as explained earlier in this consent form. The results of this 
study could be published or presented at scientific meetings, lectures, or other events, but would not 
include any information that would let others know who you are, unless you give separate permission 
to do so.
The Principal Investigator may also use and share the results of these tests and procedures to treat 
you in collaboration with others in the Mount Sinai Health System. 
The research team and other authorized members of The Mount Sinai Health System (“Mount Sinai”) 
workforce may use and share your information to ensure that the research meets legal, institutional or 
accreditation requirements. For example, the School’s Program for the Protection of Human Subjects 
is responsible for overseeing research on human subjects, and may need to see your information. If 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 17 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
you receive any payments for taking part in this study, the Mount Sinai Finance Department may need 
your name, address, social security number, payment amount, and related information for tax 
reporting purposes.  If the research team uncovers abuse, neglect, or reportable diseases, this 
information may be disclosed to appropriate authorities. 
Who, outside Mount Sinai, might receive your protected health information?
As part of the study, the Principal Investigator, study team and others in the Mount Sinai workforce 
may disclose your protected health information, including the results of the research study tests and 
procedures, to the following people or organizations: (It is possible that there may be changes to the 
list during this research study; you may request an up-to-date list at any time by contacting the 
Principal Investigator).
-
Other collaborating research center(s) and their associated research/clinical staff who are 
working with the investigators on this project: the Mount Sinai Hospital, Mount Sinai Beth 
Israel, Mouth Sinai West.
-
Research data coordinating office and/or their representative(s) who will be responsible for 
collecting results and findings from all the centers: the Mount Sinai Hospital.
-
A Data Safety Monitoring Board or other committee that will monitor the study on an 
ongoing basis for safety.
-
The United States Food and Drug Administration.
-
The United States Department of Health and Human Services and the Office of Human 
Research Protection.
In all disclosures outside of Mount Sinai, you will not be identified by name, social security number, 
address, telephone number, or any other direct personal identifier unless disclosure of the direct 
identifier is required by law. Some records and information disclosed may be identified with a unique 
code number. The Principal Investigator will ensure that the key to the code will be kept in a locked 
file, or will be securely stored electronically. The code will not be used to link the information back to 
you without your permission, unless the law requires it, or rarely if the Institutional Review Board 
allows it after determining that there would be minimal risk to your privacy. It is possible that a sponsor 
or their representatives, a data coordinating office, a contract research organization, may come to 
inspect your records. Even if those records are identifiable when inspected, the information leaving 
the institution will be stripped of direct identifiers.  Additionally, when applicable, the monitors, 
auditors, the IRB, the Office of Human Subjects Protection (OHRP) of the Department of Health and 
Human Services as well as the Food and Drug Administration (FDA) will be granted direct access to 
your medical records for verification of the research procedures and data. OHRP and FDA are 
authorized to remove information with identifiers if necessary to complete their task. By signing this 
document you are authorizing this access. We may publish the results of this research. However, we 
will keep your name and other identifying information confidential.
For how long will Mount Sinai be able to use or disclose your protected health information? Your 
authorization for use of your protected health information for this specific study does not expire.
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 18 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
Will you be able to access your records?
During your participation in this study, you will have access to your medical record and any study 
information that is part of that record. The investigator is not required to release to you research 
information that is not part of your medical record.
Do you need to give us permission to obtain, use or share your health information?
NO! If you decide not to let us obtain, use or share your health information you should not sign this 
form, and you will not be allowed to volunteer in the research study. If you do not sign, it will not affect 
your treatment, payment or enrollment in any health plans or affect your eligibility for benefits.
Can you change your mind?
You may withdraw your permission for the use and disclosure of any of your protected information for 
research, but you must do so in writing to the Principal Investigator at the address on the first page. 
Even if you withdraw your permission, the Principal Investigator for the research study may still use 
your protected information that was already collected if that information is necessary to complete the 
study. Your health information may still be used or shared after you withdraw your authorization if you 
should have an adverse event (a bad effect) from being in the study. If you withdraw your permission 
to use your protected health information for research that means you will also be withdrawn from the 
research study, but standard medical care and any other benefits to which you are entitled will not be 
affected. You can also tell us you want to withdraw from the research study at any time without 
canceling the Authorization to use your data.
If you have not already received it, you will also be given The Hospital’s Notice of Privacy Practices 
that contains more information about how The Hospital uses and discloses your protected health 
information.
It is important for you to understand that once information is disclosed to others outside Mount Sinai, 
the information may be re-disclosed and will no longer be covered by the federal privacy protection 
regulations. However, even if your information will no longer be protected by federal regulations, 
where possible, Mount Sinai has entered into agreements with those who will receive your information 
to continue to protect your confidentiality.
If as part of this research project your medical records are being reviewed, or a medical history is 
being taken, it is possible that HIV-related information may be revealed to the researchers.  If that is 
the case, the following information concerns you.  If this research does not involve any review of 
medical records or questions about your medical history or conditions, then the following section may 
be ignored.  
_________________________________________________________________________________
Notice Concerning HIV-Related Information
If you are authorizing the release of HIV-related information, you should be aware that the recipient(s) is 
(are) prohibited from re-disclosing any HIV-related information without your authorization unless permitted 
to do so under federal or state law.  You also have a right to request a list of people who may receive or 
use your HIV-related information without authorization.  If you experience discrimination because of the 
Effective Date: 6/29/2021
End Date: 9/4/2021


THE MOUNT SINAI HEALTH SYSTEM
CONSENT FORM TO VOLUNTEER IN A RESEARCH STUDY
AND AUTHORIZATION FOR USE AND DISCLOSURE OF MEDICAL INFORMATION
Icahn School of Medicine at Mount Sinai, 
Mount Sinai Beth Israel, Mount Sinai West 
Page 19 of 19
Study ID #: IRB-17-02073
Form Version Date: 8.23.2019 
---------------------------------------------------------FOR IRB USE ONLY--------------------------------------------------------------
Rev6.22.16
release or disclosure of HIV-related information, you may contact the New York State Division of Human 
Rights at (888) 392-3644 or the New York City Commission on Human Rights at (212) 306-5070.  These 
agencies are responsible for protecting your rights.
Signature Block for Capable Adult
Your signature below documents your permission to take part in this research and to the use and 
disclosure of your protected health information. A signed and dated copy will be given to you.
Signature of subject
Date 
Printed name of subject
Time
Person Explaining Study and Obtaining Consent 
Signature of person obtaining consent
Date 
Printed name of person obtaining consent
Time 
Witness Section: For use when a witness is required to observe the consent process,, 
document below (for example, subject is illiterate or visually impaired, or this accompanies a 
short form consent):
My signature below documents that the information in the consent document and any other 
written information was accurately explained to, and apparently understood by, the subject, and 
that consent was freely given by the subject.
Signature of witness to consent process
Date 
Printed name of person witnessing consent process
Time 
Effective Date: 6/29/2021
End Date: 9/4/2021