A Phase II Study of NEOADjuvant Aromatase Inhibitor and Pertuzumab/Trastuzumab (NEOADAPT)
Phase: PHASE2
Conditions: Breast Neoplasms
Sponsor: Midwestern Regional Medical Center

Protocol:  NEOADAPT: Neoadjuvant aromatase inhibitor with pertuzumab and 
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PROTOCOL 
STUDY TITLE: 
A phase II study of NEOADjuvant Aromatase 
inhibitor and Pertuzumab/Trastuzumab 
(NEOADAPT)  
STUDY DRUG: 
HERCEPTIN (trastuzumab) 
 
PERJETA (pertuzumab) 
 
SPONSOR: 
 
Midwestern Regional Medical Center, Inc.  
INVESTIGATOR: 
Eugene Ahn MD 
2520 Elisha Avenue  
Zion IL 60099  
(847) 731-1539 
Eugene.Ahn@ctca-hope.com 
 
PROTOCOL NO.:  
 
PROTOCOL VERSION/DATE: 
MZ2016006_NEOADAPT  
 
4.0 07JUN2017 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
Page 
1. 
INTRODUCTION ..........................................................................................  
5 
1.1 
Disease Background ...................................................................................  
5 
1.2 
HER2 and Breast Cancer ...........................................................................  
5 
1.3 
 Trastuzumab and Pertuzumab Clinical Experience .....................................  
6 
1.4 
Trastuzumab and Pertuzumab Safety.........................................................  
10 
1.5 
Trastuzumab and Pertuzumab Pharmacokinetics ......................................  
12 
1.6 
Data Supporting Trastuzumab and Pertuzumab without Chemotherapy ....  
14 
1.7 
Other Study Drug(s) Background ................................................................  
15 
2. 
OBJECTIVES ...............................................................................................  
15  
2.1 
Primary Objectives .......................................................................................  
15  
2.2 
Secondary Objectives ..................................................................................  
15  
3. 
STUDY DESIGN ..........................................................................................  
16 
3.1 
Description of the Study ...............................................................................  
16 
3.2 
Rationale for Study Design ...........................................................................  
19 
3.3 
Outcome Measures ......................................................................................  
20 
3.3.1 
Primary Outcome Measure ..........................................................................  
21 
3.3.2 
Secondary Outcome Measures ....................................................................  
21 
3.4 
Safety Plan ...................................................................................................  
24 
3.5 
Risk of EGFR-related Toxicities………………………………………… ..........  
27 
3.6 
Risk of Neutropenia ......................................................................................  
28 
3.7 
Compliance with Laws and Regulations .......................................................  
29 
4. 
MATERIALS AND METHODS .....................................................................  
29 
4.1 
Subjects .......................................................................................................  
29 
4.1.1 
Subject Selection .........................................................................................  
29 
4.1.2 
Inclusion Criteria ..........................................................................................  
29  
4.1.3 
Exclusion Criteria .........................................................................................  
30 
4.2 
Method of Treatment Assignment ................................................................  
31 
4.3 
Study Treatment ...........................................................................................  
31 
4.3.1 
Trastuzumab and pertuzumab Formulation..................................................     31 
4.3.2 
Dosage, Preparation, Administration, and Storage ......................................  
32  
4.3.3 
Dosage Modification .....................................................................................  
36  
 
4.3.4     Overdosage ..................................................................................................  
36  

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TABLE OF CONTENTS (cont'd) 
 
 
 
Page 
4.4 
Concomitant and Excluded Therapy ............................................................  
36 
4.5 
Study Assessments ......................................................................................  
37 
4.5.1 
Assessments during Treatment ....................................................................  
37  
4.5.2 
Follow-Up Assessments ...............................................................................  
38 
4.6 
Discontinuation of Protocol-Specified Therapy .............................................  
39 
4.7 
Subject Discontinuation ................................................................................  
39 
4.8 
Study Discontinuation ..................................................................................  
39 
4.9 
Statistical Methods .......................................................................................   40 
4.9.1 
Analysis of the Conduct of the Study ...........................................................  
40 
4.9.2 
Analysis of Treatment Group ........................................................................  
40 
4.9.3 
Efficacy Analysis ..........................................................................................  
41 
4.9.4 
Safety Analysis .............................................................................................  
42 
4.9.5 
Missing Data ................................................................................................  
42 
4.9.6 
Determination of Sample Size ......................................................................  
42 
4.10       Data Quality Assurance ...............................................................................  
42  
5. 
REPORTING OF ADVERSE EVENTS ........................................................  
42  
5.1 
Assessment of Safety ..................................................................................  
42 
5.2 
Methods and Timing for Assessing and Recording Safety Variables ...........  
43 
5.3 
Procedures for Eliciting, Recording, and Reporting Adverse Events ............  
45  
 
6. 
INVESTIGATOR REQUIREMENTS .............................................................  
48 
6.1 
Study Initiation ..............................................................................................  
48 
6.2 
Study Completion .........................................................................................  
48 
6.3 
Informed Consent .........................................................................................  
48 
6.4 
Institutional Review Board or Ethics Committee Approval ...........................  
48 
6.5 
Study Monitoring Requirements ...................................................................  
49 
6.6 
Data Collection .............................................................................................  
49 
6.7 
Study Medication Accountability ...................................................................  
49 
6.8 
Disclosure and Publication of Data ..............................................................  
49 
6.9 
Retention of Records ...................................................................................  
50 
REFERENCES .............................................................................................  
51 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLES AND FIGURES 
 
 
Table 1: Trastuzumab and pertuzumab infusion time and post-infusion 
observation period (page 35) 
 
 
 
Figure 1: Study Schema (page 57) 
 
Figure 2: Overview of how breast MRI will guide protocol treatment 
(page 58) 
 
 
APPENDICES  
 
Appendix A: 
Study Flowchart (page 59) 
 
Appendix B:  
Response Evaluation Criteria in Breast Cancer via RECIST 
Criteria Modified for Neoadjuvant Treatment (page 61) 
Appendix C: 
NCI Common Toxicity Criteria (page 62) 
Appendix D:  
Safety Reporting Fax Cover Sheet (page63) 
Appendix E:   
Algorithm for Continuation and Discontinuation of Pertuzumab 
and Trastuzumab based on LVEF Assessments (page 64) 
Appendix F: 
Data collection form (page 65)  
 
 
 
 

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1. 
INTRODUCTION 
1.1 
DISEASE BACKGROUND 
Breast cancer is the most common cancer in women with a global prevalence of 
more than 1 million patients and a mortality rate of approximately 400,000 
deaths per year (International Agency for Research on Cancer; http://www-
dep.iarc.fr; Globocan 2002). While improved early detection and advances in 
systemic therapy for early stage disease have resulted in a small decline in 
breast cancer mortality since 1989, patient advocacy groups have cited an 
unmet patient need for clinical research to validate more treatment options with 
less long-term toxicity. Major untested opportunities exist in the area of HER2-
targeted therapy of early stage breast cancer, specifically in the area of a 
chemotherapy-free approach to early stage hormone receptor (HR) positive and 
HER2 positive breast cancer.  
 
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 often results in intracellular 
activation of 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 
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 the 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 breast 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 

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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 duration of 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 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 paclitaxel or paclitaxel plus trastuzumab. Patients randomized to 
trastuzumab and paclitaxel 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% 

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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)(Slamon et al. 2001). 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 that 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 new 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 recently 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 
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).  At 8.4 years 
of median follow-up, the magnitude of DFS benefit and OS were maintained 

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over time, with HRs of 0.60 (p<0.0001) and 0.63 (p<0.0001), respectively (Perez 
et al. 2012). In HERA (trastuzumab adjuvant), single agent trastuzumab 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 
survival (OS) in the HER2-positive population.  In the HER2-positive population, 
both ORR and pCR in breast tissue were significantly higher in the trastuzumab 
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). 
 
Pertuzumab Clinical Experience 
 
Pertuzumab, a humanized monoclonal antibody to the HER2 receptor, 
represents a promising new anti-HER2 agent with a novel mechanism of action 
targeting inhibition of HER2 dimerization. Nonclinical and clinical data to date 

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indicate that pertuzumab provides a broader 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 the HER2 receptor 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). 
 
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 PFS, 
based on tumor assessments by an independent review facility (IRF), was 
observed in patients treated with pertuzumab, trastuzumab and docetaxel 
(N=406) compared with 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. Results of the investigator-assessed PFS analysis (HR 
= 0.65 [0.54, 0.78], p < 0.0001; median 12.4 vs 18.5 months, respectively) were 
consistent with those observed for IRF-assessed PFS.  A second interim 
analysis of OS (performed one year after the primary analysis of efficacy) 
crossed the predefined stopping boundary for statistical significance (p≤0.0138), 
demonstrating that treatment with pertuzumab, trastuzumab and docetaxel 
significantly improved OS when compared with the placebo arm (HR = 0.66; 
95% CI: 0.52, 0.84; p = 0.0008). The updated analysis of investigator-assessed 
PFS demonstrated that the PFS benefit observed at the primary analysis was 
maintained after an additional year of follow-up. The HR of 0.69 and the 
increase in median PFS of 6.3 months (from 12.4 months in the placebo arm to 
18.7 months in the treatment arm) were highly consistent with those from the 

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first analysis of investigator-assessed PFS and consequently also with the 
primary IRF analysis (Swain et al. 2013). 
 
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. 2010). 
 
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) (Gianni et al. 2012). The primary endpoint pCR in the breast was defined as 
the absence of invasive neoplastic cells at microscopic examination of the 
primary tumor at surgery.    Remaining in-situ lesions were allowed.  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). High 
pCR rates (57-66%) were achieved with all three treatment regimens 
(Schneeweiss et al. 2013). 
 
 
1.4 
TRASTUZUMAB AND PERTUZUMAB 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-
containing regimen. 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. 
 
There are no adequate or well-controlled studies in pregnant women, and 
animal reproduction studies are not always predictive of human response.  

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Therefore, trastuzumab should be used during pregnancy only if the potential 
benefit to the mother outweighs the potential risk to the fetus.  In the post-
marketing setting, oligohydramnios (decreased amniotic fluid) has been reported 
in women who received trastuzumab during pregnancy, either in combination 
with chemotherapy or as a single agent. Advise pregnant women and women of 
childbearing potential that trastuzumab exposure can result in fetal harm.  
Advise women of childbearing potential to use effective contraceptive methods 
during treatment and for seven months after last dose of trastuzumab (TWIMC 
letter 2014).  Advise nursing mothers treated with trastuzumab to discontinue 
nursing or discontinue trastuzumab, taking into account the importance of the 
drug to the mother.  Encourage women who are exposed to trastuzumab during 
pregnancy to enroll in the MotHER Pregnancy Registry (phone: 1-800-690-
6720). 
 
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 February 2014, safety data are available from 2949 patients with cancer 
treated with pertuzumab in company-sponsored pertuzumab trials, and from an 
additional 167 patients treated with pertuzumab in combination with 
investigational compounds. 
 
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 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 

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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 
months after completion of treatment. 
 
1.5 
TRASTUZUMAB AND PERTUZUMAB CLINICAL 
PHARMACOKINETICS 
 
Clinical Pharmacokinetics of Trastuzumab 
 
A Phase I single dose study (H0407g) of intravenous trastuzumab infusions 
ranging from 10-500 mg resulted in dose-dependent pharmacokinetics (PK) with 
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 in 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)(Bruno et al. 2005). 
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 

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with paclitaxel (175 mg/m2)(Leyland-Jones et al. 2000), 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 
exposure 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. 
 
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.  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. 
 
Clinical Pharmacokinetics of Pertuzumab 
 
A comprehensive population pharmacokinetics (popPK) analysis was conducted 
by using concentration data obtained from 481 cancer patients across twelve 
Phase I/II/III studies in patients with solid tumors, ovarian cancer, prostate 
cancer, NSCLC, and breast cancer.  In the popPK analysis, a two-compartment 
linear model with first-order elimination from the central compartment described 
serum pertuzumab PK in the dose range 2.0 to 25.0 mg/kg (equivalent to 140-
1750 mg for a 70-kg patient). In the final model, clearance (CL), central volume 
of distribution (Vc), and terminal elimination half-life were 0.235 L/day, 3.11 L, 
and 18 days, respectively. Lean body weight and serum albumin were identified 
as statistically significant covariates for pertuzumab PK. CL decreased in 
patients with higher baseline albumin concentrations and increased in patients 
with greater lean body weight. However, sensitivity analyses indicated that 
dose-adjustment based on these covariates would not lead to a meaningful 
reduction in exposure variability since the covariate effect on pertuzumab 
exposure was relatively small compared to the overall inter-individual variability 
of the population. No statistically significant effects of other covariates on PK 

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parameters were detected, including demographic variables (age, gender, race 
[Japanese versus non-Japanese]), laboratory variables related to hepatic and 
renal function (ALT, AST, TBIL, ALK, CrCL), and disease variables 
(ECOG/KPS, MBC versus other tumor types, number of metastatic sites, liver 
metastases and concomitant chemotherapy). 
 
The fixed (non-weight based) pertuzumab dosing regimen of an 840 mg loading 
dose followed by a 420 mg maintenance dose, administered q3w, in patients 
with MBC and other solid tumors included in the model, is well supported by 
these popPK results (Ng et al. 2006).  
 
Pertuzumab PK in Study WO20697 (NEOSPHERE) were consistent with the 
previous popPK model predictions, suggesting similarity in pertuzumab PK 
between the patient population included in the NEOSPHERE study (patients 
with LABC, IBC and EBC) and patients with advanced malignancies, including 
the first-line MBC population. 
 
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     DATA SUPPORTING TRASTUZUMAB AND PERTUZUMAB WITHOUT 
CHEMOTHERAPY 
HER2 is overexpressed in 20% of early stage breast cancer diagnoses, and half 
of those will be hormone receptor positive (ER or PR positive). Although HER2 
overexpression has been shown to be an adverse prognostic factor for disease 
recurrence after curative intent treatment – the development of HER2 targeted 
antibodies, i.e. trastuzumab and now pertuzumab, has helped to neutralize this 
negative prognostic factor. As NEOSPHERE showed surprising bioactivity (pCR 
of 29.1%) of 12 weeks of neoadjuvant trastuzumab and pertuzumab without 
chemotherapy in HR- HER2+ disease, and TBCRC 006 (Rimawi et al) showed 
12 weeks of hormone therapy with trastuzumab and lapatinib yielded a pCR rate 
of 21% with another 22% having low residual disease (or <1 cm), it is 
reasonable to expect an even higher pCR rate with hormone therapy and 
trastuzumab and pertuzumab, for a treatment duration longer than 12 weeks. 
NSABP-52 is a currently active clinical trial which proposes neoadjuvant 
treatment of HER2+ breast cancer with TCHP (taxotere, carboplatin, 
trastuzumab and pertuzumab) with or without hormone treatment, with pCR rate 
as the primary endpoint. It is expected that the pCR rate observed in NSABP-52 
will be nominally higher in the HR+ HER2+ subset compared to the pCR rate 

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identified in NEOADAPT (this protocol) but it will not answer questions about a 
neoadjuvant chemotherapy free approach, again not addressing patient 
advocacy groups’ demands for more treatment options with less toxicity. The 
closest study to NEOADAPT in terms of a chemotherapy free approach for HR+ 
HER2+ breast cancer is PERTAIN another active phase II clinical trial in the 
metastatic breast cancer space. PERTAIN proposes randomized controlled first 
line treatment of metastatic HR+ HER2+ breast cancer with an aromatase 
inhibitor and trastuzumab with or without pertuzumab where concurrent 
chemotherapy is allowed if deemed necessary. The median duration of 
treatment seen in the subset of patients who randomize to trastuzumab and 
pertuzumab and do not get concurrent chemotherapy will be of interest to 
compare notes with the median duration of treatment with NEOADAPT. 
For a more detailed discussion, refer to 3.2 Rationale for Study Design. 
 
1.7 
OTHER STUDY DRUG(S) BACKGROUND 
N/A 
 
2. 
OBJECTIVES 
This is a prospective single arm phase II study of 32 evaluable patients treated 
with NEOADjuvant Aromatase inhibitor and Pertuzumab/Trastuzumab 
(NEOADAPT) without chemotherapy for HR+ (Hormone receptor positive, i.e. 
ER and/or PR+) HER2+ localized, non-metastatic stage I-II breast cancer  
  
2.1 
PRIMARY OBJECTIVE 
To document the pCR (pathological complete response) rate of an aromatase 
inhibitor, trastuzumab and pertuzumab (henceforth referred to as “biological 
therapy”) without chemotherapy for HR+ HER2+ localized, non-metastatic 
breast cancer.  
 
2.2 
SECONDARY OBJECTIVES 
To describe the median duration of neoadjuvant treatment with biological 
therapy for HR+ HER2+ localized, non-metastatic breast cancer 
To conduct an exploratory analysis of whether Agendia’s Mammaprint and 
Blueprint test could prospectively identify patients who are more likely to have a 
pCR or not with biological therapy alone. 
To describe the sensitivity and specificity of radiographic complete response 
(rCR) by dynamic contrast-enhanced breast MRI in predicting pathological 

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complete response (pCR) with neoadjuvant biological therapy for HR+ HER2+ 
localized, non-metastatic breast cancer 
3.      STUDY DESIGN 
 
See Figure 1. Study Schema for an overview (page 51).  
 
3.1 
DESCRIPTION OF THE STUDY 
This is an open-label non-randomized single arm phase II descriptive study of 
32 evaluable patients with localized, non-metastatic HR+ HER2+ breast cancer 
who will be given neoadjuvant “biological therapy” i.e. an aromatase inhibitor 
(anastrazole, letrozole or exemestane allowed), and trastuzumab and 
pertuzumab. If the patient is pre-menopausal then either a GnRH agonist 
(goserelin or leuprolide) or a bilateral oophorectomy would be required.  
Patients who have HR+ HER2+ localized, non-metastatic breast cancer (i.e. 
radiological stage I-IIb) and have not received any systemic breast cancer 
treatment nor have completed definitive surgical resection of the primary are 
eligible for study.  
A total of 32 evaluable patients will be enrolled into a single arm of neoadjuvant 
“biological therapy”.  The intent of neoadjuvant treatment is to continue 
treatment as long as there is no evidence of radiographic progression to a 
maximum of one year or until 12 weeks after a “radiographic complete 
response” (rCR) is observed. The 12 weeks of additional treatment after rCR 
accounts for a known weakness of breast MRI in monitoring neoadjuvant 
treatment: underestimation of minimal residual disease.  
Neoadjuvant “biological therapy” includes the following drugs: 
Pertuzumab: per FDA approved schedule, to be given every 3 weeks starting 
with an 840mg loading dose for 60 minutes for cycle 1 (henceforth referred to as 
Day 0), and then 420mg maintenance dose every 3 weeks over 30-60min until 
progressive disease, 3 months after suspected pCR by imaging and exam, one 
year of treatment delivered, or patient withdrawal from study.  
Trastuzumab: per FDA approved schedule, to be given every 3 weeks starting 
with an 8mg/kg loading dose over 60-90 minutes on Day 0, and then 6mg/kg 
maintenance dose every 3 weeks over 30-60min until progressive disease, 3 
months after suspected pCR by imaging and exam, or patient withdrawal from 
study. 
Aromatase inhibitor: to be started +/- 7 days before or after Day 0 and can 
include any one of several FDA approved aromatase inhibitors such as 
anastrazole 1mg/d, letrozole 2.5mg/d, or exemestane 25mg/d. For pre-
menopausal women, a GnRH agonist such as goserelin 3.6mg monthly or 

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10.8mg every 3 months or leuprolide 3.75mg every month or 11.25mg every 3 
months or bilateral oophorectomy is required to be enrolled on study as is 
standard of care for pre-menopausal women receiving an aromatase inhibitor. 
As the aromatase inhibition aspect of the intervention is current standard of care 
for (neo)adjuvant treatment of hormone receptor positive breast cancer, we will 
focus more on the study aspect of the intervention, i.e. the use of trastuzumab 
and pertuzumab. Side effects are defined in the informed consent. 
Adaptive duration of treatment. Patients should remain in the treatment phase 
of the study until investigator-assessed radiographic or clinical progressive 
disease, unmanageable toxicity, study termination, or a maximum of 12 months 
of treatment. Patients will be followed every 3 weeks with a requisite breast 
exam, CBC, BMP and review of new symptoms and/or side effects of treatment. 
An MRI of the breast will be required every 12 weeks or more frequently if 
clinical suspicion or abnormal exam warrants. Additional imaging including but 
not limited to diffusion-weighted MRI, mammogram, tomosynthesis, PET and 
breast/axillary ultrasound are allowed, if felt clinically warranted by the 
investigator although MRI has been shown to be the most effective imaging 
modality for monitoring (Esserman et al 1999, Balu-Maestro et al 2002) 
response during neoadjuvant treatment for breast cancer. It is preferred that an 
MRI is done to document progression rather than relying on clinical exam alone, 
before taking a patient off treatment protocol.  
Response evaluation criteria for breast MRI. The algorithm for treatment 
decisions based on MRI results will rely on modified RECIST 1.1 criteria where 
the target lesion (i.e. the primary tumor) and a second target lesion if applicable 
(i.e. a smaller satellite lesion or largest pathological lymph node) are assessed. 
Of note, the target lesion can be less than 1.0 cm as the intent of the study is to 
include patients with T1a-c tumors. To qualify as a second target lesion, the 
mass or lymph node should be biopsied and proven to be of the same 
phenotype (i.e. HR+ HER2+). Radiographic complete response (rCR) is defined 
as the disappearance of all target lesions in the breast with no residual 
enhancement in the breast that can be reasonably attributed to tumor. Of note 
this does not require complete disappearance of target lesions if they involve 
lymph nodes. Specifically, enhancement thought to be more likely due to marker 
placement is a possible scenario where an MRI film with residual enhancement 
might still be called a rCR. Another example is subtle enhancement only 
observed in delayed phase images and not in the early phase images can be 
considered rCR. Any pathological lymph nodes (whether target or non-target) 
must have reduction in short axis to <10mm. If a lymph node is called too small 
to measure, a default short axis measurement of 5mm will be recorded.  
Radiographic partial response will be defined as 30% decrease in the sum of the 
longest diameter of the target lesions. Progressive disease will be defined as a 
20% increase in the sum of the longest diameter of the target lesions or a 33% 
increase in the longest diameter of a non-target axillary lymph node. Stable 
disease is defined as small changes that do not meet the above criteria.  

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If an MRI documents at any time rCR, protocol treatment will be continued for 
another 12 weeks to provide consistency to the neoadjuvant strategy for 
duration of treatment and to accommodate for a known shortcoming of breast 
MRI – underestimation of minimal residual disease.  
If MRI shows stable disease, it is recommended to continue biological therapy 
until there is documented progressive disease. MRI can be increased in 
frequency to more than every 12 weeks if in the judgement of the clinician it is 
appropriate for the clinical situation. If MRI shows progressive disease, the 
patient is classified as a non-pCR and taken off treatment protocol. The 
investigator is allowed to either switch to a different neoadjuvant strategy or 
proceed to immediate surgical resection. Study follow-up will continue until 
definitive surgery. Should the patient proceed immediately to definitive surgery 
after being taken off protocol treatment with no interim tamoxifen, chemotherapy 
or radiation or alternative treatment given with the intent of anti-tumor response, 
and the surgical pathology shows no residual invasive disease in the breast or 
lymph nodes (i.e. the MRI turns out to be a false negative), only then can the 
patient be reclassified from a non-pCR to a pCR for the purposes of this study.  
See Appendix B for more on breast MRI response evaluation criteria. 
Once a patient has either definitive surgical resection of the breast cancer, 
metastatic disease, death or elects to be withdrawn from study whichever 
comes first, the patient is officially no longer in follow-up or on study. It is not the 
intent of this clinical trial to specify what should be done after definitive surgery 
with curative intent. It is recommended that standard of care be followed.  
Definition of pCR rate. The primary endpoint of the study, pCR rate, will be 
calculated based on the following definition of pathological complete response 
(pCR) per FDA guidance documents (www.fda.gov/downloads/drugs/ 
guidancecomplianceregulatory information/guidances/ucm305501.pdf): 
“absence of residual invasive cancer on hematoxylin and eosin evaluation of the 
complete resected breast specimen and all sampled regional lymph nodes 
following completion of neoadjuvant systemic therapy (i.e. ypT0Tis ypN0 in the 
current AJCC staging system).  
As implied by the above definition, choice of breast conserving surgery vs 
mastectomy and axillary LN management is up to the clinicians and not defined 
by the study protocol. The only requirement is that at minimum as per standard 
of care at Cancer Treatment Centers of America, a sentinel LN biopsy is done 
with the usual dual blue dye and radioisotope tracers, particularly when the 
radiographic axillary staging is negative. Resection of at least two nodes is 
encouraged whenever possible.  
The primary site for this clinical study, Midwestern Regional Medical Center of 
Cancer Treatment Centers of America, receives around 270 patients/year with a 
new diagnosis of stage I-III breast cancer. 10% or 27 are anticipated to have 

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ER+ HER2+ breast cancer. When accounting for physician preferences and 
logistical challenges for patients we anticipate accruing 1 patient/month and to 
assure completion of accrual within 1 year, the study will also be open at two 
sister CTCA sites, Western Regional Medical Center (Goodyear, AZ) and 
Southeastern Regional Medical Center (Atlanta, GA).   
It is anticipated that due to logistics, patient preferences and uncontrollable 
factors that about 10% of patients will withdraw from study for reasons not 
related to toxicity of treatment. If a patient on study withdraws by choice due to 
primarily logistical issues such as travel time, costs or personal non-health 
related issues including death deemed not directly related to cancer or cancer 
treatment, then the patient will still count as part of the intention to treat analysis 
but not the final reported pCR rate. Since the primary intent of this study is to 
establish efficacy of a neoadjuvant biological therapy strategy, it is anticipated 
that 36 patients will need to be recruited to achieve the goal of having 32 
evaluable patients.  
The trial will officially close when 32 evaluable patients have surgical pathology 
results.  
 
3.2 
RATIONALE FOR STUDY DESIGN 
The precedent for this clinical study was established with Neosphere (Gianni et 
al, 2012), which showed surprising bioactivity of a 12 week course of 
neoadjuvant pertuzumab and trastuzumab without chemotherapy for HER2+ 
localized breast cancer. The pCR rate overall in this subgroup was 16.8%, and 
5.9% and 29.1% for HR+ (hormone receptor positive) and HR- subsets 
respectively. Importantly, none of the patients in the HR+ subsets received 
concurrent hormone therapy.  
TBCRC 006 showed that if hormone therapy was added to dual-HER2 blockade 
therapy with lapatinib and trastuzumab for 12 weeks as neoadjuvant therapy for 
HER2+ breast cancer (a similar duration of treatment used in Neosphere), the 
pCR rate was 21% with another 22% having low residual disease or < 1 cm 
(Rimawi et al 2013). While TBCRC 006 established that a 21% pCR rate is the 
current floor for hormone treatment combined with dual-targeted HER2 therapy, 
there are 2 pivotal reasons to expect significantly higher pCR rates with this 
clinical trial.  
In the final analysis of CLEOPATRA, the addition of pertuzumab to docetaxel 
and trastuzumab led to an unprecedented improvement in PFS and OS (6.3 
months PFS difference and 15.7 month OS difference) (Gianni et al 2012) 
making trastuzumab and pertuzumab the HER2 targeted strategy of choice in 
the first line treatment of metastatic HER2+ breast cancer, not lapatinib or 
Kadcyla (TDM-1).  

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Meanwhile, our understanding of neoadjuvant hormone treatment for HR+ 
(HER2-) breast cancer is that extending aromatase inhibitor (letrozole) treatment 
beyond 3 months leads to additional reduction in clinical tumor volume, and the 
majority of patients utilizing this strategy continue to have reduction of tumor 
volume 6-12 months after start of therapy (Dixon et al 2009).  
Therefore, the primary purpose of this study is to describe the pCR rate 
associated with a non-fixed adaptive-duration of neoadjuvant aromatase 
inhibitor, trastuzumab and pertuzumab in the treatment of HR+ HER2+ breast 
cancer. We expect the secondary objective of median duration of treatment in 
this study as well as that seen in PERTAIN (phase II study looking at first line 
treatment of metastatic HR+HER2+ breast cancer with an aromatase inhibitor, 
trastuzumab and/or pertuzumab) will help provide relevant data to guide a 
possible future, larger and more definitive clinical trial of a more fixed duration of 
neoadjuvant treatment with an aromatase inhibitor with trastuzumab and 
pertuzumab. 
A randomized controlled study utilizing a fixed duration of biological therapy was 
not deemed to be a practical study mainly because the number of patients 
required to have a statistically meaningful study would be prohibitive. Also, the 
study arm would be plagued by lack of any frame of reference as to what an 
optimal duration of neoadjuvant biological therapy would be.  
The potential significance of this study is that it answers directly to patient 
advocate groups’ plea for clinical research to yield more treatment options for 
women with breast cancer, particularly those with less toxicity, even if it might 
sacrifice some degree of efficacy. It could lay down the foundation for a new era 
of chemotherapy free neoadjuvant treatment of early stage ER+HER2+ breast 
cancer. 
 
3.3 
OUTCOME MEASURES 
Patients will be screened and consented for study in between the time of 
diagnosis of localized HR+HER2+ breast cancer and the start of any definitive 
treatment including hormone therapy, surgery and/or radiation. Once enrolled, 
patients will be followed until the time of definitive surgery, with surgical 
pathology results (i.e. designation of achievement of pCR or not) being the end 
point of follow-up. Other unlikely potential end points of follow-up include death, 
metastatic disease, patient or physician decision to opt out of surgery.   
The primary and secondary outcome measures are clinically meaningful as it 
will provide clinical investigators, physicians and patients with more prospective 
data to make informed decisions regarding a chemotherapy-free approach to 
localized HR+ HER2+ breast cancer. Several studies cover similar terrain as 
this study but will not provide the information this trial, NEOADAPT, will provide. 
For example, PERTAIN a phase II randomized clinical trial, has completed 

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enrollment (as of 2015) with results not yet reported, and it too studies treatment 
with an aromatase inhibitor with trastuzumab and pertuzumab, but instead of 
neoadjuvant, as first line treatment for metastatic HR+ HER2+ breast cancer 
(with trastuzumab alone as a control). While its primary endpoint is to validate 
the results seen with pertuzumab in CLEOPATRA (marked PFS and OS benefit 
in HER2+ breast cancer of the addition of pertuzumab to docetaxel and 
trastuzumab) for patients with exclusively HR+ HER2+ metastatic breast cancer, 
it will not address the neoadjuvant or curative intent space of NEOADAPT. 
However, the median duration of treatment with the trastuzumab and 
pertuzumab arm in PERTAIN would provide synergistic information with the 
results of median duration of neoadjuvant treatment in NEOADAPT to help 
guide a future definitive neoadjuvant clinical trial.  
Also NSABP-52 will offer neoadjuvant treatment of HER2+ breast cancer with 
TCHP (taxotere, carboplatin, trastuzumab and pertuzumab) with or without 
hormone treatment) with pCR as the primary endpoint. It is expected that the 
pCR rate will be nominally higher in the HR+ HER2+ subset compared to the 
pCR rate identified in NEOADAPT but it will not answer questions about a 
neoadjuvant chemotherapy free approach, again not addressing patient 
advocacy groups’ demands for more treatment options with less toxicity.  
3.3.1 Primary Outcome Measure 
 
The primary endpoint of the study, pCR rate, will be calculated based on the 
following definition of pathological complete response (pCR) per FDA guidance 
documents (www.fda.gov/downloads/drugs/guidancecomplianceregulatory 
information/guidances/ucm305501.pdf): “absence of residual invasive cancer on 
hematoxylin and eosin evaluation of the complete resected breast specimen and 
all sampled regional lymph nodes following completion of neoadjuvant systemic 
therapy (i.e. ypT0Tis ypN0 in the current AJCC staging system).  
3.3.2 Secondary Outcome Measures 
The first secondary objective is median duration of treatment. Median duration 
of treatment is defined as the number of days between Day 0 (first treatment of 
trastuzumab and pertuzumab) and three weeks after the last dose of 
neoadjuvant trastuzumab and pertuzumab on treatment protocol. 
The intent of neoadjuvant treatment is to continue treatment as long as there is 
no evidence of radiographic progression to a maximum of one year or until 12 
weeks after a “radiographic complete response” (rCR) is observed. The 12 
weeks of additional treatment after rCR accounts for a known weakness of 
breast MRI in monitoring neoadjuvant treatment: underestimation of minimal 
residual disease.  
“Radiographic complete response” will be defined by modified RECIST 1.1 
criteria where the target lesion (i.e. the primary tumor) and a second target 

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lesion if applicable (i.e. a smaller satellite lesion or pathological lymph node) are 
assessed. To qualify as a second target lesion, the mass or lymph node should 
be biopsied and proven to be of the same phenotype (i.e. HR+ HER2+). 
Radiographic complete response (rCR) is defined as the disappearance of all 
target lesions in the breast with no residual enhancement in the breast that can 
be reasonably attributed to tumor. Of note this does not require complete 
disappearance of target lesions if they involve lymph nodes. Specifically, 
enhancement thought to be more likely due to marker placement is a possible 
scenario where an MRI film with residual enhancement might still be called a 
rCR. Another possible scenario of rCR would be subtle enhancement only 
observed in delayed phase images and not in the early phase images. Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10mm. If a lymph node is called too small to measure, a default 
short axis measurement of 5mm will be recorded.  
In some cases, rCR might be difficult to classify and another protocol-valid way 
to clarify which breast MRI is the first to document rCR is that the follow-up MRI 
required by protocol does not show any further reduction in breast enhancement 
or mass (for example, dense breasts might make it difficult to measure residual 
mass dimensions). If further reduction in enhancement or mass is seen, the 
protocol allows for reclassification of the prior film as partial response and 
identification of the latest MRI as the first film that shows complete response 
(and hence, by protocol treatment will continue and another MRI will be done in 
12 weeks). 
Cessation of protocol treatment is mandatory if progressive disease is observed, 
i.e. a 20% increase in the sum of the longest diameter of the target lesions, or a 
33% increase in the longest diameter of a non-target axillary or intramammary 
lymph node. Stable disease is defined as small changes that do not meet the 
criteria of radiographic complete response, partial response or progressive 
disease. If stable disease is observed on the 12-week breast MRI, clinical 
judgment is allowed as to whether the patient or clinician/investigator wishes to 
call the RECIST 1.1-defined stable disease as progressive enough to justify 
taking the patient off protocol treatment although at least over a 10% increase in 
the sum of the longest diameter of the target lesions is recommended. 
Stable and progressive disease is defined by the delta between the peak 
response breast MRI measurements (i.e. the baseline MRI or the follow-up MRI 
which showed the most significant reduction) and the current breast MRI being 
read.  
An echocardiogram or MUGA is required every 12 weeks or every 4 cycles of 
trastuzumab and pertuzumab or as needed based on clinical suspicion. If 
trastuzumab and pertuzumab are held due to a drop in ejection fraction (EF) > 
10% and absolute value of < 50%, (see Appendix E) a repeat echocardiogram 
or MUGA is advised no later than 3 weeks. If the EF returns either to normal 
range or within an absolute 10% of the baseline EF, trastuzumab and 

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pertuzumab may be restarted. The patient will be counted as being still on 
treatment protocol and the days of holding trastuzumab and pertuzumab will still 
be counted as part of the “duration of treatment” calculation if treatment is 
resumed. If the EF is still > 10% decreased from the baseline or < absolute 
50%, then continue to hold the treatment and repeat echo in another 3 weeks. 
Any treatment delay greater than 6 weeks will result in mandatory cessation of 
treatment protocol and duration of treatment will be calculated up to 3 weeks 
after the last dose of trastuzumab and pertuzumab. Of note, the aromatase 
inhibitor should not be held during a hold of trastuzumab and/or pertuzumab for 
cardiac reasons. If the patient develops symptomatic CHF it is mandatory to 
take patient off treatment protocol in which case a cardiology consult is highly 
recommended. 
If the patient or physician chooses to switch to another aromatase inhibitor for 
whatever reason (arimidex, letrozole or exemestane) but continues concurrent 
trastuzumab and pertuzumab then the patient is still considered on protocol 
treatment.  
If the patient or physician chooses to no longer treat with any component of 
treatment protocol (aromatase inhibitor, trastuzumab or pertuzumab) for reasons 
related to the cardiac criteria above or completely unrelated reasons, or 
chemotherapy is added to the protocol regimen, then the patient is no longer on 
protocol treatment and off study.  
Another secondary outcome measure involves Agendia’s Mammaprint and 
Blueprint testing. Mammaprint is an FDA-cleared 70-gene signature assay that 
classifies breast cancer into low or high risk. Currently, we do not have a 
validated biomarker to predict which patients with HR+ HER2+ breast cancer 
would be most likely to achieve a pCR with neoadjuvant aromatase inhibitor and 
trastuzumab and pertuzumab. A secondary objective of NEOADAPT is to do an 
exploratory analysis of whether patients who test as “low risk” by Mammaprint 
are more likely to obtain a pCR. 
Knauer et al (2010) tested Mammaprint in 168 patients with T1-3 N0-1 HER2+ 
breast cancer, 89 of which did not receive chemotherapy. 20/89 (22%) tested as 
good prognosis with a 10-year distant disease-free survival (DDFS) of 84% and 
69/89 (78%) tested as poor prognosis with a 10-year DDFS of 55%. The hazard 
ratio was 4.5 (95% confidence interval 1.1-18.7 p=0.04). Most relevant to this 
clinical study, a subset analysis of 40 patients with HER2+ and highly endocrine 
responsive tumors according to the St. Gallen criteria (both >50% ER and PR 
positive) showed that all 11 patients who tested as low risk by Mammaprint had 
10-year DDFS.  
Blueprint is an 80 gene molecular subtyping assay that rather than traditional 
and approved subtyping based on IHC and FISH focuses more on the functional 
level of gene expression to classify patients into the luminal, HER2 and basal 
subtypes of breast cancer. The Neoadjuavant Breast Registry Symphony Trial 

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(NBSRT) study generated provocative results that suggested that patients with 
HER2+ breast cancer who classify as luminal type, particularly benefited from 
the addition of pertuzumab to trastuzumab-based chemotherapy and pCR rate 
increased from 6% to 39% (SABCS 2015). It is hypothesized that Blueprint 
might help identify patients with HER2+ breast cancer (those identified as 
luminal by Blueprint) that particularly benefit from “biological” therapy with 
aromatase inhibitors and trastuzumab and pertuzumab.  
Therefore, Mammaprint and Blueprint testing will be attempted on the initial 
diagnostic biopsy, but the results need not be final prior to starting protocol 
treatment. If insufficient tissue is available for Mammaprint testing, Mammaprint 
and Blueprint testing will be requested on the definitive surgical pathology 
specimen, assuming the patient has not achieved a pCR.  
Estrogen receptor, progesterone receptor and HER2 status as determined by 
Blueprint testing is not to be used in lieu of standard of care 
immunohistochemistry and FISH when applicable (per relevant ASCO 
guidelines). Of note, neither Mammaprint nor Blueprint is currently validated nor 
FDA approved for triaging treatment decisions related to HER2+ breast cancer. 
The third and last secondary objective is self-explanatory, to identify the 
sensitivity and specificity of radiographic complete response (rCR) by dynamic 
contrast-enhanced breast MRI in predicting pathological complete response 
(pCR) under NEOADAPT protocol-defined treatment.  
3.4 
SAFETY PLAN 
Patients will be evaluated at each study visit for the duration of their participation 
in the study (see Section 4.5 and Appendix A, Study Flowchart), i.e. every 3 
weeks. Specific potential safety issues for this trial are outlined below. 
RISK OF LEFT VENTRICULAR DYSFUNCTION 
LVEF declines have been reported with drugs that block HER2 activity, including 
pertuzumab and trastuzumab.  
 
Trastuzumab can cause left ventricular cardiac dysfunction, arrhythmias, 
hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death.  
Trastuzumab can also cause asymptomatic decline in left ventricular ejection 
fraction (LVEF). (Please refer to Herceptin investigator’s brochure and 
prescribing information for details) 
 
In the pivotal trial WO20698/TOC4129g (CLEOPATRA), pertuzumab in 
combination with trastuzumab and docetaxel was not associated with increases 
in the incidence of symptomatic LVSD or LVEF declines compared with placebo 
in combination with trastuzumab and docetaxel. In this study, patients who had 
received prior anthracyclines or prior radiotherapy to the chest area were at 
higher risk of decreased LVEF (regardless of treatment arm). 

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Pertuzumab combined with trastuzumab and chemotherapy also did not result in 
a significantly greater incidence of symptomatic LVSD or LVEF declines than 
trastuzumab plus chemotherapy, in patients with EBC treated in the neoadjuvant 
setting (Study WO20697 [NEOSPHERE]). 
 
Pertuzumab has not been studied in patients with the following: a pretreatment 
LVEF ≤ 50%; a prior history of CHF; LVEF declines 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.  
 
Cardiac exclusion criteria are specified in the protocol and will be closely 
followed. 
 
Management of Cardiac Safety   
All patients must have a baseline evaluation of cardiac function including a 
measurement of LVEF by either MUGA or ECHO prior to entry into the study.  
Only patients with an LVEF ≥ 50% should be entered into this study.   
LVEF should be assessed (by ECHO or MUGA scan) at regular intervals of 
every 12 weeks or 4 treatments with pertuzumab and trastuzumab to ensure 
that LVEF does not decrease > 10% and below the institution’s normal cutoff. 
ECHO or MUGA scans should be scheduled at the same radiology facility where 
the patient’s baseline ECHO or MUGA was conducted whenever possible. LVEF 
measurements should be required at protocol-specified time-points and after a 
patient has any of the following: discontinuation of protocol therapy, congestive 
heart failure (CHF), breast cancer recurrence, or a second primary cancer.  
 
During the course of trastuzumab and pertuzumab therapy, patients should be 
monitored for signs and symptoms of CHF (i.e., dyspnea, tachycardia, new 
unexplained cough, neck vein distention, cardiomegaly, hepatomegaly, 
paroxysmal nocturnal dyspnea, orthopnea, peripheral edema, and rapid 
unexplained weight gain). The confirmation of the CHF diagnosis should include 
the same method used to measure LVEF at baseline (either ECHO or MUGA).     
Pertuzumab and trastuzumab should be discontinued in any patient who 
develops clinical signs and symptoms suggesting CHF. CHF should be treated 
and monitored according to standard medical practice. 
At present, there are inadequate data available to assess the prognostic 
significance of asymptomatic drops in LVEF.  
 
Neoadjuvant Breast Cancer Protocols (refer to Appendix E) 

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Refer to Appendix E for Algorithm for Continuation and Discontinuation of HER2 
Targeted Study Medication for Early Breast Cancer Trials 
If the criteria to hold pertuzumab treatment are met (based on Appendix G) 
repeat LVEF assessment within approximately 3 weeks. 
 
If after a repeat assessment in 3 weeks, the LVEF has not improved, or has 
declined further, discontinuation of pertuzumab and trastuzumab should be 
strongly considered, unless the benefits for the individual patient are deemed to 
outweigh the risks.  If LVEF is >50% or <10 points decline from baseline, 
pertuzumab and trastuzumab treatment may be resumed. 
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. 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 30-60minutes. 
 
Pertuzumab should be withheld or discontinued if trastuzumab treatment is 
withheld or discontinued.  
Pregnancy and Contraception Use 
There are no clinical studies of pertuzumab or trastuzumab in pregnant women. 
IgGs are known to cross the placental barrier. Nonclinical reprotoxicity data in 
cynomolgus monkeys treated with pertuzumab showed embryofetal losses, 
oligohydramnios, and renal hypoplasia (please refer to the pertuzumab 
investigator’s brochure for details). Neither pertuzumab nor trastuzumab should 
be used during pregnancy.  
It is not known whether trastuzumab or pertuzumab is excreted in human milk. 
Because maternal IgG is excreted in milk and either monoclonal antibody could 
harm infant growth and development, women should be advised to discontinue 
nursing during pertuzumab or trastuzumab therapy and not to breastfeed for at 
least seven months following the last dose of either monoclonal antibody.  
For women of childbearing potential (who have not undergone surgical 
sterilization), and the female partners of male participants; agreement must be 
obtained to use highly effective contraception. 
On the basis of pharmacokinetic considerations, contraception methods should 
start a minimum of 14 days prior to the first administration of study drug and 
continue for the duration of study treatment and for at least 7 months after the 
last dose of study treatment (please refer to trastuzumab investigator’s brochure 
for details). 

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Encourage pregnant women with breast cancer who are exposed to 
trastuzumab or pertuzumab to enroll in the MotHER Pregnancy Registry (phone 
1-800-690-6720). 
Infusion-Related Reactions (IRRs) 
 
Like other monoclonal antibodies, pertuzumab has been associated with IRRs 
(such as chills, diarrhea, fatigue, headache, nausea, and pyrexia), and with 
hypersensitivity reactions. In the pivotal Phase III trial (WO20698/TOC4129g 
[CLEOPATRA]), on the first day when only peruzumab was administered, the 
overall frequency of IRRs was 13.0% in the pertuzumab-treated group and 9.8% 
in the placebo-treated group, with the majority of reactions being mild or 
moderate.  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 an IRR occurs, the 
infusion rate 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. 
 
Anaphylaxis and Hypersensitivity 
Anaphylaxis or hypersensitivity reactions are known risks following infusion with 
monoclonal antibodies.  Patients should be observed closely for hypersensitivity 
reactions.  Severe hypersensitivity, including anaphylaxis, has been observed in 
clinical trials with treatment of pertuzumab.  The infusion should be discontinued 
immediately if a serious hypersensitivity reaction occurs.  Medications to treat 
such reactions, as well as emergency equipment, should be available for 
immediate use. 
 
Risk of Respiratory Events 
In the pivotal study CLEOPATRA, respiratory events (i.e., dyspnea, cough) were 
reported in >10% in pertuzumab-treated patients, which are unspecific 
symptoms of various conditions, including infusion associated reaction or 
hypersensitivity/anaphylaxis, cardiac dysfunction, and respiratory disease. 
Because of pertuzumab’s role in inhibiting heterodimerization with other 
members of the HER family, including EGFR, there is a potential risk of 
interstitial lung disease (ILD). However, few reports of ILD have been received 
for patients receiving pertuzumab and these indicated possible alternative 
causes for the events (eg, concomitant medication, preceding/concurrent 
neutropenia with potential infection) or relevant medical history. 
 
3.5 
RISK OF EGFR-RELATED TOXICITIES 
Although pertuzumab targets the HER2 receptor, it inhibits heterodimerization 

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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). 
 
3.5.1 Diarrhea 
Diarrhea has been observed in approximately 60% of patients (treatment related 
diarrhea in 50% of patients) being treated with pertuzumab in Phase II single 
agent studies, and in up to 90% of patients in combination therapy studies. 
Diarrhea was NCI-CTCAE 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. 
 
3.5.2 Rash 
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. 
 
3.6 
RISK OF NEUTROPENIA 
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 
4 febrile neutropenia. No febrile neutropenia events occurred after docetaxel 
discontinuation.  In the Phase Ib study, BO17021, 420 mg pertuzumab in 
combination with 75 mg/m2 docetaxel was well tolerated; however, dose-limiting 
toxicity, including febrile neutropenia, was observed with 420 mg pertuzumab in 
combination with 100 mg/m2 docetaxel.  To reduce the risk of Grade ≥ 3 
neutropenic events, patients receiving pertuzumab in combination with 
docetaxel in ongoing studies are treated initially with 75 mg/m2 docetaxel. The 
dose of docetaxel may be escalated to 100 mg/m2 after the first cycle, 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. 
Patients receiving pertuzumab without docetaxel, or other cytotoxic agents, 
would be highly unlikely to develop clinically significant neutropenic fever. 
 
3.6.1 Management of Hematologic Toxicities 

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Care should be taken to carefully monitor the patient’s hematologic status 
throughout the course of the trial.  Use of hematopoietic growth factors to 
ameliorate hematologic toxicity is at the discretion of the physician investigator 
and should be in accordance with the American Society of Clinical Oncologists 
(ASCO) guidelines.  
Please refer to the trastuzumab and pertuzumab Investigator Brochure for a 
detailed description of the safety profile of trastuzumab. 
See Section 5 (Assessment of Safety) for complete details of the safety 
evaluation for this study. 
3.7 
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. 
4.0 
MATERIALS AND METHODS 
4.1 
SUBJECTS 
The study population for this clinical trial includes patients with HR+ HER2+ 
early stage breast cancer who have not been previously treated with definitive 
surgery, radiation or systemic therapy.  
4.1.1 Subject Selection 
The clinical trial will be registered on clinicaltrials.gov and it is anticipated that 
some patients will self-refer to the study. Potential eligible patients will be 
screened by the study coordinator assigned to the clinical trial at each site and 
in cooperation with the breast site group coordinator. Patients may also be 
identified during discussions at breast tumor board.  
4.1.2 Inclusion Criteria 
Disease specific inclusion criteria: 
• Histologically or cytologically confirmed adenocarcinoma of the breast with 
localized non-metastatic disease (stage I-II) and a candidate for curative-intent 
treatment.  
• Breast cancer that is both hormone receptor positive i.e. ER and/or PR positive 
and HER2-positive (FISH-positive or IHC 3+) by latest ASCO guidelines  
• Multifocal breast cancer is allowed on the provision that satellite lesions are 
biopsied and confirmed to also be ER and/or PR positive and HER2-positive 
and felt by the pathologist to be the same tumor 
General inclusion criteria:   
• Age > 18 years 

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• Life expectancy greater than 5 years 
• Left Ventricular Ejection Fraction (LVEF) > 50% at baseline (within 30 days of 
day 0) as determined by either ECHO or MUGA (ECHO is the preferred 
method). If the patient is enrolled, the same method of LVEF assessment, 
ECHO or MUGA, should be used throughout the study, and to the extent 
possible, be obtained at the same institution. 
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.  
• Signed, written informed consent (approved by the IRB) obtained prior to any 
study procedure 
• Adequate bone marrow function as indicated by the following: 
ANC >1000/L  
Platelets 50,000/L 
Hemoglobin >8.0 g/dL, lower allowed only if it is due to readily reversible 
conditions such as iron deficiency without active blood loss.  
• Adequate renal function, as indicated by creatinine 3.0 upper limit of normal 
(ULN) 
• Adequate liver function, as indicated by bilirubin 3.0 ULN 
• AST or ALT <5.0  ULN  
• A negative serum pregnancy test must be available for premenopausal women 
and for women <12 months after the onset of menopause, unless they have 
undergone surgical sterilization. 
• Women of childbearing potential and male participants with partners of 
childbearing potential must agree to use a “highly effective”, non-hormonal form 
of contraception or two “effective” forms of non-hormonal contraception by the 
patient and/or partner.  Contraception must continue for the duration of study 
treatment. 
• Male patients are allowed, and will not be excluded. 
4.1.3 Exclusion Criteria 
Patients will be excluded from the study based on the following criteria: 
• Active infection 
• Presence of known metastases (i.e. stage IV disease) 
• Pregnant or lactating women 
• Prior chemotherapy or radiation therapy for the breast cancer primary 

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• Concomitant malignancies or previous malignancies within the last 5 years, with 
the exception of adequately treated basal or squamous cell carcinoma of the 
skin or carcinoma in situ of the cervix. 
• History of significant cardiac disease or uncontrolled arrhythmias. Specifically 
patients will be screened with an echocardiogram or MUGA to make sure they 
do not have baseline EF of ≤50%, and the intent of this exclusion criteria is to 
make sure the patient is not at significantly greater risk of 
trastuzumab/pertuzumab cardiotoxicity. Lipid profiles will not be considered a 
reason for exclusion. History of coronary artery disease also is not a reason for 
exclusion if current EF satisfies, and there is no clinical history of unstable 
angina. 
• Current severe, uncontrolled systemic disease (i.e. clinically significant 
cardiovascular, pulmonary or metabolic disease including diabetes, wound 
healing disorders, ulcers or bone fractures) 
• Major surgical procedure or significant traumatic injury within 28 days prior to 
study treatment start or anticipation of the need for major surgery during the 
course of study treatment 
• Current known infection with HIV, HBV or HCV 
• Receipt of intravenous antibiotics for infection within 14 days of study treatment 
• Current chronic daily treatment with corticosteroids (dose >10mg/d 
methylprednisolone equivalent) excluding inhaled steroids 
• Known hypersensitivity to any of the study drugs 
• Assessed by the investigator to be unable or unwilling to comply with the 
requirements of the protocol 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
As this is a single arm prospective study, there will not be any randomization 
process. Intent of inclusion and exclusion criteria is to include a more 
heterogeneous patient population with more medical comorbidities and 
challenges where a chemotherapy-free treatment option would be even more in 
demand.  
 
4.3. 
STUDY TREATMENT  
Currently, trastuzumab and pertuzumab are not FDA approved for neoadjuvant 
use without chemotherapy; however, trastuzumab and pertuzumab is generally 
approved for coverage by insurance for optimal treatment of HER2+ breast 
cancer. Aromatase inhibitors are FDA approved and part of standard of care for 
curative intent treatment of HR+ breast cancer, and will be covered by patient 

Protocol:  NEOADAPT: Neoadjuvant aromatase inhibitor with pertuzumab and 
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insurance. If insurance does not approve coverage for trastuzumab and 
pertuzumab and/or the cost of insurance copayment is too prohibitive, the study 
physician has the option to help the patient apply for Genentech/Roche’s patient 
assist and free access program. 
 
4.3.1 Trastuzumab Formulation 
Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized 
powder for intravenous (IV) administration.  Each multi-dose vial of trastuzumab 
contains 400 mg of trastuzumab, 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. 
Each single-dose vial of trastuzumab contains 150 mg of trastuzumab, 3.4 mg of 
L histidine HCl, 2.2 mg of L histadine, 136.2 mg of ,  trehalose dihydrate, and 
0.6 mg of polysorbate 20, USP.  Reconstitution with 7.4 mL of sterile Water for 
Injection (SWFI) USP yields 21 mL of a single dose solution that delivers 7.15 
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).  
 
4.3.2 Trastuzumab Dosage, Preparation, Administration and Storage 
a. Dosage and Administration 
When administered with pertuzumab, the recommended initial loading dose is 8 
mg/kg trastuzumab administered as a 60-90-minute infusion.  The 
recommended maintenance trastuzumab dose is 6 mg/kg q3wk and can be 
administered as a 30-minute infusion if the initial loading dose was well 
tolerated.  Trastuzumab may be administered in an outpatient setting.  DO NOT 
ADMINISTER AS AN IV PUSH OR BOLUS. 
b. Preparation 
Use appropriate aseptic technique.  Each multi-dose vial of trastuzumab should 
be reconstituted with 20 mL of BWFI, USP, 1.1% benzyl alcohol preserved, as 
supplied, to yield a multidose solution containing 21 mg/mL trastuzumab.  
Immediately upon reconstitution with BWFI, the vial of trastuzumab must be 
labeled in the area marked “Do not use after” with the future date that is 28 days 
from the date of reconstitution. 

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Each single-dose 150 mg vial should be reconstituted with 7.4 ml of SWFI, USP, 
to yield a solution containing 21 mg/ml trastuzumab. 
If the patient has known hypersensitivity to benzyl alcohol, trastuzumab must be 
reconstituted with sterile water for injection (see PRECAUTIONS).  Trastuzumab 
that has been reconstituted with SWFI must be used immediately and any 
unused portion discarded.  Use of other reconstitution diluents should be 
avoided. 
Determine the dose of trastuzumab needed, based on a loading dose of 8 mg 
trastuzumab/kg body weight for q3wk dosing schedules or a maintenance dose 
of 6 mg/kg trastuzumab/kg body weight for q3w dosing schedules.  Calculate 
the correct dose using 21 mg/mL trastuzumab solution.  Withdraw this amount 
from the vial and add it to an infusion bag containing 250 mL of 0.9% sodium 
chloride, USP.  DEXTROSE (5%) SOLUTION SHOULD NOT BE USED.  Gently 
invert the bag to mix the solution.  The reconstituted preparation results in a 
colorless to pale yellow transparent solution.  Parenteral drug products should 
be inspected visually for particulates and discoloration prior to administration. 
No incompatibilities between trastuzumab and polyvinylchloride or polyethylene 
bags have been observed. 
Trastuzumab should not be mixed or diluted with other drugs. An amendment 
will be made if the VELVET study proves that trastuzumab and pertuzumab can 
be safely given in one mixed preparation. 
c. Storage 
Vials of trastuzumab are stable at 2C–8C (36F–46F) prior to reconstitution.  
Do not use beyond the expiration date stamped on the vial.  A multi-dose vial of 
trastuzumab reconstituted with BWFI, as supplied, is stable for 28 days after 
reconstitution when stored refrigerated at 2C–8C (36F–46F), and the 
solution is preserved for multiple use.  Discard any remaining multi-dose 
reconstituted solution after 28 days.  If unpreserved SWFI (not supplied) is used, 
for the multi-dose vial or a 150 mg single-dose vial is utilized the reconstituted 
trastuzumab solution should be used immediately and any unused portion must 
be discarded.  DO NOT FREEZE TRASTUZUMAB THAT HAS BEEN 
RECONSTITUTED. 

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The solution of trastuzumab for infusion diluted in polyvinylchloride or 
polyethylene bags containing 0.9% sodium chloride for injection, USP, 
may be stored at 2C–8C (36F–46F) for up to 24 hours prior to use.  
Diluted trastuzumab has been shown to be stable for up to 24 hours at 
room temperature 15C–25C; however, since diluted trastuzumab 
contains no effective preservative the reconstituted and diluted solution 
should be stored refrigerated (2C–8C). 
 
Pertuzumab Dosage, Preparation, Administration, and Storage 
 
a. Dosage 
The initial dose of pertuzumab is 840 mg administered as a 60 minute 
intravenous infusion, followed every 3 weeks thereafter by a dose of 420 mg 
administered over a period of 30 - 60 minutes 
When administered with pertuzumab the recommended initial dose of 
trastuzumab is 8 mg/kg followed every 3 weeks thereafter by a dose of 6 mg/kg.  
b. Preparation 
Special Instructions for Use Handling and Disposal of pertuzumab instructions 
for Dilution: 
 
Pertuzumab is for single use only and is administered intravenously by infusion. 
Pertuzumab does not contain any antimicrobial preservative. Therefore, care 
must be taken to ensure the sterility of the prepared solution for infusion and 
should be prepared by a healthcare professional. 
 
Pertuzumab should be prepared by a healthcare professional using aseptic 
technique. 
• 14 ml pertuzumab liquid concentrate should be withdrawn from the vial 
and diluted into a 250-mL PVC or non-PVC polyolefin 0.9% sodium 
chloride infusion bag. After dilution, 1 mL of solution should contain 
approximately 3.36mg of pertuzumab (840mg/250mL) for the initial dose, 
where two vials are required, and approximately 1.68 mg of pertuzumab 
(420mg/250mL) for the subsequent dose where one vial is required. 
• Dextrose (5%) solution should not be used.  
• The bag should be gently inverted to mix the solution in order to avoid 
foaming. Parenteral drug products should be inspected visually for 
particulates and discolouration prior to administration. Once the infusion 
is prepared it should be administered immediately. 
 
c. Administration 
Treatment may be administered in an outpatient setting by administration of a 
840 mg pertuzumab loading dose by intravenous (IV) infusion over 60 minutes, 

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followed every 3 weeks thereafter by a dose of 420 mg administered over a 
period of 30 - 60 minutes.  DO NOT ADMINISTER AS AN IV PUSH OR 
BOLUS.   
When administered with pertuzumab, the recommended initial dose of 
trastuzumab is 8 mg/kg followed every 3 weeks thereafter by a dose of 6 mg/kg.  
Patients should be observed for fever and chills or other infusion-associated 
symptoms.   
 
Table 1 
Trastuzumab and Pertuzumab Infusion Time and Post-Infusion 
Observation Period 
 
Infusion Time 
(minutes) 
Post-Infusion 
Observation 
Period (minutes) 
TP Loading Doses 
(8 mg/kg and 
840mg) 
First Infusion 
60-90 
60 
TP 
(6mg/kg and 
420mg) q3w 
Subsequent 
Infusions 
30 a 
30 a 
a Only if previous dose was well tolerated, otherwise 60 
A rate-regulating device may be used for all study-drug infusions. When the 
study drug IV bag is empty, 50 mL of 0.9% sodium chloride injection may be 
added to the IV bag or an additional bag will be hung, and the infusion may be 
continued for a volume equal to that of the tubing to ensure complete delivery of 
the study drug. 
 
Should extravasation of the study drug infusion occur, the following steps should 
be taken: 
•  Discontinue the infusion, 
•  Treat the extravasation according to institutional guidelines for extravasation 
of a non-caustic agent,  
•  If a significant volume of the study drug infusion remains, restart the infusion 
at a more proximal site in the same limb or on the other side. 
 
d. Storage  
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 

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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). 
 
e. Incompatibilities 
No incompatibilities between pertuzumab and polyvinylchloride, polyethylene or 
non-PVC polyolefin bags have been observed [3.3, 3.4]. Dextrose (5%) in water 
(D5W) solution should not be used to dilute pertuzumab since it was chemically 
and physically unstable in such solutions [3.4] (dilute formulations of 
pertuzumab liquid formulations in D5W IV bags did not maintain stable pH after 
storage at room temperature (27-33°C) for 24 hours followed by 24 hours at 
refrigerator temperature [2-8°C]). 
 
Pertuzumab should not be mixed or diluted with other drugs. An amendment will 
be made if the VELVET study proves that trastuzumab and pertuzumab can be 
safely given in one mixed preparation.  
 
4.3.3. Trastuzumab and Pertuzumab Dosage Modification 
Dose modification of trastuzumab and pertuzumab is not permitted.   
 
4.3.4 Trastuzumab and Pertuzumab Overdosage 
There is no experience with overdosage in human clinical trials.   
 
4.4 
CONCOMITANT AND EXCLUDED THERAPY 
Concomitant therapy  
It is recommended but not required that all patients receive famotidine 20mg IV 
and diphenhydramine 25mg IV or oral as premedication for trastuzumab and 
pertuzumab treatment, or pharmacy equivalent. Prior adverse reactions or 
patient preference are allowed exceptions. It is not recommended to use routine 
dexamethasone or steroid equivalent as a premedication but physician 
discretion is allowed, particularly if the patient has experienced a previous 
allergic reaction with trastuzumab and/or pertuzumab.   
An assessment of serum Vitamin D 25 levels as is standard of care at Cancer 
Treatment Centers of America, and replacement with vitamin D to correct 
vitamin D deficiency is not only allowed but also encouraged. 

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Treatments focused on reducing morbidity and toxicity of protocol treatment are 
allowed, including interventions for aromatase inhibitor side effects such as hot 
flashes, arthralgias as long as it is not estrogen replacement. Discussion with 
the Principle Investigator is encouraged.  
Trials or interventions designed to improve lifestyle habits are allowed.  
 
Excluded therapy 
 
Any concomitant treatment that could be reasonably expected to interfere with 
the efficacy of trastuzumab and pertuzumab or aromatase inhibitor therapy 
should be avoided, but clinical judgment with consultation of the Principal 
Investigator is encouraged. 
 
Treatment with other systemic anti-cancer agents such as chemotherapy, non-
protocol specified hormonal therapy, immunotherapy (i.e. PD1 or PDL1 
inhibitors, TNF-alpha inhibitors, anti-T cell antibodies) not specified by protocol 
 
Concurrent investigational agents of any type with the primary intent of being 
provided as cancer treatment. Herbal remedies initiated prior to study entry by 
the patient is allowed unless in the judgment of the clinician/naturopath that 
sufficient evidence exists that harm outweighs any putative benefits. 
 
4.5 
STUDY ASSESSMENTS 
Signed, IRB-approved informed consent must be obtained from patients prior to 
the pretreatment assessments.   
The following are required evaluations: (See Appendix A: Study Flowchart) 
• Evaluation of subject’s cardiac function by either echocardiogram or MUGA 
• Immunology: evaluation of ER, PR, HER2/neu status of the primary breast 
cancer by ASCO approved methodologies. 
• Pregnancy test for pre-menopausal patients or patients who have not had active 
periods for less than a year. Exception is allowed for study patients who have 
had surgical procedures normally done to reliably induce infertility, but not for 
those whose partner has had surgical procedures for infertility.  
• Mammaprint and Blueprint testing on the diagnostic biopsy. Agendia agrees to 
cover the cost of the test if insurance does not cover the costs. If there is 
insufficient tissue, Mammaprint and Blueprint testing should be pursued on the 
final surgical pathology specimen after neoadjuvant treatment is completed. 
• CBC, BMP and liver function tests 
• Breast exam 

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• Baseline MRI of the breast 
4.5.1 Assessments during Treatment 
The following are recommended evaluations: (See Appendix A: Study flowchart) 
• Monitor CBC, chemistries, etc. per institutional guidelines. A CBC and BMP is 
required at a minimum for each infusion/clinic visit (i.e. every 3 weeks +/- 3 days 
including the day 0 visit, i.e. screening labs can be used for the day 0 visit if still 
within that date range). Routine CBC and BMP checks without clinical reason in 
between scheduled visits are discouraged. 
• Regular assessment of cardiac function by either echo or MUGA (depending on 
the baseline study chosen) is required at a minimum of every 12 weeks or every 
4 cycles of treatment (+/- 28 days) as per standard of care. 
• If trastuzumab and pertuzumab is put on hold due to a significant decline in 
LVEF, a repeat echo or MUGA (depending on the baseline study chosen) is 
required every 3 weeks until LVEF is normalized. If LVEF is not normalized 
within 6 weeks +/- 1 week then the patient is to be taken off protocol treatment. 
• An MRI of the breast is required every 12 weeks (+/- 28 days) to monitor 
response to treatment. Additional imaging, including diffusion-weighted MRI, 
mammogram, ultrasound, tomosynthesis, PET is allowed if clinically indicated or 
recommended by the treating physician or radiologist. An MRI of the breast is 
considered standard of care for neoadjuvant treatment of breast cancer both 
prior to initiation of neoadjuvant treatment and prior to surgery for surgical 
planning, and will be covered by insurance. Any additional costs associated with 
the required MRI assessment during neoadjuvant treatment will be absorbed by 
the study site and patients may not be charged for these expenses including if 
for whatever reason insurance does not cover the first and pre-surgical MRI. 
• A physical exam of the breasts must be documented with each visit for 
intravenous trastuzumab and pertuzumab (every 3 weeks +/- 3 days, but need 
not be on the same exact day as infusion of trastuzumab and pertuzumab). If 
progression is suspected, a repeat MRI and radiologist-recommended imaging 
modality is required to confirm progression. 
4.5.2 Follow-Up Assessments 
The only assessments required by the study protocol after neoadjuvant protocol 
treatment is completed are as follows: 
Date of definitive surgery and/or additional surgery to obtain clear margins 
including surgical pathology reports that ideally will include the following details 
(repeat confirmation of ER, PR and HER2 status) of the primary tumor assuming 
it is still present: size of primary tumor in 3 dimensions, size of lymph node 
involvement if applicable, number of lymph nodes removed and number of 
lymph nodes with residual disease and whether it is by IHC only, microscopic 

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disease or gross residual disease, presence or absence of lymphovascular 
invasion, margin involvement and degree of margin freedom if <1cm.  
Mammaprint testing on the surgical specimen if unable to acquire with the 
diagnostic biopsy 
If patient is taken prematurely off study – identification of the reason such as 
patient logistics, treatment toxicity, progressive disease.  
It is not an endpoint of the study to identify treatments given after surgery but if 
the patient receives further neoadjuvant treatment after protocol treatment, 
drugs used, doses and number of cycles will be documented.  
 
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) 
• Physician’s judgment 
 
4.7 
SUBJECT DISCONTINUATION 
If for whatever reason a subject is taken prematurely off study protocol, the 
patient will continue to be followed until the point of either curative intent 
surgery, documented refusal of surgery by the patient, or development of 
metastases.  
If a subject is withdrawn specifically due to the event of a pregnancy patient will 
be withdrawn from study protocol. 
The reason for premature discontinuation of a subject must be recorded on the 
Case Report Form. 
 
4.8 
STUDY DISCONTINUATION 
The Principal Investigator has the right to terminate this study at any time.  
Reasons for terminating the study may include the following: 
• The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
• Subject enrollment is unsatisfactory 

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• Data recording are inaccurate or incomplete 
• Study protocol not followed 
• Cancer Treatment Centers of America Affiliated Hospitals are no longer able to 
continue the clinical trial 
 
4.9 
STATISTICAL METHODS 
4.9.1 Analysis of the Conduct of the Study 
This study protocol will be approved through the Western IRB. The Human 
Research Protection Program, a division of Cancer Treatment Centers of 
America’s Medicine and Science will act as the monitor for this investigator-
initiated study and actively track for enrollment status, protocol violations, and 
other data that reflect the general conduct of the study. The study coordinators 
assigned to the study will be delegated authority to screen potential patients for 
clinical trial, and will inform the primary oncologist if the patient is a candidate. A 
screening log is to be used at each study site. 
 
4.9.2 Analysis of Treatment Group  
Variables will be analyzed to assess the characteristics of the treatment cohort 
such as demographics, baseline characteristics, compliance and concurrent 
treatments. 
The primary endpoint of the study is the rate of pathological complete response 
(pCR) of patients receiving treatment protocol. This will be assessed with both 
an intention-to-treat analysis and a planned subset analysis of evaluable 
patients, with pCR defined as the absence of invasive cancer in the breast and 
lymph nodes where ductal carcinoma in situ is allowed. The subset of “evaluable 
patients” will be favored for final analysis of efficacy since the intent of this 
clinical study is to establish whether an aromatase inhibitor combined with 
trastuzumab and pertuzumab is efficacious and bioactive.  Since patients 
treated at Midwestern Regional Medical Center (MRMC), Cancer Treatment 
Centers of America travel on average 400 miles from their home town to MRMC, 
we do not want to introduce a negative bias to this study towards the null 
hypothesis due to the unique logistical issues CTCA patients face. Therefore, 
evaluable patients will include those who are enrolled into study and 
successfully complete study treatment protocol until either progression or 
suspected pCR based on MRI imaging.  
The Fleming two stage design will be implemented with stopping rules (Fleming  
1982). The null hypothesis is that the pCR rate is < 0.2 (treatment warrants no 
further investigation) versus the alternative hypothesis where the pCR rate is > 
0.4 (treatment shows promising therapeutic efficacy that warrants further 
investigation). The null hypothesis will be treated against the one sided 

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alternative hypothesis. In the first stage, 15 evaluable patients will have surgical 
results and if there are two or fewer responses in these first 15 patients, the 
study will be stopped and the alternative hypothesis will be rejected. If there are 
7 or more complete responses in 15 patients, the study will be stopped and the 
null hypothesis rejected. Otherwise, the study will continue into the second 
stage and 17 additional patients will be allowed to accrue for a total of 32 
patients. The null hypothesis will be rejected if 10 or more responses are 
observed in 32 patients in the final analysis. This design yields a type I error rate 
of 0.05 and power of 80% when the true response rate is 0.4.  
 
Alternative 
pCR rate 
Null pCR rate 
Stage 1 
stopping 
rule 
Stage 1 
continuing 
rule 
Stage 2 not 
encouraging 
Stage 2 
favorable 
Power 
40% 
20% 
<=2/15 
>=3/15 
<=9/32 
>=10/32 
80% 
 
Reference: Fleming (1982) Biometrics 38: 143-151 
 
 
4.9.3 Efficacy Analysis 
a. Primary Endpoint 
Pathological Complete Response (pCR) Rate 
 
Pathological complete response (pCR) will be defined as the absence of 
invasive disease in both breast and lymph nodes and allow for residual ductal 
carcinoma in situ. Both an intention-to-treat analysis and a subset analysis of 
evaluable patients will be performed. Evaluable patients will include those who 
are enrolled into study and successfully complete study treatment protocol until 
either progression or suspected pCR based on MRI imaging. Patients can be 
omitted from the intention-to-treat analysis if it is discovered that they were 
enrolled when they did not pass all eligibility and exclusion criteria (see Section 
4.1).  
The pCR rate will be described with a range for 95% confidence interval.  
b. Secondary Endpoints 
Median duration of treatment will represent time from Day 0 i.e. first dose of 
trastuzumab and pertuzumab to 3 weeks after the last dose of trastuzumab and 
pertuzumab. 
An exploratory analysis will be performed to assess whether Mammaprint and 
Blueprint results (i.e. low risk and luminal subtype) predicts whether patients are 
more likely to obtain a pCR after neoadjuvant treatment of HR+ HER2+ 
localized breast cancer with an aromatase inhibitor and trastuzumab and 

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pertuzumab. Descriptive tables will show distribution of Mammaprint low and 
high risk results amongst those who obtain pCR and those who do not.  
Sensitivity and specificity of radiographic complete response (rCR) as detected 
by breast MRI in predicting pathological complete response (pCR) will also be 
calculated. 
4.9.4 Safety Analysis 
Since safety is not either a primary or secondary endpoint of this study and 
already established by large randomized clinical trials such as CLEOPATRA, 
and ongoing studies such as APHINITY and PERTAIN, descriptive procedures 
will be used to represent frequency of adverse events such as a significant 
decline in EF, infusion reactions, rash and diarrhea with the treatment protocol. 
4.9.5 Missing Data 
Any missing data that cannot be corrected with chart review or directed inquiry 
will be registered as not available, and if appropriate, protocol violation will be 
reported to IRB. 
4.9.6 Determination of Sample Size 
A sample size of 32 evaluable patients was selected for reasons described in 
more detail in Section 4.9.2 where 32 patients would yield a type I error rate of 
0.05 and power of 80% if the true pCR rate is 0.4.  
The sample size will be adjusted to accommodate dropouts or exclusions. The 
number of subjects that should be enrolled into clinical trial is therefore (32 
evaluable patients)/(90%, i.e. expected proportion of enrolled subjects who will 
be evaluable) = 36 patients.  
 
4.10 DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of 
standard practices and procedures. 
 
5.  
REPORTING OF ADVERSE EVENTS 
5.1 
ASSESSMENT OF SAFETY 
Specification of Safety Variables  
Safety assessments will consist of monitoring and reporting adverse events 
(AEs) and serious adverse events (SAEs) that are considered related to 
trastuzumab and pertuzumab, all events of death, and any study specific issue 
of concern. Because the study is already declared IND exempt by the FDA, and 

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the study is not specifically sponsored by Genentech/Roche, direct reporting of 
AE/SAE will be primarily reported to the WIRB. SAE’s will also be reported 
directly to the principal investigator, Dr. Eugene Ahn. See section 5.3i for 
contact info. 
Adverse Events 
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, including signs or symptoms 
associated with trastuzumab and pertuzumab, that were not present prior 
to the AE reporting period. 
• Complications that occur as a result of protocol-mandated interventions 
(i.e. aromatase inhibitor, premedication use of famotidine and benadryl, 
etc) 
 
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 
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). 
• It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the study drugs. 
• 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). 

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5.2 
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 (Western IRB or WIRB) and all SAEs are reported to the 
principal investigator Dr. Eugene Ahn 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 21 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), regulatory 
seriousness criteria if applicable, suspected relationship to the {study drug} (see 
following guidance), 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 trastuzumab and pertuzumab, 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 
trastuzumab and pertuzumab; and/or the AE abates or resolves upon 
discontinuation of the trastuzumab and pertuzumab or dose reduction and, if 
applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the trastuzumab and 
pertuzumab (e.g., preexisting medical condition, underlying disease, intercurrent 
illness, or concomitant medication); and/or the AE has no plausible temporal 
relationship to trastuzumab and pertuzumab administration (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
 
Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert or current Investigator Brochure.  

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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. 
 
5.3 
PROCEDURES FOR ELICITING, RECORDING, AND REPORTING ADVERSE 
EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation time points 
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. 
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 ok 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 (see 
Section 5.1.2), 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”. 
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 

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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 or 
• 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 21 days after the last dose of study drug, a report should be completed 
and expeditiously submitted to the WIRB and principal investigator. 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 trastuzumab and 
pertuzumab 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 
trastuzumab and pertuzumab 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. 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. If 
discrepancies are identified, the Sponsor 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. 

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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: 
• Left Ventricular Dysfunction  
• Infusion-associated Reactions, Hypersensitivity   Reactions/Anaphylaxis  
• Embryo-fetal Toxicity or Birth Defects 
 
i. 
SAE Reporting 
Investigators must report all SAEs to Western IRB (WIRB) and the principal 
investigator Dr. Eugene Ahn (PI) within the timelines described below. The 
completed Medwatch/case report should be faxed immediately upon completion 
to the WIRB and e-mailed or faxed to the PI. 
 
Western IRB 
WIRB U.S. Office 
1019 39th Avenue SE Suite 120 
Puyallup, WA 98374-2115 
Office: (360) 252-2500 or (800) 562-4789 
Fax: (360) 252-2498 
 
Principal Investigator 
If e-mailing, please send to both the PI and study coordinator 
Eugene.ahn@ctca-hope.com (principal investigator) 
Anjanette.sorensen@ctca-hope.com (study coordinator) 
If faxing, please add “Attention to: Anjanette Sorensen”) 
Office: (847) 731-1777 
Fax: (847) 731-1215 
 
• Relevant follow-up information should be submitted to WIRB and the PI 
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 
WIRB and PI within fifteen (15) calendar days of the Awareness Date. 
• Serious AE reports that are unrelated to the trastuzumab and pertuzumab 
will be transmitted to WIRB and PI within thirty (30) calendar days of the 
Awareness Date. 
• Additional Reporting Requirements to WIRB and PI include the following: 
• Any reports of pregnancy following the start of administration with the 
trastuzumab and pertuzumab will be transmitted to WIRB and PI within 
thirty (30) calendar days of the Awareness Date.  
• All Non-Serious Adverse Events originating from the Study will be 
forwarded in a bi-annual (every 6 months) report to WIRB 

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6. 
INVESTIGATOR REQUIREMENTS 
6.1 
STUDY INITIATION 
Before the start of this study, the following documents must be on file with the 
Cancer Treatment Centers affiliate site’s research office. 
• Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the local Principal 
Investigator. 
The names of any sub-investigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
• Current curriculum vitae of the local Principal Investigator 
• Written documentation of IRB approval of protocol and informed consent 
document 
• A copy of the IRB-approved informed consent document 
6.2 
STUDY COMPLETION 
All investigators will be notified when the study has one remaining patient slot 
available for enrollment, and afterwards when the last patient has officially 
enrolled. The Enterprise Review committee (ERC) will also monitor accrual pace 
and may request process improvements if pace falls behind schedule.  
 
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. 
Signed consent forms must remain in each subject’s study file and must be 
available for verification by study monitors at any time. 
 

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6.4 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the WIRB 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 the WIRB 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.  The WIRB may have other specific adverse event 
requirements that investigators are expected to adhere.  
 
6.5 
STUDY MONITORING REQUIREMENTS 
N/A 
 
6.6 
DATA COLLECTION 
Accurate and reliable data collection will be assured by verification and cross-
check of paper CRFs against the source records by the CTCA Human Research 
and Protection Program (HRPP).  
Throughout the study the study management team including the Principal 
Investigator’s office and HRPP will monitor the data periodically as a process of 
self-audit and quality control.  
 
6.7 
STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
N/A 
 
6.8 
DISCLOSURE AND PUBLICATION OF DATA 
Subject medical information obtained by this study is confidential, and disclosure 
to third parties other than those noted below is prohibited. 

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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 WIRB, HRPP and PI office, if appropriate. 
The results of this study may be published or presented at scientific meetings. 
The Sponsor will comply with the requirements for the publication of study 
results.   
Additionally, Section 801 of the Food and Drug Administration Amendments Act 
(FDAAA 801) (PDF) requires Responsible Parties to register and submit 
summary results of clinical trials with ClinicalTrials.gov. The law applies to 
certain clinical trials of drugs (including biological products) and medical 
devices. (refer to FDAAA 801 Requirements to learn about Responsible Party, 
Applicable Clinical Trials, and deadlines for registration and results submission) 
 
6.9 
RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after 
marketing application approval.  If no application is filed, these records must be 
kept 2 years after the investigation is discontinued and the U.S. FDA and the 
applicable national and local health authorities are notified.  Genentech will 
notify the Principal Investigator of these events. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record 
retention policies of the relevant national and local health authorities. 

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pertuzumab and trastuzumab in women with locally advanced, inflammatory, or 

Protocol:  NEOADAPT: Neoadjuvant aromatase inhibitor with pertuzumab and 
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early HER2-positive breast cancer (NeoSphere): a randomised multicentre, 
open-label, Phase 2 trial. Lancet Oncol 2012; 13: 25-32 . 
 
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the mammary epithelium of transgenic mice induces metastatic disease. Proc 
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4580. 
 
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Hynes NE. Amplification and overexpression of the erbB-2 gene in human 
tumors: its involvement in tumor development, significance as a prognostic 
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regulatory proteins augments lysis of breast carcinoma cells targeted with 
rhumAb anti-HER2. Immunopharmacology 1999; 42:209-218. 
 
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cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci USA 
1992; 89:5321-5325. 
 
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Herceptin in metastatic breast cancer patients overexpressing HER-2. Proc Am 
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of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol 
2012 Mar;23(3):791-800. 
 
Leyland-Jones B, Hemmings F, Arnold A, et al. Pharmacokinetics of Herceptin 
administered with paclitaxel every three weeks. Breast Cancer Res Treat 2000; 
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Ng, CM, Lum, BL, Giminez, V, Kelsey, S, Allison, D. Rationale for fixed dosing 
of pertuzumab in cancer patients based on population pharmacokinetic analysis. 
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Nicholson BP, Thor AD, Goldstein LJ, et al. Weekly docetaxel and rhuMAb 
HER2 combination therapy as first- or second-line therapy for metastatic breast 
cancer. Proc Am Soc Clin Oncol 2000; 19:139a. 
 
Pauletti G, Godolphin W, Press MF, Slamon DJ. Detection and quantitation of 
HER-2/neu gene amplification in human breast cancer archival material using 
fluorescence in situ hybridization. Oncogene1996; 13:63-71. 
 
Pegram MD, Lopez A, Konecny G, Slamon DJ. Trastuzumab and 
chemotherapeutics: drug interactions and synergies. Semin Oncol 2000; 27:21-
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chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. 
Oncogene 1997; 15:537-547. 
 
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab 
plus adjuvant chemotherapy for operable human epidermal growth factor 
receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and 
NSABP B-31. J Clin Oncol 2011;29:3366-3373 
 
Romond EH, Suman VJ, Jeong J-H, et al.  Trastuzumab plus adjuvant 
chemotherapy for HER2-positive breast cancer: final planned joint analysis of 
overall survival from NSABM B-31 and NCCTG N09831.  2012 35th Annual San 
Antonio Breast Cancer Symposium. Oral Presentation. 
 
Pietras RJ, Fendly BM, Chazin VR, et al. Antibody to HER-2/neu receptor blocks 
DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 
1994; 9:1829-1838. 
 
Rimawi MF, Mayer IA, Forero A, et al. Multicenter phase II study of neoadjuvant 
lapatinib and trastuzumab with hormonal therapy and without chemotherapy in 
patients with human epidermal growth factor receptor 2-overexpressing breast 
cancer: TBCRC 006. J Clin Oncol 2013; 31:1726-31.  
 
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant 
chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 
353:1673-1684. 
 
Schneeweiss A, Chia S, Hickish T, et al.  Pertuzumab plus trastuzumab in 
combination with standard neoadjuvant anthracycline-containing and 
anthracycline-free chemotherapy regimens in patients with HER2-positive early 
breast cancer: a randomized phase II cardiac safety study (TRYPHAENA)  Ann 
Oncol 2013; 24: 2278–2284. 
Seidman AD, Fornier M, Hudis C, et al.  Phase II trial of weekly 1-hour Taxol 
and Herceptin for metastatic breast cancer: toward further exploitation of proven 

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synergistic antitumor activity.  Cancer Invest 1999;17(Suppl 1):44-45. 
Seidman AD, Fournier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel 
therapy for metastatic breast cancer with analysis of efficacy by HER2 
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Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of 
relapse and survival with amplification of the HER-2/neu oncogene. Science 
1987; 235:177-182. 
 
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-
oncogene in human breast and ovarian cancer. Science 1989; 244:707-712. 
 
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that 
overexpresses HER2. N Engl J Med 2001; 344:783-792. 
 
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive 
breast cancer. N Engl J Med 2011;365:1273-1283. 
 
Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after 
adjuvant chemotherapy in HER2-positive breast cancer: a randomised 
controlled trial. Lancet 2007;369:29-36. 
 
Swain S, Kim, S, Cortés J, et al.  Pertuzumab, trastuzumab, and docetaxel for 
HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival 
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Tripathy D, Slamon D, Leyland-Jones B, et al. Treatment beyond progression in 
the Herceptin pivotal combination chemotherapy trial. Breast Cancer Res Treat 
2000; 64:32. 
 
 
 
 
 

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Figure 1. STUDY SCHEMA 
 
 

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APPENDIX A 
Study Flowchart 
 
 
Days  
–30 to –1 
Cycle #1 
(Day 0) 
Every 3 weeks 
beginning with 
Cycle #2 
(+/- 7days) 
Every 12 
weeks 
(+/- 4 
weeks) 
End of 
study 
Trastuzumab and pertuzumab administration 
 
X 
X 
 
 
Review of AI compliance 
 
 
X2 
 
 
Complete medical history 
X 
 
 
 
 
Complete physical exam 
X 
 
 
 
 
Clinical assessment 
X 
X2 
X2 
 
 
Vital signs, weight, height 
X 
X2 
X2 
 
 
ECOG performance status 
X 
 
 
 
 
Toxicity evaluation 
 
 
X2 
 
 
Mammaprint and Blueprint 
 
X1 
 
 
X1 
Serum or urine pregnancy test 
X 
 
 
 
 
Echo/MUGA 
X 
 
 
X 
 
CBC, BMP 
X 
X2 
X2 
 
 
LFT 
X 
 
 
 
 
MRI 
X 
 
 
X 
 
Physical exam of breast 
X 
X2 
X2 
 
 
Surgical pathology of breast 
 
 
 
 
X 
1 Blueprint/Mammaprint (not required to be successful prior to day 0 as the information should not be used to determine whether or not patient should 
start treatment, but another attempt should be done on the surgical pathology specimen if patient does not achieve pCR) 
2 Can be done +/- 3 days around actual infusion day

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APPENDIX B 
 
Response Evaluation Criteria in Breast Cancer via RECIST Criteria Modified 
for Neoadjuvant Treatment 
 
 
Modified RECIST criteria as detailed below should be used to assess response 
to treatment.  Only subjects with measurable disease either based on mass or 
enhancement should be entered in the study.  Measurable disease is defined as 
the presence of one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded) via MRI imaging. If for whatever 
reason another imaging study such as mammogram or ultrasound is helpful at 
following response to neoadjuvant treatment, the mammogram or ultrasound 
may be used as a complement to MRI.  Evaluable lesions will be followed for the 
assessment of response.   
All measurable lesions, up to a maximum of 2 lesions since for the purposes of 
this protocol focus is confined to one organ, the breast/axilla, should be identified 
as target lesions and recorded and measured at baseline.  A sum of the longest 
diameter for the target lesions will be calculated and reported as the baseline 
sum longest diameter. The index lesion can be less than 1.0 cm. The baseline 
sum longest diameter will initially be used as the reference by which to 
characterize the objective tumor response, but if any reduction in diameter is 
seen on a subsequent MRI, the shortest sum longest diameter will always be 
used as the reference point to calculate the following: 
• 
Radiographic complete response (rCR) 
Disappearance of all evidence of tumor including any residual enhancement 
interpreted by the radiologist to be due to residual tumor in the breast on two MRI 
scans separated by 12 weeks (only one MRI required if the first complete 
response MRI occurs at the end of one year of treatment). If a lymph node is 
identified as a target lesion, obviously disappearance of the lymph node is not a 
reasonable requirement. As long as the lymph node (target or non-target) is 
shrunk to <1 cm, the MRI still qualifies as a complete response.  
• 
Radiographic partial response (rPR) 
At least a 30% decrease in the sum of the longest diameter of target lesions, 
taking as 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) 

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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. If a non-
target lesion in the breast/axilla increases by >33% the patient can also be 
classified as progressive disease. 
 

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APPENDIX C 
 
National Cancer Institute Common Toxicity Criteria v4.03 
obtained from http://evs.nci.nih.gov/ftp1/CTCAE/About.html

 
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APPENDIX D 
 
SAFETY REPORTING FAX COVER SHEET 
 
WIRB FAX# (360) 252-2498  
 
PI FAX# (847) 731-1215 
 
 
Study Number 
ML30001 
Principal Investigator 
Eugene Ahn MD 
Site Name 
Cancer Treatment Centers of America 
Midwestern Regional Medical Center 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY]   (leave blank if N/A) 
 
Subject Initials 
(Enter a dash if patient has no middle 
name) 
[ ] - [ ] - [ ] 
 
 
PLEASE PLACE SAFETY REPORT BEHIND THIS COVER SHEET 

 
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APPENDIX E:  Algorithm for Continuation and Discontinuation of 
Pertuzumab and Trastuzumab Based on LVEF Assessments  
 
 
Protocol allows for 6 weeks of q 3 week echo/MUGA follow up testing prior to 
being required to stop protocol treatment 
 

 
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APPENDIX F 
 
Data Collection Form (to be kept for each enrolled patient) 
 
Preferred data entry will be through the CTMS Merge software when available at 
each site.  
 
An excel spreadsheet will be provided to each site upon request. 
 
Name 
 
Date of Birth 
 
Date(s) of diagnostic biopsy(ies) 
 
Diagnostic pathology result including ER%, PR%, HER2 result by IHC and/or 
FISH, nuclear grade 1-3, presence of lymphovascular invasion, presence of 
perineural invasion 
 
MRI measurement of primary lesion 
 
MRI measurement of pathological lymph nodes 
 
Mammaprint result 
 
Day 0 date: 
 
Aromatase inhibitor(s) used and date of use 
 
Serious adverse events 
 
End of protocol treatment date 
 
Reason for end of protocol treatment among following reasons 
- 
rCR 
- 
unacceptable toxicity 
- 
progressive disease (describe best result including radiographic partial 
response, one radiographic complete response followed by 
progressive disease, stable disease then progression, etc) 
- 
patient election to discontinue therapy (provide descriptive reason) 
- 
physician judgment (provide descriptive reason) 
 
Additional neoadjuvant treatment given off protocol 
 
Date of surgery 

 
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Surgical pathology results with both details and determination of pCR or not and 
quantification of residual disease