Clinical trial NCT01855828
Conditions: Her2-Positive Breast Cancer
Sponsor: Yale University
Start date: 2013-09-01; Completion date: 2018-08-01
Enrollment: 50 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main goal of this clinical trial is to test if adding pertuzumab (Perjeta), improves the anticancer activity of the combination chemotherapy regimen of trastuzumab (Herceptin) concomitant with paclitaxel, 5-fluorouracil, epirubicin, and cyclophosphamide (T-FEC). The study will also test the safety of this therapy.

Detailed description:
Subjects will receive 6 months of T-FEC chemotherapy concomitant with trastuzumab and pertuzumab before surgery. Subsequently, subjects will undergo surgery to remove any cancer from the breast and axillary lymph nodes that may have survived the chemotherapy. It is expected that the majority of women will have no viable cancer left in the breast or lymph nodes by the time all chemotherapy is completed.

Arms: arm 1: During weeks 1-12, patients will receive pertuzumab, trastuzumab, and paclitaxel at the same time; during weeks 13-24 patients will receive pertuzumab and trastuzumab at the same time with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC).
Interventions: intervention 1: Pertuzumab intervention 2: Trastuzumab intervention 3: Paclitaxel intervention 4: 5-fluorouracil intervention 5: Epirubicin intervention 6: Cyclophosphamide
Intervention descriptions: intervention 1: First dose is 840mg, maintenance dose is 420mg. Pertuzumab will be administered once every 3 weeks for 24 weeks (8 doses total) intervention 2: For weeks 1-12, first dose is 4 mg/kg, maintenance dose is 2 mg/kg administered every week (12 doses total).

For weeks 13-24, dose is 6mg/kg administered every 3 weeks (4 doses total). intervention 3: Administered at 80mg/m2 every week from week 1 to 12 (12 doses total). intervention 4: Administered at 500 mg/m2 for every 3 weeks during weeks 13-24 (4 doses total). intervention 5: Administered at 75mg/m2 every 3 weeks during weeks 13-24 (4 doses total). intervention 6: Administered at 500mg/m2 for every 3 weeks during weeks 13-24 (4 doses total).

Protocol documents:
Prot_SAP_001.pdf: 
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CONFIDENTIAL 
This is a Yale University document that contains confidential information. 
It is intended solely for the recipient clinical investigator(s) and must not 
be disclosed to any other party. This material may be used only for 
evaluating or conducting clinical investigations; any other proposed use 
requires written consent from Yale University and the Principal 
Investigator. 
Protocol: TRASTUZUMAB® and PERTUZUMAB® Yale Cancer Center IST, study # ML28772 
P/IST template 05-2012 
23-Jun-2016 
 
 
v14.0 (23-Jun-2016) 
 
PROTOCOL 
 
 
STUDY TITLE 
STUDY DRUGS: 
SINGLE ARM, NEOADJUVANT, PHASE II 
TRIAL OF PERTUZUMAB AND 
TRASTUZUMAB ADMINISTERED 
CONCOMITANTLY WITH WEEKLY 
PACLITAXEL AND FEC FOR CLINICAL 
STAGE I-III HER2-POSITIVE BREAST 
CANCER 
HERCEPTIN (trastuzumab) 
PERJETA (pertuzumab) 
PACLITAXEL (Taxol),5-FLUOROURACIL 
(5FU), EPIRUBICIN (Ellence), 
CYCLOPHOSPHAMIDE (Cytoxan) 
SUPPORT PROVIDED BY: 
Genentech, Inc. 
INVESTIGATOR: 
PI: Lajos Pusztai, MD, DPhil 
Co-PI: Michael P. DiGiovanna, MD/PhD 


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CONFIDENTIAL 
This is a Yale University document that contains confidential information. 
It is intended solely for the recipient clinical investigator(s) and must not 
be disclosed to any other party. This material may be used only for 
evaluating or conducting clinical investigations; any other proposed use 
requires written consent from Yale University and the Principal 
Investigator. 
Protocol: TRASTUZUMAB® and PERTUZUMAB® Yale Cancer Center IST, study # ML28772 
P/IST template 05-2012 
23-Jun-2016 
 
 
v14.0 (23-Jun-2016) 
 
COLLABORATORS: 
Donald Lannin, MD, Surgery  
Susan A Higgins, MD, Radiation Oncology 
 
Suzanne Evans, MD, Radiation Oncology 
 
 
Gina Chung, MD 
 
Erin Hofstatter, MD 
 
Tara Sanft, MD 
 
Kathleen Bober-Sorcinelli, MD 
 
Brigid Killilea, MD 
 
Nina Horwitz, MD 
 
Anees Chagpar, MD 
 
Sarah Mougalian, MD 
 
 
 
RESEARCH COORDINATOR: 
Zubin Dastur, Tel: (203) 737-2848 
 
 
STUDY NUMBER: 
1306012136 
 
 
PROTOCOL VERSION/DATE: 
v14.0 (23-Jun-2016) 


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TABLE OF CONTENTS  
 
Page 
1. 
INTRODUCTION ................................................................................... 4 
1.1 
Disease Background ................................................................................... 4 
1.2 HER2 and Breast Cancer ............................................................................ 4-5 
1.3 
Trastuzumab and Pertuzumab Clinical Experience ...................................... 5-9 
1.4 
Safety.......................................................................................................... 9-13 
1.5 
Trastuzumab and Pertuzumab Pharmacokinetics ....................................... 13-15 
1.6 
Other Study Drug(s) Background ................................................................ 15-22 
2. 
OBJECTIVES ........................................................................................ 23 
2.1 Primary Objectives ....................................................................................... 23 
2.2 Secondary Objectives ................................................................................... 23 
3. 
STUDY DESIGN ................................................................................... 24 
3.1 Description of the Study ............................................................................... 24 
3.2 Rationale for Study Design ........................................................................... 25 
3.3 Outcome Measures ...................................................................................... 25 
3.3.1 Primary Outcome Measure ........................................................................... 25 
3.3.2 Secondary Outcome Measures .................................................................... 25-26 
3.4 Safety Plan .......................................................................................................26 
3.5 Compliance With Laws and Regulations ...................................................... 26 
4. 
MATERIALS AND METHODS ............................................................... 26 
4.1 Subjects ....................................................................................................... 26 
4.1.1 
Subject Selection……………………………………………………………… .... 26 
4.1.2 Inclusion Criteria ........................................................................................... 26-27 
4.1.3 Exclusion Criteria ......................................................................................... 27-28 
4.2 Method of Treatment Assignment ................................................................. 28 
4.3 
Study Treatment ........................................................................................... 28-30 
4.3.1 Trastuzumab and Pertuzumab Formulations ................................................ 30 
4.3.2 
Dosage, Preparation, Administration, and Storage ....................................... 30 
4.3.3 Dosage Modification ..................................................................................... 30-33 
4.3.4 
Overdosage ................................................................................................ 33 


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4.4 Concomitant and Excluded Therapy .............................................................. 33 
TABLE OF CONTENTS (Continued) 
4.5 Study Assessments ...................................................................................... 33 
4.5.1 Assessments at Baseline Before Treatment ................................................. 33-34 
4.5.2 Assessments During Therapy ....................................................................... 34 
4.5.3 Treatment After Completion of Surgery ......................................................... 35 
4.6 Discontinuation of Protocol-Specified Therapy .............................................. 35 
4.7 
Study Discontinuation ................................................................................... 35-36 
4.8 Statistical Methods ....................................................................................... 36 
4.8.1 Analysis of the Conduct of the Study ............................................................ 36 
4.8.2 Analysis of Treatment Group Comparability .................................................. 36 
4.8.3 Analysis Plan ................................................................................................ 36-37 
4.8.4 Missing Data ................................................................................................. 37 
4.8.5 Determination of Sample Size ...................................................................... 37-38 
4.9 
Data Quality Assurance ................................................................................. 38 
5. 
Definition and Reporting of Adverse Events ............................................ 39 
5.1 
Methods and Timing for Assessing and Recording Safety Variables ............ 39-40 
5.2 
Procedures for Eliciting, Recording, and Reporting Adverse Events ............ 41-44 
5.3 MedWatch 3500 Reporting Guidelines ......................................................... 44 
5.4 
Additional Reporting Requirements for IND Holders ...................................... 44 
6. 
INVESTIGATOR REQUIREMENTS ...................................................... 45 
6.1 
Study Initiation .............................................................................................. 44-45 
6.2 Study Completion ......................................................................................... 45 
6.3 Informed Consent ......................................................................................... 45 
6.4 
Institutional Review Board or Ethics Committee Approval .............................. 46 
6.5 Study Monitoring Requirements .................................................................... 46 
6.6 
Data Collection ............................................................................................. 46-47 
6.7 Study Medication Accountability ................................................................... 47 
6.8 
Disclosure of Data ........................................................................................ 47-48 
6.9 Retention of Records .................................................................................... 48 
REFERENCES ............................................................................................. 49-53 


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APPENDICES 
Appendix A:  Study Flowchart…………………………………………………55-56 
Appendix B:  Response Evaluation Criteria in Solid Tumors………………57 
Appendix C: HFSA Guidelines for CHF Treatment…………………………58-78 
Appendix D: Genentech Safety Reporting Fax Cover Sheet………………79 


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1. 
INTRODUCTION 
1.1 
DISEASE BACKGROUND 
Each year approximately 40,000 women are diagnosed with clinical stage I-III 
HER2-positive breast cancer. Neoadjuvant chemotherapy is often administered 
to these patients because clinical tumor response is very common, is associated 
with smaller tumor resection and higher rates of breast conservation, and the 
extent of residual cancer after chemotherapy provides important prognostic 
information (Wolff et al 2008, Symmans et al, 2007). Patients with pathologic 
complete response (pCR) have excellent overall survival and therefore an 
important clinical research direction is to develop regimens that maximize pCR. 
The US Food and Drug Administration (FDA) has recently recognized this  
strong association between pCR and long-term survival in this disease subset 
and expressed interest in accepting this endpoint for accelerated drug approval 
(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati  
on/Guidances/UCM305501.pdf). 
 
 
The purpose of this Phase II study is to estimate the pathologic complete 
response rate when pertuzumab is added to the regimen that currently produces 
the highest pCR rates in HER-2 positive breast cancers, weekly 
trastuzumab/paclitaxel followed by trastuzumab/FEC (5-fluorouracil/epirubicin/ 
cyclophosphamide), in a single-arm phase II neoadjuvant study. Pathologic 
complete response is defined as complete absence of any viable invasive 
cancer cells in the resected breast and lymph nodes.  Because pCR rates differ 
between estrogen receptor (ER) positive and ER negative breast cancers, we 
will determine the sample size and analyze pCR rates separately for ER positive 
and negative cancers. However, this is conducted as a single clinical trial, 
although accrual may finish sooner for one cohort than for the other (see 
statistical section). The goal is to estimate if pCR rates could be improved from 
50% to 70% in ER positive breast cancers and from 70% to 90% in ER negative 
breast cancers by adding pertuzumab to the weekly trastuzumab/paclitaxel 
followed by trastuzumab/FEC treatment regimen. 
 
 
1.2 
HER2 AND BREAST CANCER 
 
 
Growth factors and their receptors play critical roles in development, cell growth, 
differentiation, and apoptosis (Cross and Dexter 1991). Such receptors span the 
cell membrane, with the extracellular domain binding specific growth factors and 
the intracellular domain transmitting growth signals. Interaction of the 
extracellular domain with its cognate ligand typically results in activation of 
intracellular tyrosine kinase activity. Overexpression of human epidermal growth 
factor receptor 2 (HER2, also known as erbB2, neu, and p185HER2) is 
observed in approximately 25-30% of human breast cancers (Slamon et al. 
1987). HER2 overexpression has been reported to only rarely occur in the 


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absence of gene amplification (Kallioniemie et al. 1992; Pauletti et al. 1996). 
High level of HER2 expression has been correlated with poor clinical outcome 
(Slamon et al. 1987). 
 
Several lines of evidence support a direct role for HER2 overexpression in the 
pathogenesis and poor clinical course of human tumors (Hynes 1994). When  
the mutated gene is transfected into murine fibroblast (NIH 3T3) cells, it causes 
transformation, and the resulting cells are tumorigenic in nude mice (Di Fiore et 
al. 1987; Hudziak et al. 1987). Additionally, transgenic mice that overexpress the 
rodent homolog of the human HER2 gene develop mammary cancer (Guy et al. 
1992). Finally, specific antibodies to the extracellular domain of HER2 inhibit the 
experimental growth of tumors that overexpress the gene (Drebin et al. 1985, 
1988; Fendly et al. 1990). These data suggest a direct role for HER2 in both 
malignant transformation and enhanced tumorigenicity. Therefore a strategy to 
antagonize the abnormal function of overexpressed HER2 was developed to 
improve the course of patients with HER2-overexpressing tumors. Monoclonal 
antibodies directed against the HER2 protein were developed and humanized to 
minimize the likelihood of immunogenicity. One of these antibodies 
(trastuzumab) was very effective in inhibiting both in vitro and in vivo  
proliferation of human breast cancer tumor cells overexpressing the HER2 
protein and in mediating antibody-dependent cellular cytotoxicity in the presence 
of human effector cells (Jurianz et al. 1999). 
 
There is substantial preclinical evidence that inhibition of signal transduction 
pathways can potentiate the cytotoxic activity of chemotherapeutic drugs. 
Indeed, trastuzumab has been shown to have synergy, in vitro and in vivo, with 
several chemotherapeutic drugs including cisplatin, doxorubicin, thiotepa, 
etoposide, vinorelbine, and taxanes (Pegram et al. 2000; Pietras et al. 1994; 
Arteaga et al. 1994; Hancock et al. 1991; Baselga et al. 1998; Pegram et al. 
1997). Given this promising preclinical data, trastuzumab was tested in the clinic 
both as a single agent and in combination with chemotherapy. 
1.3 
TRASTUZUMAB AND PERTUZUMAB CLINICAL EXPERIENCE 
Trastuzumab Clinical Experience in Metastatic Breast Cancer 
The clinical benefit of trastuzumab in women with metastatic breast cancer has 
been demonstrated in two pivotal studies. A large Phase II trial (H0649g) 
assessed the activity of trastuzumab as a single agent in 222 women with HER2 
overexpressing metastatic breast cancer with progressive disease after one or 
more chemotherapy regimens (Cobleigh et al. 1999). A blinded, independent 
response evaluation committee identified 8 complete and 26 partial responses, 
for an objective response rate of 15% in the intent-to-treat population (95% 
confidence interval, 11% to 21%). The median duration of response was 9.1 
months, and the median survival was 13 months. The most common adverse 
events, which occurred in approximately 40% of patients, were mild to moderate 
infusion-associated fever and/or chills. These symptoms usually occurred only 


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during the first infusion. The most clinically significant event was cardiac 
dysfunction, which occurred in 4.7% of patients. 
 
A large, open-label, randomized Phase III study (H0648g) in 469 patients with 
HER2-positive metastatic breast cancer was conducted to evaluate the efficacy 
of trastuzumab in combination with chemotherapy as first-line treatment. 
Patients who were anthracycline-naïve were randomized to receive either 
anthracycline plus cyclophosphamide (AC) or trastuzumab plus AC. Patients 
who had received prior anthracyclines in the adjuvant setting were randomized 
to receive either paclitaxel or trastuzumab plus paclitaxel. Patients randomized 
to trastuzumab and chemotherapy measurably benefited in comparison to 
patients treated with chemotherapy alone in terms of time to disease 
progression, overall response rate, median duration of response, and survival. 
As determined by an independent Response Evaluation Committee (REC), 
trastuzumab prolonged median time to disease progression from 4.6 months to 
7.4 months (p<0.001), improved the overall response rate (complete and partial 
responses) from 32% to 50% (p<0.001), and increased median duration of 
response from 6.1 to 9.1 months (p<0.001). Compared to chemotherapy alone, 
the addition of trastuzumab significantly lowered the incidence of death at one 
year from 33% to 22% (p=0.008) and increased median overall survival 24% 
from 20.3 months to 25.1 months (p=0.046). The observed survival advantage 
remained despite crossover of 66% of patients initially randomized to 
chemotherapy alone who elected to receive trastuzumab upon disease 
progression (Tripathy et al. 2000). Fever/chills were observed with the initial 
trastuzumab infusion in approximately 25% of patients. Class III or IV cardiac 
dysfunction was observed in 16% of the trastuzumab + AC subgroup; increasing 
age was an associated risk factor for the development of cardiotoxicity in this 
treatment cohort. 
 
Based on these data, trastuzumab was approved by the U.S. Food and Drug 
Administration (FDA) for use in HER2-overexpressing metastatic breast cancer 
in combination with paclitaxel for first-line treatment and as a single agent for 
patients failing prior chemotherapy for metastatic disease. However, current 
usage patterns of trastuzumab indicate that the drug is now being used in a 
broader array of circumstances than in the pivotal clinical trials. Since initiation 
of the pivotal clinical trials, docetaxel has become a commonly used taxane in 
the treatment of metastatic breast cancer (Chevallier et al. 1995) and data have 
emerged on the weekly use of paclitaxel (Akerley et al. 1997). Trastuzumab has 
been studied in combination with paclitaxel and docetaxel using a variety of 
doses and schedules with promising results (Seidman et al. 1999; Nicholson et 
al. 2000; Kuzur et al. 2000). In addition, the combination of trastuzumab with 
vinorelbine has been studied (Burstein et al. 2001). In this study, 30 of 40 
women treated with trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and 
vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil 
count) responded to therapy, for an overall response rate of 75% (95% 
confidence interval 57% to 89%). Neutropenia was the only grade IV toxicity. No 
patients had symptomatic heart failure. Grade 2 cardiotoxicity was observed in 3 


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patients; prior cumulative doxorubicin dose in excess of 240 mg/m2 and 
borderline pre-existing cardiac function were associated with this toxicity. 
 
Trastuzumab Clinical Experience in Adjuvant Breast Cancer 
 
Four large, randomized, phase III trials showed significant reduction in risk of 
disease recurrence with the addition of 1 year of trastuzumab to adjuvant 
therapy in patients with HER2-positive, early breast cancer. The 3-year planned 
joint interim analysis of the National Surgical Adjuvant Breast and Bowel Project 
(NSABP B-31) and the North Central Cancer Treatment Group (NCCTG N- 
9831) trials demonstrated significant improvements in disease-free survival 
(DFS) (hazard ratio [HR] 0.48, p<0.0001) and overall survival (OS) (HR 0.67, 
p=0.015) when 1-year of trastuzumab is added to adjuvant chemotherapy in 
patients with HER2-positive breast cancer (Romond et al 2005). At the 4-year 
follow-up, DFS and OS results were consistent (Perez et al 2011).  In the HERA 
trial, single agent trastuzumab given sequentially after adjuvant chemotherapy 
demonstrated significant improvements in DFS (HR 0.64, p<0.0001) and OS 
(HR 0.66, p=0.0115) compared with observation alone at a median follow-up of 
23.5 months (Smith et al 2007). At a median follow-up of 48.4 months, a DFS 
benefit was observed (HR 0.66, p=0.0115) with 1 year of trastuzumab, however, 
the OS benefit was not statistically significant at 4 years (HR 0.85, p=0.11). At 
the time of analysis, over 50% of patients in the observation arm had crossed- 
over to receive trastuzumab (Gianni et al 2011) The third protocol-specified 
analysis of the Breast Cancer International Research Group (BCIRG) 006 study 
continued to show that the addition of 52 weeks of trastuzumab to docetaxel- 
based adjuvant regimens significantly improved DFS. At a median follow-up of 
65 months, 5-year DFS rates were 84% (HR 0.64, p<0.001) and 81% (HR 0.75, 
p=0.04) in the doxorubicin-containing trastuzumab and non-anthracycline- 
containing trastuzumab arms, respectively (Slamon et al 2011). 
 
Trastuzumab Clinical Experience in Neoadjuvant-Adjuvant Treatment of 
Early Breast Cancer 
 
Study MO16432/NOAH investigated the effect of adding trastuzumab to 
neoadjuvant chemotherapy using doxorubicin plus paclitaxel, then paclitaxel, 
then cyclophosphamide plus methotrexate plus fluorouracil (CMF) in patients 
with HER2-positive locally advanced breast cancer. Patients who were 
randomized to trastuzumab received it for a total of one year before and after 
surgery. The primary endpoint was event-free survival; secondary endpoints 
included pathological complete response (pCR) rate, and safety. At the time of 
the primary analysis, 118 HER2-positive patients were enrolled in the 
chemotherapy-alone arm with 116 HER2-positive patients enrolled in the 
chemotherapy plus trastuzumab arm. Baseline characteristics were 
well-balanced across treatment arms. Thirty-six percent of HER2-positive 
tumors were hormone-receptor positive. In the HER2-positive population, the 3- 
year EFS was 71% (95% CI, 61%-78%) in the Herceptin-containing combination 
arm compared with 56% (95% CI, 46%-65%) in the chemotherapy-alone arm. 
The unadjusted HR were 0.59 (p=0.0123) for EFS and 0.62 (p=0.114) for overall 


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survival (OS) in the HER2-positive population. In the HER2-positive population, 
both ORR and pCR in breast tissue were significantly higher in the Herceptin 
with chemotherapy arm compared with chemotherapy alone: 87% vs 74% for 
ORR (p=0.009); 43% vs 22% for pCR in breast tissue (p=0.0007), respectively. 
Overall, treatment was well-tolerated with acceptable cardiac safety (Gianni et al 
2010). 
 
A Phase III neoadjuvant study compared four cycles of paclitaxel followed by 
four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) with and 
without weekly trastuzumab for 24 weeks. The study reported significantly 
higher pCR rate in the group receiving trastuzumab (66.7% vs 25%, p = 0.02) 
(Buzdar et al 2005). A three year follow up study showed 100% disease-free 
survival (p = 0.041) with 0% recurrence, with no cardiac dysfunction and no 
deaths from cardiac reasons (Buzdar et al 2007). Similar results were obtained 
by another group in Spain which reported 61% pCR with the same regimen 
(Pernas et al, 2012). A retrospective single institution study examining 
anthracycline and non-anthracycline based trastuzumab-containing neoadjuvant 
chemotherapies in HER2 positive breast cancer confirmed increased pCR rate 
in the anthracycline group (60.6% vs. 43.3%, p = 0.016) (Bayraktar et al, 2011). 
These pCR rates represent the highest rates reported in any clinical trial for the 
HER2 positive patient population. 
 
Pertuzumab Clinical Experience 
 
Pertuzumab, a humanized monoclonal antibody to HER2, represents a 
promising new anti-HER2 agent with a novel mechanism of action targeting 
inhibition of HER2 dimerization. Nonclinical and clinical data to date indicate that 
pertuzumab provides HER2 blockade through inhibition of HER2 
heterodimerization. Pertuzumab has been shown in preclinical experiments to 
have superior anti-tumor effects when combined with other anti-HER2 
treatments such as trastuzumab than when used as monotherapy. 
Trastuzumab and pertuzumab monoclonal antibodies bind to distinct epitopes 
on HER2 without competing with each other, resulting in distinctive mechanisms 
for disrupting HER2 signaling. These mechanisms are complementary and 
result in augmented therapeutic efficacy when pertuzumab and trastuzumab are 
given in combination. Preclinical data indicate at least additive efficacy when the 
two agents are administered together, resulting in significantly reduced tumor 
volume compared with either agent alone. 
Clinically, pertuzumab may have optimal therapeutic effects when given in 
combination with trastuzumab to patients with HER2-positive cancers,  
evidenced by data generated in a Phase II study of patients with previously 
treated HER2-positive MBC (Baselga et al. 2010). A recently published meta- 
analysis of pertuzumab phase II trials concluded that pertuzumab has a low 
cardiac risk and there is no notable increase in cardiac events when pertuzumab 
is used in combination with other anticancer agents (Lenihan et al. 2011). 


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Trastuzumab and Pertuzumab Combination Therapy in Patients with HER2-
positive Tumors 
 
Metastatic Breast Cancer: In the Phase III, pivotal study WO20698/TOC4129g 
(CLEOPATRA; N=808) in patients with previously-untreated HER2-positive 
MBC, a statistically significant and clinically meaningful improvement in 
progression-free survival (PFS) was observed in patients treated with 
pertuzumab, trastuzumab and docetaxel (N=406) compared to those receiving 
placebo, trastuzumab and docetaxel (N=402). PFS was prolonged at the median 
by 6.1 months and the risk of disease progression or death was reduced by 38% 
(Hazard ratio [HR] = 0.62; 95% CI = 0.51, 0.75; p < 0.0001) with an  
improvement in median PFS from 12.4 months to 18.5 months (Baselga et al 
2011). There were no significant differences in toxicity in the two treatment  
arms. In a Phase II, single-arm study (BO17929; N= 66) in patients with 
previously-treated HER2-positive MBC, four complete responses and 12 partial 
responses (24% objective response rate) were observed following combined 
treatment with pertuzumab and trastuzumab (Baselga et al 2007). The 
combination resulted in minimal cardiotoxicity, with no changes in overall mean 
LVEF. 
 
Early Breast Cancer: In the Phase II study WO20697 (NEOSPHERE; N=417) 
patients with HER2-positive early breast cancer (EBC) receiving combination 
neoadjuvant therapy with pertuzumab, trastuzumab and docetaxel (N=107) had 
a pathological complete response (pCR) rate of 46%, compared with 29% in 
patients receiving trastuzumab plus docetaxel (N=107) (P=0.0141, 95% CI 21- 
39) (Ginani et al 2011). The Phase II study BO22280 (TRYPHAENA; N=223) 
investigated neoadjuvant pertuzumab and trastuzumab a) concomitantly with 
anthracycline-based treatment (N=72); b) following anthracycline-based 
treatment (N=75) or c) concomitantly with a carboplatin-based regimen in 
patients with HER2-positive EBC (N=76). All three treatment regimens were 
efficacious, with 57%-66% of patients achieving a pCR (Schneeweiss et al. 
2011). The primary end point of this study was cardiac safety and it reported 
transient, reversible decline in left ventricular ejection fraction (defined as drop in 
LVEF > 10% or to below 50%) in 3.9% to 5.3% of patients. 
 
Together, these findings suggest that pertuzumab confers minimal cardiotoxicity 
when added to trastuzumab, and that the pertuzumab/trastuzumab combination 
is more effective than either treatment alone. 
 
1.4 
SAFETY 
 
TRASTUZUMAB SAFETY 
 
Experience with trastuzumab administration has shown that the drug is relatively 
safe. The most significant safety signal observed during clinical trials was 
cardiac dysfunction (principally clinically significant heart failure [CHF]), 
particularly when trastuzumab was given in combination with an anthracycline- 


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containing regimen in metastatic breast cancer. Much of the cardiac dysfunction 
was reversible on discontinuation of trastuzumab. 
 
In addition, during the first infusion with trastuzumab, a symptom complex most 
commonly consisting of fever and/or chills was observed in approximately 40% 
of patients. The symptoms were usually mild to moderate in severity and 
controlled with acetaminophen, diphenhydramine, or meperidine. These 
symptoms were uncommon with subsequent infusions. However, in the post- 
approval setting, more severe adverse reactions to trastuzumab have been 
reported. These have been categorized as hypersensitivity reactions (including 
anaphylaxis), infusion reactions, and pulmonary events. Rarely, these severe 
reactions culminated in a fatal outcome. 
 
Trastuzumab appears to be relatively non-immunogenic. Only 1 of 903 patients 
evaluated developed neutralizing antibodies to trastuzumab. The development 
of anti-trastuzumab antibodies in this patient was not associated with clinical 
signs or symptoms. 
 
 
PERTUZUMAB SAFETY 
 
As of 7 November 2011, 1757 patients with cancer have been treated with 
pertuzumab in all company-sponsored pertuzumab trials, and an additional 114 
patients have received pertuzumab in combination studies with trastuzumab 
emtansine. Overall, data indicate that pertuzumab is well-tolerated as 
monotherapy and that it can be given in combination with trastuzumab and a 
range of other therapeutic agents with manageable additional toxicity. No new or 
unexpected toxicities were encountered other than those that are known for 
agents that target the HER family of receptors. Serious or severe infusion- 
associated symptoms have been rarely observed in patients receiving 
pertuzumab. A low level of cardiac toxicities, predominantly asymptomatic 
declines in left ventricular ejection fraction (LVEF), has been reported. In the 
pivotal CLEOPATRA Phase III trial WO20698/TOC4129g the rates of 
symptomatic and asymptomatic left ventricular systolic dysfunction (LVSD) were 
not higher in patients receiving pertuzumab, trastuzumab and docetaxel than in 
those receiving placebo, trastuzumab and docetaxel. 
 
No fetal studies in humans have been performed but pertuzumab caused 
oligohydramnios, delayed renal development and embryo-fetal deaths in 
pregnant cynomolgus monkeys. Moreover, in the post-marketing setting, cases 
of oligohydramnios, some associated with fatal pulmonary hypoplasia of the 
fetus, have been reported in pregnant women receiving trastuzumab (for further 
details, see trastuzumab prescribing information). Therefore, pertuzumab should 
not be used in pregnant women. Protocols for ongoing pertuzumab studies 
indicate that highly effective contraceptive measures must be used; continuous 
pregnancy monitoring must be performed during the trials and for six months 
after the last dose of study drug is administered. Because of the long half-life of 
pertuzumab women should be warned not to become pregnant for at least six 


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months after completion of treatment. 
 
Infusion-Associated Symptoms. Like other monoclonal antibodies, 
pertuzumab has been associated with infusion associated reaction (IAR) (such 
as chills, diarrhea, fatigue, headache, nausea, and pyrexia), and with 
hypersensitivity reactions. Close observation of the patient during and for 60 
minutes after the first infusion and during and for 30 minutes following 
subsequent infusions is recommended following the administration of 
pertuzumab. If a significant IAR occurs, the infusion should be slowed down or 
interrupted and appropriate medical therapies should be administered. Patients 
should be evaluated and carefully monitored until complete resolution of signs 
and symptoms. Permanent discontinuation should be considered in patients with 
severe infusion reactions. This clinical assessment should be based on the 
severity of the preceding reaction and response to administered treatment for 
the adverse reaction. 
 
Serious Infusion-Associated Events. Serious adverse reactions including 
dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently with 
trastuzumab and pertuzumab administration. In rare cases (4 per 10,000), 
these events were associated with a clinical course culminating in a fatal 
outcome in trastuzumab trials. Serious reactions have been treated with 
supportive therapy such as oxygen, beta-agonists, corticosteroids and 
withdrawal of trastuzumab as indicated. 
 
Hematologic Toxicity and Neutropenic Infections with Trastuzumab. In 
clinical trials, an increased incidence of anemia was observed in patients 
receiving trastuzumab plus chemotherapy compared with patients receiving 
chemotherapy alone. The majority of these anemia events were mild or 
moderate in intensity and reversible; none resulted in discontinuation of 
trastuzumab therapy.  In clinical trials, the per-patient incidences of moderate to 
severe neutropenia and of febrile neutropenia were higher in patients receiving 
trastuzumab in combination with myelosuppressive chemotherapy as compared 
to those who received chemotherapy alone. In the post marketing setting, 
deaths due to sepsis in patients with severe neutropenia have been reported in 
patients receiving trastuzumab and myelosuppressive chemotherapy, although 
in controlled clinical trials (pre- and post-marketing), the incidence of septic 
deaths was not significantly increased. The pathophysiologic basis for 
exacerbation of of neutropenia has not been determined; the effect of 
trastuzumab on the pharmacokinetics of chemotherapeutic agents has not been 
fully evaluated. 
Risk of Neutropenia with Pertuzumab and Pertuzumab/Trastuzumab 
combination.  Neutropenic events are virtually absent with chemotherapy-free 
Pertuzumab regimens and with single-agent pertuzumab. In the pivotal study 
WO20698/TOC4129g incidence of neutropenic events was increased in patients 
receiving pertuzumab, trastuzumab and docetaxel, compared to patients in the 
placebo-controlled arm. This was largely driven by an increase in Grades 3 and 


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4 febrile neutropenia. No febrile neutropenia events occurred after docetaxel 
discontinuation. Pertuzumab, at a dose of 420 mg, was well tolerated in 
combination with docetaxel up to 75 mg/m2 in the Phase Ib study, BO17021. 
However, pertuzumab in combination with 100 mg/m2 docetaxel was not well 
tolerated. Dose-limiting toxicity was observed, including febrile neutropenia. 
However, the registered dose of docetaxel in combination with trastuzumab 
ranges from 65 to 100 mg/m2, and there is evidence that outcomes might be 
improved when higher doses of docetaxel are given. Given that the DLTs in 
Study BO17021 were not life threatening and that exposure to docetaxel shows 
interpatient variability, patients receiving pertuzumab in combination with 
docetaxel in ongoing studies are treated initially with 75 mg/m2 docetaxel, and 
then dose escalation of docetaxel to 100 mg/m2 is recommended (as described 
in the protocol dose escalation rules), provided that the patient does not 
experience significant toxicities at the starting dose. This strategy is intended to 
ensure optimum individual exposure for patients receiving docetaxel in 
combination with pertuzumab. The tolerability of the combination therapy at the 
higher (100 mg/m2) dose of docetaxel is encouraging in those patients who 
tolerate the 75 mg/m2 starting dose well. Patients receiving pertuzumab in 
combination with docetaxel or other cytotoxic agents should undergo careful 
hematological monitoring for neutropenia during treatment, and should be 
treated promptly with antibiotics and other supportive measures as clinically 
indicated. 
Secondary acute leukemia or myelodysplastic syndrome has been reported 
in 4 of approximately 1200 patients who participated in trastuzumab clinical 
trials.  Patients treated with chemotherapeutic agents are known to be at 
increased risk for secondary leukemia. The observed incidence of leukemia 
among trastuzumab-treated patients appears to be consistent with the expected 
incidence of leukemia among patients treated with chemotherapy for metastatic 
breast cancer. Therefore, the contribution of trastuzumab to the etiology of 
acute leukemia or myelodysplastic syndrome in these cases is unclear. 
Risk of respiratory events. A low rate of respiratory events that are compatible 
with an IAR or hypersensitivity reaction/anaphylaxis has been reported. 
Although pertuzumab targets the HER2 receptor it inhibits heterodimerization 
with other members of the HER family (eg, EGFR [HER1]). Accordingly, it may 
cause toxicities associated with the use of EGFR inhibitors,such as ILD. The few 
reports of ILD occurring in pertuzumab-treated patients received so far also had 
evidence of alternative causes, eg, concomitant medication, 
preceding/concurrent neutropenia with potential infection or relevant medical 
history. 
 
Risk of EGFR-related toxicities. Although pertuzumab targets the HER2 
receptor, it inhibits heterodimerization with other members of the HER family 
(eg, EGFR [HER1]). Accordingly, it may cause toxicities associated with the use 
of EGFR inhibitors such as diarrhea, rash and other dermatologic toxicities (eg, 
dry skin, pruritus, nail disorders, mucositis). Diarrhea. In the 7-week IV and 26- 
week toxicity studies in cynomolgus monkeys, there was a treatment-related 
increase in the incidence of diarrhea. Diarrhea has been observed in 


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approximately 60% of patients (treatment-related diarrhea in 50% of patients) 
being treated with pertuzumab in phase II single-agent studies, and up to 
approximately 70% of patients in combination therapy studies. Diarrhea was 
CTC Grade 1 or 2 in the majority of cases. To prevent dehydration, early 
treatment of diarrhea with anti-diarrheal medication should be considered and 
patients treated with fluids and electrolyte replacement, as clinically indicated. 
Rash has also been observed with EGFR inhibitors, mostly of mild to moderate 
intensity. Rash has been observed in approximately 17% of patients receiving 
pertuzumab in Phase II single-agent studies and up to 73% of patients in 
combination studies. The rash was generally of CTC Grade 1 or 2 in severity. 
Treatment recommendations for EGFR associated rash include topical or oral 
antibiotics, topical pimecrolimus, topical or (for severe reactions) systemic 
steroids. These agents may be used in patients experiencing pertuzumab- 
related rash, as clinically indicated, although they have not been studied in this 
context. 
 
 
Risk of left ventricular dysfunction. Decreases in LVEF have been reported 
with drugs that block HER2 activity.  Trastuzumab and pertuzumab both target 
HER2, thus there is a risk of cardiac dysfunction with these agents. In the 
CLEOPATRA pivotal trial WO20698/TOC4129g, pertuzumab in combination 
with trastuzumab and docetaxel was not associated with increases in the 
incidence of symptomatic LVSD or decreases in LVEF compared with placebo 
in combination with trastuzumab and docetaxel.  Pertuzumab combined with 
trastuzumab and chemotherapy also did not result in any significantly greater 
incidence of symptomatic LVSD or decreases in LVEF than trastuzumab and 
chemotherapy in patients with EBC (Study WO20697). However, in the pivotal 
MBC trial (CLEOPATRA Study WO20698/TOC4129g) a greater proportion of 
patients who developed symptomatic LVSD had received prior anthracyclines 
and/or radiotherapy compared to the proportion of patients receiving prior 
anthracyclines and/or radiotherapy in the overall pertuzumab-treated population. 
Therefore patients who have received prior anthracyclines or prior radiotherapy 
to the chest area may be at higher risk of decreased LVEF. 
 
Pertuzumab has not been studied in patients with: a pretreatment LVEF value of 
≤ 50%; a prior history of CHF; decreases in LVEF to <50% during prior 
trastuzumab adjuvant therapy; conditions that could impair left ventricular 
function such as uncontrolled hypertension, recent myocardial infarction, serious 
cardiac arrhythmia requiring treatment or a cumulative prior anthracycline 
exposure to > 360mg/m2 of doxorubicin or its equivalent. 
 
 
1.5 TRASTUZUMAB AND PERTUZUMAB PHARMACOKINETICS 
Trastuzumab 
A Phase I single dose study (H0407g) of intravenous trastuzumab infusions 
ranging from 10-500 mg resulted in dose-dependent pharmacokinetics (PK) with 


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serum clearance of trastuzumab decreasing with an increasing dose at doses 
<250 mg.  PK modeling of trastuzumab concentration-time data from 7 patients 
that were administered doses of 250 mg and 500 mg had a mean half-life of 5.8 
days (range 1-32 days).  Additionally, PK modeling showed that weekly 
trastuzumab doses ≥250 mg resulted in serum trough levels of >20 g/mL that 
was above the minimum effective concentration observed in preclinical 
xenograft studies in tumor-bearing mice. The Phase I data supported the weekly 
dosing schedule that was implemented in all subsequent Phase II and Phase III 
clinical trials. A weight-based dose schedule was adopted after two Phase II 
trials (H0551g and H0552g) suggested that inter-subject variability in 
trastuzumab PK was related to body weight.  These findings resulted in a 
trastuzumab dose schedule of a 4 mg/kg loading dose followed by a weekly 
2 mg/kg maintenance dose utilized in the two pivotal Phase III trials (H0648g 
and H0649g) that were the basis of the BLA filing and subsequent FDA approval 
of trastuzumab for HER2+ metastatic breast cancer. 
 
The trastuzumab PK data from studies H0407g (Phase I), H0551g (Phase II), 
and H0649 (pivotal) have been subsequently reanalyzed by a population PK 
approach using nonlinear mixed effect modeling (NONMEM). A linear two- 
compartment model best described the concentration-time data, and accounted 
for the accumulation of trastuzumab serum concentrations seen in the Phase II 
and Phase III clinical studies.  A covariate analysis was conducted using the 
subjects from these single agent studies to evaluate the effect of 
pathophysiologic covariates (e.g. age, weight, shed antigen) on the PK 
parameter estimates. The covariates that significantly influenced clearance 
were the level of shed antigen and the number of metastatic sites. Volume of 
distribution was significantly influenced by weight and shed antigen level. 
Additionally, data from the Phase III study, H0648g, were added to assess the 
influence of concomitant chemotherapy on trastuzumab PK.  Importantly, 
chemotherapy (AC or paclitaxel) did not significantly alter trastuzumab PK.  
The estimated half-life of trastuzumab based on the final model was 28.5 days. 
 
Analysis of data obtained from two Phase II studies which utilized a loading 
dose of 8 mg/kg trastuzumab followed by a 6 mg/kg maintenance dose 
administered every 3 weeks (q3 week) as a single-agent, and in combination 
with paclitaxel (175 mg/m2), confirmed that a two-compartment model best 
describes the PK of trastuzumab.  Model-independent analysis of the of the data 
obtained in these studies gives comparable PK parameter estimates to those 
obtained by the population PK model, thus confirming the validity of the 
population PK model.  In addition, the population PK model adequately 
predicted trastuzumab serum concentrations obtained independently in these 
studies. After two treatment cycles, trastuzumab exposures were similar to 
those measured in the once weekly dosing regimen used in the pivotal trials. 
Trough levels were in excess of the targeted serum concentrations established 
from preclinical xenograft models, and as expected, peak levels were greater 
than those observed upon weekly administration. The apparent half-life of 
trastuzumab in these studies was determined to be approximately 21 days, and 
the PK was supportive of a q3 week dosing schedule. 


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The efficacy and safety results from these Phase II studies with q3 week dosing 
do not appear to be different from those with weekly dose-schedules {ref 
Slamon, Cobleigh, Vogel}.  In the trastuzumab q3 weekly monotherapy study, 
105 patients with HER2+ metastatic breast cancer were treated, with an 
objective response rate of 19% (23% in patients with measurable centrally 
confirmed HER2+ disease). The median baseline LVEF was 63%, which did not 
significantly change during the course of the study.  One patient experienced 
symptomatic CHF, which resolved with medical treatment for CHF and 
discontinuation of trastuzumab. In the study of q3 weekly trastuzumab and 
paclitaxel, 32 patients were treated with an investigator-assessed response rate 
of 59%. Ten patients had a decrease in LVEF of 15% or greater.  One patient 
experienced symptomatic CHF, which improved symptomatically after medical 
therapy for CHF and discontinuation of trastuzumab. 
 
Pertuzumab 
 
Similar pharmacokinetics (PK) have been observed across clinical studies, with 
no dose dependent changes in clearance at doses ranging from 2.0 to 25.0 
mg/kg (equivalent to 140 mg to 1750 mg for a 70 kg patient). A two- 
compartment model adequately described the concentration-time data with a 
systemic serum clearance of 0.239 L/day and a median terminal half-life of 17.2 
days for a typical patient. Population PK analysis and simulations based on data 
from Phase Ib/II studies, with pertuzumab administered as a single agent, 
predicted that > 90% of patients receiving the fixed, non-weight-based dosing 
regimen (840 mg loading dose with a 420 mg maintenance dose every three 
weeks [q3w]) would have steady-state serum concentrations that were higher 
than the target serum concentration (> 20 μg/mL) identified in nonclinical 
xenograft models. This flat dosing regimen was used in subsequent studies. 
Population PK modeling of data from Phase I, II, and III studies supports the use 
of fixed, non-weight based dosing based on the rationale described above, 
regardless of sex and race (Japanese vs. Non-Japanese). Results from studies 
where pertuzumab was administered in combination with various small molecule 
chemotherapeutic agents (gemcitabine, capecitabine, erlotinib or docetaxel), 
indicate that pertuzumab does not alter the PK of these agents and the PK of 
pertuzumab is similar to that observed in single-agent pertuzumab studies. In 
addition, data from the Phase IIl trial WO20698/TOC4129g demonstrate that 
pertuzumab administration did not change the PK of trastuzumab, and there  
was no evidence of drug-drug interactions (DDI) when docetaxel was combined 
with pertuzumab plus trastuzumab. 
 
 
1.6 
OTHER STUDY DRUG(S) BACKGROUND 
 
 
PACLITAXEL (TAXOL®) 


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Paclitaxel is a natural product with antitumor activity. Paclitaxel is obtained via a 
semi-synthetic process from Taxus baccata. The chemical name for paclitaxel is 
5β,20-Epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4,10-diacetate 2- 
benzoate 13-ester with (2R,3S)-N-benzoyl-3-phenylisoserine. Paclitaxel is a 
white to off-white crystalline powder with the empirical formula C47H51NO14 and 
a molecular weight of 853.91. It is highly lipophilic, insoluble in water, and melts 
at approximately 216°C to 217°C.Paclitaxel is an antimicrotubule agent that 
promotes the assembly of microtubules from tubulin dimers and stabilizes 
microtubules by preventing depolymerization. This stability results in the 
inhibition of the normal dynamic reorganization of the microtubule network that 
is essential for vital interphase and mitotic cellular functions. Paclitaxel induces 
abnormal arrays of microtubules throughout the cell cycle and multiple asters of 
microtubules during mitosis. 
 
Human Toxicology:  Unless otherwise noted, the following discussion refers to 
the overall safety database of 812 patients with solid tumors treated with single- 
agent paclitaxel in clinical studies. 
 
Hematologic: Bone marrow suppression was the major dose-limiting toxicity of 
paclitaxel. Neutropenia, the most important hematologic toxicity, was dose and 
schedule dependent and was generally rapidly reversible. Fever was frequent 
(12% of all treatment courses). Infectious episodes occurred in 30% of all 
patients and 9% of all courses; these episodes were fatal in 1% of all patients, 
and included sepsis, pneumonia and peritonitis.  Thrombocytopenia was 
reported. Twenty percent of the patients experienced a drop in their platelet 
count below 100,000 cells/mm3 at least once while on treatment; 7% had a 
platelet count <50,000 cells/mm3 at the time of their worst nadir. Bleeding 
episodes were reported in 4% of all courses and by 14% of all patients, but most 
of the hemorrhagic episodes were localized and the frequency of these events 
was unrelated to the paclitaxel dose and schedule. In an adjuvant breast 
carcinoma trial, the incidence of severe thrombocytopenia and platelet 
transfusions increased with higher doses of doxorubicin.  Anemia (Hb <11 g/dL) 
was observed in 78% of all patients and was severe (Hb <8 g/dL) in 16% of the 
cases. No consistent relationship between dose or schedule and the frequency 
of anemia was observed. Among all patients with normal baseline hemoglobin, 
69% became anemic on study but only 7% had severe anemia. Red cell 
transfusions were required in 25% of all patients and in 12% of those with 
normal baseline hemoglobin levels. 
 
Neurologic: In general, the frequency and severity of neurologic manifestations 
were dose-dependent in patients receiving single-agent paclitaxel. Peripheral 
neuropathy was observed in 60% of all patients (3% severe) and in 52% (2% 
severe) of the patients without pre-existing neuropathy. The frequency of 
peripheral neuropathy increased with cumulative dose. Paresthesia commonly 
occurs in the form of hyperesthesia. Neurologic symptoms were observed in 
27% of the patients after the first course of treatment and in 34 to 51% from 
course 2 to 10. Peripheral neuropathy was the cause of paclitaxel 
discontinuation in 1% of all patients. Sensory symptoms have usually improved 


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or resolved within several months of paclitaxel discontinuation. Pre-existing 
neuropathies resulting from prior therapies are not a contraindication for 
paclitaxel therapy. Other than peripheral neuropathy, serious neurologic events 
following paclitaxel administration have been rare (<1%) and have included 
grand mal seizures, syncope, ataxia, and neuroencephalopathy. 
 
Arthralgia/Myalgia: There was no consistent relationship between dose or 
schedule of paclitaxel and the frequency or severity of arthralgia/myalgia. Sixty 
percent of all patients treated experienced arthralgia/myalgia; 8% experienced 
severe symptoms. The symptoms were usually transient, occurred 2 or 3 days 
after paclitaxel administration, and resolved within a few days. The frequency 
and severity of musculoskeletal symptoms remained unchanged throughout the 
treatment period. 
 
Gastrointestinal (GI): Nausea/vomiting, diarrhea, and mucositis were reported  
by 52%, 38%, and 31% of all patients, respectively. These manifestations were 
usually mild to moderate. Mucositis was schedule dependent and occurred more 
frequently with the 24-hour than with the 3-hour infusion. 
 
Other Clinical Events: Alopecia was observed in almost all (87%) of the patients. 
Transient skin changes due to paclitaxel-related hypersensitivity reactions have 
been observed, but no other skin toxicities were significantly associated with 
paclitaxel administration. 
 
 
 
Paclitaxel Pharmacology: 
 
Kinetics:  Following IV administration of TAXOL, paclitaxel plasma 
concentrations decline in a biphasic manner. The pharmacokinetics of paclitaxel 
have been shown to be nonlinear. On average, 89% of drug is bound to serum 
proteins; the presence of cimetidine, ranitidine, dexamethasone, or 
diphenhydramine does not affect protein binding of paclitaxel. Paclitaxel is 
extensively metabolized in the liver primarily to 6α-hydroxypaclitaxel by the 
cytochrome P450 isozyme CYP2C8; and to 2 minor metabolites, 3'-p- 
hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the 
metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of 
agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, 
cyclosporin, teniposide, etoposide, and vincristine). The pharmacokinetics of 
paclitaxel may also be altered in vivo as a result of interactions with compounds 
that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4. Patients 
with hepatic dysfunction had increased plasma paclitaxel exposure with no 
apparent increase in the frequency or severity of toxicity. The effect of renal 
dysfunction on the disposition of paclitaxel has not been investigated. 
 
Formulation: Paclitaxel is available in 30 mg (5 mL), 100 mg (16.7 mL), and 300 
mg (50 mL) multidose vials. Each mL of sterile nonpyrogenic solution contains 6 
mg paclitaxel, 527 mg of purified Cremophor® EL (polyoxyethylated castor oil) 
and 49.7% (v/v) dehydrated alcohol, USP. 


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Storage and Stability:  Unopened vials of paclitaxel are stable until indicated 
date between 20°–25°C. Neither freezing nor refrigeration adversely affects the 
stability of the product. Solutions for infusion prepared as recommended are 
stable at ambient temperature (approximately 25° C) and lighting conditions for 
up to 27 hours. 
 
 
 
5-FLUOROURACIL 
 
5-fluoro-2,4-(1H,3H)-pyrimidinedione, 5-fluorouracil, is metabolized and blocks 
the methylation reaction of deoxyuridylic acid to thymidylic acid, interfering with 
DNA and RNA synthesis. 
 
Human Toxicology: 
 
Stomatitis and esophagopharyngitis (which may lead to sloughing and 
ulceration), diarrhea, anorexia, nausea and emesis are commonly seen during 
therapy. Leukopenia usually follows every course of adequate therapy with 
fluorouracil. The lowest white blood cell counts are commonly observed 
between the 9th and 14th days after the first course of treatment, although 
uncommonly the maximal depression may be delayed for as long as 20 days. 
By the 30th day the count has usually returned to the normal range. 
Alopecia and dermatitis may be seen in a substantial number of cases. The 
dermatitis most often seen is a pruritic maculopapular rash usually appearing on 
the extremities and less frequently on the trunk. It is generally reversible and 
usually responsive to symptomatic treatment. 
 
The administration of 5-fluorouracil has been associated with the occurrence of 
palmar-plantar erythrodysesthesia syndrome, also known as hand-foot 
syndrome. This syndrome has been characterized as a tingling sensation of 
hands and feet which progress over the next few days to pain when holding 
objects or walking. The palms and soles became symmetrically swollen and 
erythematous with tenderness of the distal phalanges, possibly accompanied by 
desquamation. Interruption of therapy is followed by gradual resolution over 5 to 
7 days. Although pyridoxine has been reported to ameliorate the palmar-plantar 
erythrodysesthesia syndrome, its safety and effectiveness has not been 
established. 
 
5-Fluorouracil Pharmacology: 
 
Kinetics:  Following IV injection, fluorouracil distributes into tumors, intestinal 
mucosa, bone marrow, liver and other tissues throughout the body. In spite of its 
limited lipid solubility, fluorouracil diffuses readily across the blood-brain barrier 
and distributes into cerebrospinal fluid and brain tissue. Seven percent to 20%  
of the parent drug is excreted unchanged in the urine in 6 hours; of this over 
90% is excreted in the first hour. The remaining percentage of the administered 
dose is metabolized, primarily in the liver. The catabolic metabolism of 


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fluorouracil results in inactive degradation products, which are excreted in the 
urine. The mean half-life of 5-fluorouracil elimination from plasma is 
approximately 16 minutes and is dose dependent. No intact drug can be 
detected in the plasma 3 hours after an IV injection. 5-Fluorouracil should be 
used with extreme caution in patients with a history of impaired hepatic or renal 
function. 
 
Formulation: 5-fluorouracil is supplied in 10 mL aliquots containing 500 mg 
fluorouracil, with pH is adjusted to approximately 9.2 with sodium hydroxide. 
 
Storage and Stability:  5-fluorouracil should be stored at room temperature 15° 
to 30°C (59° to 86°F), protected from light, and retained in carton until time of 
use. 
 
 
 
EPIRUBICIN (ELLENCE®) 
Epirubicin hydrochloride is the 4-epimer of doxorubicin and is a semi-synthetic 
derivative of daunorubicin. The chemical name is (8S-cis)-10-[(3-amino-2,3,6- 
trideoxy-α-L-arabinohexopyranosyl)oxy]-7,8,9,10-tetrahydro6,8,11-trihydroxy-8- 
(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione hydrochloride. Epirubicin is 
an anthracycline cytotoxic agent that binds to DNA through intercalation, 
triggering DNA cleavage by topoisomerase II, and resulting in cell death. 
 
Human Toxicology: 
 
Hematologic: Dose-dependent, reversible leukopenia and/or neutropenia is the 
predominant manifestation of hematologic toxicity associated with epirubicin 
hydrochloride injection and represents the most common acute dose-limiting 
toxicity of this drug. In most cases, the white blood cell (WBC) nadir is reached 
10 to 14 days from drug administration. Leukopenia/neutropenia is usually 
transient, with WBC and neutrophil counts generally returning to normal values 
by Day 21 after drug administration. Clinical consequences of severe 
myelosuppression include fever, infection, septicemia, septic shock, 
hemorrhage, tissue hypoxia, symptomatic anemia, or death. 
 
Gastrointestinal: A dose-dependent mucositis (mainly oral stomatitis, less often 
esophagitis) may occur in patients treated with epirubicin hydrochloride 
injection. Clinical manifestations of mucositis may include a pain or burning 
sensation, erythema, erosions, ulcerations, bleeding, or infections. Mucositis 
generally appears early after drug administration and, if severe, may progress 
over a few days to mucosal ulcerations; most patients recover from this adverse 
event by the third week of therapy. Hyperpigmentation of the oral mucosa may 
also occur. Nausea, vomiting, and occasionally diarrhea and abdominal pain 
can also occur. Severe vomiting and diarrhea may produce dehydration. 
Antiemetics may reduce nausea and vomiting; prophylactic use of antiemetics 
before therapy should be considered. 


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Cardiovascular: In a retrospective survey, including 9,144 patients, mostly with 
solid tumors in advanced stages, the probability of developing CHF increased 
with increasing cumulative doses of epirubicin hydrochloride injection. The 
estimated risk of epirubicin hydrochloride injection-treated patients developing 
clinically evident CHF was 0.9% at a cumulative dose of 550 mg/m2, 1.6% at 
700 mg/m2, and 3.3% at 900 mg/m2. The risk of developing CHF in the absence 
of other cardiac risk factors increased steeply after an epirubicin hydrochloride 
injection cumulative dose of 900 mg/m2. In another retrospective survey of 469 
epirubicin hydrochloride injection-treated patients with metastatic or early breast 
cancer, the reported risk of CHF was comparable to that observed in the larger 
study of over 9,000 patients. 
 
Cutaneous Reactions: Alopecia occurs frequently, but is usually reversible, with 
hair regrowth occurring within 2 to 3 months from the termination of therapy. 
 
Secondary Leukemia: An analysis of 7,110 patients who received adjuvant 
treatment with epirubicin hydrochloride injection in controlled clinical trials as a 
component of poly-chemotherapy regimens for early breast cancer showed a 
cumulative risk of secondary acute myelogenous leukemia or myelodysplastic 
syndrome (AML/MDS) of about 0.27% (approximate 95% CI, 0.14 to 0.40) at 3 
years, 0.46% (approximate 95% CI, 0.28 to 0.65) at 5 years, and 0.55% 
(approximate 95% CI, 0.33 to 0.78) at 8 years. The risk of developing AML/MDS 
increased with increasing epirubicin hydrochloride injection cumulative doses. 
The cumulative probability of developing AML/MDS was found to be particularly 
increased in patients who received more than the maximum recommended 
cumulative dose of epirubicin hydrochloride injection (720 mg/m2) or 
cyclophosphamide (6,300 mg/m2). 
Epirubicin Pharmacology: 
 
Epirubicin displays linear pharmacokinetics and its plasma concentration 
declines in a triphasic manner. Following IV administration, epirubicin is rapidly 
and widely distributed into the tissues. About 77% is bound to plasma proteins 
and is not affected by drug concentration. It also concentrates in red blood cells. 
Epirubicin is extensively and rapidly metabolized by the liver and red blood cells. 
Four main metabolic routes have been identified: (1) reduction of the C-13 keto- 
group with the formation of the 13(S)-dihydro derivative, epirubicinol; (2) 
conjugation of both the unchanged drug and epirubicinol with glucuronic acid; 
(3) loss of the amino sugar moiety through a hydrolytic process with the 
formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the 
amino sugar moiety through a redox process with the formation of the 7- 
deoxydoxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol 
has ~10% activity of epirubicin; no significant activity or toxicity has been 
reported for the other metabolites. Epirubicin and its major metabolites are 
eliminated primarily through biliary excretion and, to a lesser extent, by urinary 
excretion. Plasma clearance of epirubicin is reduced in elderly women, patients 
with hepatic dysfunction, and patients with significant kidney injury (creatinine > 


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5 mg/dL). Preadministration of paclitaxel (but not docetaxel), or coadministration 
of cimetidine causes variable increases in the mean AUC of epirubicin. 
 
Formulation: Epirubicin hydrochloride injection is supplied as a sterile, clear, red 
solution in glass vials containing 50 or 200 mg of epirubicin hydrochloride, at a 
concentration of 2 mg/mL epirubicin hydrochloride. Inactive ingredients include 
sodium chloride and water for injection. The pH of the solution is adjusted to 3.0 
with hydrochloric acid. 
 
Storage and Stability:  Epirubicin should be refrigerated between 2°-8°C. 
Refrigeration can result in the formation of a gel. The gel will return to a slightly 
viscous to mobile solution after 2-4 hours equilibration at room temperature. The 
solution should be used within 24 hours after removal from refrigeration. 
 
 
 
CYCLOPHOSPHAMIDE (CYTOXAN®) 
2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemo- 
nohydrate, Cyclophosphamide, is biotransformed principally in the liver to active 
alkylating metabolites which cross-link DNA. 
 
Human Toxicology: 
 
Toxicity from cyclophosphamide includes bone marrow suppression which 
usually occurs 10 to 12 days after administration, nausea, vomiting, anorexia, 
abdominal discomfort, diarrhea, stomatitis, hemorrhagic colitis, jaundice, 
reversible alopecia, hemorrhagic cystitis which can frequently be prevented with 
increased hydration, hematuria, ureteritis, tubular necrosis, fibrosis of the 
bladder, cardiac toxicity which may potentiate doxorubicin-induced 
cardiotoxicity, rare anaphylactic reaction, skin rash, hyperpigmentation of the 
skin and nails, interstitial pulmonary fibrosis, and cross sensitivity with other 
aklylating agents. Treatment with cyclophosphamide may cause significant 
suppression of the immune system. 
 
Second malignancies, most frequently of the urinary bladder and hematologic 
systems, have been reported when cyclophosphamide is used alone or with 
other anti-neoplastic drugs.  It may occur several years after treatment has been 
discontinued.  It interferes with oogenesis and spermatogenesis and may cause 
sterility in both sexes, which is dose and duration related. It has been found to 
be teratogenic, and women of childbearing potential should be advised to avoid 
becoming pregnant. Increased myelosuppression may be seen with chronic 
administration of high doses of phenobarbital.  Cyclophosphamide inhibits 
cholinesterase activity and potentiates the effect of succinylcholine chloride. If a 
patient requires general anesthesia within 10 days after cyclophosphamide 
administration, the anesthesiologist should be alerted.  Adrenal insufficiency 
may be worsened with cyclophosphamide.  Cyclophosphamide is excreted in 
breast milk, and it is advised that mothers discontinue nursing during 
cyclophosphamide administration. The occurrence of acute leukemia has been 


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reported rarely in patients treated with anthracycline/alkylator combination 
chemotherapy. 
 
Cyclophosphamide Pharmacology: 
 
Kinetics:  Cyclophosphamide is activated principally in the liver by a mixed 
function microsomal oxidase system.  PO administration is well absorbed, with 
bioavailability greater than 75%. Five to twenty-five percent of unchanged drug 
is excreted in the urine.  Several active and inactive metabolites have been 
identified with variable plasma protein binding. There appears to be no 
evidence of clinical toxicity in patients with renal failure, although elevated levels 
of metabolites have been observed. 
 
Formulation: Cyclophosphamide is supplied in 100 mg, 200 mg, 500 mg, 1 
gram and 2 gram vials as a white powder.  The drug should be reconstituted 
with Sterile Water for Injection, USP, and may be diluted in either normal saline 
or D5W. 
 
Storage and Stability:  Although the reconstituted cyclophosphamide is stable 
for six days under refrigeration, it contains no preservatives and therefore 
should be used within 6 hours. Tablets are stable at room temperature. 
 
Administration:  Cyclophosphamide should be diluted in about 150 mL of normal 
saline or D5W and infused IV.  An added dose of IV fluids may help prevent 
bladder toxicity. 


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2. 
OBJECTIVES 
 
 
2.1 
PRIMARY OBJECTIVES 
To estimate the pathologic complete response rate (pCR) when pertuzumab is 
added to weekly trastuzumab/paclitaxel followed by + trastuzumab/FEC 
neoadjuvant chemotherapy in HER2-positive breast cancer. This study will 
assess pCR rates separately in ER+ and ER- cancers. Pathologic complete 
response is defined as no evidence of viable invasive tumor cells at the primary 
tumor site and axillary lymph nodes in the surgical specimen. Residual Disease 
(RD) is defined as: Any invasive cancer in the breast or axillary lymph nodes in 
the surgical specimen. 
 
 
2.2 
SECONDARY OBJECTIVES 
(i) To assess the safety and tolerability of the regimen. 
 
a. Assess cardiac safety measured by rates of clinically symptomatic 
congestive heart failure, asymptomatic decrease in LVEF >10%, 
and decrease of LVEF below normal level. 
 
b. Assess general tolerability measured by the standard NCI 
Common Toxicity Criteria. 
 
(ii) To assess clinical response rate according to RECIST criteria (Appendix 
B). 
 
(iii) To assess Residual Cancer Burden. 
 
(iv) To collect pretreatment and residual cancer tissue after completion of 
chemotherapy for correlative science studies (biopsies and archival 
tissue will be collected under a separate protocol, Yale University 
HIC# 1310012919). 


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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a single arm, neoadjuvant, Phase II open label trial of pertuzumab and 
trastuzumab administered concomitant with sequential weekly paclitaxel 
followed FEC chemotherapies for clinical stage I-III HER 2-positive breast 
cancer. The primary objective of this study is to estimate the pathologic 
complete response rate (pCR) of this pertuzumab containing regimen. In this 
study, pertuzumab is added to a trastuzumab containing chemotherapy regimen 
that has produced the highest pCR rates in HER2 positive breast cancers so far. 
Pathologic complete response is defined as absence of any viable invasive 
cancer in the resected breast and lymph nodes. Because pCR rates differ 
between estrogen receptor (ER) positive and ER negative breast cancers, we 
will calculate the sample sizes separately for ER positive and ER negative 
cancers in this trial. Our goal is to estimate if pCR rates could be improved from 
50% to 70% in ER positive breast cancers and from 70% to 90% in ER negative 
breast cancers by adding pertuzumab to weekly paclitaxel/trastuzumab x12 and 
FEC/trastuzumab x 4 treatment regimen. This is a single clinical trial but accrual 
may finish sooner for one ER cohort than for the other. 
The historical pCR rate for ER negative patients treated with trastuzumab 
concomitant with weekly paclitaxel x 12 followed by trastuzumab and 5- 
fluorouracil/epirubicin/cyclophosphamide  x 4 (HT/HFEC) is 70% (n=140). Our 
goal is to estimate if the pCR rate can be increasing to 90% when pertuzumab is 
added to the above regimen. With an alpha = 10%, beta = 10%, we will accrue 
16 ER negative patients in the first stage and will halt accrual until pathologic  
CR results become available for all patients. We will stop the study if 11 or fewer 
patients have pathologic CR. The probability of early termination under the null 
hypothesis (i.e. the pertuzumab containing combination yields pCR rate equal to 
the historical data) is 55%.  If the study proceeds to full accrual, the total sample 
size for the ER negative cohort is 25. We declare the treatment of potential 
interest if more than 20 of 25 patients achieve pathologic CR. The historical pCR 
rate for ER positive patients treated with HT/HFEC is 50% (n=178). Our goal is 
to estimate if the pCR rate can be increasing to 70% when pertuzumab is added 
to the above regimen. With an alpha = 10%, beta = 10%, we will accrue 23 ER 
positive patients in the first stage and will halt accrual until pathologic CR results 
become available for all patients; we will stop the study if 11 or fewer patients 
have pathologic CR. The probability of early termination under the null 
hypothesis is 50%. If the study proceeds to full accrual, the total sample size for 
the ER positive cohort is 39. We declare the treatment of potential interest if 
more than 23 of 39 patients achieve pathologic CR. 
Our practice includes 8 full time academic medical oncologists who see breast 
cancer patients only, and the Cancer Center also acquired 8 community 
oncology practices; physicians in these practices are members of Yale Cancer 
Center and provide a broader referral and accrual basis for this trial. We plan to 
accrue 2-3 patients per months end expect to complete the trial in 24 months. 


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3.2 
RATIONALE FOR STUDY DESIGN 
Patients with stage I-III HER2 positive breast cancer who experience pathologic 
complete response (pCR) to neoadjuvant chemotherapy have excellent overall 
survival. The US Food and Drug Administration (FDA) has recently recognized 
this strong association between pCR and long-term survival in this disease 
subset and expressed interest in accepting this endpoint for accelerated drug 
approval. Currently, trastuzumab administered concomitantly with weekly 
paclitaxel and subsequent 5-fluorouracil, epirubicin, cyclophosphamide 
neoadjuvant chemotherapy achieves the highest pCR rate reported in HER2 
positive breast cancer (Bayraktar S et al 2012). All previous studies that 
combined pertuzumab with trastuzumab or with a trastuzumab and 
chemotherapy combination have shown improved response rates and increased 
clinical benefit when pertuzumab was added to a regimen. Our hypothesis is 
that adding pertuzumab to trastuzumab and weekly paclitaxel FEC will increase 
pCR rates by 20%, which will translate to pCR rates of 90% and 70% for ER 
negative and ER positive cancers, respectively. 
 
 
3.3 
OUTCOME MEASURES 
 
 
3.3.1 Primary Outcome Measure 
 
The primary efficacy endpoint of this study is pathologic complete response rate. 
Pathologic Complete Response (pCR) is defined as:  No evidence of viable 
invasive tumor cells at the primary tumor site and axillary lymph nodes in the 
surgical specimen. Residual Disease (RD) is defined as:  Any invasive cancer in 
the breast or axillary lymph nodes in the surgical specimen. 
 
3.3.2 Secondary Outcome Measures 
Cardiac safety including rates of clinically symptomatic congestive heart failure 
(defined as the occurrence of objective findings on clinical examination including 
rales, S3, elevated jugular venous pressure, confirmed by chest X-ray and/or 
either MUGA or ECHO) and asymptomatic drops in LVEF >10% or to below 
normal level. 
 
General tolerability assessed by the standard NCI Common Toxicity Criteria as 
per http://ctep.cancer.gov/forms/CTCAEv4.pdf. 
Clinical response according to RECIST v1. criteria (Appendix B) 
Residual Cancer Burden distribution calculated as: 
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3 


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Collection of pretreatment and residual cancer tissue after completion of 
chemotherapy for correlative science studies. 
 
 
3.4 
SAFETY PLAN 
 
 
Patients will be evaluated for toxicity at each study visit. Every 3 months cardiac 
monitoring will continue after surgery to complete a total of 12 months after 
starting therapy.  See Section 4.5 for Study Assessment and Appendix A for 
Study Flowchart. 
 
See Section 4.3.3 for Dose Modification guidelines. 
See Section 5 for reporting of adverse events. 
3.5 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in accordance with current U.S. Food and Drug 
Administration (FDA) Good Clinical Practices (GCPs), and local ethical and legal 
requirements. 
 
4.1 
MATERIALS AND METHODS 
 
 
4.2 
SUBJECTS 
 
 
Patients will be accrued at the Yale Cancer Center (YCC) Smilow Cancer 
Hospital. The Breast Center at YCC has 8 medical oncologists and 4 surgeons 
specializing in breast cancer care and the center sees approximately 400 new 
cases per year. The hospital is also affiliated with 8 community care centers 
staffed by physician employees of Smilow Hospital. The study may be extended 
into a multicenter trial with Sarah Cannon Cancer Research Center that has a 
strategic alliance with Yale Cancer Center to conduct joint clinical trials to 
increase accrual rate. 
 
4.2.1 Subject Selection 
 
 
4.2.2 Inclusion Criteria 
Patients must meet each of the following eligibility criteria: 
 
Patients with histologically confirmed stage I-III, HER2-positive invasive breast 
cancer for which adjuvant/neoadjuvant chemotherapy is indicated based on 
physician judgment following NCCN practice guidelines. 
HER2 overexpression or amplification will be based on local test results and 
is defined as either: 


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(i) 
IHC staining of 3+ (uniform, intense membrane staining) in > 10% 
of invasive tumor cells or, 
(ii) 
Fluorescent in situ hybridization (FISH) result of more than six 
HER2 gene copies per nucleus or, 
(iii) 
FISH ratio (HER2 gene signals to chromosome 17 signals) of >2.0. 
These criteria differ from the ASCO - CAP definitions of HER2 positivity, and 
were requested by the study sponsor in order to make trial results 
comparable with all previous trastuzumab and pertuzumab clinical trials. 
 
Patients with synchronous bilateral breast cancers are eligible if at least one of 
the tumors is HER2-positive. 
 
Left Ventricular Ejection Fraction (LVEF) greater or equal to 50% at baseline as 
determined by either ECHO or MUGA, or within the institution’s normal limits. 
 
Women of childbearing potential must have a negative pregnancy test (serum or 
urine beta HCG) prior to initiation of chemotherapy. Both female and male 
breast cancer patients who are sexually active have to agree to practice 
contraception while participating in the trial and for 3 month after completion of 
therapy. 
 
Adequate bone marrow function as indicated by the following: 
 
ANC >1500/L 
Platelets 100,000/L 
Hemoglobin >10 g/dL 
 
Adequate renal function, as indicated by creatinine 1.5upper limit of 
normal (ULN) 
 
Adequate liver function, as indicated by bilirubin 1.5ULN and AST or ALT 
<2ULN. 
 
Signed informed consent. 
 
 
4.2.3 Exclusion Criteria 
Patients will be excluded from the study based on any of the following criteria: 
 
Patients who underwent partial excisional biopsy, lumpectomy, segmental 
mastectomy, modified radical mastectomy or sentinel node biopsy and, 
therefore cannot be assessed for pathologic response accurately. 
 
Patients who are high risk for developing the following anthracycline, paclitaxel, 
trastuzumab or pertuzumab related toxicities including: 


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History of congestive heart failure, myocardial infarction or 
cardiomyopathy, uncontrolled hypertension despite adequate 
medications 
Pre-existing peripheral neuropathy > grade 3 
Prior anthracycline therapy 
Known hypersensitivity to any of the study medications 
Patients older than age 65 due to increased risk of cardiotoxicity 
 
Active infection requiring systemic antibiotic therapy. 
 
Pregnant or lactating women 
 
 
4.3 
METHOD OF TREATMENT ASSIGNMENT 
 
This is a single arm Phase II trial and all patients will receive the same therapy. 
 
 
4.3. 
STUDY TREATMENT 
Pertuzumab and Trastuzumab will be provided free of charge by Genentech. 
The Sponsor Investigator of the study will ensure maintenance of complete and 
accurate records of the receipt, dispensation, and disposal or return of all study 
drugs in accordance with 21 Code of Federal Regulations (C.F.R.), Part 312.57 
and 312.62 and Genentech requirements. All cytotoxic chemotherapies and 
supportive medications given in the context of this study are considered 
standard of care and will be charged to third party insurer. 
 
During the first 1-12 weeks patients will receive pertuzumab, trastuzumab, and 
paclitaxel concomitantly; during weeks 13-24 patients will receive pertuzumab 
and trastuzumab concomitantly with 5-fluorouracil, epirubicin, and 
cyclophosphamide (FEC). 
 
Pertuzumab and trastuzumab administration should precede chemotherapy 
administration.  Patients should be observed for fever and chills or other 
infusion-associated symptoms. 
 
The standard weekly paclitaxel (T) and 5-fluorouracil, epirubicin, 
cyclophosphamide (FEC) chemotherapy regimens can be administered as per 
institutional guidelines. If no institutional treatment orders exist for these 
regimens then the treatment should be administered as specified in the current 
protocol. 
 
 
 
 
 
 
 
 
 
 


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AGENT 
DOSE 
ROUTE 
RETREATMENT 
INTERVAL 
Trastuzumab 
First dose: 
4 
mg/kg. 
Maintenance 
dose: 2 mg/kg 
IV 
Once every week x 12 weeks from 
week 1 to week 12 (12 doses total) 
Trastuzumab 
6 mg/kg 
IV 
Once every 3 weeks from week 13 to 
week 24 (4 doses total) 
Pertuzumab 
First dose: 840 
mg. 
Maintenance 
dose: 420 mg 
IV 
Once every 3 weeks x 24 weeks (8 
doses total) 
Paclitaxel 
80 mg/m2 
IV 
Once  every  week  from  week  1  to 
week 12 (12 weekly cycles total) 
5-fluorouracil 
500 mg/m2 
IV 
Once every 3 weeks from week 13 to 
week 24 ( 4 cycles total) 
Epirubicin 
75 mg/m2 
IV 
Once every 3 weeks from week 13 to 
week 24 (4 cycles total) 
Cyclophosphamide 
500 mg/m2 
IV 
Once every 3 weeks from week 13 to 
week 24 (4 cycles total) 
 
 
Treatment weeks 1-12: 
 
- 
Trastuzumab 4 mg/kg loading dose on Day 1, week 1, over 60 minutes 
infusion in 250 ml Normal Saline (NS), followed by 2 mg/kg weekly over 30 
minutes infusion before each course of paclitaxel chemotherapy from Day 
1, weeks 2-12. 
 
- 
Pertuzumab 840 mg loading dose in 250 ml NS on Day 1, week 1 over 60 
min infusion followed by 420 mg once every 21 days over 30 minutes 
infusion before paclitaxel chemotherapy. 
 
- 
Paclitaxel 80 mg/m2 administered in 250 mL (NS) IV over 60 minutes. 
 
Premedication will include famotidine 20 mg orally and diphenhydramine 25 mg 
orally 30 minutes prior to the first two doses of paclitaxel which can be omitted for 
future doses if no infusion reaction has occurred. Dexamethasone 10 mg IV will be 
given 30 min prior to the first three doses of paclitaxel. The Dexamethasone dose 
should be reduced to 4 mg IV after 3rd dose if no infusion related reactions are 
noted. 
 
 
Treatment weeks 13-24: 
 
- 
Trastuzumab 6 mg/kg in 250 ml NS over 30 minutes infusion, once every 21 
days before each FEC chemotherapy (loading dose for q 3 week schedule 
not needed). 
 
- 
Pertuzumab 420 mg in 250 ml NS over 30 minutes infusion once every 21 


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days before each FEC chemotherapy. 
 
- 
5-Fluorouracil 500 mg/m2 as a bolus in 50 ml NS once every 21 days for 4 
cycles total. 
 
- 
Epirubicin 75 mg/m2 over 30 min infusion in 100 ml NS once every 21 
days for 4 cycles total. 
 
- 
Cyclophosphamide 500 mg/m2 IV over 30 minute infusion in 250 ml NS 
once every 21 days for 4 cycles total. 
 
 
Premedications can be given as per local institutional guidelines. 
4.3.1 Trastuzumab and Pertuzumab Formulations 
Trastuzumab Formulation 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized 
powder for intravenous (IV) administration. Each vial of trastuzumab contains 
440 mg of tratuzumab, 9.9 mg of L-histidine HCl, 6.4 mg of L-histadine, 400 mg 
of ,-trehalose dihydrate, and 1.8 mg of polysorbate 20, USP. Reconstitution 
with 20 mL of the supplied Bacteriostatic Water for Injection (BWFI) USP, 
containing 1.1% benzyl alcohol as a preservative, yields 21 mL of a multidose 
solution containing 21 mg/mL trastuzumab, at a pH of ~6. 
 
Pertuzumab Formulation 
Pertuzumab drug product is provided as a single use formulation containing 30 
mg/mL pertuzumab in 20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 
0.02% polysorbate 20. Each 20 mL vial contains 420 mg of Pertuzumab (14.0 
mL/vial). Upon receipt, pertuzumab vials are to be refrigerated at 2°C–8°C 
(36°F–46°F) until use. Pertuzumab vials should not be used beyond the 
expiration date provided by the manufacturer. Because the formulation does not 
contain a preservative, the vial seal may only be punctured once. Any remaining 
solution should be discarded. Vial contents should be protected from light, and 
should not be frozen. The solution of pertuzumab for infusion, diluted in PVC or 
non-PVC polyolefin bags containing 0.9% Sodium Chloride Injection, USP, may 
be stored for up to 24 hours prior to use. Diluted pertuzumab has been shown to 
be stable for up to 24 hours at a temperature range of 2°C–25°C. However, 
since diluted pertuzumab contains no preservative, the diluted solution should 
be stored refrigerated (2°C–8°C). 
 
4.3.2 Dosage, Preparation, Administration and Storage 
 
All study drugs used in this trial are administered at the FDA recommended 
doses and routes. Smilow Cancer Hospital pharmacy will follow standard clinical 
practice in storing, preparing and administering the drugs. 
 


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4.3.3. Dosage Modification 
 
 
Trastuzumab and Pertuzumab 
 
There are no dose modifications for pertuzumab or trastuzumab. 
 
(i) 
Pertuzumab and trastuzumab should be discontinued in any 
patient who develops clinical signs and symptoms of CHF. 
Weekly paclitaxel chemotherapy may be continued alone. CHF 
should be treated and monitored according to standard medical 
practice. This included ACE-inhibitors or angiotensin receptor 
blockers, beta-blockers and diuretics when needed (Appendix 
C). 
 
(ii) 
In case of asymptomatic decrease in LVEF, the following 
algorithm will guide the continuation or discontinuation of 
pertuzumab and trastuzumab: 
 
 
 
 
 
If the criteria to hold pertuzumab and trastuzumab are met paclitaxel (but not 
 
FEC) can be continued. 
 
For delayed or missed doses, if the time between 2 sequential infusions is less than 
6 weeks, the 420 mg IV dose of pertuzumab should be administered along with 


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Trastuzumab maintenance dose. Do not wait until the next planned dose. 
 
If the time between 2 sequential infusions is 6 weeks or more, the initial dose of 
840 mg pertuzumab should be re-administered as a 60 minute IV infusion followed 
every 3 weeks thereafter by a dose of 420 mg IV administered over 30- 60 
minutes. Similarly, Trastuzumab loading dose should be repeated followed by 
maintenance dose thereafter. 
 
Paclitaxel 
(i) 
For grade 3 peripheral neuropathy (i.e. sensory alteration or paresthesia 
interfering with normal daily activities) paclitaxel, will be held for a 
maximum of 14 days. If symptoms improve within this time period to grade 
1 or less resume paclitaxel at standard 60 mg/m2 dose. If neuropathy does 
not resolve to grade 1 discontinue paclitaxel and start the 5-
fluorouracil/epirubicin/cyclophosphamide phase of the treatment. 
 
(ii) 
If Absolute Neutrophil Count (ANC) is below 1000/microliter or Platelet 
count is below 100,000/microliter on the day of chemotherapy 
administration, paclitaxel should be held and complete blood count 
repeated 24 hours later. Resume administration of paclitaxel at full dose 
once ANC >1000 and Plt > 100,000. Use G-CSF with subsequent 
treatments to prevent dose delays as recommended by ASCO practice 
guidelines. 
 
 
While paclitaxel is on hold for toxicity Trastuzumab and Pertuzumab should be 
continued as scheduled. 
 
5-fluorouracil, epirubicin, cyclophosphamide (FEC) 
 
(i) 
If Absolute Neutrophil Count (ANC) is below 1000/microliter or Platelet 
count is below 100,000/microliter on the day of chemotherapy 
administration, FEC chemotherapy should be held and complete blood 
count repeated 24 hours later. Resume administration of FEC at full dose 
once ANC >1000 and Plt > 100,000. Use G-CSF with subsequent 
treatments to prevent dose delays as recommended by ASCO practice 
guidelines. 
 
(ii) 
If clinically symptomatic CHF develops discontinue FEC (and also 
trastuzumab and pertuzumab). CHF should be treated and monitored 
according to standard medical practice. This included ACE-inhibitors or 
angiotensin receptor blockers, beta-blockers and diuretics when needed 
(Appendix C). Patients should be referred to surgery. 
(iii) 
In case of asymptomatic decrease in LVEF, FEC (and also trastuzumab 
and pertuzumab) should be held and cardiology consultation should be 
obtained to initiate appropriate therapy. Assessment of LVEF should be 
repeated within 3 weeks. If LVEF returns to normal, resume therapy. If 
reversible asymptomatic decrease in LVEF recurs reduce dose of 
Epirubicin to 50 mg/m2. 


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(iv) 
Grade 3 non-hematologic toxicity, other than alopecia, fatigue, and 
nausea/vomiting, hold treatment until symptoms resolve to grade 1 or 
less and resume therapy with 20% dose reduction of all 3 chemotherapy 
drugs. 
 
4.3.4  Trastuzumab and Pertuzumab Overdosage 
There is no experience with overdosage in human clinical trials. 
 
 
4.4 
CONCOMITANT AND EXCLUDED THERAPY 
Non-study related anti-tumor therapy is not allowed. There are no restrictions on 
non-oncology medications. 
 
4.5 
STUDY ASSESSMENTS 
All pretreatment assessments are standard of care. 
 
 
4.5.1 Assessments at baseline before treatment 
 
 
Determination of tumor HER2, ER and PR status 
 
Complete medical history including symptom/toxicity assessment. 
 
Physical examination including breast and regional lymph nodes, weight and 
height, and vital signs. Record tumor measurements by physical exam. 
 
ECOG performance status 
 
Bilateral mammograms and clip placement to mark tumor bed . Other imaging, 
such as ultrasonography or MRI, is at the discretion of the treating physicians. 
The most recent breast imaging that documents the size of the cancer must be 
within the past 6 weeks. 
 
Ultrasongraphic evaluation of the regional lymph nodes 
If suspicious lymph nodes are detected clinically or by imaging, a 
diagnostic image guided fine needle aspiration of the suspicious node is 
required. 
 
CBC and differential, electrolytes, BUN, creatinine, total bilirubin, AST, ALT, 
alkaline phosphatase. 


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 
Cardiac function assessment by either MUGA or echocardiography. 
 
Women of childbearing potential must have a serum or urine beta hCG 
pregnancy test prior to initiation of first chemotherapy and counseling about 
need of contraception during treatment and for 6 months after completion of 
therapy must be performed. Similar counseling about contraception while on 
therapy is also required for male breast cancer patients. 
 
Systemic staging with CT scan of the chest/abdomen/pelvis and bone scan or 
PET scan should follow NCCN staging guidelines and are currently 
recommended routinely only for patients with clinical Stage III disease. 
 
 
 
4.5.2 Assessments during therapy 
 
 
CBC and differential within 24 hours before each chemotherapy administration. 
 
Physical examination including vital signs, weight, breast and regional lymph 
nodes every 3 weeks. 
 
Medical history every 3 weeks. 
 
ECOG performance status every 3 weeks. 
 
Toxicity evaluation every 3 weeks. 
 
Cardiac function assessment using the same method as baseline after 
completion of the 12 courses of paclitaxel, trastuzumab and pertuzumab before 
starting FEC chemotherapy, and after completion of the 4 cycles of FEC 
chemotherapy prior to surgery and every 3 months after surgery for a total of 12 
months. 
Cardiac evaluation may be repeated at any time if cardiac adverse effects 
are suspected clinically. 
 
Mammogram, or the most recent imaging study that was obtained at baseline, of 
the affected breast after completion of the 12 courses of paclitaxel, trastuzumab 
and pertuzumab before starting FEC chemotherapy and also after completion of 
all chemotherapy before surgery. (Other imaging, such as ultrasonography or 
MRI, is at the discretion of the treating physicians.) 
Breast imaging may be repeated any time during therapy if clinical suspicion 
of progression of disease. 


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• 
BUN, creatinin, total bilirubin, AST, ALT, alkaline phosphatase every 3 weeks 
before chemotherapy administration. 
 
 
 
Surgery will be scheduled 3-6 weeks after completion of last chemotherapy. 
 
 
 
The final study follow up visit will be 4 weeks +/- 1 week after completion of surgery 
and will include complete medical history, toxicity assessment and physical 
examination. 
 
 
 
4.5.3. Treatment after completion of preoperative chemotherapy. 
 
 
All patients will undergo breast surgery after completion of preoperative therapy. 
The decision regarding lumpectomy or mastectomy will be at the discretion of 
the treating surgeon. All patients will have axillary lymph node sampling with a 
technique that is deemed appropriate by the surgeon: 
For clinically node negative disease at baseline, defined as negative clinical 
exam and ultrasonogram or negative lymph node biopsy in case of a 
suspicious lymph node by imaging, sentinel node sampling is preferred, with 
subsequent full axillary lymph node dissection at the discretion of the treating 
physicians. 
For patients with clinically palpable, matted metastatic lymph nodes and/or 
histologically confirmed node positive disease at baseline, sentinel node 
sampling is permitted but subsequent full axillary lymph node dissection 
must be performed even if there is complete clinical response in the nodes 
after preoperative therapy. 
 
Patients who progress clinically or by imaging assessment during therapy will be 
removed from protocol treatment and further treatment including immediate 
referral to surgery or preoperative radiation or additional chemotherapy will be at 
the discretion of the treating physician. 
 
Postoperative adjuvant therapy should follow current standard NCCN practice 
guidelines. Participation in subsequent adjuvant clinical trials is allowed. 
 
 
4.6 
DISCONTINUATION OF PROTOCOL-SPECIFIED THERAPY 
Protocol-specified therapy may be discontinued for any of the following reasons: 
 
Progressive disease 
 
Unacceptable toxicity 
 
Patient election to discontinue therapy (for any reason) 


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 
Physician’s judgment 
 
 
 
4.7. 
STUDY DISCONTINUATION 
 
 
 
 
The study will be terminated after all planned patients are accrued, all primary 
endpoints are recorded and final data analysis has been completed. 
 
Genentech and the Principal Investigator has the right to terminate the study at 
any time. Reasons for terminating the study may include the following: 
- 
The incidence and severity of adverse events in this or other similar trials 
indicate unacceptable health hazards for the participants. 
- 
Unsatisfactory slow enrollment 
- 
Major violations to the protocol and major inaccuracies in data collection. 
 
 
 
4.8. 
STATISTICAL METHODS 
 
 
4.8.1 Analysis of the Conduct of the Study 
 
The responsibility for the conduct of the study lies with the Principle 
Investigators. The Sponsor’s Data Safety and Monitoring Committee will 
conduct annual reviews. The Yale Quality Assurance Compliance and Safety 
Committee (QUACS) will conduct internal audits at time points they deem 
appropriate. 
 
4.8.2 Analysis of Treatment Group Comparability 
 
This is a single arm study. 
 
4.8.3 Analysis Plan 
 
 
a. Primary Endpoint Definition and Reporting 
 
 
The primary study endpoint is pathologic complete response (pCR) defined as 
no evidence of viable invasive tumor cells at the primary tumor site and in 
axillary lymph nodes assessed in the surgical specimen on routine histology 
examination. Residual Disease (RD) is defined as: Any invasive cancer in the 
breast or axillary lymph nodes in the surgical specimen. These results will be 
retrieved from the routine pathology report. 


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The pCR rates will be reported using descriptive statistics and 95% confidence 
intervals. This study will assess and report pCR rates separately in ER+ and 
ER- cancers. 
 
 
b. Secondary Endpoint Definitions and Reporting 
- 
Cardiac safety endpoints will include (i) clinically symptomatic congestive 
heart failure (CHF), (ii) asymptomatic drops in left ventricular ejection fraction 
(LVEF) >10% compared to pre-treatment value (even if it remains above the 
lower limit of normal), (iii) LVEF drop below normal level. Symptomatic CHF 
is defined as clinical signs and symptoms of CHF including dyspnea, 
tachycardia, new unexplained cough, neck vein distention, cardiomegaly, 
hepatomegaly, paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, 
and rapid unexplained weight gain, chest X-ray findings suggestive of CHF; 
these clinical findings must be supported by MUGA or ECHO results 
indicating systolic or diastolic heart failure. The frequency of cardiac adverse 
events will be reported as descriptive statistics with 95% confidence  
intervals. 
 
- 
Toxicity will be recorded using the standard NCI Common Toxicity Criteria as 
per http://ctep.cancer.gov/forms/CTCAEv4.pdf.and . Results will be reported 
in a tabular format by worst grade and occurrence per patient over the entire 
study period and also by chemotherapy type (paclitaxel versus FEC phases 
of the treatment) 
 
- 
Clinical response rate will be assessed by two measures. Mammographic 
tumor size measurements and physical examination after completion of all 
chemotherapy compared to baseline. Response will be categorized 
following RECIST criteria (Appendix B). The results will be reported as 
descriptive statistics with 95% confidence intervals. 
 
- 
Residual Cancer Burden (RCB) scores after chemotherapy will be 
determined by routine pathology examination and scores will be calculated 
using the  
http://www3.mdanderson.org/app/medcalc/index.cfm?pagename=jsconvert3 
website. Results will be presented as categorical variables (i.e. frequencies 
of RCB-0, I, II, III response categories) and also as distribution of continuous 
variable RCB score. 
 
- 
Baseline and residual cancer tissue will be collected for future biomarker 
analysis. Considering the small sample size of the study the biomarker 
results will be exploratory and hypothesis generating. The planned molecular 
analysis of these tissues will include gene expression profiling, metabolomics 
profiling, DNA sequencing and establishment of primary tumor cultures to 
search for potential markers of treatment response. 


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4.8.4 Missing Data 
 
We do not expect any missing data for the primary endpoint of the study. All 
patients will undergo breast surgery. Patients who cannot undergo surgery due 
to deteriorating health related to study medications or progression of cancer will 
be considered having “Residual Cancer” for the purpose of statistical analysis. 
 
4.8.5 Determination of Sample Size 
 
This study will follow Simons’ minimax two-stage trial design based on one- 
sample binomial test with a goal to minimize the maximum sample size. The 
primary study endpoint is pathologic complete response (pCR) rate. All patients 
will be HER2 positive (HER2+) in this study. The pCR rates differ between 
HER2+/estrogen receptor (ER)-positive and HER2+/ER-negative breast cancers 
when the same trastuzumab-containing regimen is used. Therefore we calculate 
the sample size separately for ER-positive and ER-negative cancers. This is a 
single clinical trial but accrual may finish sooner for one ER cohort than for the 
other. Setting a single pCR target for a mixed cohort of ER-positive and - 
negative patients is statistically not sound; the observed overall pCR rate would 
depend on the proportion of ER-positive versus -negative cases that were 
accrued to the trial. 
 
The historical pCR rate for ER-negative patients treated with trastuzumab 
concomitant with weekly paclitaxel x 12 followed by trastuzumab concomitant 
with 5-fluorouracil/epirubicin/cyclophosphamide  x 4 is 70% (n=140). Our goal is 
to assess if the pCR rate can be increased to 90% when pertuzumab is added  
to the above regimen. With an alpha = 10%, beta = 10%, p0 (historic pathologic 
CR rate) = 70% and p1 (expected pathologic CR rate with Pertuzumab) = 90%, 
we will accrue 16 ER-negative patients in the first stage and will halt accrual 
until pCR results become available for all 16 patients. We will stop the ER- 
positive arm of the study if fewer than 11 patients had pathologic CR. The 
probability of early termination under the null hypothesis (i.e. the pertuzumab 
containing combination yields pCR rate equal to the historical data) is 55%. If 
the arm proceeds to full accrual, the total sample size for the ER-negative 
cohort is 25. We declare the treatment of potential interest if 20 or more of 25 
patients achieve pCR and would recommend conducting a randomize trial to 
formally compare the Paclitaxel/FEC/Trastuzumab regimen with Pertuzumab 
plus Paclitaxel/FEC/Trastuzumab in ER-negative cancers. A definitive 
randomized trial  with 90% power and 5% two-sided alpha would require 164 
ER-negative patients (82/per arm) to demonstrate an increase from 70 to 90% in 
pCR rate. 
 
The historical pCR rate for ER-positive patients treated with trastuzumab 
concomitant with weekly paclitaxel x 12 followed by trastuzumab concomitant 
with 5-fluorouracil/epirubicin/cyclophosphamide x 4 is 50% (n=178). Our goal is 
to assess if the pCR rate can be increased to 70% when pertuzumab is added 
to the above regimen. With an alpha = 10%, beta = 10%, p0 = 50% and p1 = 
70%, we will accrue 23 ER-positive patients in the first stage and will halt 
accrual until pCR results become available for all 23 patients; we will stop the 
study if fewer than 11 patients have pCR. The probability of early termination 
under the null hypothesis is 50%. If the study proceeds to full accrual, the total 


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sample size for the ER positive cohort is 39. We declare the treatment of 
potential interest if 23 or more of 39 patients achieve pCR and would 
recommend conducting a randomize trial to formally compare the 
Paclitaxel/FEC/Trastuzumab regimen with Pertuzumab plus 
Paclitaxel/FEC/Trastuzumab in ER positive cancers. A definitive randomized 
trial  with 90% power and 5% two-sided alpha would require 248 ER positive 
patients (124/per arm) to demonstrate an increase from 50 to 70% in pCR rate. 
 
 
4.9 
DATA COLLECTION AND QUALITY ASSURANCE 
The Yale Cancer Center Clinical Trial Office will be responsible to collect, QC 
and provide data for the Principal Investigator and Sponsor. 
5. 
DEFINITION AND REPORTING OF ADVERSE EVENTS 
Adverse Events (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally 
associated with the use of an investigational medicinal product (IMP) or other 
protocol-imposed intervention, regardless of attribution. 
 
This includes the following: 
 
 
AEs not previously observed in the subject that emerge during the protocol- 
specified AE reporting period. 
 
Complications that occur as a result of protocol-mandated interventions (e.g., 
invasive procedures such as cardiac catheterizations). 
 
If applicable, AEs that occur prior to assignment of study treatment associated 
with medication washout, no treatment run-in, or other protocol-mandated 
intervention. 
 
Preexisting medical conditions (other than the condition being studied) judged 
by the investigator to have worsened in severity or frequency or changed in 
character during the protocol-specified AE reporting period. 
 
Serious Adverse Events (SAE) 
 
An AE should be classified as an SAE if the following criteria are met: 
 
 
It results in death (i.e., the AE actually causes or leads to death). 
 
It is life threatening (i.e., the AE, in the view of the investigator, places the 
subject at immediate risk of death. It does not include an AE that, had it 
occurred in a more severe form, might have caused death.). 
 
It requires or prolongs inpatient hospitalization. 
 
It results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the subject’s ability to conduct normal life functions). 


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 
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
 
It is considered a significant medical event by the investigator based on medical 
judgment (e.g., may jeopardize the subject or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
 
 
 
5.1 
METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES 
 
The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study are collected and reported to the 
appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND 
Safety Reports). 
 
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of study treatment and ends 30 days 
following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment. 
 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, 
laboratory test, or other means will be reported appropriately. Each reported AE 
or SAE will be described by its duration (i.e., start and end dates), seriousness 
criteria, suspected relationship to the study drugs, and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 
 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the study drugs, and the AE cannot be readily explained by the 
subject’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
AE follows a known pattern of response to the study drugs; and/or the AE 
abates or resolves upon discontinuation of the study drugs or dose reduction 
and, if applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than the study drugs (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship 
to study drugs administration (e.g., cancer diagnosed 2 days after first dose of 
study drug). 


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Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert or current Investigator Brochure. 
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or 
current Investigator Brochure (I.B.) or not identified. This includes adverse 
events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B. For example, under this definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. 
 
5.2 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints 
should be adopted. Examples of non-directive questions include: 
 
 
“How have you felt since your last clinical visit?” 
 
“Have you had any new or changed health problems since you were last here?” 
 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs. Avoid colloquialisms and abbreviations. This study will use NCI 
Common Toxicity Criteria as per obtained from 
http://ctep.cancer.gov/forms/CTCAEv4.pdf 
 
 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, it is acceptable to report 
the information that is currently available. If a diagnosis is subsequently 
established, it should be reported as follow-up information. 
 
b. 
Deaths 
All deaths that occur during the protocol-specified AE reporting period 
regardless of attribution, will be reported to the appropriate parties. When 
recording a death, the event or condition that caused or contributed to the fatal 
outcome should be reported as the single medical concept. If the cause of death 
is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death”. 


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c. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start of the study. 
Such conditions should be reported as medical and surgical history. A 
preexisting medical condition should be re-assessed throughout the trial and 
reported as an AE or SAE only if the frequency, severity, or character of the 
condition worsens during the study. When reporting such events, it is important 
to convey the concept that the preexisting condition has changed by including 
applicable descriptors (e.g., “more frequent headaches”). 
 
d. 
Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an SAE. If a subject is hospitalized to undergo a 
medical or surgical procedure as a result of an AE, the event responsible for the 
procedure, not the procedure itself, should be reported as the SAE. For 
example, if a subject is hospitalized to undergo coronary bypass surgery, record 
the heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for preexisting conditions. 
 
Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
 
Hospitalization or prolonged hospitalization for scheduled therapy of the target 
disease of the study. 
 
e. 
Pregnancy 
If a female subject becomes pregnant while receiving investigational therapy or 
within 90 days after the last dose of study drug, a report should be completed 
and expeditiously submitted to Genentech, Inc. Follow-up to obtain the outcome 
of the pregnancy should also occur. Abortion, whether accidental, therapeutic, 
or spontaneous, should always be classified as serious, and expeditiously 
reported as an SAE. Similarly, any congenital anomaly/birth defect in a child 
born to a female subject exposed to the study drugs should be reported as an 
SAE. 
 
f. 
Post-Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a subject 
has completed or discontinued study participation if attributed to prior study drug 
exposure. If the investigator should become aware of the development of cancer 
or a congenital anomaly in a subsequently conceived offspring of a female 
subject who participated in the study, this should be reported as an SAE. 
 
g. 
Reconciliation 
The Sponsor agrees to conduct reconciliation for the product. Genentech and 
the Sponsor will agree to the reconciliation periodicity and format, but agree at 
minimum to exchange monthly line listings of cases received by the other party. 


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If discrepancies are identified, the Sponsor and Genentech will cooperate in 
resolving the discrepancies. The responsible individuals for each party shall 
handle the matter on a case-by-case basis until satisfactory resolution. 
 
h. AEs of Special Interest (AESIs) 
AEs of Special Interest are defined as a potential safety problem, identified as a 
result of safety monitoring of the Product. 
 
The Trastuzumab and Pertuzumab Events of Special Interest are: 
 
a. Left Ventricular Dysfunction, defined as LVEF drop > 20 points 
from baseline, or drop to below 50% or below the institution’s 
normal limits. When a cardiac event occurs, the Cardiac Report 
Form must be submitted within 14 days of learning of the event. 
 
b. Grade 3 or 4 infusion-associated reactions, hypersensitivity 
reactions, or anaphylaxis. 
 
 
c. Embryo-fetal toxicity or birth defects. 
 
 
i. 
SAE Reporting 
 
Investigators must report all SAEs to Genentech within the timelines described 
below. The completed report should be faxed within fifteen (15) calendar days of 
discovery to Genentech Drug Safety at: 
 
(650) 225-4682 
OR 
(650) 225-5288 
 
 
Relevant follow-up information should be submitted to Genentech Drug Safety 
as soon as it becomes available. 
 
 
Serious AE reports that are related to the trastuzumab and pertuzumab and AEs 
of Special Interest (regardless of causality) will be transmitted to Genentech 
within fifteen (15) calendar days of the Awareness Date. 
 
 
Serious AE reports that are unrelated to the trastuzumab and pertuzumab will 
be transmitted to Genentech within thirty (30) calendar days of the Awareness 
Date. 
 
 
Additional Reporting Requirements to Genentech include the following: 
o Any reports of pregnancy following the start of administration with 
the trastuzumab and pertuzumab will be transmitted to Genentech 
within thirty (30) calendar days of the Awareness Date. 


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o All Non-serious Adverse Events originating from the Study will be 
forwarded in a quarterly report to Genentech. 
 
Note: Investigators should also report events to their IRB as required. 
 
The report should include the following information: 
 
 
Description of event, severity, treatment, and outcome if known 
 
Supportive laboratory results and diagnostics 
 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
Follow-up Information 
 
Additional information may be added to a previously submitted report as new 
information becomes available. 
 
For questions related to safety reporting, please contact Genentech Drug 
Safety: 
 
Tel: (888) 835-2555 
Fax: (650) 225-4682 
OR 
(650) 225-5288 
 
 
5.3 
MedWatch 3500A Reporting Guidelines 
 
MedWatch 3500A forms will be used for reporting safety results to the sponsor 
Genentech Inc. 
 
 
5.4 
Additional Reporting Requirements for IND Holders 
 
Not applicable 
 
5.5. 
Reporting to the Yale Human Investigation Committee 
 
All SAEs, whether originating at Yale or a collaborating center, meeting the 
criteria for expedited reporting will be reported to the Yale University Human 
Investigation Committee (HIC) using HIC Form 6A within 48 hours of discovery. 
 
The HIC expedited reporting criteria are: 
a. Serious AND unexpected AND possibly, probably or definitely related 
events 
b. Anticipated Adverse Events occurring with a greater frequency than 
expected. 


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The HIC does not require reporting of any other Adverse Event type. A copy of 
the HIC reporting policy is available at  
http://info.med.yale.edu/hic/policy/AdverseEventPolicy.pdf 
 
 
6. 
INVESTIGATOR REQUIREMENTS 
 
 
6.1 
STUDY INITIATION 
 
 
Before the start of this study, the following documents must be on file with 
Genentech or a Genentech representative: 
 
Current curriculum vitae of the Principal Investigator. 
 
Written documentation of IRB approval of protocol and informed consent 
document. 
 
A copy of the IRB-approved informed consent document. 
 
A signed Clinical Research Agreement. 
 
 
 
6.2 
STUDY COMPLETION 
The following materials are requested by Genentech when a study is considered 
complete or terminated: 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical Study 
Report (final study report). Additionally, any literature articles that are a result of 
the study should be sent to Genentech. Copies of such reports should be mailed 
to the assigned Clinical Operations contact for the study: 
 
Email : Pertuzumab-gsur@gene.com 
 
Fax : 650-360-6908 
 
 
 
6.3 
INFORMED CONSENT 
The informed consent document must be signed by the subject or the subject’s 
legally authorized representative before his or her participation in the study.  The 
case history for each subject shall document that informed consent was 
obtained prior to participation in the study.  A copy of the informed consent 
document must be provided to the subject or the subject's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the 
local language. 


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Signed consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 
 
 
 
6.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB for review and must be approved 
before the study is initiated. The study will be conducted in accordance with 
U.S. FDA, applicable national and local health authorities, and IRB 
requirements. 
 
The Principal Investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB must be updated at least once a year. The 
Principal Investigator must also keep the IRB informed of any significant 
adverse events. 
 
Investigators are required to promptly notify their respective IRB of all adverse 
drug reactions that are both serious and unexpected. This generally refers to 
serious adverse events that are not already identified in the Investigator 
Brochure and that are considered possibly or probably related to the molecule or 
study drug by the investigator.  Some IRBs may have other specific adverse 
event requirements that investigators are expected to adhere. Investigators 
must immediately forward to their IRB any written safety report or update 
provided by Genentech (e.g., IND safety report, Investigator Brochure, safety 
amendments and updates, etc.). 
 
 
6.5 
STUDY MONITORING REQUIREMENTS 
This investigator initiated study will be monitored by and according to the 
policies of Yale University Yale Cancer Center. 
 
 
6.6 
DATA COLLECTION 
 
Data will be collected using study-specific electronic case report forms (OnCore) 
by research personnel assigned to the trial by the Yale Cancer Center Clinical 
Trials Office. 
 
Case Report Forms 
 
A subset of the National Cancer Institute (NCI) CRFs, in electronic format, will 
be utilized to record data required by the study.  Electronic CRFs (e-CRFs) will 
reside in the OnCore database. Completion of the electronic CRFs (e-CRFs) 
will be done in accordance with the instructions in a study specific data capture 
plan. All e-CRFs will be completed by clinical research staff of the Yale Cancer 
Center Clinical Trials Office (CTO). 


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When a cardiac event occurs, the Cardiac Report Form will be submitted within 
14 days of learning of the event. 
 
 
Data Submission Timeline and Forms 
 
Completion of e-CRFs will occur in accordance with NCI guidelines. Baseline 
(pre-study) e-CRFs (e.g., enrollment, medical history, concomitant medications, 
disease assessment, etc.) will be completed no later than 14 days after the start 
of treatment.  Treatment e-CRFs (e.g., drug administration, adverse events, 
chemistries, etc.) will be completed no later than 14 days following each cycle of 
treatment.  Off-treatment information (e.g., follow-up, best response, etc.) will be 
completed no later than 14 days after the end of protocol treatment. 
 
Research Charts 
 
A research chart (i.e., shadow chart) is maintained at the CTO for each patient 
enrolled. Copies of significant study source documents will be maintained in the 
research chart. Examples of source document copies that will be maintained in 
the research chart include: signed informed consent form, documents that verify 
eligibility and treatment, and documents that verify Grade 3-4 adverse events 
and response. This information will be updated on a prospective basis and will 
be confidentially maintained at the CTO. 
 
Reports 
 
Publications and annual reports for submission to the IRB will be written by the 
principal investigator using the data captured on the e-CRFs. 
 
6.7 
STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
Trastuzumab and Pertuzumab will be provided by Genentech. The recipient will 
acknowledge receipt of the drug by returning the INDRR-1 form indicating 
shipment content and condition.  Damaged supplies will be replaced. 
 
Accurate records of all study drug dispensed from and returned to the study site 
should be recorded by using the institution’s drug inventory log or the NCI drug 
accountability log. 
 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.  Return unopened, 
expired, or unused study drug with the Inventory of Returned Clinical Material 
form as directed by Genentech. 


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6.8 
DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and disclosure 
to third parties other than those noted below is prohibited. 
 
Upon the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or 
her welfare. 
 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, 
Genentech if appropriate. 
 
 
6.9 
RETENTION OF RECORDS 
Records of this study will be retained according the policies of Yale Cancer 
Center Clinical Trial Office. 


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APPENDIX A: Study Flowchart 
Baseline 
(Days 
-42 to -1) 
Week 1 
(Day 1) 
Weeks 2- 
12 
(weekly) 
Weeks 4-10 
(q 3 weeks) 
Weeks 12- 
13 
Weeks 13-22 (q 
3 weeks) 
Weeks 23-26 
(Post Chemo) 
Final visit 
(4 wks +/- 1 
week after 
surgery) 
Informed Consent 
x 
HER2, ER, PR 
assessment 
x 
Tumor assessment by 
imaginga 
x 
x 
x 
Complete medical history 
x 
x 
x 
x 
Complete physical exam 
x 
x 
x 
x 
Clinical tumor assessment 
x 
x 
x 
x 
ECOG performance status 
x 
x 
x 
x 
Toxicity evaluation 
x 
x 
x 
x 
MUGA 
scan/echocardiogramb 
x 
x 
x 
Serum or urine pregnancy 
testc 
x 
Hematology (CBC, diff) 
x 
x 
x 
Chemistry paneld 
x 
x 
x 
Pertuzumab administration 
x 
x 
x 
Trastuzumab 
administration 
x 
x 
x 
Paclitaxel administration 
x 
x 
FEC administration 
x 
Surgerye 
x 


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a  Bilateral mammograms and clip placement to mark tumor bed. Other imaging, such as ultrasonography or MRI, is at the 
discretion of the treating physicians. The most recent breast imaging that documents the size of the cancer must be within the 
past 6 weeks. Mammogram or the most recent imaging study that was obtained at baseline of the affected breast after 
completion of the 12 courses of weekly paclitaxel, trastuzumab and pertuzumab before starting FEC chemotherapy and also 
after completion of all chemotherapy before surgery. (Other imaging, such as ultrasonography or MRI, is at the discretion of 
the treating physicians.). Regional lymph nodes must be evaluated by ultrasonography; if lymph nodes are suspicious 
clinically or by imaging, an image guided fine needle aspiration o the suspicious node is required. Baseline staging scans for 
assessment of distant disease should follow NCCN guidelines and is at the discretion of the treating physicians; scans are 
recommended for patients with clinical stage III disease. 
b  Week 13 and MUGA scan/echocardiogram should be done before the administration of week 13 treatment. Same testing 
method must be used for week 13 and week 24-28 cardiac assessment as at Days -42 to -1. Cardiac assessment will 
continue every 12 weeks after surgery until completion of 12 months total. 
c  Women of childbearing potential. Counseling about need of contraception during treatment and for 3 months after completion 
of therapy must be performed. 
d  Chemistry panel should include electrolytes, BUN, creatinine, total bilirubin, AST, ALT, alkaline phosphatase. 
e  Surgery will be scheduled 3-6 weeks after receiving the last dose of chemotherapy. 


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APPENDIX B 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
 
 
The baseline longest diameter of the primary breast cancer assessed by 
mammogram (or ultrasonogram or MRI at physicians discretion) will be used as 
the reference by which to characterize objective tumor response in the breast. 
 
Complete response (CR) 
Disappearance of all evidence of tumor for at least two cycles of therapy. 
 
Partial response 
At least a 30% decrease in the sum of the longest diameter of target lesions, 
taking a reference the baseline sum longest diameter. 
 
Stable disease (SD) 
Neither sufficient shrinkage to qualify for partial response nor sufficient increase 
to qualify for progressive disease, taking as reference the smallest sum longest 
diameter since the treatment started. 
 
Progressive disease (PD) 
At least a 20% increase in the sum of the longest diameter of target lesions, 
taking as reference the smallest sum longest diameter recorded since the 
beginning of treatment or the appearance of one or more new lesions Clinical 
progressive disease 
Subjects, who in the opinion of the treating physician investigator have had a 
substantial decline in their performance status and have clinical evidence of 
progressive disease may be classified as having progressive disease. 


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APPENDIX C 
HFSA Guidelines 
Recommendations for Pharmacological Therapy: 
Left Ventricular Systolic Dysfunction ß-
Adrenergic Receptor Blockers 
Background for Recommendations 
 
The single most significant addition to the pharmacological management of heart 
failure since the publication of previous guidelines involves the use of ß-receptor 
antagonists. This represents a noteworthy departure from traditional doctrine in 
which ß-blocking agents were classified as contraindicated in the setting of left 
ventricular systolic dysfunction. A solid foundation of both clinical and 
experimental evidence now firmly supports their use in heart failure with the aim 
of reducing both morbidity and mortality (16,22,23). 
 
ß-Blocker therapy for heart failure has been advocated by some investigators 
since the 1970s (24). During the subsequent 2 decades, many small- to medium- 
sized placebo-controlled trials, which used a variety of agents, showed several 
common findings: 1) the use of ß-blockers in mild to moderate heart failure was 
generally safe when initiated at low doses and gradually titrated up under close 
observation; 2) improvement in left ventricular ejection fraction was observed in 
all trials that lasted at least 3 months; and 3) there was wide variability in the 
effects of ß-blockade on exercise tolerance but improvement in outcome and 
symptomatic benefits was noted in many studies. These generally positive 
findings stimulated additional, large-scale clinical trials that have provided an 
impressive body of evidence that supports the use of ß-blockers in patients with 
heart 
failure 
caused 
by 
left 
ventricular 
systolic 
dysfunction. 
The 
recommendations that follow are derived from nearly 2 decades of research that 
include basic science data, animal models, and clinical trial experience in over 
10,000 patients (25,26). 
 
Although this is a major advance in efficacy, identification of appropriate 
candidates for ß-blocker therapy is essential to ensure safe and effective 
treatment. Prescribing physicians should understand the potential risks of ß- 
blocker therapy, as well as the benefits. The interested practitioner who is 
unfamiliar with ß-blocker initiation and titration may first seek further education 
and counsel from sources such as the Heart Failure Society of America or local 
and regional heart failure specialty centers. 
 
Recommendation 1. ß-blocker therapy should be routinely administered to 
clinically stable patients with left ventricular systolic dysfunction (left 
ventricular ejection fraction less than or equal to 40%) and mild to 
moderate heart failure symptoms (ie, NYHA class II-III, Appendix A) 
who are on standard therapy, which typically includes ACE inhibitors, 
diuretics as needed to control fluid retention, and digoxin (Strength of 
Evidence = A). 


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The most persuasive outcome in heart failure management remains all-cause 
mortality. Combined endpoints, including mortality or hospitalization and mortality 
or hospitalization for heart failure, have also emerged as key outcomes. These 
latter endpoints reflect a more comprehensive assessment of the influence of 
therapy on quality of life and disease progression and are assuming more 
importance as mortality rates decline with treatment advances. The substantial 
beneficial effect of ß-blocker therapy on these endpoints has been well shown in 
clinical trials of symptomatic patients (NYHA class II - III) treated with carvedilol, 
bisoprolol, or metoprolol controlled release/extended release (CR/XL) (27-29). 
Trials with these agents encompass the combined, worldwide experience with ß- 
blocker therapy in patients with chronic heart failure who were stable on 
background therapy, including ACE inhibitors (over 90%) and diuretics (over 
90%). Digoxin was common as background therapy, particularly in studies 
conducted in the United States. Trial results indicate that both selective and 
nonselective ß-blockers, with and without ancillary properties, have significant 
efficacy in heart failure. ß-Blocking agents with intrinsic sympathomimetic activity 
appear to have a negative impact on survival and should not be used in heart 
failure patients. 
 
Metoprolol. The MDC Study was an early trial that included 383 patients with 
heart failure caused by nonischemic causes, NYHA class II-III symptoms, and a 
left ventricular ejection fraction of less than or equal to 40% (30). Patients with 
coronary artery disease were excluded. Study results showed a 34% reduction in 
risk in patients treated with metoprolol, although this strong trend toward benefit 
(P = .058) was entirely attributable to a reduction in the frequency of cardiac 
transplantation listing in the treatment group. In fact, the absolute number of 
deaths in the metoprolol group was higher than in the placebo group (23 v 19, P 
= .69). 
 
The MERIT-HF Trial evaluated the effect of metoprolol CR/XL with all-cause 
mortality as the primary endpoint. The trial included 3,991 patients with NYHA 
class II-IV heart failure, although 96% of the study patients were functional class 
II or III (31). In this study, investigators were allowed to select the starting dose of 
metoprolol CR/XL. Seventy-nine percent chose 25 mg as the starting dose for 
class II patients, and 77% chose 12.5 mg for class III-IV patients. The target dose 
was 200 mg and doses were up-titrated over a period of 8 weeks. Premature 
discontinuation of blinded therapy occurred in 13.9% of those treated with 
metoprolol CR/XL and 15.3% of those in the placebo group (P = .90). The study 
results revealed a 34% reduction in mortality in the metoprolol group (relative risk 
of .66; 95% confidence interval [CI], .53 to .81; p=.0062 after adjustment for 
interim analyses), with annual mortality rates of 11% in the placebo 
and 7.2% in the metoprolol CR/XL group (29). 
 
Bisoprolol. The CIBIS Study evaluated the effects of bisoprolol in 641 patients 
with left ventricular systolic dysfunction caused by ischemic or nonischemic 
causes and NYHA class III-IV heart failure (32). The primary endpoint was all- 
cause mortality, and hospitalization for worsening heart failure was one of the 


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secondary outcomes of interest. The initial bisoprolol dose was 1.25 mg/day, 
which was increased to a maximum dose of 5 mg/day. The trial found no significant 
reduction in all-cause mortality in patients treated with bisoprolol (20% reduction 
bisoprolol v placebo, P = .22) (32). The risk of hospitalization was significantly 
reduced by 34% (28% placebo group v 19% bisoprolol group, P < 
.01). 
The favorable trends seen in CIBIS led to the larger CIBIS II Study, which 
ultimately was prematurely terminated as a result of a significant reduction in 
mortality in the bisoprolol arm (28). These results were obtained in 2,647 patients 
who were followed for an average of 1.3 years. Over 80% of the patients were 
judged to be NYHA class III at enrollment. Background therapy included ACE 
inhibitors in 96% and diuretic in 99% of the study patients, whereas 52% were 
taking digoxin. In contrast to the original CIBIS study, CIBIS II had a similar 
starting dose of 1.25 mg but had a greater target dose of 10 mg daily of bisoprolol. 
More stringent criteria for defining ischemic cardiomyopathy  were used. Treatment 
with bisoprolol reduced the annual mortality rate by 34% (13.2% placebo v 8.8% 
bisoprolol; hazard ratio .66; 95% CI, .54 to .81; P< .0001). Hospitalizations 
for worsening heart failure were also decreased by 32% (18% placebo  v 12% 
bisoprolol,  hazard  ratio  .64;  95% CI, .53 to .79; P<  .0001). 
Although a post hoc 
analysis of the CIBIS Study had suggested benefit might be consigned to patients 
without coronary disease, the survival benefit, with significant reductions apparent 
in both ischemic or nonischemic patients, was not influenced by disease origins. 
Carvedilol. Carvedilol, a nonselective ß-blocker and -blocker, has been 
extensively investigated for treatment of heart failure caused by left ventricular 
systolic dysfunction. In the United States carvedilol trials, 4 separate study 
populations were examined and the data from 1,094 patients were combined to 
evaluate the effect of carvedilol therapy on the clinical progression of heart failure 
(27). Clinical progression was defined as worsening heart failure  leading  to death, 
hospitalization, or, in one study, a sustained increase in background medications. 
Patients with a left ventricular ejection fraction of 35% or less and NYHA class 
II-IV were eligible if they tolerated 6.25 mg of carvedilol twice per day for a 2-
week, open-label, run-in period. Although this run-in phase biased the ultimately 
randomized patient population, less than 8% of eligible patients failed the open-
label challenge. Target dosages for the studies were 50 to 100 mg/day of 
carvedilol that were administered in divided doses twice daily. Patients 
completing the run-in period were randomized based on results from their 6- 
minute walk test into mild, moderate, or severe trials. These studies were 
prematurely terminated (median follow-up 6.5 months) by the Trial Data and 
Safety Monitoring Board because of reduced mortality across the 4 combined 
trials of patients treated with carvedilol. 
Data from these combined trials indicated a substantial benefit from carvedilol 
treatment. The risk of mortality was 65% lower (7.8% placebo v 3.2% carvedilol; 
95% CI, 39% to 80%; P< .001) and the combined risk of hospitalization or death 
was reduced by 38% (20% on placebo v 14% on carvedilol; 95% CI, 18% to 
53%; P< .001). A significant mortality reduction was also noted when deaths that 


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occurred in the run-in period were included in the analysis. The statistical validity 
of the survival analysis across the trials has been questioned because mortality 
was not the primary endpoint, and only 1 of the 4 trials achieved a significant 
result when analyzed based on the primary endpoint. Nevertheless, the 
magnitude of the survival benefit and the reduction in hospitalization were 
impressive. The survival benefit was not influenced by the cause of disease, age, 
gender, or baseline ejection fraction. Overall, 7.8% of the placebo group and 
5.7% of the carvedilol group discontinued study medication. Data from the 
individual trials, PRECISE and MOCHA, which evaluated patients with moderate 
to severe heart failure, found that carvedilol reduced the risk of the combined 
endpoint of mortality or heart failure hospitalization by 39% to 49% (33,34). The 
MOCHA Study provided strong evidence for increased benefit from higher 
dosages (25 mg twice per day) versus lower dosages (6.25 mg twice per day) of 
carvedilol, so uptitration of carvedilol dosages to 25 mg twice per day is generally 
recommended. However, favorable effects were noted at 6.25 mg twice per day, 
so intolerance of high doses should not be a reason for discontinuation  of therapy. 
The Australia-New Zealand Carvedilol Trial enrolled 415 patients with ischemic 
cardiomyopathy and a left ventricular ejection fraction of less than 45% (35). 
Although patients with NYHA functional classes I-III were eligible, the majority 
enrolled were NYHA functional class I (30%) or II (54%). ACE inhibitors were 
used in 86% of the participants, whereas 76% were on diuretic therapy, and 38% 
were on digoxin. This trial also had a run-in phase during which 6% of the 
patients discontinued ß-blocker therapy. During an average follow-up of 19 
months, carvedilol decreased the combined risk of all-cause mortality or any 
hospitalization by 26% (relative risk .74; 95% CI, .57 to .95; P= .02). Overall 
mortality was 12.5% in the placebo group and 9.6% in the carvedilol group which 
was not statistically significant (relative risk .76; 95% CI, .42 to 1.36; P > .10). 
 
Unreported or Ongoing Trials. Studies that are underway will provide additional 
data concerning specific aspects of the efficacy of ß-blocker therapy in heart 
failure. The effect of bucindolol on mortality and morbidity in patients with 
moderate to severe heart failure has been evaluated in the BEST Study. This 
study enrolled a substantial number of women so the potential influence of gender 
on the efficacy of ß-blocker therapy can be investigated. The trial has been 
stopped, and no results are available for analysis. 
 
The COPERNICUS Trial is designed to assess the effect of carvedilol treatment 
on disease progression and survival in patients with advanced heart failure with 
symptoms at rest or on minimal exertion. The COMET protocol is a 3,000 patient 
study that directly compares the survival benefit of carvedilol versus metoprolol. 
This trial will provide important data concerning the relative efficacy of a selective 
ß-blocker versus a nonselective ß-blocker with ancillary properties. 
 
Recommendation 2. ß-blocker therapy should be considered for 
patients with left ventricular systolic dysfunction (left ventricular 
ejection fraction less than or equal to 40%) who are asymptomatic 
(ie, NYHA class I) and standard therapy, including ACE inhibitors 


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(Strength of Evidence = C). 
 
Data from the SOLVD Prevention Trial prospectively illustrated the efficacy of 
ACE inhibitors in delaying the onset of heart failure symptoms and the need for 
treatment or hospitalization for heart failure in asymptomatic patients with a left 
ventricular ejection fraction less than or equal to 35% (36). Similar controlled, 
clinical trial data that support the use of a ß-blocker in this clinical circumstance 
are not available. However, significant support for the use of ßblocker therapy in 
patients with asymptomatic left ventricular dysfunction can be derived from clinical 
trials in coronary artery disease and hypertension. Previous data indicate that ß-
blocker therapy should be used in patients after myocardial infarction (MI) and in 
patients with myocardial revascularization who have good symptomatic and 
functional recovery but residual ventricular systolic dysfunction. Trials in 
hypertension indicate that ß-blocker therapy decreases the risk of developing 
heart failure. Given the potential of ß-blockers to retard disease progression and 
improve ventricular function, the risk to benefit ratio seems sufficiently low to 
support ß-blocker use in asymptomatic patients with left ventricular dysfunction, 
especially when the dysfunction is marked, and coronary artery disease is 
present. 
 
Recommendation 3. To maximize patient safety, a period of clinical 
stability on standard therapy should occur before ß-blocker therapy 
is instituted. Initiation of ß-blocker therapy in patients with heart 
failure requires a careful baseline evaluation of clinical status 
(Strength of Evidence = B). 
 
Initiation of ß-blocker therapy has the potential to worsen heart failure signs 
and symptoms. This risk increases with the underlying severity of the heart 
failure that is present. To minimize the likelihood of worsening failure, a period of 
treatment with standard therapy and evidence of clinical stability without acute 
decompensation or fluid overload is recommended before initiation of ß-blocker 
therapy. The majority of the large-scale, ß-blocker heart failure trials required that 
chronic heart failure be present 3 months or more before initiation of ß-blocker 
therapy. Patients enrolled in these trials were typically treated with ACE inhibitors 
(if tolerated), diuretic, and digoxin for at least 2 months and were observed to be 
clinically stable for 2 to 3 weeks before beginning ß-blocker therapy. Thus, many 
heart failure clinicians favor a minimum of 2 to 4 weeks of clinical stability on 
standard therapy before ß-blocker therapy is instituted. Likewise, most clinicians 
discourage the initiation of ß-blocker therapy in the hospital setting after 
treatment for new or decompensated heart failure (with or without associated 
inotrope administration). Some experienced clinicians initiate ß-blocker therapy in 
the hospital in selected patients who have responded well to inpatient treatment 
and who can be followed closely after discharge. 
 
Recommendation 4. There is insufficient evidence to recommend the use 
ofß-blocker therapy for inpatients or outpatients with symptoms of heart 
failure at rest (ie, NYHA class IV) (Strength of Evidence = C). 


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ß-Blocker therapy cannot be routinely recommended for NYHA class IV 
patients because there are currently no clinical trial data to indicate favorable 
long-term efficacy and safety of ß-blocker therapy in this patient population. A 
substantial body of observational data indicates that successful institution of ß- 
blocker therapy in patients with this degree of heart failure is problematic. If used, 
these agents may precipitate deterioration, and patients so treated should be 
monitored by a physician who has expertise in heart failure. 
The number of patients with class IV heart failure at the time of ß-blocker 
initiation in controlled clinical trials is small. Available trials, which report data on 
patients with severe heart failure mostly labeled as NYHA class III, show the 
potential problems of ß-blocker therapy in this part of the heart failure spectrum. 
This experience is reflected in a 14-week study that evaluated the effects of ß- 
blocker therapy in 56 patients (51 NYHA class III and 5 NYHA class IV at 
randomization) with severe left ventricular dysfunction (average left ventricular 
ejection fraction of 16% ± 1% and left ventricular filling pressure of 24 mm Hg ± 1 
mm Hg) (37). These patients had significant impairment of exercise capacity 
(mean VO2  max of 13.6  mL/kg/min ± 0.6  mL/kg/min) despite ACE-inhibitor, 
digoxin and diuretic therapy. Patients were believed to be clinically stable 
(requiring no medication adjustments) for a 2-week period before an open-label 
challenge was conducted. Seven patients (12%) failed to complete the open- 
label, run-in period, during which 5 died and 2 had nonfatal adverse reactions. 
Clinical parameters did not distinguish these patients from those who were able 
to continue in the trial. Eighteen of the 49 patients (37%) completing the run-in 
period experienced worsened dyspnea or fluid retention during this phase. Also, 
22% experienced dizziness and required medication adjustment, which delayed 
up-titration during the run-in. Subsequently, an additional 12% of the patients 
randomized to carvedilol withdrew from the blinded arm of the study. One of the 
United States carvedilol trials studied patients with severe left ventricular 
dysfunction who had markedly reduced exercise capacity as assessed by the 6- 
minute walk test (38). In this trial, 131 patients with a mean left ventricular 
ejection fraction of 22% and severe impairment in quality of life underwent a 2- 
week, open-label challenge phase of 6.25 mg of carvedilol twice per day. Ten of 
these 131 patients (8%) were unable to complete this run-in phase, most because 
of worsening heart failure, dyspnea, or dizziness. Subsequently, 11% of the 
patients randomized to carvedilol withdrew, as did a similar number of patients 
(11%) in the placebo group. In the recently completed large-scale BEST Trial, the 
mortality trend in NYHA class III-IV patients favored the ß-blocker bucindolol, 
but the difference from placebo was not significant. Further analysis of these 
preliminary findings is necessary, but the data suggest that the striking benefit of 
ß-blockers in mild-to-moderate heart failure may not be extrapolated to those with 
severe symptoms. 
 
Recommendation 5. ß-Blocker therapy should be initiated at low doses 
and up-titrated slowly, generally no sooner than at 2-week intervals. 
Clinical reevaluation should occur at each titration point and with 
worsening of patient symptoms. Patients who develop worsening heart 
failure or other side effects after drug initiation or during titration require 
adjustment of concomitant medications. These patients may also require a 


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reduction in ß-blocker dose and, in some cases, temporary or permanent 
withdrawal of this therapy (Strength of Evidence = B). 
 
ß-Blocker therapy should be initiated at doses substantially less than target 
doses. Clinical trials required patient reassessment at up-titration of each dose. 
This careful evaluation by trained nurses and/or heart failure specialists likely 
contributed to the relatively low withdrawal rates and safety profiles observed in 
the clinical trials. 
Treatment for symptomatic deterioration may be required during ß-blocker 
titration, but with appropriate adjustments in therapy, most patients can be 
maintained and generally achieve target doses. There is a risk of worsening 
heart failure, and vasodilatory side effects may occur with certain agents. 
Worsening heart failure is typically reflected by increasing fatigue, lower exercise 
tolerance, and weight gain. Increased diuretic doses may be required for signs 
and symptoms of worsened fluid retention. Treatment options also include 
temporary down-titration of the ß-blocker to the last tolerated dose. Abrupt 
withdrawal should be avoided. A minimum period of stability of 2 weeks should 
occur before further up-titration is attempted. Hypotensive side effects may often 
resolve with reduction in diuretic dose. Temporary reductions in ACE inhibitor 
dose may be helpful for symptomatic hypotension not obviated by staggering the 
schedule of vasoactive medications. Administration of carvedilol with food may 
alleviate vasodilatory side effects as well. 
If ß-blocker treatment is interrupted for a period exceeding 72 hours and the 
patient is still judged a candidate for this therapy, drug treatment should be 
reinitiated at 50% of the previous dose. Subsequent up-titration should be 
conducted as previously described. 
 
Recommendation 6. In general, patients who experience a deterioration in 
clinical status or symptomatic exacerbation of heart failure during chronic 
maintenance treatment should be continued on ß-blocker therapy (Strength of 
Evidence = C). 
 
Clinical decompensation that occurs during stable maintenance therapy is less 
likely caused by chronic ß-blocker therapy than other factors (diet or medication 
noncompliance, ischemia, arrhythmia, comorbid disease, infection, or disease 
progression). In these situations, maintaining the current ß-blocker dose while 
relieving or compensating for the precipitating factor(s) is most often the best 
course. Data from patients randomized to continue or discontinue ß-blocker 
therapy in this setting are not currently available. However, studies of the 
withdrawal of ß-blocker therapy in patients with persistent left ventricular systolic 
dysfunction but improved and stable clinical heart failure have revealed a 
substantial risk of worsening heart failure and early death after discontinuation of 
ß-blocker therapy (39,40). 
 
Recommendation 7. Patient education regarding early recognition of 
symptom exacerbation and side effects is considered important. If clinical 
uncertainty exists, consultation with clinicians who have expertise in heart 


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failure and/or specialized programs with experience in ß-blocker use in 
patients with heart failure is recommended (Strength of Evidence = B). 
 
In certain patients, frequent return visits for dose-titration may be difficult to 
accommodate in a busy clinical practice. Trained personnel, including nurse 
practitioners, physicians’ assistants, and pharmacists with physician supervision, 
may more efficiently perform patient education and reevaluation during up- 
titration. Heart failure specialty programs are more likely to have the resources to 
provide this follow-up and education (41). Consultation or referral may be 
particularly beneficial when the clinical heart failure status of the patient is 
uncertain or problems arise during initiation of therapy or dose-titration that may 
cause unwarranted discontinuation of therapy. Ideal patients for ß-blocker 
therapy should be compliant and have a good understanding of their disease and 
their overall treatment plan. Patients should be aware that symptomatic 
deterioration is possible early in therapy and that symptomatic improvement may 
be delayed for weeks to months. 
 
Unresolved Therapeutic Issues 
 
Combining ß-Blocking Agents With Amiodarone Therapy. Concomitant use 
of amiodarone was generally precluded in the trials evaluating carvedilol and 
most other ß-blockers. However, the use of this agent for rate control of atrial 
arrhythmia or for maintenance of sinus rhythm is common in heart failure patients. 
Drug interactions between ß-blockers and amiodarone are possible, including 
symptomatic bradycardia, and may limit the maximum tolerated dose of the ß-
blocker. When the combination is used, the smallest effective dose of 
amiodarone should be employed. Given the lack of a clear survival benefit, 
amiodarone is not a substitute for ß-blocker therapy in heart failure patients who 
are candidates for this therapy. 
 
Implantation of Cardiac Pacemakers. Given the strength of evidence that 
supports ß-blocker therapy in patients with symptomatic heart failure, some 
physicians 
would 
consider 
pacemaker 
implantation 
when 
symptomatic 
bradycardia or heart block occur during the initiation of this therapy, although no 
data are available to support such use. Consideration should be given, after 
weighing risks and benefits, to the withdrawal of other drugs that may have 
bradycardia effects. 
 
Duration of Therapy. Whether patients experiencing marked improvement in left 
ventricular systolic dysfunction and heart failure symptoms during therapy can be 
successfully withdrawn from ß-blocker therapy remains to be established. 
Concern continues that such patients would experience worsening after ß- blocker 
withdrawal, either in systolic function or symptoms, over a time period that is 
undefined. Until clinical trial data indicate otherwise, the duration of ßblocker 
therapy must be considered indefinite. 


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Digoxin 
Background for Recommendations 
Although little controversy exists as to the benefit of digoxin in patients with 
symptomatic left ventricular systolic dysfunction and concomitant atrial fibrillation, 
the debate continues over its current role in similar patients with normal sinus 
rhythm. Recent information regarding digoxin’s mechanism of action and new 
analyses of clinical data from the DIG Trial and the combined PROVED and 
RADIANCE Trial databases provide additional evidence of favorable efficacy that 
was unavailable to previous guideline committees (42-47). In  fact,  this information 
has recently formed the basis of Food and Drug Administration (FDA) approval of 
digoxin for the treatment of mild to moderate heart failure (48). Digoxin, a 
drug that is inexpensive and can be given once daily, represents the only orally 
effective drug with positive inotropic effects approved for the management of 
heart failure. The committee’s consensus is that digoxin, when used in 
combination with other standard therapy, will continue to play an important role 
in the symptomatic management of the majority of patients with heart failure. 
The efficacy of digoxin for the treatment of heart failure caused by systolic 
dysfunction has traditionally been attributed to its relatively weak positive 
inotropic action that comes from inhibition of sodium-potassium adenosine 
triphosphatase (ATPase) that results in an increase in cardiac myocyte 
intracellular calcium. However, in addition to positive inotropy, digitalis has 
important, neurohormonal-modulating effects in patients with chronic heart 
failure, including a sympathoinhibitory effect that cannot be ascribed to its 
inotropic action (49,50). Digoxin also ameliorates autonomic dysfunction as 
evidenced by studies of heart rate variability, which indicates increased 
parasympathetic and baroreceptor sensitivity during therapy (51). 
 
Recommendation 1. Digoxin should be considered for patients who have 
symptoms of heart failure (NYHA class II-III, Strength of Evidence = A 
and NYHA class IV, Strength of Evidence = C) caused by left ventricular 
systolic dysfunction while receiving standard therapy. 
 
Digoxin increases left ventricular ejection fraction and alleviates symptomatic 
heart failure as evidenced by drug-related improvement in exercise capacity and 
reductions in heart-failureassociated hospitalization and emergency room visits. 
Digoxin should be used in conjunction with other forms of standard heart failure 
therapy including ACE inhibitors, diuretics and ß-blockers. 
The DIG Trial, a randomized, double-blind, placebo-controlled trial in over 
7,000 patients with heart failure, showed a neutral effect on the primary study 
endpoint and mortality from any cause during an average follow-up of 
approximately 3 years (42). In the main trial, 6,800 patients with left ventricular 
ejection fraction less than or equal to 45% were randomized to digoxin or placebo, 
in addition to diuretics and ACE inhibitors. A total of 1,181 deaths occurred 
on digoxin (34.8%) and 1,194 on placebo (35.1%) for a risk ratio of .99 (95% CI, 
.91 to 1.07; P = .80). These results differ from other oral agents with inotropic 
properties that have been associated with an adverse effect on mortality. In 
addition, the need for hospitalization and cointervention (defined as 


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increasing the dose of diuretics and ACE inhibitors or adding new therapies for 
worsening heart failure) was significantly lower in the digoxin group, even in 
those patients who were not previously taking digoxin. Fewer patients on digoxin 
compared with placebo were hospitalized for worsening heart failure (26.8%v 
34.7%; risk ratio .72; 95% CI, .66 to .79; P < .001). These long-term data are 
consistent with recent results obtained from an analysis of the combined 
PROVED and RADIANCE databases (45). In this analysis, patients who 
continued digoxin as part of triple therapy with diuretics and an ACE inhibitor 
were much less likely to develop worsening heart failure (4.7%) than those 
treated with a diuretic alone (39%, P < .001), diuretic plus digoxin (19%, P = 
.009) or diuretic plus an ACE inhibitor (25%, P = .001). 
Although there are no clinical trial data (level A evidence) for the efficacy of 
digoxin in patients with NYHA Class IV heart failure, there is evidence that 
digoxin works across the spectrum of left ventricular systolic dysfunction. A 
prespecified subgroup analysis of patients enrolled in the DIG Trial with evidence 
of severe heart failure (as manifested by left ventricular ejection fraction less than 
25%, or cardiothoracic ratio [CTR] greater than .55) showed the benefit of digoxin 
(48). The following reductions in the combined endpoint of all-cause mortality or 
hospitalization were seen on digoxin compared with placebo: 16% reduction 
(95% CI, 7% to 24%) in patients with a left ventricular ejection fraction of less 
than 25%, and a 15% reduction (95% CI, 6% to 23%) in patients with a CTR of 
greater than .55 (43). Reductions in the risk of the combined endpoint of heart- 
failure related mortality or hospitalization were even more striking: 39% (95% CI, 
29% to 47%) for patients with left ventricular ejection fraction less than 25%, and 
35% (95% CI, 25% to 43%) for patients with a CTR greater than .55 (48). 
Evidence for the efficacy of digoxin in patients with mild symptoms of heart 
failure has been provided by a recent retrospective, cohort analysis of the 
combined PROVED and RADIANCE data (52). The outcome of patients in these 
trials who were randomized to digoxin withdrawal or continuation  was categorized 
by using a prospectively obtained heart failure score based  on clinical signs and 
symptoms. Patients in the mild heart failure group (heart failure score of 2 or 
less) who were randomized to have digoxin withdrawn were at increased risk 
of treatment failure and had deterioration of exercise capacity and left ventricular 
ejection fraction compared with patients who continued digoxin (all P < .01). 
Patients in the moderate heart failure group who had digoxin withdrawn were 
significantly more likely to experience treatment failure than either patients in the 
mild heart failure group or patients who continued digoxin (both P < .05). These 
data suggest that patients with left ventricular systolic dysfunction benefit from 
digoxin despite only mild clinical evidence of heart failure. 
In summary, a large body of evidence supports the efficacy of digoxin in 
patients with symptomatic heart failure caused by left ventricular systolic 
dysfunction. Digoxin has been shown to decrease hospitalizations, as well as 
emergency room visits; decrease the need for co-intervention; and improve 
exercise capacity (42-44,53,54). Taken as a whole, these clinical trial data provide 
support for digoxin’s beneficial effect on morbidity and neutral effect on mortality 
(42). 


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Recommendation 2. In the majority of patients, the dosage of digoxin should 
be .125 mg to .25 mg daily (Strength of Evidence = C). 
 
Recent data suggest that the target dose of digoxin therapy should be lower 
than traditionally assumed. Although higher doses may be necessary for maximal 
hemodynamic effects (55), beneficial neurohormonal and functional effects 
appear to be achieved at relatively low serum digoxin concentrations (SDC) 
typically associated with daily doses of .125 mg to .25 mg of digoxin (55-57). The 
utility of lower SDC is supported by recent clinical trial data; the mean SDC 
achieved in the RADIANCE Trial was 1.2 ng/mL and in the DIG Trial was 0.8 
ng/mL (42,44). Recent retrospective, cohort analysis of the combined PROVED 
and RADIANCE databases indicates that patients with a low SDC (less than .9 
ng/mL) were no more likely to experience worsening symptoms of heart failure 
on maintenance digoxin than those with a moderate (.9 to 1.2 ng/mL) or high 
(greater than 1.2 ng/mL) SDC (41). All SDC groups were significantly less likely 
to deteriorate during follow-up compared with patients withdrawn from digoxin. 
Therefore, patients with left ventricular systolic dysfunction and normal sinus 
rhythm should be started on a maintenance dosage of digoxin (no loading dose) 
of .125 or .25 mg once daily based on ideal body weight, age, and renal function 
For patients with normal renal function, a dosage of digoxin of .25 mg/day will be 
typical. Many patients with heart failure have reduced renal function and should 
begin on .125 mg daily. In addition, patients with a baseline conduction 
abnormality, or who are small in stature or elderly, should be started at .125 
mg/day, which can be up-titrated if necessary. Once dosing has continued for a 
sufficient period for serum concentration to reach steady state (typically in 2 to 3 
weeks), some clinicians consider the measurement of a SDC, especially  in elderly 
patients or those with impaired renal function in which the digoxin dose is often 
not predictive of SDC. SDC measurements may be considered when 1) a 
significant change in renal function occurs; 2) a potentially interacting drug 
(amiodarone, quinidine, or verapamil) is added or discontinued; or 3) confirmation 
of suspected digoxin toxicity is necessary in a patient with signs or symptoms 
and/or electrocardiographic changes consistent with this diagnosis. Samples 
for  trough SDC should be drawn more than 6 hours after dosing. Otherwise, 
the result is difficult to interpret because the drug may not be fully distributed 
into tissues. 
 
Recommendation 3. In patients with heart failure and atrial fibrillation 
with a rapid ventricular response, the administration of high doses of 
digoxin (greater than .25 mg) for the purpose of rate control is not 
recommended. When necessary, additional rate control should be achieved 
by the addition of ß-blocker therapy or amiodarone (Strength of Evidence = 
C). 
 
 
Digoxin continues to be the drug of choice for patients with heart failure and 
atrial fibrillation. However, the traditional practice of arbitrarily increasing the dose 
(and SDC) of digoxin until ventricular response is controlled should be 
abandoned because the risk of digoxin toxicity increases as well. Digoxin alone is 


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often inadequate to control ventricular response in patients with atrial fibrillation, 
and the SDC should not be used to guide dosing to achieve rate control. 
Therefore, digoxin should be dosed in the same manner as in a patient with heart 
failure and normal sinus rhythm. 
Digoxin slows ventricular response to atrial fibrillation through enhancement of 
vagal tone. However, with exertion or other increases in sympathetic activity, 
vagal tone may decrease and ventricular rate accelerate. Addition of a ß-blocker 
or amiodarone 1) complements the pharmacological action of digoxin and 
provides more optimal rate control; 2) allows the beneficial clinical effects of 
digoxin to be maintained; and 3) limits the risk of toxicity that may occur if digoxin 
is dosed to achieve a high SDC (58). For patients who have a contraindication to 
ß-blockers, amiodarone is a reasonable alternative. If amiodarone is added, the 
dose of digoxin should be reduced, and the SDC should be monitored so that the 
serum concentration can be maintained in the desired range. Some clinicians 
advocate the short-term, intravenous administration of diltiazem for the acute 
treatment of patients with very rapid ventricular response, especially those with 
hemodynamic compromise. This drug is not indicated for long-term management 
because its negative inotropic effects may worsen heart failure. 
 
Unresolved Therapeutic Issues 
 
Combination With ß-blockers. ß-Blocker therapy has become pivotal in the 
management of heart failure. However, the majority of patients enrolled in 
controlled clinical trials that study the efficacy of digoxin were not taking ß- 
blockers. Therefore, it is uncertain whether or not digoxin should be routinely 
included as part of a ß-blocker regimen for symptomatic heart failure caused by 
left ventricular systolic dysfunction. There are attractive features of combining 
digoxin with ß-blocker therapy in the treatment of heart failure. The majority of 
heart failure patients have coronary artery disease and may be at risk for transient 
episodes of myocardial ischemia that could cause catecholamine release and 
sudden cardiac death. Combining digoxin with a ß-blocker may preserve the 
beneficial effects of digoxin on the symptoms of heart failure while minimizing 
the potential detrimental effects of this therapy on catecholamine release in 
the setting of ischemia (47). 
 
Combination with Diuretics. Non-potassium-sparing diuretics can produce 
electrolyte abnormalities such as hypokalemia and hypomagnesemia, which 
increases the risk of digoxin toxicity. The combination of digoxin with a 
potassium- sparing diuretic would be a potentially safer alternative. Further study 
will be necessary to carefully elucidate the efficacy and safety of combining 
digoxin with these agents. 
 
Anticoagulation and Antiplatelet Drugs 
Background for Recommendations 
Patients with heart failure are recognized to be at increased risk for 
thromboembolic events that can be arterial or venous in origin. In addition to 
atrial fibrillation and poor ventricular function (which promote stasis and increase 
the   risk   of   thrombus   formation),   patients   with   heart   failure   have   other 


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v14.0 (23-Jun-2016) 
 
manifestations of hypercoagulability. Evidence of heightened platelet activation; 
increased plasma and blood viscosity; and increased plasma levels of 
fibrinopeptide A, ßthromboglobulin, D-dimer, and von Willebrand factor (59-61) 
have been found in many patients. Despite a predisposition, estimates regarding 
the incidence of thromboemboli in patients with heart failure vary substantially 
between 1.4 and 42 per 100 patient years (62-65). Although variability in the 
reported incidence likely results from differences in the populations studied and 
the methods used to identify these events, the consensus is that pulmonary and 
systemic emboli are not common in heart failure patients. Traditionally, the issue 
of anticoagulation in patients with heart failure centered on warfarin. Growing 
recognition of the importance of ischemic heart disease as a cause of heart 
failure suggests that the role of antiplatelet therapy must be considered in patients 
with this syndrome as well. 
Previous guidelines have recommended warfarin anticoagulation in patients 
with heart failure complicated by atrial fibrillation and in heart failure patients with 
prior thromboembolic events (18,19). Warfarin anticoagulation specifically was 
not recommended in patients with heart failure in the absence of these 
indications. There have been no randomized, controlled trials of warfarin in 
patients with heart failure. Therefore, recommendations regarding its use, in the 
absence of atrial fibrillation or clinically overt systemic or pulmonary 
thromboemboli, must be made on the basis of cohort data and expert opinion. 
The likely incidence of thromboembolic events and the possibility of averting 
them 
with 
warfarin 
are 
important 
considerations 
for 
any 
guideline 
recommendation. In addition, the potential beneficial effects of warfarin on 
coronary thrombotic events, independent of embolic phenomenon, must be taken 
into account. The substantial clinical trial data that reflect the beneficial effects of 
antiplatelet therapy in patients with ischemic heart disease suggest that new 
guideline recommendations for heart failure should address the role of this form 
of therapy in patients with left ventricular dysfunction. 
 
Anticoagulation 
 
Recommendation 1. All patients with heart failure and atrial fibrillation 
should be treated with warfarin (goal, international normalized ratio (INR) 
2.0 to 3.0) unless contraindicated (Strength of Evidence = A). 
 
The committee agrees with previous guideline recommendations that concern 
warfarin therapy in patients with heart failure complicated by atrial fibrillation. The 
benefit of warfarin anticoagulation in this setting is well established through several 
randomized trials (66). Patients with heart failure commonly have atrial 
fibrillation. Warfarin anticoagulation should be implemented in all of these 
patients unless clear contraindications exist. 
 
Recommendation 2. Warfarin anticoagulation merits consideration for 
patients with left ventricular ejection fraction of 35% or less. Careful 
assessment of the risks and benefits of anticoagulation should be 
undertaken in individual patients (Strength of Evidence = B). 


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v14.0 (23-Jun-2016) 
 
 
Cohort analyses examining the relationship between warfarin use and 
noncoronary thromboembolism in patients with heart failure have not consistently 
yielded positive findings (62,63,65,67-69). It is possible that the lack of consistent 
benefit was related to the low incidence of identifiable embolic events in these 
populations. However, these studies do not make a convincing argument for the 
use of warfarin to prevent embolic events in the absence of atrial fibrillation or a 
previous thromboembolic episode. 
In contrast, a recent cohort analysis of the SOLVD population focused on the 
relation between warfarin use and the risk of all-cause mortality rather than risk 
for embolic events (70). After adjustment for baseline differences, patients treated 
with warfarin at baseline had a significantly lower risk of mortality during follow-
up (adjusted hazard ratio .76; 95% CI, .65 to .89, P = .0006). In addition to a 
mortality benefit, warfarin use was also associated with a significant reduction in 
the combined endpoint of death or hospitalization for heart failure (adjusted 
hazard ratio .82; 95% CI, .72 to .93, P = .002). In the SOLVD population, the 
benefit associated with warfarin use was not significantly influenced by 1) 
presence or absence of symptoms (treatment trial v prevention trial), 2) 
randomization to enalapril or placebo, 3) gender, 4) presence or absence of atrial 
fibrillation; 5) age, 6) ejection fraction, 7) NYHA class, or 8) origins of disease. 
The benefit associated with warfarin use in the cohort analysis of the SOLVD 
population was related to a reduction in cardiac mortality. Specifically, there was 
a significant reduction among warfarin users in deaths that were identified as 
sudden, in deaths associated with heart failure, and in fatal MI. In contrast (yet in 
agreement with previous cohort analyses), there was no significant difference in 
deaths considered cardiovascular but noncardiac, including pulmonary embolism 
and fatal stroke. Some caution is needed in consideration of this finding because 
the number of cardiovascular deaths that were noncardiac was far less than the 
number of cardiac deaths. 
Reduction in ischemic events is one potential explanation for the apparent 
benefit from warfarin in the SOLVD Study. Warfarin users showed a reduced rate 
of hospitalization for unstable angina or nonfatal MI. Prior investigations of patients 
after acute MI showed that warfarin anticoagulation, when started within 4 weeks, 
reduces the incidence of fatal and nonfatal coronary events, as well as pulmonary 
embolus and stroke (71). 
As with other post hoc, cohort analyses, it is possible that the findings from the 
SOLVD Study may result from differences between the treatment groups that 
were not identified and for which statistical correction could not  adequately adjust. 
For this reason, evidence from any cohort study must be considered less powerful 
compared with evidence derived from randomized, controlled trials. Nevertheless, 
in the absence of randomized data, the SOLVD cohort analysis represents 
reasonable evidence to support more aggressive use of warfarin anticoagulation 
than previously recommended in patients with reduced left ventricular ejection 
fraction and sinus rhythm. The data from this analysis provide no information 
regarding the ideal warfarin dose in this patient population. Therefore, the dosing 
recommendation should likely conform to that derived from previous randomized 
trials performed in patients without mechanical prosthetic valves (INR 2.0 to 3.0). 


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v14.0 (23-Jun-2016) 
 
 
Antiplatelet Drugs 
 
Recommendation 1. With regard to the concomitant use of ACE 
inhibitors and acetylsalicylic acid (ASA), each medication should be 
considered on its own merit for individual patients. Currently, there is 
insufficient evidence concerning the potential negative therapeutic 
interaction between ASA and ACE inhibitors to warrant withholding either 
of these medications in which an indication exists (Strength of Evidence = 
C). 
 
Strong evidence supports the clinical benefit of aspirin in ischemic heart disease 
and atherosclerosis (72-75). However, recent post hoc analyses of large 
randomized trials involving ACE inhibitors in heart failure and post-MI suggest 
the possibility of an adverse drug interaction between ASA and ACE inhibitors 
(76-78). A retrospective cohort analysis of the SOLVD Study found that patients 
on antiplatelet therapy (assumed to be ASA in the great majority of patients) 
derived no additional survival benefit from the addition of enalapril. Data from 
CONSENSUS II and GUSTO-1 in post-MI patients, suggest not only no additive 
benefit, but the possibility of a negative effect on mortality from the combination 
of ASA and ACE inhibition. In contrast, an unadjusted, retrospective registry 
study in patients with chronic coronary artery disease did not support an adverse 
interaction (79). Interestingly, in an adjusted analysis of the subset of patients 
with heart failure in this study, the beneficial effects of aspirin seemed less 
evident in patients taking ACE inhibitors. Despite these provocative post hoc 
findings, no prospective studies have yet been reported that concern the possible 
adverse interaction between ACE inhibitors and aspirin. To date, there is no clear 
evidence of harm from the combination of ASA and ACE inhibitors in patients 
with heart failure (76). 
There is also some evidence that the potential interaction between ASA and 
ACE inhibitors may be dose related. A recent meta-analysis of all hypertension 
and heart failure patients who have received both ASA and ACE inhibitors 
suggests that ASA at doses equal to or less than 100 mg showed no interaction 
with ACE inhibitors (80). Any interaction, if observed, occurred at higher doses of 
aspirin. 
A potential mechanism for the hypothesized adverse interaction between ASA 
and ACE inhibitors in patients with heart failure involves prostaglandin synthesis. 
ACE inhibition is believed to augment bradykinin which, in turn, stimulates the 
synthesis of various prostaglandins that may contribute vasodilatory and other 
salutary effects. In the presence of ASA, the bradykinin-induced increase in 
prostaglandins should be attenuated or blocked, which potentially reduces the 
benefits of ACE inhibition. Invasive hemodynamic monitoring has shown that the 
acute hemodynamic effect of enalapril is blunted by concomitant administration 
of aspirin (81). Another possibility is that ASA and ACE inhibitors act in a similar 
fashion in heart failure, therefore no added benefit is gained from the 
combination. ACE inhibitors appear to reduce ischemic events in heart failure 
patients  possibly through  antithrombotic  effects,  which  could  mimic  those  of 


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v14.0 (23-Jun-2016) 
 
antiplatelet agents. Recent study results that suggest ASA may have independent 
beneficial action on ventricular remodeling support the hypothesis of similar 
mechanisms of action for ACE inhibitors and ASA (82). 
Development of the adenosine diphosphate (ADP) antagonists, ticlopidine and 
clopidogrel, provides alternative therapy for platelet inhibition that does not appear 
to influence prostaglandin synthesis (83). In direct comparison with aspirin, large-
scale  clinical trial results have established the efficacy of clopidogrel in the 
prevention of vascular events in patients with arteriosclerotic disease (84). 
Clinical data are limited with ADP antagonists in heart failure. However, 
hemodynamic evaluation found a similar reduction in systemic vascular resistance 
in heart failure patients treated with the combination of ACE inhibitors and 
ticlopidine 
versus 
ACE 
inhibitors 
alone, 
which 
suggests 
no 
adverse 
hemodynamic interaction with ACE inhibition with this type of antiplatelet 
compound (85). Definitive resolution of the therapeutic implications of the 
ASA/ACE inhibitor interaction and the appropriate alternative therapy, if any, in 
heart failure awaits the results of additional clinical research studies. 
Angiotensin II Receptor Blockers 
Background for Recommendations 
Angiotensin ll (AT) receptor blockers (ARBs) differ in their mechanism of action 
compared with ACE inhibitors. Rather than inhibiting the production of AT by 
blockade of ACE, ARBs block the cell surface receptor for AT. ARBs that are 
currently available are selective and only effectively inhibit the AT1 subtype of 
this receptor. Theoretical benefits of ARBs include receptor blockade of AT 
produced by enzymes other than ACE and maintenance of ambient AT to maintain 
or increase stimulation of AT2 receptors. AT1 receptor antagonism is important 
because this receptor appears to mediate the classical adverse effects associated 
with AT in heart failure. In contrast, the AT2 receptor subtype appears to 
counterbalance AT1 receptor stimulation by causing vasodilation and inhibiting 
proliferative and hypertrophic responses (86). Thus, the selective receptor 
blockade of the current ARBs may be particularly advantageous. Theoretical 
concerns about ARB therapy include the potential deleterious effects of 
increased AT levels and AT2 receptor-mediated enhancement of apoptosis. 
Whether ARBs have beneficial effects similar to ACE inhibitors on the course of 
coronary artery disease remains to be determined. ARBs may or may not 
influence bradykinin concentrations, which are anticipated to rise with ACE 
inhibitor therapy and may contribute to their efficacy. 
The hemodynamic actions of ARBs have, thus far, been similar to ACE 
inhibitors for 
reduction of blood pressure in hypertension and lowering of systemic vascular 
resistance in heart failure (87). ARBs have a similar mild-to-modest effect on 
exercise capacity and produce a comparable reduction in norepinephrine relative 
to ACE inhibitors (88). 
 
Recommendation 1. ACE inhibitors rather than ARBs continue to be the 
agents of choice for blockade of the renin-angiotensin system in heart 
failure, and they remain the cornerstone of standard therapy for patients 


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v14.0 (23-Jun-2016) 
 
with left ventricular systolic dysfunction with or without symptomatic heart 
failure (Strength of Evidence = A). 
 
At present, it is not possible to predict where ARBs will ultimately reside 
among accepted therapies for heart failure. Although the initial small ELITE Trial 
suggested a greater benefit from a losartan dosage of 50 mg daily than from a 
captopril dosage of 50 mg 3 times daily on mortality in elderly patients with heart 
failure (89), the ELITE II Mortality Trial, which included more than 3,000 patients 
(90), showed no comparative benefit from losartan and a trend for a better 
outcome and fewer sudden deaths with captopril (91). This result provides no 
evidence that the low dose (50 mg ) of losartan that was tested is better than an 
ACE inhibitor for treating heart failure, but it does not exclude the efficacy of a 
higher dose designed to provide continuous inhibition of the AT1 receptor. 
Tolerability of losartan was better than of captopril, primarily because of an ACE 
inhibitor cough. But the well-established efficacy of the ACE inhibitors on 
outcome in the post-MI period, in diabetes, in atherosclerosis, and in heart failure 
mandates that this drug group remains agents of choice for inhibiting the renin- 
angiotensin system in heart failure. The RESOLVD Trial suggested no major 
differences in efficacy of candesartan and enalapril, with a trend favoring 
enalapril during the study period of 43 weeks (92). The OPTIMAAL and VALIANT 
Studies will provide information specifically about the role of ARBs versus ACE 
inhibitors in the post-MI population. 
Currently, ACE inhibitors continue to be regarded as the therapy of choice to 
inhibit the renin-angiotensin system in patients with asymptomatic and 
symptomatic left ventricular dysfunction. There is no current rationale to 
recommend initiating ARBs in patients with new onset heart failure or for 
switching from a tolerated ACE-inhibitor regimen to an ARB in patients with 
chronic heart failure. 
 
Recommendation 2. All efforts should be made to achieve ACE 
inhibitor use in patients with heart failure caused by left ventricular 
dysfunction. Patients who are truly intolerant to ACE inhibitors 
should be considered for treatment with the combination of hydralazine 
and isosorbide dinitrate (Hyd-ISDN) (Strength of Evidence = B) or an ARB 
(Strength of Evidence = C). 
 
Previous large-scale trials do not specifically address the role of ARB and Hyd- 
ISDN in patients who are intolerant to ACE inhibitors. One arm of the CHARM 
Study has been specifically designed to test the effectiveness of candesartan in 
patients with systolic dysfunction who are intolerant to ACE inhibitors. The 
primary endpoint in this study will be a composite of cardiovascular death and 
time until first hospitalization for heart failure. For now, ARBs offer a reasonable 
alternative in the heart failure or post-MI patient who is truly intolerant to ACE 
inhibition. Intolerance because of cough should always trigger a careful 
reevaluation for congestion. If congestion is present, cough should abate with 
increases in diuretic that should allow ACE-inhibitor use to continue (93). It 
should be emphasized that patients intolerant to ACE inhibitor because of renal 
dysfunction, hyperkalemia, or hypotension are often intolerant to ARBs as well. 


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ACE inhibitor intolerance because of persistent symptomatic hypotension in 
advanced heart failure may represent severe dependence on the hemodynamic 
support of the renin-angiotensin system, which generally would predict 
hypotension with ARB use as well. 
The combination of Hyd-ISDN has not been studied in the post-MI population, 
but sufficient experience exists to support its use in the ACE-inhibitor-intolerant 
patient with symptomatic heart failure. Hydralazine blocks the development of 
nitrate tolerance, which argues for the use of combination therapy. Although they 
were not studied alone in a heart failure mortality trial, oral nitrates represent 
another reasonable alternative for patients intolerant to both ACE inhibitors and 
hydralazine. 
 
Unresolved Therapeutic Issues 
 
Combination Therapy With ACE Inhibitors and ARBs. Interest has grown in 
the potential utility of combining ACE inhibitors and ARBs in patients with heart 
failure. Initial data suggest that the combination yields more vasodilation and 
decreased blood pressure than either agent alone. The addition of losartan to an 
ACE inhibitor has been found to improve exercise capacity compared with an 
ACE inhibitor alone (94). Preliminary data from the RESOLVD Trial suggest that 
ventricular dilation and neuroendocrine activation may be best reduced with 
combination therapy, but other endpoints were not clearly affected. Trials are 
currently underway to determine the safety, as well as benefit, of more complete 
blockade of the renin-angiotensin system. The Val-HeFT Trial is a large-scale 
investigation of the effect of valsartan in addition to ACE inhibitors on morbidity 
and mortality in symptomatic patients with heart failure caused by systolic 
dysfunction. One arm of the CHARM Study will also examine the effect of the 
addition of candesartan in patients with symptomatic, systolic dysfunction treated 
with an ACE inhibitor. Preliminary data from the RESOLVD Trial suggest that 
combination therapy may be even more efficacious when used in conjunction 
with ß-blocker treatment. Results from Val-HeFT and CHARM in the subset of 
patients treated with ß-blocker therapy will provide more information concerning 
this strategy. 
Combination therapy represents a rational option when treating severe 
hypertension or other vasoconstriction but cannot, at present, be recommended 
as routine therapy in the absence of a proven superiority to ACE-inhibitor therapy 
alone. 


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76 
HFSA Guidelines 
 
 
Criteria for NYHA functional classification for chronic heart failure patients, 
functional capacity 
 
CLASS 1 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea. 
 
CLASS 2 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea. 
 
CLASS 3 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or dyspnea. 
 
CLASS 4 
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is 
increased. 


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77 
HFSA Guidelines 
 
 
Glossary of Clinical Trials 
 
AVID 
Antiarrhythmics Versus Implantable Defibrillators 
BEST 
Beta-blocker Evaluation of Survival Trial 
CAMIAT      Canadian Amiodarone Myocardial Infarction Arrhythmia Trial CAPRIE          
Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events 
CASH                      
Cardiac Arrest Study Hamburg 
CHF-STAT 
Congestive Heart Failure-Survival Trial of Antiarrhythmic 
Therapy 
CHARM 
Candesartan Cilexetil in Heart Failure Assessment of 
Reduction in Mortality and Morbidity 
CIBIS 
Cardiac Insufficiency BIsoprolol Study 
CIBIS II 
Cardiac Insufficiency Bisoprolol Study II 
CIDS 
Canadian Implantable Defibrillator Study 
COMET 
Carvedilol or Metoprolol European Trial 
CONSENSUS 
Cooperative North Scandinavian Enalapril Survival Study 
CONSENSUS II 
Cooperative New Scandinavian Enalapril Survival Study II 
COPERNICUS 
Carvedilol Prospective Randomized Cumulative Survival 
Trial 
DEFINITE 
Defibrillators in Nonischemic Cardiomyopathy Treatment 
Evaluation 
DIAMOND 
Danish Investigation of Arrhythmia and Mortality on 
Dofetilide 
DIG 
Digitalis Investigation Group 
ELITE 
Evaluation of Losartan In The Elderly 
ELITE II 
Losartan Heart Failure Survival Study - ELITE II 
EMIAT 
Infarction Amiodarone Trial 
GESICA 
 Grupo de Estudio de Sobrevida en Insuficiencia Cardiaca en 
Argentina 
GUSTO 1 
 Global Utilization of Streptokinase and TPA for Occluded 
coronary arteries 
MADIT 
Multicenter Automatic Defibrillator Implantation Trial 
MADITII 
Multicenter Automatic Defibrillator Implantation Trial II 
Metoprolol in Dilated Cardiomyopathy trial 
MERIT-HF 
 Metoprolol CR/XL Randomized Intervention Trial in Heart 
Failure 
MOCHA 
Multicenter Oral Carvedilol in Heart-failure Assessment 
MTT 
Myocarditis                     Treatment Trial 
OPTIMALL 
Optimal Therapy in Myocardial Infarction with the 
Angiotensin II 
Antagonist Losartan 
PRECISE 
Prospective Randomized Evaluation of Carvedilol In 
Symptoms and Exercise 
PROVED 
Prospective Randomized study Of Ventricular failure and the 
Efficacy of Digoxin 
RADIANCE 
Randomized Assessment of Digoxin on Inhibitors of the 
Angiotensin Converting Enzyme 
RALES 
Randomized Aldactone Evaluation Study 


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78 
 
 
RESOLVD 
Randomized Evaluation of Strategies for Left Ventricular 
Dysfunction 
SAVE 
Survival And Ventricular Enlargement 
SCD-HeFT 
Sudden Cardiac Death in Heart Failure: Trial of prophylactic 
amiodarone versus implantable defibrillator therapy 
SOLVD 
Studies Of Left Ventricular Dysfunction 
SWORD 
Survival With Oral D-sotalol 
ValHeFT 
Valsartan Heart Failure Trial 
VALIANT 
Valsartan in Acute Myocardial Infarction 


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79 
 
 
APPENDIX D 
 
 
SAFETY REPORTING FAX COVER SHEET 
Genentech Supported Research 
 
AE / SAE FAX No: (650) 225-4682 
 
Alternate Fax No: (650) 225-5288 
 
 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
 
 
 
Subject Initials 
 
(Enter a dash if patient has no 
middle name) 
 
 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
PLEASE PLACE SAFETY REPORT BEHIND THIS COVER SHEET 

ICF_000.pdf: 
Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 1 of 15 
COMPOUND AUTHORIZATION AND CONSENT FOR PARTICIPATION IN A 
RESEARCH PROJECT 
 
YALE UNIVERSITY SCHOOL OF MEDICINE – YALE-NEW HAVEN HOSPITAL: 
SMILOW CANCER CENTER 
 
Study Title: A SINGLE ARM, NEOADJUVANT, PHASE II TRIAL OF PERTUZUMAB 
AND TRASTUZUMAB ADMINISTERED CONCOMITANTLY WITH WEEKLY 
PACLITAXEL AND FEC FOR CLINICAL STAGE I-III HER2-POSITIVE BREAST 
CANCER 
 
Principal Investigator: Lajos Pusztai, MD, DPhil  
333 Cedar Street, PO Box 2080032 
New Haven, CT 06520 
Funding Source: Genentech, Inc. 
 
Invitation to Participate and Description of Project 
 
You are invited to take part in a research study because you have clinical stage I-III, HER2-
positve breast cancer that may benefit from preoperative chemotherapy. The main goal of this 
clinical trial is to test if adding a new drug, pertuzumab (Perjeta), improves the anticancer 
activity of the currently most effective treatment that includes trastuzumab (Herceptin) given 
together with chemotherapy (paclitaxel, 5-fluorouracil, epirubicin, and cyclophosphamide). The 
study will also test the safety of this therapy. If you agree to participate, you will receive 6 
months of chemotherapy concomitant with trastuzumab and pertuzumab before surgery. 
Subsequently, you will undergo surgery to remove any cancer from your breast and axillary 
lymph nodes that may have survived the chemotherapy.  
 
This clinical trial represents experimental therapy because pertuzumab is not approved by the US 
Food and Drug administration to be given concomitant with epirubicin. Several clinical studies 
demonstrated that when pertuzumab is given together with chemotherapy and/or trastuzumab the 
combination treatment has greater anti-cancer effect than any of the drugs alone which provides 
the rationale for our study. All treatments other than pertuzumab that you will receive during this 
clinical trial are standard of care. 
 
Up to 64 subjects will take part in this study. 
 
In order to decide whether or not you wish to be a part of this research study you should know 
enough about its risks and benefits to make an informed decision.  This consent form gives you 
detailed information about the study, which a member of the research team will discuss with you.  
This discussion should go over all aspects of this research: its purpose, the procedures that will 
be performed, any risks of the procedures, possible benefits and possible alternative treatments. 
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Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 2 of 15 
Once you understand the study, you will be asked if you wish to participate; if so, you will be 
asked to sign this form. 
 
Description of Procedures 
 
Tests and procedures that would be performed for your care whether you are on this study or not 
are referred to as “standard of care.” All of the tests and procedures listed below that will be 
performed at your study visits should you choose to participate are considered to be standard of 
care.   
 
If you agree to take part in this study, you will be asked to do the following: 
 
Before you begin the study …  
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  These exams, tests or procedures are part of regular cancer care and would be done even 
if you do not join the study.  If you have had some of them recently, they may not need to be 
repeated; this will depend of the date of the exam. 
• Medical history and complete physical exam including your breasts and regional lymph 
nodes. 
• Bilateral mammograms and ultrasonogram of the regional lymph nodes if clinically 
suspicious. During these exams a marker clip will need to be placed in the breast to 
identify the cancer for surgery.  
• CT scans of the chest, abdomen, pelvis and bone scan or PET-CT may be needed to 
assess if the cancer has spread beyond the breast and lymph nodes. Your physician will 
decide if you need these tests or not.  
• Routine laboratory blood tests to measure your blood counts and your kidney and liver 
function and electrolytes in your blood. 
• Assessment of your heart function through a nuclear scan or echocardiography. 
• Pregnancy test for women of childbearing potential. 
 
Tests during the study …  
If the above assessment shows that you can be in the study, and you choose to take part, then you 
will need the following tests and procedures.  All of these are part of regular cancer care.  
• Before each chemotherapy you will need to have a test called complete blood count to 
check the number of red blood cells, white blood cells, and platelets in your blood. This 
will be done once a week during weekly treatments and once every 3 weeks during every 
3-week treatments (see section below on treatment). Results from this test will determine 
if you can receive chemotherapy on that day or a treatment needs to be delayed. 
• Every 3 weeks during treatment you will have a clinic visit with your physician who will 
review your medical history and perform physical examination. 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 3 of 15 
• Repeat assessment of your heart function after the first 12 weeks of therapy, after 
completion of all chemotherapy and every 3 months thereafter for a total of 12 months  (5 
heart studies total) using the same method as used before treatment started. 
• Repeat laboratory blood tests to measure kidney and liver function every 3 weeks during 
your therapy. 
• Mammography and ultrasonogram of the regional lymph nodes after the first 12 weeks of 
therapy is completed and at the completion of all chemotherapy before surgery. 
 
Your treatment during this study….. 
 
This is a single arm, Phase II clinical trial which means that all women will receive the same 
treatment and the goal of the study is to determine how well this treatment works to eradicate 
cancer from your breast (and lymph nodes). The total duration of treatment is 24 weeks. During 
the first 12 weeks (weeks 1-12) you will receive paclitaxel (also called Taxol) chemotherapy 
once weekly x 12 treatments concomitant with weekly trastuzumab (also called Herceptin) as 
well as pertuzumab (also called Perjeta) given once every 3 weeks. During the second 12 weeks 
(weeks 13-24), you will receive  5-fluorouracil (also called 5FU), epirubicin (also called Ellence) 
and cyclophosphamide (also called Cytoxan) concomitant with trastuzumab and pertuzumab 
each given once every 3 weeks (21 days) for 4 treatments. 
 
The duration of each treatment session lasts between 1.5 – 3.0 hours.  All drugs in this study are 
given through a needle in your vein (intravenously). You will need to have a central venous 
access, a catheter or port inserted in a large vein, in order to receive therapy. You and your 
physician will decide together what catheter is most convenient for you.  The exact dose and 
schedule of your treatment is included in the table below.  
 
AGENT 
DOSE 
ROUTE 
RETREATMENT 
INTERVAL 
Pertuzumab 
First dose: 840 mg. 
Maintenance 
dose: 
420 mg 
IV 
Once every 3 weeks x 24 
weeks (8 treatments total) 
Trastuzumab 
weekly 
First dose: 4 mg/kg. 
Maintenance dose: 2 
mg/kg 
IV 
Once every week x 12 weeks 
durings 
weeks 
1-12 
(12 
treatments total) 
Trastuzumab every 
3 weeks  
6 mg/kg 
IV 
Once every 3 weeks during 
weeks 13 - 24 
Paclitaxel 
80 mg/m2  
IV 
Once every week from during 
1 -12 (12 weekly cycles total) 
5-fluorouracil 
500 mg/m2  
IV 
Once every 3 weeks during 
weeks 13 - 24 (4 cycles total) 
Epirubicin 
75 mg/m2  
IV 
Once every 3 weeks during 
weeks 13 - 24 (4 cycles total) 
Cyclophosphamide 500 mg/m2  
IV 
Once every 3 weeks during 
weeks 13 - 24 (4 cycles total) 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 4 of 15 
You will be given anti-nausea medications and additional medicines to reduce the risk of allergic 
reactions to drugs before each chemotherapy.  
 
After completion of all chemotherapy treatments… 
• You will have surgery to remove any cancer from the breast and regional lymph nodes. You 
and your surgeon will decide together what the most appropriate surgery is for you. You may 
have your whole breast removed (mastectomy) or only parts of the breast that contained 
cancer (lumpectomy). All patients will have sampling of the lymph nodes in the axilla (arm 
pit) during the breast surgery. 
After Surgery … 
• Your treatment after surgery will follow standard clinical practice. This includes completion 
of a total of 12 months of treatment with trastuzumab (including the 6 months before 
surgery) and patients with estrogen receptor positive cancer will also take anti-estrogen 
therapy (tamoxifen or an aromatase inhibitor drug) for 5-10 years. Depending on the type of 
surgery that you had, you may also require radiation therapy to the breast and lymph node 
regions. After completion of all treatment, your physician will continue to see you regularly 
every 3 months and your cardiac function will be monitored with repeat cardiac tests as part 
of routine care at month 9 and month 12.  
• Your medical records may be checked periodically in the future to find out your health status. 
You may also be contacted by the phone to find out about your health status as part of good 
clinical, practice. 
• After completion of your surgery you may opt to participate in other clinical studies. 
 
How long will I be in the study? 
 
Your experimental treatment will last for 6 months and then you will continue to be followed for 
an additional 6 months. Your participation in this study will last a total of 12 months. 
 
Can I stop being in the study? 
 
Yes.  You can decide to stop at any time.  Tell the treating physician, your study doctor, if you 
are thinking about stopping or decide to stop.  He or she will tell you how to stop safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from 
stopping early can be discussed with you by your study doctor.  Another reason to tell your 
doctor that you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you. 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 5 of 15 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest or if you do not follow the study rules; or if the study is stopped. 
 
 
Risks and Inconveniences 
 
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen.  
Side effects may be mild or very serious.  Your health care team will give you medicines to help 
lessen side effects.  Many side effects go away soon after the completion of this experimental 
chemotherapy combination.  In some cases, side effects can be serious, long lasting, or may 
never go away.  
 
You should talk to your study doctor about any side effects that you have while taking part in the 
study.  This is very important to do, even if the side effects are occurring in between your visits 
with the study doctor, because if you are having side effects your chemotherapy dose may be 
held or adjusted. 
 
The most important side effect of this experimental therapy is increased risk for heart damage 
due to the combined treatment with trastuzumab pertuzumab and epirubicin.  
 
There is small risk (1-2%) that your cancer may continue to grow despite treatment. You doctor 
will closely follow your cancer by physical exam and repeat mammogram or ultrasonogram if 
necessary. If the cancer grows, you will discontinue therapy and may undergo surgery to remove 
the cancer or receive other treatment. 
 
Risks and side effects related to the paclitaxel treatment include the following: 
 
Likely (occurring in > 20% of patients) 
 
• Fatigue  
• Hair loss 
• Pain, numbness, tingling, swelling, or muscle weakness in hands and/or feet 
(neuropathy).  These symptoms usually get better or go away without medication within 
3 weeks of stopping treatment.   
• You may get joint and muscle pain a few days after your treatment. These symptoms 
usually disappear in a few days. 
 
Less Likely (occurring in < 20% of patients) 
 
• Nausea (feeling as if you’re about to throw up) or vomiting (throwing-up) 
• Low blood pressure 
• Shortness of breath 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 6 of 15 
• Cough 
• Inflammation or irritation of the mucous membranes in the mouth or throat. 
• Heart burn 
• Diarrhea – increased frequency of bowel movements with loose, watery stool 
• Low white blood cell counts which may make you more susceptible to infection 
• Low platelet counts which may make you bruise more easily and bleed longer if injured 
• Low red blood cell counts which may cause tiredness, shortness of breath or fatigue 
• Abnormal blood tests reflecting problems with liver function 
 
 
 
Rare but serious (occurring in < 3% of patients) 
 
• Liver failure including brain and nervous system damage that occurs as a complication of 
liver disorders.   
• Severe heart problems including chest pain, high blood pressure, and abnormal heart 
rhythms that prevent the heart from pumping blood normally and could be life 
threatening 
• Blood clots in the lungs 
• Damage to the eyes resulting in decreased vision.   
• Serious, sometimes life threatening gastrointestinal (GI) perforations have occurred 
rarely.  A GI perforation is the development of an opening or hole in the wall of the 
bowel or stomach that may require surgery to repair.   
 
Risks and side effects related to the 5-fluorouracil, epirubicin, and cyclophosphamide 
treatment include: 
 
Likely (occurring in > 20% of patients) 
 
• Fatigue 
• Hair loss 
• Low white blood cell counts which may make you more susceptible to infection 
• Low platelet counts which may make you bruise more easily and bleed longer if injured 
• Low red blood cell counts which may cause tiredness, shortness of breath or fatigue 
 
Less Likely: (occurring in < 20% of patients) 
 
• Nausea and vomiting 
• Sores in the mouth 
• Heartburn 
•  Tingling pain and redness of the hands and feet (Hand-foot syndrome) 
• Change in color of fingernails and toenails 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 7 of 15 
• Loosening of fingernails and toenails 
• Inflammation or damage to the skin and around the IV tubing. 
• Bone or joint pain  
• Cramps in the legs or back  
 
Rare but Serious: (occurring in < 3% of patients) 
• Heart damage 
• Increased risk of blood cancer or other secondary cancers 
 
Irritation at the Chemotherapy Infusion Site:   
 
Chemotherapy may cause irritation and tissue damage at the site of injection.  These reactions 
are caused by the intravenous fluid that contains chemotherapy leaking into the surrounding area. 
Reactions may include pain, redness, swelling of the surrounding skin or of the vein itself, and 
ulceration of the skin (open sores).  If you notice anything unusual at the site of the injection 
(where the needle is inserted), either during or after treatment, tell your nurse right away who 
will notify your study doctor. 
 
Risks and side effects related to the trastuzumab (Herceptin) treatment include the 
following: 
 
Likely (occurring in > 20% of patients) 
• 
Chills 
• 
Fever 
• 
Body pain  
Less likely (occurring in < 20% of patients) 
• 
Headache  
• 
Diarrhea  
• 
Abdominal pain  
• 
Back pain  
• 
Infection  
• 
Flu-like symptoms  
• 
Vomiting  
• 
Cough  
• 
Shortness of breath  
• 
Rhinitis or pharyngitis – Runny nose and sore throat  
• 
Insomnia  
• 
Rash  
• 
Dizziness  
• 
Swelling (usually of the feet, ankles or hands) 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 8 of 15 
• 
Weakness  
• 
Nausea 
Rare but serious (occurring in < 3% of patients) 
• 
Allergic reactions that may include itching and rash, shortness of breath or even a drop in 
your blood pressure. Most of these events occur within 24 hours of infusion. However, 
delayed reactions have occurred. If a person experiences severe allergic reaction, 
trastuzumab will be discontinued.  
• 
Interference with the pumping action of the heart leading to heart failure. The incidence 
of heart problems (heart failure) increase in people with heart disease or other risk factors 
such as radiation to the chest, advancing age, and use of other heart-toxic drugs (such as 
epirubicin and cyclophosphamide).  Your doctor will check your heart function before 
you start taking Trastuzumab and will monitor your heart closely during your 
treatment.  Trastuzumab will be discontinued if symptoms of heart failure appear. 
Risks and side effects related to the pertuzumab (Perjeta) treatment include the following: 
 
Note, pertuzumab is not used alone and the following side effects were observed when it was 
used in combination with trastuzumab and docetaxel chemotherapy. 
 
Likely (occurring in > 20% of patients).  
• 
Diarrhea  
• 
Hair loss  
• 
Low white blood cell count  
• 
Nausea  
• 
Fatigue  
• 
Rash  
• 
Peripheral neuropathy (numbness & tingling in hands and feet) 
   
Less likely (occurring in <20% of patients).  
• 
Decreased appetite  
• 
Mouth irritation or mouth sores  
• 
Weakness  
• 
Anemia  
• 
Swelling  
• 
Muscle aches  
• 
Nail changes  
• 
Joint aches  
• 
Shortness of breath  
• 
Headache  
• 
Fever  
• 
Abnormal taste   
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 9 of 15 
• 
Upper respiratory tract infection  
• 
Vomiting  
• 
Itching   
• 
Watery eyes  
• 
Difficulty sleeping  
• 
Dizziness  
• 
Abdominal pain  
• 
Dry skin  
• 
Allergic reactions/hypersensitivity reactions 
 
Rare but serious (occurring in < 3% of patients) 
• 
Hypersensitivity reactions, anaphylaxis, and allergic reactions.  
• 
Interference with the pumping action of the heart leading to heart failure.  
 
 
 
Other instructions 
 
Tell your study doctor about all of your medicines.  Include prescription medicines, over the 
counter drugs, vitamins, and herbal products.  Some medicines can react with the study drugs 
that you receive and may cause serious side effects.  
 
Keep a list of your medicines, and show it to your study doctor or pharmacist.  Talk to your 
study doctor before starting any new medicines.   
 
 
Reproductive risks:  
 
You should not become pregnant or father a baby while on this study or within six months from 
completion of treatment because the drugs in this study can affect an unborn baby and cause 
serious birth defects.   
 
Women should not breastfeed a baby while on this study.  It is important you understand that you 
need to use birth control while on this study.   
 
Check with your study doctor about what kind of birth control methods to use and how long to 
use them. If you become pregnant while participating in this study, inform your study doctor 
immediately. 
 
For more information about risks and side effects, ask your study doctor. 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 10 of 15 
 
Risks associated with procedures during this study: 
 
This study does not involve any special procedures. Placement of either an intravenous (IV) line 
or port-o-cath for chemotherapy administration is part of routine care and are very safe 
procedures.  However, there is a slight chance that multiple needle-sticks may be necessary to 
make sure the IV is placed correctly.  You might feel a small amount of pain when the IV is 
placed but it does not last very long.  A bruise or an infection might develop where the IV is 
placed.  A bruise will go away by itself and it might help if you wrap a warm towel around your 
arm.  Infections can also be treated with outpatient antibiotics but rarely they may require 
hospital admission. Rarely a blood clot may develop in the vein where the intravenous line is 
placed.   
 
Benefits 
 
This treatment combination may make your cancer completely disappear from your breast (and 
lymph nodes) and could improve your chance for cure. During this clinical trial you will receive 
the currently most effective chemotherapy for HER2 positive breast cancer (trastuzumab 
concomitant with paclitaxel, 5 fluorouracil, cyclophosphamide and epirubicin) and in addition 
you will also receive a new HER2 targeted drug, pertuzumab.  
 
While doctors hope this chemotherapy combination will be more useful against cancer compared 
to the best current treatment, there is no proof of this yet.   
 
We hope the information learned from this study will benefit other patients with breast cancer in 
the future.  
 
Economic Considerations 
 
You and/or your health plan/ insurance company will need to pay for the routine standard of care 
portions of your treatment. Some health plans will not pay these costs for people taking part in 
studies.  Check with your health plan or insurance company to find out what they will pay for.  
Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment.  
 
Pertuzumab (the only experimental part of your treatment) and trastuzumab will be provided by 
Genentech, Inc free of charge. The chemotherapy drugs paclitaxel, 5-fluorouracil, epirubicin, and 
cyclophosphamide are commercially available and considered standard of care and will be 
charged to you or your insurance company.  The research requires that you receive certain 
standard medical tests and examinations. These standard tests and examinations will be charged 
in the usual way, to your insurance company. 
 
You will not be paid for taking part in this study. 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 11 of 15 
 
 
Treatment Alternatives/Alternatives 
 
Your other choices, if you choose not to take part in this study, may include: 
• Getting similar but not identical treatment for your cancer without being in a 
study 
• Taking part in another study 
• Getting no treatment 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
 
Confidentiality and Privacy 
 
Any identifiable information that is obtained in connection with this study will remain 
confidential and will be disclosed only with your permission or as permitted by U.S. or State 
law.  Examples of information that we are legally required to disclose include abuse of a child or 
elderly person, or certain reportable infectious diseases. When the results of the research are 
published or discussed in conferences, no information will be included that would reveal your 
identity.   
 
We understand that information about you obtained in connection with your health is personal, 
and we are committed to protecting the privacy of that information.  If you decide to be in this 
study, the researcher will get information that identifies you and your personal health 
information.  This may include information that might directly identify you, such as your name 
and address. This information will be de-identified at the earliest reasonable time after we 
receive it, meaning we will replace your identifying information with a code that does not 
directly identify you. The principal investigator will keep a link that identifies you to your coded 
information, and this link will be kept secure and available only to the PI or selected members of 
the research team. Any information that can identify you will remain confidential. The research 
team will only give this coded information to others to carry out this research study. The link to 
your personal information will be kept indefinitely. The data will be kept in this anonymous form 
indefinitely.   
 
Information about your study participation will be entered into your Electronic Medical Record 
(EMR). Once placed in your EMR, these results are accessible to all of your providers who 
participate in the EMR system. Information within your EMR may also be shared with others who 
are appropriate to have access to your EMR (e.g., health insurance company, disability provider.) 
 
The information about your health that will be collected in this study includes: 
• The entire research record and any study related medical records held by Yale New Haven 
Hospital  
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 12 of 15 
 
 
Information about you and your health which might identify you may be used by or given to:  
• Representatives from Yale University, the Yale Human Research Protection Program 
and the Yale Human Investigation Committee (the committee that reviews, approves, 
and monitors research on human subjects), who are responsible for ensuring research 
compliance.  These individuals are required to keep all information confidential.  
• Your providers who are participants in the Electronic Medical Record (EMR) system 
• Those individuals at Yale who are responsible for the financial oversight of research 
including billings and payments 
• The Principal Investigator: Lajos Pusztai, MD, DPhil  
• The Co-Principal Investigator: Michael DiGiovanna, MD, Ph.D. 
• Genentech, Inc. (the study sponsor) 
• Health care providers who provide routine or research services to you in connection with 
this study. 
• Laboratories and other individuals and organizations that analyze your health 
information in connection with this study, according to the study plan. 
• Study collaborators and other investigators 
• Study Coordinator and Members of the Research Team  
• Data and Safety Monitoring Boards and others authorized to monitor the conduct of 
the Study 
 
By signing this form, you authorize the use and/or disclosure of the information described 
above for this research study.  The purpose for the uses and disclosures you are authorizing is 
to ensure that the information relating to this research is available to all parties who may need 
it for research purposes. 
 
All health care providers subject to HIPAA (Health Insurance Portability and Accountability 
Act) are required to protect the privacy of your information.  The research staff at the Yale 
School of Medicine, Yale-New Haven Hospital, and the Smilow Cancer Center are required to 
comply with HIPAA and to ensure the confidentiality of your information.  Some of the 
individuals or agencies listed above may not be subject to HIPAA and therefore may not be 
required to provide the same type of confidentiality protection. They could use or disclose 
your information in ways not mentioned in this form.  However to better protect your health 
information, agreements are in place with these individuals and/or companies that require that 
they keep your information confidential.  
 
The sponsor will see the research information we collect about you when they come to Yale to 
monitor the conduct of this research study. For this study the sponsor includes Genentech, Inc. Yale 
researchers will also send the sponsor your health information during the study or at the end of the 
study.  When Yale researchers send information about you to the sponsor, they will not send 
information that directly identifies you such as your name, street address, or social security number. 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 13 of 15 
The sponsor may also use the information about you for other purposes related to this research or 
to similar research studies. 
 
You have the right to review and copy your health information in your medical record in 
accordance with institutional medical records policies.  
 
This authorization to use and disclose your health information collected during your participation 
in this study will never expire. 
 
In Case of Injury 
 
If you are injured as a result of your participation in this study, treatment will be provided.  You 
or your insurance carrier will be expected to pay the costs of this treatment.  No additional 
financial compensation for injury or lost wages is available. You do not give up any of your legal 
rights by signing this form 
 
Voluntary Participation and Withdrawal 
 
Participating in this study is voluntary. You are free to choose not to take part in this study.   
Refusing to participate will involve no penalty or loss of benefits to which you are otherwise 
entitled. Your health care outside the study, the payment for your health care, and your health 
care benefits will not be affected if you do not agree to participate.  However, you will not be 
able to enroll in this research study and will not receive study procedures as a study participant if 
you do not allow use of your information as part of this study. 
 
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. 
 
You will be told of any significant new findings that are developed during the course of your 
participation in this study that may affect your willingness to continue to participate. 
 
 
Withdrawing From the Study 
 
If you do become a study participant, you are free to stop and withdraw from this study at any 
time during its course. To withdraw from the study, you can call a member of the research team 
at any time and tell them that you no longer want to take part.  This will cancel any future study 
related appointments. 
 
The study doctor may decide to take you off this study if your disease gets worse despite the 
treatment; if the side effects of the treatment are too dangerous for you; or if new information 
about the treatment becomes available and this information suggests the treatment will be 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 14 of 15 
ineffective or unsafe for you.  It is unlikely, but the study may also be stopped early due to lack 
of funding. 
 
Withdrawing from the study will involve no penalty or loss of benefits to which you are 
otherwise entitled.  If you choose not to participate or if you withdraw, it will not harm your 
relationship with your doctors or with Yale School of Medicine, Yale New Haven Hospital, the 
Smilow Cancer Center, or St. Francis Hospital and Medical Center. We would still treat you with 
standard therapy or, at your request, refer you to a clinic or doctor of your choice. 
 
Withdrawing Your Authorization to Use and Disclose Your Health Information 
 
You may withdraw or take away your permission to use and disclose your health information at 
any time.  You may withdraw your permission by telling the study staff or by sending written 
notice to the study doctor: 
 
Lajos Pusztai M.D. (Medical Oncology) 
Yale University Cancer Center 
 
Smilow Cancer Hospital 
 
Section of Medical Oncology 
 
333 Cedar St., PO Box 208032 
 
 
New Haven, CT 06520-8032 
 
 
 
 
Tel:  203-737-8309 
 
Fax:  203-785-5792 
 
 
If you withdraw your permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you will be 
gathered after that date.  Information that has already been gathered may still be used and given 
to others until the end of the research study, as necessary to insure the integrity of the study 
and/or study oversight.  
 
Questions 
We have used some technical terms in this form.  Please feel free to ask about anything you don't 
understand and to consider this research and the consent form carefully – as long as you feel is 
necessary – before you make a decision. 
 
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017


Principal Investigator: 
Lajos Pusztai, MD, DPhil 
HIC #: 
1306012136 
Funding Source: 
Genentech, Inc. 
Sponsor Protocol Number: 
n/a 
Sponsor ICF Template 
Version: 
n/a 
Protocol Version: 
14.0 
Sponsor ICF Template Date: 
n/a 
Protocol Date: 
23-Jun-2016 
 
 
 
 
 
YCC Version 6.0 (23-Jun-2016) 
Page 15 of 15 
Authorization and Permission 
 
I have read (or someone has read to me) this form and have decided to participate in the project as 
described above.  Its general purposes, the particulars of my involvement and possible hazards and 
inconveniences have been explained to my satisfaction.  My signature also indicates that I have received a 
copy of this consent form. 
 
By signing this form, I give permission to the researchers to use and give out information about me for 
the purposes described in this form.  By refusing to give permission, I understand that I will not be able to 
participate in this research.  
 
I also confirm that I have received a Trial Alert Card providing contact details of the study doctor and 
agree to carry this card with me at all times.  
 
 
 
 
 
 
 
Study Participant (print name) 
 
Signature 
 
Date 
 
 
 
 
 
 
Person obtaining consent (print 
name) 
 
Signature 
 
Date 
 
 
 
 
 
 
Person obtaining consent (print 
name) – only if applicable, 
otherwise blank 
 
Signature 
 
Date 
 
 
 
 
 
 
Interpreter/ Witness (print name)  
– only if applicable, otherwise blank 
 
Signature 
 
Date 
  
If after you have signed this form you have any questions about your privacy rights, please contact the 
Yale Privacy Officer at (203) 432-5919. 
 
If you have further questions about this project or if you have a research-related problem, you may 
contact the Principal Investigator, Dr. Lajos Pusztai, at 203-737-8309.  If you would like to talk with 
someone other than the researchers to discuss problems, concerns, and questions you may have 
concerning this research, or to discuss your rights as a research subject, you may contact the Yale Human 
Investigation Committee at (203) 785-4688.  
  
APPROVED BY THE YALE UNIVERSITY HIC ON 22-JUL-2016 VALID THROUGH 07-AUG-2017