Conditions: Breast Cancer
Keywords: MAB 2C4 (PERTUZUMAB) MAB HER 2 (HERCEPTIN) (TRASTUZUMAB) TAXOL (PACLITAXEL) 10-142 Stage IV HER2 (+) breast cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 70
Healthy volunteers: no

Brief summary:
The purpose of this study is to see if a combination of drugs can help to treat this type of cancer. One drug is a chemotherapy agent called paclitaxel (Taxol®). Paclitaxel will be given every week through the vein. Although the weekly schedule of paclitaxel is not included in the label, the schedule and dose of weekly paclitaxel have been studied and have been proven to be more effective than an old standard schedule. The other two work against HER2. One is called trastuzumab (Herceptin®) and it is commonly given to women with early HER2 positive breast cancer or with advanced HER2 positive breast cancer that has spread to other parts of the body. Trastuzumab will be given through the vein every 3 weeks (or every week at the doctor's discretion). The third drug, pertuzumab, is an investigational drug. It has not been approved by the Food and Drug Administration. It has been given in studies to over 800 people. It has been effective in treating HER2 positive breast cancer. Pertuzumab will be given every 3 weeks through the vein. This study is looking at the effectiveness of these three drugs together.

Detailed description:

Arms:
arm 1: This is a phase II study of pertuzumab in combination with trastuzumab and paclitaxel for the treatment of patients with Stage IV HER2 (+) breast cancer.

Interventions: intervention 1: pertuzumab in combination with trastuzumab and paclitaxel
Intervention descriptions: intervention 1: The regimen will consist of paclitaxel (80 mg/m2) weekly + trastuzumab every 3 weeks (8 mg/kg loading dose → 6 mg/kg every 3 weeks) + pertuzumab every 3 weeks (840 mg as a loading dose → 420 mg), all given intravenously (IV). Patients may be given trastuzumab weekly in lieu of every 3 weeks (4 mg/kg loading dose → 2 mg/kg every 3 weeks). Patients will be on treatment until progression of disease.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  1 of 61 
 
 
 
Paclitaxel, Trastuzumab, and Pertuzumab in the Treatment of Metastatic HER2-Positive 
Breast Cancer 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: 
Chau Dang, MD 
Medicine 
Co-Principal Investigator(s)/Department: Sarat Chandarlapaty, MD, PhD 
Medicine 
Investigator(s)/Department: 
Shanu Modi, MD 
Maura Dickler, MD 
Jacqueline Bromberg, MD, PhD 
Teresa Gilewski, MD 
Larry Norton, MD 
Mark Robson, MD 
Gabriella D’Andrea, MD 
Diana Lake, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Mary Ellen Moynahan, MD 
Tiffany A. Traina, MD 
Shari Goldfarb, MD 
Victoria Blinder, MD 
Monica Fornier, MD 
Devika Gajria, MD, MPH 
Elizabeth Comen, MD 
Richard Steingart, MD 
Jennifer Liu, MD 
Ayca Gucalp, MD 
Neil Iyengar, MD 
José Baselga, MD, PhD 
Lillian Smyth, MD 
Pedram Razavi, MD, PhD 
Komal Jhaveri, MD 
Ting Bao, MD, DABMA, MS 
Christopher Klebanoff, MD 
Rui Wang, MD 
Linda Vahdat, MD 
Valentina Sterlin, NP 
Lauren Wood, RN 
Tina Alano, RN 
Emer Heaney, RN 
Maureen Cannon, NP 
Karen Drucker, NP 
Aimee Rogado, RN 
Odessa Williams, NP 
Danielle Alleva, NP 
Nicole Devine, NP 
Catherine Keane, NP 
Renee Wisniewski, NP 
Nora Messinger, NP 
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Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  2 of 61 
 
 
 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Roseann Caruso, NP 
Sarah Schweber, MD 
Wanqing Iris Zhi, MD, PhD 
Krysti Corrado, CRN 
Lori Gofter, CRN 
 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Paul Hamlin, MD 
Louise Ligresti, MD 
Neha Korde, MD 
Isidore Tepler, MD 
Karen Dougherty NP 
Leticia Smith, APN 
Janet Cogswell, CRN 
Jennifer Howgate-Klingaman 
 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Tiffany Troso-Sandoval, MD 
Oscar Lahoud, MD 
Erin Scansarole, CRN 
Katherine O’Connor, NP 
 
Jasmeet Singh, MD 
Rachel Grisham, MD 
Rachel Sanford, MD 
Chrisann Kyi, MD 
Karin Budrock, NP 
Gloria Wasilewski, CRN 
Sherie Mar-Chaim, RN 
 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Curtis Chong, MD 
Raylene Langish, RN 
Doris Pindilli, APN 
 
Sujata Patil, PhD 
Martin Fleisher, MD 
Maxine Jochelson, MD 
Sara Hayes, MD 
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Biostatistics 
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Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  3 of 61 
 
 
 
Consenting Professional(s)/Department: 
Shanu Modi, MD 
Maura Dickler, MD 
Jacqueline Bromberg, MD, PhD 
Teresa Gilewski, MD 
Larry Norton, MD 
Mark Robson, MD 
Gabriela D’Andrea, MD 
Diana Lake, MD 
Andrew Seidman, MD 
Nancy Sklarin, MD 
Mary Ellen Moynahan, MD 
Tiffany A. Traina, MD 
Shari Goldfarb, MD 
Victoria Blinder, MD 
Monica Fornier, MD 
Sarat Chandarlapaty, MD, PhD 
Chau Dang, MD 
Devika Gajria, MD, MPH 
Elizabeth Comen, MD 
Ayca Gucalp, MD 
Neil Iyengar, MD 
José Baselga, MD, PhD 
Lillian Smyth, MD 
Pedram Razavi, MD, PhD 
Komal Jhaveri, MD 
Ting Bao, MD, DAMBA, MS 
Christopher Klebanoff, MD 
Linda Vahdat, MD 
 
Stuart Lichtman, MD 
Steven Sugarman, MD 
Sarah Schweber, MD 
Wanqing Iris Zhi, MD, PhD 
 
 
 
Audrey Hamilton, MD 
Mila Gorsky, MD 
Paul Hamlin, MD 
Louise Ligresti, MD 
Neha Korde, MD 
Isidore Tepler, MD 
 
Pamela Drullinsky, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Arlyn Apollo, MD 
Tiffany Troso-Sandoval, MD 
Oscar Lahoud, MD 
 
Jasmeet Singh, MD 
Rachel Grisham, MD 
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Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  4 of 61 
 
 
 
Rachel Sanford, MD 
Chrisann Kyi, MD 
 
Jason Konner, MD 
Serena Wong, MD 
Azadeh Namakydoust, MD 
Colette Owens, MD 
Loren Michel, MD 
Marina Shcherba, DO 
Curtis Chong, MD 
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Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Westchester 
Commack 
Basking Ridge 
Rockville Centre 
Monmouth 
 
 
Participating Institutions: 
PI's Name 
Site's Role 
University of Pennsylvania Core 
Laboratory 
Bonnie Ky, PhD 
Specimen Analysis 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  5 of 61 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA......................................................................... 5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS.................................................................................. 5 
 
3.0 
BACKGROUND AND RATIONALE ....................................................................................... 6 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ............................................................. 18 
 
4.1 
Design .............................................................................................................................. 18 
 
4.2 
Intervention ....................................................................................................................... 19 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 19 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 25 
 
6.1 
Subject Inclusion Criteria .................................................................................................. 25 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 26 
 
7.0 
RECRUITMENT PLAN......................................................................................................... 26 
 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 27 
 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................................. 27 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 33 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 38 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 40 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 41 
 
14.0 BIOSTATISTICS .................................................................................................................. 41 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES .. 43 
 
15.1 Research Participant Registration ..................................................................................... 43 
 
16.0 DATA MANAGEMENT ISSUES........................................................................................... 43 
 
16.1 Quality Assurance............................................................................................................. 43 
 
16.2 Data and Safety Monitoring............................................................................................... 43 
 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 44 
 
17.1 Privacy.............................................................................................................................. 44 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 44 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 48 
 
19.0 REFERENCES ..................................................................................................................... 49 
 
20. 
APPENDICES ...................................................................................................................... 56 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  6 of 61 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a phase II study of pertuzumab in combination with trastuzumab and paclitaxel for 
the treatment of patients with Stage IV HER2 (+) breast cancer.  The regimen will consist 
of paclitaxel (80 mg/m2) weekly + trastuzumab every 3 weeks (8 mg/kg loading dose → 6 
mg/kg every 3 weeks) + pertuzumab every 3 weeks (840 mg as a loading dose → 420 mg), 
all given intravenously (IV).  Patients may be given trastuzumab weekly in lieu of every 3 
weeks (4 mg/kg loading dose → 2 mg/kg every 3 weeks).  Patients will be on treatment until 
progression of disease. Study blood will be collected serially for cardiac biomarker analysis 
[troponin I (cTnI), brain type natruretic peptide (BNP), neuregulin-1ß (NRG-1ß)]. We will 
also assess the left ventricular ejection fraction (LVEF) at baseline and every 4th cycle of 
treatment with an echocardiogram (ECHO) with a strain imaging analysis. When an ECHO 
cannot be done, a multi-gated acquisition scan (MUGA) may be done. 
 
 
 
Schema 
 
 
Schema 
 
Accrual Goal = 69 patients 
 
 
 
N = 69 
HER2 + 
0-1 prior Rx 
q w eek …………………………… 
 
 
q 3 w eeks…………………………. 
 
 
q 3 w eeks………………………… 
 
q 4 cycles………………………… 
cardiac biomarkers 
q 2 cycles………………………… 
Paclitaxel at 80 mg/m2 
 
Pertuzumab at 840mg load  → 420 mg q 3 w  
 
 
Trastuzumab at 8 mg/kg load → 6 mg/kg q 3 w  
ECHO 
 
• 
Research bloods (TnI, BNP, NRG-1ß) every other cycle (pre- and post-infusion on 
day 1).  If research blood work is missed on day 1, it can be done on day 8 or 15 
pre- and post-infusion. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
• 
The primary objective of this study will be the proportion of patients who are progression 
free at 6 months or later.  Patients who are considered progression-free at 6 months are 
deemed successes.   Failures are those patients who progressed before the 6 month 
mark. 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  7 of 61 
 
 
 
• 
The secondary objectives will be response, safety (including cardiac safety) and 
tolerability.  A cardiac event will be defined as a) “symptomatic” left ventricular systolic 
dysfunction (LVSD) (deaths and non-deaths), b) non-LVSD cardiac death, or c) 
probable cardiac death. 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
Anti-HER2 Therapies for Patients with Metastatic HER2-Postive Breast Cancer 
 
HER2/neu (c-erb-B2) is a proto-oncogene which encodes the 185kDa HER2 protein, a 
transmembrane tyrosine kinase receptor that is part of the human epidermal growth factor 
receptor family1. The HER2/neu gene is amplified in approximately 20-30% of human 
breast cancers, leading to HER2 protein overexpression, which is associated with clinically 
aggressive disease associated with poor prognostic features and shortened disease-free 
and overall survival.1 Trastuzumab (Herceptin®) (T) is a humanized monoclonal antibody 
which binds to the extracellular domain of HER2, and in clinical trials has improved 
outcomes for patients with both metastatic and early stage HER2 positive breast cancer2,3,4. 
Although the precise mechanism of action of trastuzumab in vivo is not fully understood, its 
effects may be multiple and include the following: disruption of intracellular signaling leading 
to cell cycle arrest and apoptosis, 5,6 antibody-dependent cellular cytotoxicity7, and inhibition 
of angiogenesis8. 
 
Trastuzumab has synergistic activity with a number of different chemotherapy agents 2,9-10 
and additionally, has activity as a single agent in women with metastatic breast cancer 
overexpressing HER2 with response rates of 11.6%-15% in pretreated patients and 35% in 
the first-line setting 11,12,13. For patients with metastatic breast cancer overexpressing 
HER2, the addition of trastuzumab to chemotherapy has been shown to improve time to 
progression (TTP), time to treatment failure (TTF), overall response rate (ORR), duration of 
response (DOR) and overall survival (OS) when compared to chemotherapy alone as front- 
line treatment 2,9. Slamon et al reported the results of the pivotal phase III trial in which 
chemotherapy alone was compared to chemotherapy plus trastuzumab in 469 women with 
HER2 overexpressing metastatic breast cancer who had not previously received 
chemotherapy for metastatic disease2.  Patients were randomized to an anthracycline or 
paclitaxel with or without trastuzumab. The results were in favor of chemotherapy with 
trastuzumab vs chemotherapy alone in terms of TTP (7.4 months vs 4.6 months, p < 
.0001), ORR (50% vs 32%, p < .001), DOR (9.1 months vs 6.1 months, p < .001), median 
TTF (6.9 months vs 4.5 months, p < .001) and median OS (25.1 months vs 20.3 months, p 
= .05). 
 
Marty et al reported similar results from a randomized trial of trastuzumab plus docetaxel vs 
docetaxel alone in 186 patients9.  Patients were randomized to six cycles of docetaxel at 
100 mg/m2 every 3 weeks with or without trastuzumab weekly until disease progression. 
Trastuzumab plus docetaxel resulted in a significant improvement over docetaxel alone in 
outcomes in terms of ORR (61% vs 34%, p = .0002), median TTF (9.8 vs 5.3 months, p = 
.0001), median TTP (11.7 vs 6.1 months, p = .0001), median DOR (11.7 vs 5.7 months, p = 
.009), and median OS (31.2 vs 22.7 months, p = .0325). 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
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In other front-line trials trastuzumab resulted in response rates of 62%-84% when combined 
with vinorelbine 14-17 and of 63%-65% when combined with capecitabine 18-19. In the 
pretreated population, trastuzumab combined with various chemotherapy agents with 
paclitaxel, docetaxel, vinorelbine, gemcitabine, or capecitabine resulted in the response 
rates of 20%-55% 20-29. 
 
In spite of these results, only a proportion of patients with HER2 positive breast cancer 
respond to trastuzumab and the vast majority of patients with metastases ultimately 
experience disease progression despite this treatment. The dependence of HER2 over- 
expressing breast cancers on this signal transduction pathway for growth has thus 
motivated the search for more potent and/or complementary anti-HER2 strategies.  In this 
regard, Lapatinib (Tykerb®) has emerged as an active anti-HER2 therapy and is the 
second agent approved by the US Food and Drug Administration (FDA) for this subtype of 
breast cancer30. 
 
 
 
Pertuzumab 
 
Pertuzumab is a humanized monoclonal antibody which binds to the extracellular domain of 
HER2; however unlike trastuzumab which binds at domain IV, pertuzumab binds domain II 
of the receptor and is thus able to disrupt HER2 dimerization and ligand-activated signaling 
with other growth factor receptors, including other HER family members 31.  Animal model 
studies using HER2 positive breast cancer xenografts have shown a synergistic antitumor 
activity for pertuzumab in combination with trastuzumab 32. 
 
Non-Clinical Studies 
 
In Vitro 
 
In in vitro studies pertuzumab blocks heregulin-induced activation of the PI3 kinase cell 
survival pathway whereas trastuzumab does not.  In the breast carcinoma cell line MCF-7, 
pertuzumab, but not trastuzumab, blocked heregulin-induced activation of the PI3 kinase 
cell survival pathway, as indicated by a lack of phosphorylation of a key enzyme (Akt) in this 
pathway. 33 Juntilla showed that pertuzumab blocks ligand-dependent HER2-3 dimerization 
while trastuzumab blocked ligand-independent HER2-3 dimerization in a HER2+ cell line 
(SKBR3).  34 The ability of pertuzumab to inhibit ligand activation of HER2 has also been 
demonstrated in transfected cell lines of fibroblast origin and with purified soluble 
receptors.34-35 
 
 
 
Pertuzumab blocks heregulin-dependent in vitro growth of a number of breast cancer cell 
lines as well as cell lines derived form other solid tumors.36-38 For example in the heregulin- 
secreting MDA-MB-175VII breast carcinoma cell line, which expresses low/moderate levels 
of HER2 protein (1+ by immunohistochemistry), cell proliferation was inhibited in a dose- 
dependent fashion by both pertuzumab and trastuzumab but the magnitude of the inhibition 
was far greater with pertuzumab. 37 The calculated pertuzumab concentration at which the 
half-maximal growth inhibition (IC50) occurred was120 ng/ml or 0.8 nM, and was consistent 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  9 of 61 
 
 
 
with biochemical measurements of pertuzumab inhibition of hereugulin binding or receptor 
activation. 33, 35, 36   The combination of trastuzumab and pertuzumab was shown to have a 
synergistic growth inhibiting effect on BT474 breast tumors, which express high levels of 
HER2 underscoring the complementary mechanism of action of the 2 drugs.39 
 
In Vivo 
 
In human tumor xenograft models in mice, pertuzumab is active against various tumors 
including breast, ovarian, lung, and prostate cancers.40-43 For example, growth inhibition 
ranged from 50-70% compared with control in 5 of 18 NSCLC xenografts.41 Similar studies 
using 6 different human mammary tumor explants revealed one clear responder with more 
than 70%.43 The dosage of 6 mg/kg/week was the optimal schedule to achieve the maximal 
therapeutic effect.44 
 
Pertuzumab also augmented the anti-tumor effect of various cytotoxic drugs, including 
paclitaxel, irinotecan, cisplatin, gemcitabine, and capecitabine.45-50The augmentation by 
pertuzumab of the various chemotherapeutic agents with differing modes of action is 
possibly explained by the deprivation of PI3-kinase mediated cellular survival signals after 
inhibition of the HER2 activation. 
 
Pertuzumab enhances other HER pathway inhibitors, such as erlotinib in human lung 
cancer xenograft models.47, 51, 52 In HER2 (+) xenografts derived from HER2-over- 
expressing NSCLC Calu-3 cells and from KPL-4 breast cancer cells, pertuzumab had 
synergistic antitumor activity in combination with trastuzumab.53-54   The synergistic action of 
pertuzumab and trastuzumab may be explained by their complementary modes of action. 
While pertuzumab prevents ligand-activated formation of HER2 heterodimers, trastuzumab 
can block the shedding of HER2 extracellular domain that would result in constitutively 
activated truncated receptors.  Furthermore, as the 2 antibodies are not competing for the 
same epitope on HER2, their combination may lead to an increased cell killing via antibody 
dependent cell-mediated cytotoxicity (ADCC). 
 
Non-clinical Pharmacokinetics 
 
Consistent with its IgG1 framework pertuzumab has a long terminal half-life in mice, rats, 
and primates (approximately 10 days) following an initial rapid distribution phase (<1 day). 
In nude mice implanted with NSCLC tumors and breast cancer tumors that were given 
weekly doses (0.4-60 mg/kg), > 80% suppression of tumor growth was seen at steady-state 
trough levels of 5-25 ug/ml.55 
 
 
 
Pertuzumab administered weekly IV was well tolerated in primates at doses up to 150 
mg/kg. Treatment-related diarrhea was noted at doses of 15 mg/kg and higher.  More 
chronic dosing (>12 weeks of weekly dosing) resulted in diarrhea-related dehydration in 
monkeys.  In vitro studies demonstrated that pertuzumab is compatible with human blood 
and does not cause hemolysis. Tissue binding of the antibody is consistent with HER2 
expression.  In reproductive toxicity study, pertuzumab administered to pregnant 
cynomolgus monkeys twice weekly from gestation day (GD) 19-50 caused dose-related 
increase in embryo-fetal abortion and death. Evidence of delayed renal development was 
seen at all doses.55 


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IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  10 of 61 
 
 
 
Clinical Studies 
 
Summary of Clinical Pharmacology 
 
The clinical information has been obtained from company sponsored studies.55   In clinical 
studies, similar pharmacokinetics (PK) was observed across all trials with no change in 
clearance at doses from 2.0-15.0 mg/kg (140 mg to 1050 mg for a 70 kg patient).  A two- 
compartment model adequately described the concentration-time data with a systemic 
serum clearance of approximately 0.24 L/day and a terminal half-life of 17 days for a typical 
patient.  Based on these clinical data, a dosing interval of 3 weeks is recommended in 
clinical studies. In phase II studies, a loading dose of 840 mg (followed by 420 mg every 3 
weeks) was capable of attaining a steady state trough and peak concentrations by the 
second cycle. Population PK modeling of data from Phase I and Phase II studies support 
the combined use of fixed, non-weight-based dosing in female patients. There was no 
evidence of an impact of pertuzumab on the co-administered chemotherapeutic agents, 
docetaxel and capecitabine in Phase Ib studies.55 
 
Pharmacokinetics in Single-Agent Studies 
 
In phase II single-agent studies, concentration-time data show that the loading dose of 840 
mg (followed by 420 mg q 3 weeks) was capable of attaining steady-state trough and peak 
concentrations by the second cycle.  The PK parameters were estimated using a two- 
compartment model. The mean systemic clearance of these patients (0.335-0.28 L/day) 
and the mean volume of distribution of the central compartment (2.70-3.11 L) were similar 
to that observed in the phase Ia study (TOC2297g).56 The initial half-life and the serum, 
terminal half-life were also within the ranges observed across 2-15 mg/kg dose groups in 
the phase Ib study. 
 
Pharmacokinetics in Combination Studies 
 
Analyses of the PK of capecitabine (study BO17003) and docetaxel (study BO17021) 
indicate that pertuzumab does not alter the PK of these two cytotoxic agents.55 In both of 
these studies, the PK parameters of pertuzumab were similar to those obtained in single- 
agent studies. 
 
Support for the Dose Regimen 
 
A dosing regimen of pertuzumab given every 3 weeks to patients in Phase II studies 
(TOC2689g, BO16934) using a fixed dose of 840 mg loading dose (equivalent to 12 mg/kg 
for a 70 kg patient) for cycle 1 and a fixed dose of 420 mg maintenance dose (equivalent to 
6 mg/kg) for subsequent cycles resulted in a steady state trough concentrations of 
approximately 60 ug/L by the second treatment cycle.  In non-clinical dose-response 
xenograft studies using nude mice implanted with NSCLC and breast cancer tumors (low 
and high HER2 expression levels), >80% suppression of tumor growth was achieved when 
steady-state trough concentrations of pertuzumab were 5-25 ug/mL. Thus, the steady-state 
serum trough concentrations obtained in patients are in excess of concentrations shown to 
be efficacious in animal tumor models, and thus expected to result in a biologic effect. 
 
A preliminary population PK analysis of the Phase Ia (TOC2297g) and Phase IIa 
(TOC2689g), BO16934) studies, comprising 153 patients (weight range: 45.0-150. 


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Page  11 of 61 
 
 
 
6 kg) and 1458 concentration-time points, showed that the population variability of steady- 
state trough concentration and exposure were similar with fixed-, body surface area- (BSA), 
weight-based dosing. Thus, a dose based on BSA or weight was not superior to a fixed 
dose supporting the continued use of a fixed dose of pertuzumab in female patients with 
MBC and ovarian cancer.55 
 
 
 
 
 
Clinical Efficacy 
 
Summary 
 
Clinical activity has been observed in patients with HER2 low expressing tumors who have 
received pertuzumab either as a single agent or in combination with cytotoxic 
chemotherapy.  Complete responses (CR) have not been observed in any of these trials. 
Partial responses (PR) or stable disease (SD) lasting for > 6 months have been observed in 
11% of patients with ovarian cancer and in 8% of patients with HER2 low expressing breast 
cancer.  No responses were observed for hormone-refractory prostate cancer or NSCLC. 
Pertuzumab with gemcitabine given to patients with platinum-resistant ovarian cancer 
showed prolongation of progression-free survival (PFS) over gemcitabine alone.  However, 
in platinum-sensitive ovarian cancer patients, the addition of pertuzumab to carboplatin- 
based doublet of chemotherapy did not improve PFS.  Five CRs and 11 PRs (24% 
objective response rate) were observed in patients with previously treated HER2 positive 
MBC following combined treatment with pertuzumab and trastuzumab. The rate and 
duration of SD observed across all studies suggest that pertuzumab may not have a direct 
cytotoxic effect, but may function as a cytostatic agent.55-56 
 
Efficacy in Breast Cancer 
 
Four studies have been designed to evaluate pertuzumab in breast cancer. Data from the 
primary analysis of efficacy have been available from 2 studies. The first study, BO16934, 
studied patients with HER2 low expressing disease. The second study, BO17929, is a trial 
in patients with HER2 overexpressing MBC.  Two additional studies are ongoing.  Study 
WO20697 is evaluating neoadjuvant treatment of HER2 positive early breast cancer and 
WO20698 is a phase III study of HER2 positive MBC.55 
 
Study BO16934 is a phase II study that evaluated the efficacy of pertuzumab given either at 
420 mg or 1050 mg to patients with previously treated and low HER2 expressing MBC. 
During the study, patients received a median of 2 cycles (range 1-24). Two patients in the 
low dose group had a PR with durations of 18 weeks in 1 patient and 31 weeks in the other. 
No patients in the higher dose group had an objective response. In total, 32 patients had 
SD as best response, of which 2 patients in the low dose arm and 2 in the high-dose arm 
had SD for > 6 months. The overall clinical benefit response rate was 7.7%.55 
 
Study BO17929 is a two-stage phase II, single arm study of efficacy and safety of 
pertuzumab and trastuzumab in patients with HER2 (+) MBC who had relapsed during 
trastuzumab following up to 3 lines of chemotherapy with or without trastuzumab.  Patients 
in cohorts 1 and 2 (N=66) received trastuzumab plus pertuzumab for up to 8 cycles and 
those who did not progress by this time were eligible to continue receiving study drug until 


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progression, intolerable toxicity, or death. The primary endpoints of the study were overall 
response rate and clinical benefit. Baselga et al presented the result of this study and 
showed that the response rate was 24% and an additional 17 (25.8%) patients had SD for ≥ 
6months, comprising a clinical benefit rate of 50%.57The most common toxicities were 
grade 1 and 2 diarrhea, fatigue, nausea, rash and headache.  The mean LVEF in this study 
did not fluctuate significantly over 12 cycles of therapy.  There appeared to be no 
concerning cardiac signal with the combination of the two antibodies. There were only 3/66 
(4.5%) of patients who had asymptomatic LVEF declines of > 10% to < 50%. The 
promising results of the combination of pertuzumab and trastuzumab led to a protocol 
amendment to include a 3rd cohort of patients receiving pertuzumab monotherapy, to 
assess the activity of pertuzumab as a single agent in this clinical setting. If the patient’s 
disease failed to respond to pertuzumab monotherapy or responded and relapsed, then 
patients could have trastuzumab added to pertuzumab at the physician’s discretion.  Cortes 
et al reported the result of pertuzumab as monotherapy.58 In this study, 29 patients were 
enrolled, and only 2/29 (7%) patients responded. Fourteen patients then had trastuzumab 
added to pertuzumab due to inadequate monotherapy response, and 2 of 14 (14%) who 
had previously progressed on trastuzumab and pertuzumab had a response. 
 
Portera and colleagues conducted a separate study and evaluated the safety and efficacy of 
pertuzumab with trastuzumab in 11 patients with HER2-positive breast cancer who 
progressed on prior trastuzumab based treatments.59    In this small study 2/11 (18%) 
patients had an objective response and an additional 3/11 (27%) of patients had SD. Thus, 
the clinical benefit rate occurred in 5/11 (45%) patients.  Cardiac evaluation and tumor 
response were assessed every 3 and 6 weeks, respectively.  Overall, 6/11 (54.5%) patients 
experienced a reduction in left ventricular ejection fraction (LVEF) most of which was 
asymptomatic [3/11 (27%) had G 1 LVEF decline to 50-55% and 2/11 (18%) had G2 LVEF 
decline to 40-49%]; 1/11 (9%) patients had clinical congestive heart failure (CHF).  These 
promising phase 2 results have now led to a phase III first-line registration trial where 
patients with HER2 positive MBC are randomized to treatment with trastuzumab plus 
docetaxel +/- pertuzumab, namely CLEOPATRA. 
 
Safety 
 
As of November of 2008, approximately 840 patients with advanced cancers or early stage 
HER2 (+) breast cancer have been treated with pertuzumab.  Gastrointestinal toxicities 
(diarrhea, nausea, vomiting, abdominal pain) and fatigue are the most frequently reported 
adverse events (AEs) with single therapy.55 
 
Diarrhea and rash 
 
Although pertuzumab targets HER2, because of its role in heterodimerization with other 
members of the HER family (ie: HER1/EGFR), it may cause toxicities associated with the 
use of EGFR inhibitors.  Diarrhea and rash are common events increased with pertuzumab 
given in combination with chemotherapy compared with chemotherapy alone.  Diarrhea has 
been reported in 60-70% of patients treated with pertuzumab and was mostly of grades 1-2. 
The mechanism of diarrhea and rash are unknown, but the nature is similar to that of other 
agents causing HER1 inhibition.  In the event of diarrhea, early intervention with anti- 


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diarrhea medication should be considered and patients treated with fluid and electrolyte 
replacement, as clinically indicated.55 
 
Infusion-related Symptoms 
 
Monoclonal antibodies may cause infusion-associated symptoms such as fever, chills, 
hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting.  Serious 
or severe infusion-related symptoms have been rarely observed with 7 patients 
experiencing serious reactions to date [hypersensitivity, fatal ARDS, pulmonary edema, 
anaphylaxis, dyspnea with hypertension, infusion-related reaction (unsteady on feet, 
headache, blurred vision)].  In pertuzumab single-agent studies, less than 5% of patients 
experienced adverse reactions during pertuzumab infusions.  Serious infusion-related 
reactions with pertuzumab have been infrequently reported (< 1%).   Intravenous 
pertuzumab administration should be performed in the setting with emergency equipment 
and staff who re trained to monitor medical situations and respond to medical emergencies. 
Patients should be monitored during each pertuzumab infusion for any adverse effects, as 
infusion reactions may occur with the first or subsequent doses.   The infusion should be 
stopped for patients who develop dyspnea, clinically significant hypotension, or other 
clinically significant events.  Patients who experience an NCI-CTC grade 4 allergic reaction 
or acute respiratory distress syndrome should not receive additional peruzumab.55 
 
Cardiac Toxicities 
 
Since pertuzumab targets HER2, as with trastuzumab, there is a potential risk of cardiac 
dysfunction, particularly in patients who have received prior anthracycline treatment. 
Cardiac toxicities, predominantly asymptomatic left ventricular ejection fraction (LVEF) 
declines, and 4 cases of cardiac failure have been reported in approximately 840 patients 
with advanced malignant disease or early stage HER2 (+) breast cancer treated with 
pertuzumab. Two of these cases occurred in patients with metastatic breast cancer who 
had received prior anthracyclines and two in patients with ovarian cancer.  No clear 
association between the frequency, nature, and severity of pertuzumab-related toxicities 
and dose level has been observed.55 
 
Patients with significant cardiac disease or baseline LVEF below the institution’s lower limit 
of normal (LLN) should not commence treatment with pertuzumab.  Risk factors for 
pertuzumab-associated cardiac dysfunction are not known at this time. This risk should be 
carefully weighed against the potential benefit in patients who have received prior 
anthracyclines.  Monitoring of the LVEF is advised while patients are receiving pertuzumab. 
If symptomatic LVEF decline develops (NCI-CTC grade 3 or 4), the patient must 
discontinue pertuzumab.  Left ventricular dysfunction, symptomatic or not, should be 
treated and followed according to standard medical practice. 
 
Paclitaxel 
 
The taxanes, paclitaxel and docetaxel, are well established in metastatic breast cancer 
treatment and can increase response rate and duration of response.60-61   Taxanes lack 
cross-resistance with anthracyclines and were therefore quickly deemed worthwhile for 
evaluation in the adjuvant setting. Results from several randomized trials demonstrate a 
benefit from the addition of a taxane to an anthracycline-based regimen.62 There is strong 


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data to support the use of paclitaxel given on a weekly schedule. There is a large body of 
evidence that weekly paclitaxel is superior to the same taxane given every 3-weeks in the 
metastatic setting 20-22 as well as the early setting.63-64. Weekly paclitaxel at 80 mg/m2 has 
been studied in a prospective randomized phase III study in which it was compared against 
a previous standard schedule of every 3 week paclitaxel at 175 mg/m2.20   In this study, 
patients with metastatic breast cancer were randomized to every 3 week or weekly 
paclitaxel.  Those with HER2-positive breast cancer had trastuzumab added to 
chemotherapy and those with HER2-normal disease were randomized to trastuzumab or 
not. Initially, those on the weekly chemotherapy arm received paclitaxel at 100 mg/m2 for 6 
doses followed by a dose at 80 mg/m2 continuously.  However, due to a 30% incidence of 
grade 3 sensory neuropathy, the study was amended to start with a reduced dose of 80 
mg/m2 which was then continued until progression of disease or limiting toxicity.  Overall, 
weekly paclitaxel was superior to every 3 week paclitaxel in terms of response, time to 
progression, and median overall survival.  Another study by Seidman et al evaluated the 
schedule of weekly paclitaxel at 90 mg/m2 with trastuzumab in patients with HER2-positive 
and HER2-normal disease. 21   However, the median delivered dose of paclitaxel was 82 
mg/m2.  Some of the reasons for the dose reduction included toxicities related to the higher 
dose of paclitaxel, primarily due to neurotoxicity, when given continuously.  Perez ret al 
have also shown that weekly paclitaxel at 80 mg/m2 is active against breast cancer. 22. 
Sparano and colleagues have shown that weekly paclitaxel after doxorubicin and 
cyclophosphamide is superior to paclitaxel every 3 weeks in both DFS and OS while 
docetaxel every 3 weeks was only superior in terms of DFS, but not OS. There were more 
hematologic and non-hematologic toxicities with every 3-weekly docetaxel. 64  These 
studies have established weekly paclitaxel at 80 mg/m2 given continuously as a standard 
schedule.20-22, 63-64 Therefore, for this study the continuous weekly paclitaxel schedule at 80 
mg/m2 was chosen. Thus, it is worthwhile to assess the weekly paclitaxel schedule in 
combination with trastuzumab and pertuzumab. 
 
Cardiac biomarkers 
 
Cardiac toxicity is a potentially grave toxicity of certain cytotoxic chemotherapy agents, 
particularly the anthracycline drugs. In the adjuvant management of breast cancer when 
cure is the goal of treatment, the potential long-term cardiac sequelae of treatment are 
particularly relevant. While it may not be possible to prevent every case of treatment – 
induced cardiac dysfunction, early detection of evolving cardiac damage and the institution 
of medical management may help to decrease the morbidity associated with this toxicity. 
Studies of patients with asymptomatic LV dysfunction have shown that the risk of 
developing symptomatic heart failure or cardiac death over time can be decreased with the 
use of angiotensin converting enzyme (ACE) inhibitors.65-66 With the existence of potential 
therapeutic interventions, much interest has focused on the development and validation of 
cardiac biomarkers that might identify subclinical cardiac damage and patients who may 
benefit from cardioprotective measures.  Preliminary data suggest that the use of ACE 
inhibitors may prevent cardiotoxicity in patients receiving high-dose chemotherapy identified 
as increased risk on the basis of cardiac biomarkers.66 To date, the majority of experience 
with cardiac biomarkers has been in the setting of anthracycline chemotherapy. 
 
Cardiac Troponins 


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The incidence of elevation of cardiac troponins I or T (cTnI or cTnT) with each 
chemotherapy cycle may be as high as 30-34% in patients treated with potentially 
cardiotoxic (primarily anthracycline) chemotherapy across studies.67 Many of these studies 
were in pediatric patients and/or those with hematologic malignancies, and in adults with 
high dose chemotherapy. In addition, methods of troponin detection and cut-off 
concentrations varied across studies, although most studies used the lowest troponin 
concentration at which signal-to-noise ratio can be reliably interpreted. In practice, this 
concentration has been defined across most studies as the concentration measured with an 
analytic imprecision expressed as the coefficient of variation of 10% or less. The etiology of 
the troponin rise appears to be non-ischemic as it is not associated with symptoms or 
classical EKG changes, and it predates LV dysfunction rather than accompanying it.68 
Troponin determination in breast cancer patients has been found to predict the occurrence 
of clinically significant LV dysfunction as well as the degree and severity of future LV 
dysfunction683. 
 
 
 
 
Cardiac Troponin I (cTnI) 
 
Cardinale et al studied 211 patients receiving high dose therapy for breast cancer (mean 
age 46) using cTnI measurements at six time points before and after each chemotherapy 
cycle (up to 72 hours after) and correlated these to ECHO findings at 1,2,3,4,7 and 12 
months69. A positive cTnI was defined as ≥0.5ng/mL. The cTnI level was normal at baseline 
and before each cycle. The patients were divided into a troponin positive group (at least 
one positive cTnI value) and a troponin negative group. In this study, 52% of the positive 
patients had only one positive result. The number of positive results were highest just after 
chemotherapy and lowest at 72 hours; the number of positive tests was higher after each 
additional cycle. A close relationship was found between the maximal cTnI value obtained 
and maximum LVEF decrement seen in follow up. In addition, there was a significant 
correlation between the number of positive cTnI values and the LVEF maximal decrement. 
The presence of normal cTnI levels after therapy was associated with no significant decline 
in LVEF in follow-up. 
 
Another study from the same group in patients receiving high dose therapy measured “early 
troponin I” (E-cTnI) by taking the highest value from a group of values taken immediately 
after therapy and at 12, 24, 36 and 72 hours.68 This was repeated for each cycle of therapy 
but the single highest troponin value was considered as the E-TnI for analysis. A “late 
troponin I” (L-cTnI) was taken 1 month after the last administration of HDT. Patients were 
divided into 3 groups: negative E-cTnI and L-cTnI (-/-), positive E-cTnI and negative L-cTnI 
(+/-), and positive E-cTnI and L-cTnI (+/+). The persistence of positive troponin values >1 
month after chemotherapy (+/+) was related to an 85% risk of major cardiac events within a 
year of follow-up. Conversely, there was only a 1% incidence of cardiac events over 1 year 
in the patients with consistently negative results after therapy. Again, there was a significant 
correlation between the early cTnI value (i.e. the maximum cTnI value seen after any 
chemotherapy cycle) and LVEF maximal reduction. 


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A further study used cTnI measurements from 99 healthy volunteers to determine a 
threshold level of ≥0.08µg/L using ROC area under the curve analysis.70 Troponin I was 
assessed in patients receiving high dose therapy at five time points during each cycle. In 
this study, 32% of patients were found to have positive cTnI (one or more positive results); 
61% of these had 2 or more positive results. The ECHOs were performed at 1, 2,3,4,7 and 
12 months. Patients with positive cTnI values had a mean decrease in LVEF at 12 months 
of 18% compared to 2.5% in the cTnI-negative group. A study in 79 patients with leukemia 
measured cTnI at various intervals during induction therapy, and found elevated cTnI levels 
at day 7-14 correlated with reversible decreases in LVEF7.71 Reports of smaller patient 
cohorts ranging from 15 to 31 patients showed more variable levels of cTnI detection after 
anthracycline therapy.72-74 
 
B-type natriuretic peptide (BNP) 
 
Natriuretic peptides are rapidly produced by the heart in response to hemodynamic stress. 
Both BNP and NT-proBNP are widely tested in heart failure as markers of heart failure 
diagnosis, prognosis, and overall risk assessment.67 Several studies examined BNP levels 
at prolonged intervals from chemotherapy. A Dutch study evaluated BNP and NT-BNP 
levels at two time points after anthracycline chemotherapy at a median of 2.7 years later 
and a median of 6.5 years afterwards.75 Elevated BNP levels were found in 14 out of 54 
patients 6.5 years after chemotherapy. The BNP levels were significantly higher in patients 
receiving 450 mg/m2 epirubicin than those who received 360 mg/m2. Cardiac function was 
not assessed. However, a similar study evaluating BNP levels in 63 patients at least 1 year 
from anthracycline therapy found cardiac dysfunction in 41% and significantly higher mean 
BNPs in this group.76 Similarly, Germanakis et al found a high rate of cardiotoxicity (as 
measured by decreased LV mass) in 19 children a mean of 3.9 years from anthracycline 
therapy, with significantly higher NT-pro-BNP levels in the patients with reduced LVM.77 
Hayakawa et al also found significantly higher levels of NT-BNP and BNP in pediatric 
patients previously treated with anthracyclines who had evidence of cardiotoxicity as 
compared to healthy controls and patients with preserved cardiac function.78 A Saudi 
Arabian study in 31 pediatric patients found significant elevation of NT-pro-BNP when 
checked at least one month after chemotherapy in patients with echocardiographic cardiac 
toxicity compared with healthy controls and compared to those patients with conserved 
cardiac function.74 
 
Cardiac biomarkers with trastuzumab 
 
Limited data exist regarding the use of cardiac biomarkers as predictors of cardiotoxicity in 
patients treated with trastuzumab. Plasma cTnI and NT-proBNP levels were assayed in 15 
patients taking part in a study of an imaging modality (indium-111 labeled trastuzumab 
scintigraphy) as a predictor of cardiotoxicity.79 Patients received trastuzumab as part of a 
non-anthracycline containing regimen. While the imaging test was not shown to be of value, 
pre-treatment plasma NT-proBNP levels were found to be higher in patients who developed 
cardiotoxicity. A pilot study examined established and novel measures of metabolic and 
vascular risk factors for cardiovascular disease (including BNP) in a small subset of patients 
participating in the BCIRG 006 adjuvant trastuzumab study.80 These were compared to 


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healthy controls. Patients entered the study at a median time from chemotherapy and 
trastuzumab of 20 months. In this study, 38.4% of patients had an LVEF value 10% or more 
below their baseline assessment; BNP was significantly elevated in 40% of patients and 
was a predictor of LVEF on univariate analysis. In N9831, an adjuvant study of AC followed 
by TH vs chemotherapy alone, a correlative study of potential cardiac biomarkers including 
BNP, C-reactive peptide (CRP), and troponin T and I, with LVEF identified that elevated 
BNP and troponin I at baseline and the doubling of BNP may have possible predictive 
values for cardiac toxicity, but the evaluation was done in a small group.81 
 
Neuregulin 
 
Neuregulin-1 (NRG-1) is a cardioprotective, paracrine growth factor released by 
microvascular endothelial cells.  This pathway, which is necessary for the maintenance of 
cardiac function and survival during states of increased stress, is believed to be an 
important mediator of heart failure and chemotherapy-induced cardiac dysfunction.82  In 
vitro studies demonstrate that NRG-1 administration protects doxorubicin-treated 
cardiomyocytes from myofibrillar disarray and death, and NRG-1 or ErbB2 deficient mice 
have dramatically worse survival with anthracycline exposure.83-84   Trastuzumab, and 
pertuzumab, specifically target the ErbB2 receptor, a major mediator of NRG-1 activity, and 
its association with clinical cardiac dysfunction may be related to effects on this signaling 
pathway.85 
 
 
 
 
In order to define the mechanistic and translational significance of NRG-1 signaling in 
humans, Ky and colleagues recently quantified serum NRG-1ß levels in a large cohort 
(N=899) of patients with chronic heart failure in the Penn Heart Failure Study.86   Elevated 
NRG-1ß levels were significantly associated with more advanced heart failure (NYHA Class 
IV median 6.2 ng/ml versus those with Class I CHF 4.4 ng/ml, p=0.002). Furthermore, 
NRG-1ß was independently associated with an elevated risk of all-cause death or cardiac 
transplantation over a median follow-up of 2.4 months (adjusted HR 1.58, 95% C.I of 1.04- 
2.3, p=0.003), comparing the 4th vs the 1st quartile of NRG-1ß.  Associations differed 
according to heart failure cause and severity, with stronger relationships observed in those 
with ischemic heart failure (interaction p=0.008) and advanced NYHA Class III/IV symptoms 
(interaction, p=0.01).  In addition, patients with chemotherapy-induced cardiac dysfunction 
had significant alterations in their circulating NRG-1 levels compared to all other etiologies 
(p=0.02). 
 
Our goal is to extend these findings and provide mechanistic, translational insight into the 
potential dysregulation of NRG-1/ErbB signaling with trastuzumab and pertuzumab. In 
doing so, we will bridge the gap between our basic science and clinical observations and 
determine the effects and potential clinical relevance of NRG-1ß on chemotherapy-induced 
cardiac dysfunction. We will quantify the relationship between NRG-1 and incident cardiac 
dysfunction, and determine the clinical, predictive utility of this biomarker in this important 
population. As of A(15), we will no longer be quantifying the relationship between NRG-1 
and incident cardiac dysfunction since the incidence of cardiac dysfunction based on the 
LVEF data has been minimal. 


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Echocardiograms and Strain Imaging Analysis 
 
Monitoring of chemotherapy-induced cardiotoxic effects has relied primarily on the 
measurement of ejection fraction by echocardiography or radionuclide ventriculography. 
However, these parameters are too insensitive to detect subtle changes in myocardial 
dysfunction. When a clear reduction in LV ejection fraction can be measured, functional 
deterioration often proceeds rapidly. 
 
Strain and strain rate imaging are new ultrasound applications in the field of 
echocardiography which have emerged in the last few years. Strain measures the 
deformation of the myocardium during cardiac contraction and relaxation and strain rate 
measures the speed of the myocardial deformation. This technique provides  a more 
sensitive and quantitative  assessment of cardiac contractile function than conventional 
indices such as ejection fraction and are less affected by loading conditions and 
translational motion of the heart.  Strain imaging has shown to be useful in unmasking 
subtle cardiac pathology and cardiomyopathy, objective assessment of regional and global 
function and therapy evaluation in patient follow-up.875-89 There are limited data available on 
the usefulness of this technique in the evaluation of anthracycline cardiotoxicity.  Using 
strain imaging, myocardial  systolic and diastolic dysfunction have been reported in 
asymptomatic pediatric patients with normal ejection fraction 5 years after low dose 
treatment with anthracycline when compared with age matched normal controls.90   Acute 
reduction in strain and strain rate have also been demonstrated during low dose 
anthracycline treatment with no change in the conventional indices of systolic function.91  A 
recent study92 has shown subclinical LV systolic dysfunction in elderly women with early 
breast cancer treated with a total of 180 mg/m2 of liposomal doxorubicin (Doxil®) by strain 
imaging, despite normal ejection fraction and fractional shortening. These results indicate 
that strain imaging is likely superior to ejection fraction or fraction shortening in the 
detection of early subclinical myocardial dysfunction.  However, these studies are limited by 
the small sample size and the period of follow-up and are unable to address whether the 
abnormalities of the deformation parameters noted on strain imaging are clinically 
significant in predicting development of cardiomyopathy. 
 
Rationale 
 
Based on promising results of the combination of pertuzumab with trastuzumab in a 
pretreated population, it makes sense to test this combination with paclitaxel given weekly 
in the treatment of patients with metastatic HER2-positive breast cancer. With the 
superiority of the weekly over every 3 week schedule of paclitaxel and since there are less 
toxicities seen with weekly paclitaxel than docetaxel given every 3 weeks, 20-22, 63-64   it is 
worthwhile to combine weekly paclitaxel with pertuzumab and trastuzumab.  There are 
strong data to support the use of weekly paclitaxel at 80 mg/m2 continuously.20-22, , 63-64 
Although, CLEOPATRA is evaluating docetaxel every 3 weeks with trastuzumab +/- 
pertuzumab, it is important to evaluate pertuzumab with a better taxane schedule (weekly 
paclitaxel) and trastuzumab. 
 
In this study patients with HER2 (+) breast cancer who have had 0-1 prior treatment in the 
metastatic setting will be enrolled.  Trastuzumab in the adjuvant setting is allowed.  Slamon 


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et al showed that the combination of paclitaxel and trastuzumab led to a median TTP of 7.4 
months in patients with untreated HER2 (+) metastatic breast cancer.2 The primary endpoint 
will be 6 month progression-free survival (PFS).  We chose 6 months, as opposed to 7 
months, as patients with one prior treatment are included. Patients who are considered 
progression-free at 6 months are deemed successes.   Failures are those patients who 
progressed before the 6 month mark.  Based on results from the Slamon trial, we define 
50% as the unpromising rate and 65% as the promising 6 month progression-free rate. 
Based on these proportions, we would need 69 patients, at alpha level=.05 and 80% power 
for a single stage design.  The secondary endpoints will be the safety (including cardiac 
safety) and tolerability and the assessments of biomarkers and tissue sample collections. 
Patients will be given weekly IV paclitaxel (80 mg/m2). Trastuzumab will be given IV every 
3 weeks (8 mg/kg loading dose → 6 mg/kg every 3 weeks).  Trastuzumab may be given IV 
weekly (4 mg/kg loading dose → 2 mg/kg weekly) in lieu of the every 3 week schedule. 
Pertuzumab will be given IV at 840 mg as a loading dose → 420 mg every 3 weeks. We 
will also assess the left ventricular ejection fraction at baseline and after every 4th cycle of 
treatment with an ECHO, and strain imaging will be evaluated.  Study blood will be 
collected serially for biomarker analysis (ie: TnI, BNP, and NRG-1ß). 
 
This is an important study to conduct to assess if pertuzumab in addition to a standard 
combination (trastuzumab + paclitaxel) has promising activity in the treatment of patients 
with HER2 (+) MBC.  Furthermore, it will be important to identify potential cardiac 
biomarkers (ie: TnI, BNP) to assess if there is any correlation between elevated markers 
with any decline in LVEF (asymptomatic or symptomatic). If there is a positive correlation, 
a future study will be done to assess the role of cardiac medications (ie: an ACE-inhibitor, 
ß-blocker, alpha-blocker) in those with elevated cardiac biomarkers to determine if there is 
an improvement in cardiac outcomes in treated patients.  Additionally, we will explore if the 
strain imaging analysis with each ECHO has a role in the detection of early subclinical 
myocardial dysfunction.  Finally, if this treatment combination is proven to be effective and 
is feasible, then it will be tested in the adjuvant setting against the standard chemotherapy- 
trastuzumab (ie: AC followed by paclitaxel + trastuzumab) regimen where the goal for a 
cure is most important. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
This is a phase II study of pertuzumab in combination with trastuzumab and paclitaxel for 
the treatment of patients with Stage IV HER2 (+) breast cancer.  The regimen will consist 
of paclitaxel (80 mg/m2) weekly + trastuzumab every 3 weeks (8 mg/kg loading dose → 6 
mg/kg every 3 weeks) + pertuzumab every 3 weeks (840 mg as a loading dose → 420 mg), 
all given intravenously (IV).  Patients may be given trastuzumab weekly in lieu of every 3 
weeks (4 mg/kg loading dose → 2 mg/kg every 3 weeks).  Patients will be on treatment until 
progression of disease. The primary objective of this study will be the proportion of patients 
who are progression free at 6 months or later.  Patients who are considered progression- 
free at 6 months are deemed successes.  Failures are those patients who progressed 
before the 6 month mark. The secondary objectives will be response, safety (including 
cardiac safety) and tolerability.  Study blood will be collected serially for cardiac biomarker 


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analysis [troponin I (cTnI), brain type natriuretic peptide (BNP), neuregulin-1ß (NRG-1ß)]. 
We will also assess the left ventricular ejection fraction (LVEF) at baseline and after every 
4th cycle of treatment with an echocardiogram (ECHO) with a strain imaging analysis. If an 
ECHO cannot be done, a multi-gated acquisition scan (MUGA) may be done. 
4.2 
Intervention 
 
This is a phase II study of pertuzumab in combination with trastuzumab and paclitaxel for 
the treatment of patients with Stage IV HER2 (+) breast cancer.  Based on promising 
results of the combination of pertuzumab with trastuzumab in a pretreated population, it 
makes sense to test this combination with paclitaxel given weekly in the treatment of 
patients with metastatic HER2-positive breast cancer. With the superiority of the weekly 
over every 3 week schedule of paclitaxel and since there are less toxicities seen with 
weekly paclitaxel than docetaxel given every 3 weeks, 20-22, 63-64   it is worthwhile to combine 
weekly paclitaxel with pertuzumab and trastuzumab. 
The regimen will consist of paclitaxel (80 mg/m2) weekly + trastuzumab every 3 weeks (8 
mg/kg loading dose → 6 mg/kg every 3 weeks) + pertuzumab every 3 weeks (840 mg as a 
loading dose → 420 mg), all given intravenously (IV).  Trastuzumab may also be given 
weekly (4 mg/kg loading dose → 2 mg/kg) in lieu of the every 3 week schedule.  Patients 
will be on treatment until progression of disease. The primary endpoint of this study will be 
the proportion of patients who are progression free at 6 months or later.  Patients who are 
considered progression-free at 6 months are deemed successes.   Failures are those 
patients who progressed before the 6 month mark. The secondary endpoints will be 
response, safety (including cardiac safety) and tolerability.  Study blood will be collected 
serially for cardiac biomarker analysis (TnI, BNP, NRG-1ß) and banked for future studies. 
We will also assess the LVEF at baseline and after every 4th cycle of treatment with an 
ECHO with a strain imaging analysis. When an ECHO cannot be done, a MUGA scan may 
be done. Patients who have surpassed the 6 month period may complete ECHO with strain 
imaging analysis or MUGA every 6 months +/- 1 month starting from the most recent ECHO 
scan date. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
Trastuzumab (Herceptin®) 
a.  Dosage 
 
The recommended initial loading Herceptin dose is 4 mg/kg (for weekly dosing schedules) 
or 8 mg/kg (for every 3 weeks) administered over approximately 90 minutes. The 
recommended maintenance Herceptin dose is 2 mg/kg weekly or 6 mg/kg every 3 weeks 
and can be administered over approximately 30 minutes if the initial loading dose was well 
tolerated.  Herceptin may be administered in an outpatient setting.  DO NOT ADMINISTER 
AS AN IV PUSH OR BOLUS (see ADMINISTRATION). 
 
b.  Preparation 
 
Use appropriate aseptic technique.  Each vial of Herceptin 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 Herceptin. Immediately upon reconstitution with BWFI, the vial of 
Herceptin 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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If the patient has known hypersensitivity to benzyl alcohol, Herceptin must be reconstituted 
with Sterile Water for Injection (see PRECAUTIONS).  Herceptin which 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 Herceptin needed.  Calculate the correct dose using 21 mg/mL 
Herceptin 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 Herceptin and polyvinylchloride or polyethylene bags have been 
observed. 
 
c.   Administration 
 
Treatment may be administered in an outpatient setting by administration of a 4 mg/kg 
Herceptin loading dose for weekly dosing schedules (OR 8 mg/kg Herceptin loading dose 
for q3wk dosing schedules) by intravenous (IV) infusion given over approximately 
90 minutes.  DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.  If Herceptin is being 
administered concomitantly with chemotherapy, Herceptin administration may be given 
before or after chemotherapy administration.  Patients should be observed for fever and 
chills or other infusion-associated symptoms (see ADVERSE REACTIONS). If prior 
infusions are well tolerated subsequent doses of 2 mg/kg Herceptin weekly (OR 6 mg/kg 
Herceptin q3wk) may be administered over approximately 30 minutes. 
 
Herceptin should not be mixed or diluted with other drugs.  Herceptin infusions should not 
be administered or mixed with Dextrose solutions. 
 
d.  Storage 
 
Vials of Herceptin 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 vial of Herceptin 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, the reconstituted Herceptin solution should be used immediately and any 
unused portion must be discarded. DO NOT FREEZE HERCEPTIN THAT HAS BEEN 
RECONSTITUTED. 
 
The solution of Herceptin 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 Herceptin has been shown to be stable for up to 24 
hours at room temperature 15C–25C; however, since diluted Herceptin contains no 
effective preservative the reconstituted and diluted solution should be stored refrigerated 
(2C–8C). 
 
e.  Safety 
 
Infusion-Associated Symptoms. During the first infusion with Herceptin, a symptom complex 
consisting of chills and/or fever is observed in approximately 40% of patients. Other signs 
and/or symptoms may include nausea, vomiting, pain, rigors, headache, cough, dizziness, 
rash, and asthenia. These symptoms are usually mild to moderate in severity, and occur 
infrequently with subsequent Herceptin infusions. These symptoms can be treated with an 
analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as 
diphenhydramine. 


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Serious Infusion-Associated Events. Serious adverse reactions to Herceptin infusion 
including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently.   In rare cases (4 per 
10,000), these events were associated with a clinical course culminating in a fatal outcome. 
Serious reactions have been treated with supportive therapy such as oxygen, beta- 
agonists, corticosteroids and withdrawal of Herceptin as indicated. 
 
Hematologic Toxicity.  In the clinical trials, an increased incidence of anemia was observed 
in patients receiving Herceptin plus chemotherapy compared with patients receiving 
chemotherapy alone. The majority of these anemia events were mild or moderate in 
intensity and reversible; none resulted in discontinuation of Herceptin therapy.  In the 
clinical trials, the per-patient incidences of moderate to severe neutropenia and of febrile 
neutropenia were higher in patients receiving Herceptin in combination with 
myelosuppressive chemotherapy as compared to those who received chemotherapy alone. 
In the post marketing setting, deaths due to sepsis in patients with severe neutropenia have 
been reported in patients receiving Herceptin and myelosuppressive chemotherapy, 
although in controlled clinical trials (pre- and post-marketing), the incidence of septic deaths 
was not significantly increased. The pathophysiologic basis for exacerbation of neutropenia 
has not been determined; the effect of Herceptin on the pharmacokinetics of 
chemotherapeutic agents has not been fully evaluated. The observed incidence of leukemia 
among Herceptin-treated patients appears to be consistent with the expected incidence of 
leukemia among patients treated with chemotherapy for metastatic breast cancer. 
Therefore, the contribution of Herceptin to the etiology of acute leukemia or myelodysplastic 
syndrome in these cases is unclear. 
Paclitaxel (Taxol®) 
 
a.  Dosage 
 
Paclitaxel is an antimicrotubule agent that promotes microtubule assembly and stabilizes 
tubulin polymers by preventing their depolarization, resulting in the formation of extremely 
stable and nonfunctional microtubules, and consequently inhibition of many cell functions. 
The dose of paclitaxel is 80 mg/m2 IV weekly. 
Paclitaxel is commercially available. 
b.  Preparation 
Paclitaxel will be prepared as per MSKCC chemotherapy guidelines (MSKCC and 
affiliates). 
 
c.   Administration 
 
Treatment may be administered in an outpatient setting by administration of an 80 mg/m2 IV 
weekly dosing. If paclitaxel is being administered concomitantly with trastuzumab and 
pertuzumab, chemotherapy administration may be given before or after either antibody.  A 
strict sequence of administration of paclitaxel relative to trastuzumab and pertuzumab is not 
mandated.  Patients should be observed for fever and chills or other infusion-associated 
symptoms. 
 
d.  Storage 


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Unopened vials of paclitaxel are stable until the date as indicated on the package.  Vials of 
paclitaxel should be stored at 20-25º C (68-77º F) in the original package. Neither freezing 
nor refrigeration adversely affects the stability of the product.  Upon refrigeration, 
components of paclitaxel may precipitate but will re-dissolve upon reaching room 
temperature with little or no agitation. 
 
e.  Safety 
 
Side-effects include myelosuppression, hypersensitivity (hypotension, flushing, chest pain, 
abdominal or extremity pain, skin reactions, pruritus, dyspnea, bronchospasm, and 
tachycardia), sinus bradycardia, complete heart block, sinus tachycardia, premature 
ventricular beats, ventricular tachycardia, bigeminy, syncope, myocardial infarction, 
hypotension, hypertension, peripheral neuropathy, taste changes, arthralgia, myalgia, 
seizures, mood alterations, neuroencephalopathy, motor neuropathy, autonomic 
neuropathy, alopecia, radiation recall dermatitis, nausea, vomiting, diarrhea, stomatitis, 
mucositis, pharyngitis, typhlitis, ischemic colitis, pancreatitis, elevated liver function, hepatic 
failure, fatigue, headache, light-headedness, elevated creatinine, elevated triglyceride, and 
blurred vision. 
 
Pertuzumab 
 
a.  Dosage 
 
Pertuzumab is a humanized monoclonal antibody based on the human IgG1 framework 
sequences and consists of 2 heavy chains and 2 light chains.  Pertuzumab will be 
administered as 840 mg loading dose followed by 420 mg IV every 3 weeks. 
 
b.  Preparation 
 
Pertuzumab is produced in Chinese hamster ovary cell cultures and purified by protein A 
column affinity chromatography, followed by ion exchange column chromatography. 
Because of the high degree of homology between pertuzumab and trastuzumab, 
procedures similar to those developed for trastuzumab are used for the manufacturing 
process, the in-process controls, and the characterization of pertuzumab. No bovine- 
derived raw materials are used in the manufacture of pertuzumab. 
 
Each lot of the recombinant antibody produced for clinical purposes meets the USP 
requirements for sterility and safety.  Additionally, each lot is extensively characterized and 
meets the required specifications for identity, purity, and potency. 
 
Pertuzumab is provided as a single use formulation containing 30 mg/ml in 20 mM L- 
histidine acetate (pH 6.0), 120 nM sucrose and 0.02% polysorbate 20. Each 20 ml vial 
contains 420 mg of pertuzumab (14.0 ml/vial). 
 
c.   Administration 
 
Treatment may be administered in an outpatient setting by administration of 840 mg 
followed by 420 mg IV every 3 weeks. The first two doses will be given over approximately 
60 minutes and the subsequent doses will be given over approximately 30-60 minutes.  If 


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pertuzumab is being administered concomitantly with trastuzumab and paclitaxel, there is 
no strict sequence of administration of these 3 drugs mandated.  Patients should be 
observed for fever and chills or other infusion- associated symptoms. 
 
d.  Storage 
 
Pertuzumab vials are to be refrigerated at 2º C-8º C (36º F-46º F) until use.  Pertuzumab 
vials should not be used beyond the expiration date provided by the manufacturer 
(Genentech).  Because the formulation does not contain a preservative, the vial seal may 
only be punctured once. Any remaining solution should be discarded.  Vial contents should 
not be frozen.  The solution of pertuzumab fro infusion diluted in PVC or non-PVC polyolefin 
bags containing 0.9% sodium chloride injection and may be stored at 2º C-8º C (36º F-46º 
F) for up to 24 hours prior to use.  Diluted pertuzumab has been shown to be stable for up 
to 24 hours at room temperature (2º C-25º C).  However, since diluted pertuzumab contains 
no preservative, the diluted solution should be stored refrigerated at 2º C-8º C. 
 
e.  Safety 
 
As of November of 2008, approximately 840 patients with advanced cancers or early stage 
HER2 (+) breast cancer have been treated with pertuzumab. Gastrointestinal toxicities 
(diarrhea, nausea, vomiting, abdominal pain) and fatigue are the most frequently reported 
adverse events (AEs) with single therapy.53 
 
Diarrhea and rash 
 
Although pertuzumab targets HER2, because of its role in heterodimerization with other 
members of the HER family (ie: HER1/EGFR), it may cause toxicities associated with the 
use of EGFR inhibitors. Diarrhea and rash are common events increased with pertuzumab 
given in combination with chemotherapy compared with chemotherapy alone.  Diarrhea has 
been reported in 60-70% of patients treated with pertuzumab and was mostly of grades 1-2. 
The mechanism of diarrhea and rash are unknown, but the nature is similar to that of other 
agents causing HER1 inhibition.  In the event of diarrhea, early intervention with anti- 
diarrhea medication should be considered and patients treated with fluid and electrolyte 
replacement, as clinically indicated.55 
 
 
 
Infusion-related Symptoms 
 
Monoclonal antibodies may cause infusion-associated symptoms such as fever, chills, 
hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting. Serious 
or severe infusion-related symptoms have been rarely observed with 7 patients 
experiencing serious reactions to date [hypersensitivity, fatal ARDS, pulmonary edema, 
anaphylaxis, dyspnea with hypertension, infusion-related reaction (unsteady on feet, 
headache, blurred vision)].  In pertuzumab single-agent studies, less than 5% of patients 
experienced adverse reactions during pertuzumab infusions.  Serious infusion-related 
reactions with pertuzumab have been infrequently reported (< 1%).  Intravenous 
pertuzumab administration should be performed in the setting with emergency equipment 
and staff who re trained to monitor medical situations and respond to medical emergencies. 


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Patients should be monitored during each pertuzumab infusion for any adverse effects, as 
infusion reactions may occur with the first or subsequent doses.  The infusion should be 
stopped for patients who develop dyspnea, clinically significant hypotension, or other 
clinically significant events.  Patients who experience an NCI-CTC grade 4 allergic reaction 
or acute respiratory distress syndrome should not receive additional peruzumab.55 
 
Cardiac Toxicities 
 
Since pertuzumab targets HER2, as with trastuzumab, there is a potential risk of cardiac 
dysfunction, particularly in patients who have received prior anthracycline treatment. 
Cardiac toxicities, predominantly asymptomatic left ventricular ejection fraction (LVEF) 
declines, and 4 cases of cardiac failure have been reported in approximately 840 patients 
with advanced malignant disease or early stage HER2 (+) breast cancer treated with 
pertuzumab. Two of these cases occurred in patients with metastatic breast cancer who 
had received prior anthracyclines and two in patients with ovarian cancer. No clear 
association between the frequency, nature, and severity of pertuzumab-related toxicities 
and dose level has been observed.55 
 
Patients with significant cardiac disease or baseline LVEF below the institution’s lower limit 
of normal (LLN) should not commence treatment with pertuzumab.  Risk factors for 
pertuzumab-associated cardiac dysfunction are not known at this time. This risk should be 
carefully weighed against the potential benefit in patients who have received prior 
anthracyclines.  Monitoring of the LVEF is advised while patients are receiving pertuzumab. 
If symptomatic LVEF decline develops (NCI-CTC grade 3 or 4), the patient must 
discontinue pertuzumab.  Left ventricular dysfunction, symptomatic or not, should be 
treated and followed according to standard medical practice. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 
 
• 
Age > 18 
 
• 
Stage IV HER2 (+) breast cancer 
 
• 
Histologically documented HER2 (+) breast cancer as defined as IHC 3+ or FISH 
amplification of > 2.0 of primary or metastatic site; results from the local lab are acceptable. 
(Optional tumor sample collection from primary or metastatic site may be obtained for 
HER2 testing at MSKCC) 
 
• 
ECOG performance 0 -1 (Appendix A) 
 
• 
0-1 prior treatment in the metastatic setting (ie: hormone, chemotherapy, biologic, targeted 
agents).  Prior anthracycline, paclitaxel, and trastuzumab in the adjuvant setting are 
allowed. If the patient has one trastuzumab-based treatment in the metastatic setting and is 
given a break (even intermittently) from the partner drug given with trastuzumab and is 
continued on trastuzumab alone, this would still be considered as one treatment. For 
example, if the patient was given paclitaxel + trastuzumab and was later continued on 
trastuzumab alone or then restarted on paclitaxel + trastuzumab (at the physician’s 


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discretion for any reason), the regimen paclitaxel + trastuzumab followed by trastuzumab 
alone (or followed by paclitaxel + trastuzumab again) may be considered as one treatment. 
 
• 
Measurable or non-measurable disease.  Measurable lesions are defined as those that can 
be measured accurately in at least one diameter, that is   20 mm using conventional 
imaging techniques (including incremental CT) or 10 mm using spiral CT equipment and a 
lymph node ≥15 mm along the short axis.  Non-measurable lesions are all other lesions, 
including small lesions (longest diameter <10mm, pathological lymph nodes with 10 to less 
than 15 mm along the short axis, bony metastases, leptomeningeal disease, ascites, 
pleural/pericardial effusions, inflammatory breast cancer, lymphangitis carcinomatosis, and 
heavily calcified and cystic/necrotic lesions. 
 
• 
LVEF > 50% 
 
• 
Hematologic parameters: white blood cell (WBC) count of > 3000/ul, absolute neutrophil 
count (ANC) > 1500/ul, platelets > 100,000/ul, hemoglobin > 10.0 g/dl 
 
• 
Non-hematologic parameters: bilirubin < 1.5 mg/dl, AST/ALT < 2.5 x upper limit of normal 
(ULN), alkaline phosphatase < 5 x ULN. 
 
• 
Creatinine < 1.5 mg/dl 
 
• 
Patients with stable and treated brain lesions of a duration of > 2 months may be enrolled. 
 
6.2 
Subject Exclusion Criteria 
 
• 
History of prior cardiac morbidities within 12 months (unstable angina, myocardial infarction, 
CHF, uncontrolled ventricular arrhythmias) 
 
• 
Prior pertuzumab 
 
• 
History of prior > G 3 hypersensitivity (HSR) or any toxicity to trastuzumab that warranted 
permanent cessation of this antibody 
 
• 
History of prior > G 3 HSR or any toxicity to paclitaxel warranted permanent cessation of 
this chemotherapy 
 
• 
> G 2 peripheral neuropathy 
 
• 
Patients with a history of chronic hepatitis B or C should be excluded from the study as 
paclitaxel is potentially hepatotoxic 
 
• 
Pregnant patients 
 
7.0 
RECRUITMENT PLAN 
 
This study is open to patients with metastatic HER2 (+) breast carcinoma at MSKCC or 
MSKCC satellites. These patients will be identified and recruited from the breast cancer 
patients seen at the Breast Cancer Center at MSKCC or MSKCC satellites. 


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Patients who are potentially eligible will be evaluated at the Breast Cancer Center at 
MSKCC or MSKCC satellites. This initial encounter will include a discussion of the 
proposed treatment and the rationale for its use. Eligible patients will be required to 
review and sign an informed consent. 
 
 
 
8.0 
PRETREATMENT EVALUATION 
 
o Evidence of disease evaluation within 4 weeks prior to starting treatment: 
 
▪ 
CT of chest/abdomen +/- pelvis or MRI of chest/abdomen +/- pelvis 
 
▪ 
Bone scan and PET are optional 
 
o ECHO (with strain imaging if possible). When an ECHO cannot be done, a MUGA 
scan may be done within 4 weeks of treatment. 
 
o EKG within 4 weeks of treatment 
 
o History and physical examination (including vitals and ECOG performance status) 
within 4 weeks prior to starting treating 
 
o Blood work within 2 weeks prior to starting treatment 
 
▪ 
CBC 
 
▪ 
Comprehensive profile 
 
▪ 
Pregnancy test (serum if pre- or perimenopausal) 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
The regimen will consist of paclitaxel (80 mg/m2) weekly + trastuzumab every 3 weeks (8 
mg/kg loading dose → 6 mg/kg every 3 weeks) + pertuzumab every 3 weeks (840 mg as a 
loading dose → 420 mg), all given intravenously (IV) (+/- 3 days). Trastuzumab may be 
given weekly (2 mg/kg) at the physician’s discretion. 
 
 
 
Due to the potential for an allergic reaction to paclitaxel, all patients should be 
premedicated as per institutional guidelines: approximately 30-60 minutes prior to paclitaxel 
infusion with a steroid, H1 and H2 receptor antagonists (ie: dexamethasone 10-20 mg IV or 
20 mg orally night and morning of paclitaxel, diphenhydramine 50 mg IV, and ranitidine 50 
mg IV or another H2 antagonist equivalent). If the patient tolerates the first dose of 
paclitaxel, the premedications may be modified at the physician’s discretion.  Both 
trastuzumab and pertuzumab may cause an infusion related reaction. 
 
 
 
Premedications for trastuzumab and pertuzumab should include acetaminophen 650 mg 
orally and diphenhydramine 25-50 mg IV for the loading dose (diphenhydramine dose that 


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is used for paclitaxel premedication does not need to be repeated for trastuzumab). 
Subsequent doses of trastuzumab and pertuzumab do not require premedications. 
 
Patients will be on treatment until progression of disease. 
 
Each cycle will consist of 3 weeks (days 1, 8, and 15) of weekly paclitaxel (+/- 3 days) and 
trastuzumab and pertuzumab given on day 1 every 3 weeks (+/- 3 days). Trastuzumab 
may be given weekly at the physician’s discretion. 
 
Dose Reductions and Modifications: 
 
This study will use the NCI Common Toxicity Criteria (CTC) AE version 4.0 for toxicity. 
 
Note:  Actual weight should be used rather than the ideal body weight. 
 
Note:  If a weight change of > 10% occurs, the dose of paclitaxel, trastuzumab, and 
pertuzumab should be adjusted accordingly. 
 
Paclitaxel 
 
• 
After each paclitaxel treatment, dose adjustments of the taxane should be based on 
hematologic and non-hematologic toxicities.  Patients experiencing neutropenic fever (ANC 
<1,000/µL and body temperature > 38.5°C) should use filgrastim with subsequent 
treatments, in accordance with ASCO guidelines. If patients experience febrile neutropenia 
again despite the use of filgrastim, then a 25% dose reduction is allowed.  If on the day that 
paclitaxel is due and > Grade 3 non-hematologic toxicities have not recovered to < Grade 2 
(except neuropathy), treatment may be delayed up to 3 weeks.  Up to 3 consecutive weeks 
of a delay in the administration of paclitaxel is allowed.  If there is a delay of > 3 
consecutive weeks from the intended treatment date due to toxicities, the patient will be 
removed from study.  Once the patient is re-started on paclitaxel, a dose reduction is 
allowed.  If > Grade 3 non-hematologic toxicities occur again with one dose reduction, 
another dose reduction is allowed.  A maximum of 2 dose reductions are allowed (from 80 
mg/m2 →60 mg/m 2 and from 60 mg/m2 → 45 mg/m 2). 
 
• 
If on the day that paclitaxel is due, platelet counts are <75,000/µL and/or ANC <1000/µL 
have not recovered to < Grade 2 (except neuropathy), treatment should be delayed by < 1 
week and CBC and toxicity grading should be repeated.  Filgrastim should be used with the 
subsequent chemotherapy dose (in accordance with ASCO guidelines) if the delay in 
treatment is due to an ANC of <1000/µL. If the platelet counts are still <75,000/µL and/or 
ANC <1000/µL and/or non-hematologic toxicities have not recovered to < Grade 2 (except 
for neuropathy), a further delay of < 1 week is required.  Up to 3 consecutive weeks of a 
delay in the administration of paclitaxel is allowed.  If there is a delay of > 3 consecutive 
weeks from the intended treatment date due to toxicities, the patient will be removed from 
study. 
 
• 
In terms of neuropathy, if on the day that paclitaxel is due and neuropathy has not 
recovered to < Grade 1, then treatment may be held up to 3 weeks. If neuropathy has 
recovered to < G 1 within these 3 weeks, then the patient may be re-challenged with 


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paclitaxel but at one 25% dose reduction (from 80 mg/2 → 60 mg/m2).  If > G2 neuropathy 
occurs again at a reduced paclitaxel dose and has not recover to < G 1 on the day that 
paclitaxel is due, paclitaxel may be held again up to 3 weeks. If neuropathy has recovered 
to < G 1 within these 3 weeks, then the patient may be re-challenged with paclitaxel at a 
second dose reduction (from 60 mg/m2 → 45 mg/m2). Only 2 dose reductions are allowed. 
If the patient’s neuropathy does “not” return to G  < 1 within 3 weeks at any point, the patient 
should not be re-challenged with paclitaxel. Upon re-challenging the patient with paclitaxel 
and at the physician’s discretion, there may be one treatment break from paclitaxel per 
cycle in order to avoid cumulative neurotoxicity (ie: paclitaxel given on days 1 and 8 and off 
on day 15). 
 
• 
In terms of nail toxicities and paronychia, if on the day that paclitaxel is due and the patient 
has > Grade 2 nail changes, then treatment may be held up to 3 weeks. Once the nail 
changes are managed, upon treatment resumption, the patient may be re-challenged with 
paclitaxel at one 25% dose reduction (from 80 mg/m2 → 60 mg/m2).  Another dose 
reduction may be allowed if necessary (from 60 mg/m2 → 45 mg/m2).  Only 2 dose 
reductions are allowed.   Upon re-challenging the patient with paclitaxel and at the 
physician’s discretion, there may be one treatment break from paclitaxel per cycle in order 
to avoid cumulative nail toxicities (ie: paclitaxel given on days 1 and 8 and off on day 15). 
 
• 
If paclitaxel cannot be given on day 1 (for any reason), trastuzumab and pertuzumab may 
be given as planned, and subsequent weekly doses of paclitaxel will be given when 
appropriate. 
 
• 
Hypersensitivity reactions:  Please see Appendix B for treatment. Treatment should be 
discontinued for Grade 4 hypersensitivity reactions. There are no dose reductions for 
hypersensitivity reactions.  Consider discontinuation of taxane therapy if patient 
experiences 2 episodes of Grade 3 hypersensitivity reaction. 
 
• 
Note:   At 6 months if the patient is deemed to have responded to the combination of 
paclitaxel, trastuzumab, and pertuzumab, at the physician’s discretion, the paclitaxel may 
be stopped and the patient may continue on trastuzumab and pertuzumab alone.  If the 
patient has met the 6 month PFS endpoint and paclitaxel is stopped per physician’s 
discretion, the patient may have paclitaxel re-initiated at a later time based on clinical 
indications per the treating physician. The patient will be followed and safety data will be 
collected. This would mimic real-life practice. This will not affect the primary or secondary 
end-points. Once paclitaxel is re-initiated, patient will not need to have ECHO (or MUGA) 
every 4th cycle as the cardiac toxicity of these 2 antibodies have been minimal.  ECHO (or 
MUGA) may be ordered infrequently at physician’s discretion. If patient had paclitaxel re- 
initiated due to progression of disease, the interval between CT of chest/abdomen +/- pelvis 
is at physician’s discretion. It does not have to be every 4th cycle as the patient would have 
already met the primary 6-month PFS endpoint. This will not affect study’s primary 
endpoint. 
 
• 
Note:  Paclitaxel is metabolized by the CYP3A4 and CYP2C8 enzymes.  There is a 
potential for drug interaction with paclitaxel and CYP3A4 inhibitors and inducers as well as 


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caution should be taken with CYP2C8 substrates.  Appendix D is a list of CYP3A4 inhibitors 
and inducers and CYP2C8 substrates. 
 
 
 
 
 
Trastuzumab 
 
Trastuzumab loading dose (8 mg/kg) IV will be administered on same day as day 1 of cycle 
1 of paclitaxel and is continued every 3 weeks at 6 mg/kg. Trastuzumab may be given 
weekly (4 mg/kg loading dose → 2 mg/kg weekly). There is no dose modification for 
trastuzumab. 
 
Pertuzumab 
 
Pertuzumab loading dose (840 mg) IV will be administered on same day as day 1 of cycle 1 
of paclitaxel and is continued every 3 weeks at 420 mg. There is no dose modification for 
pertuzumab. 
 
Note:  Vital signs should be monitored before, during, and after each pertuzumab infusion. 
 
Note:  If there is a > 2 week delay from the last administration of trastuzumab and 
pertuzumab, then a re-loading of both antibodies is recommended.  Up to 3 weeks of delay 
in the administration of trastuzumab and pertuzumab may be allowed for any reason. 
 
Note:  Patients will have both trastuzumab and pertuzumab held for significant 
asymptomatic LVEF declines as outlined in the table below. 
 
 
 
RELATIONSHIP 
OF LVEF TO THE 
LOWER LIMIT OF 
NORMAL (LLN) 
ABSOLUTE 
DECREASE OF < 
10 
PERCENTAGE 
POINTS 
ABSOLUTE 
DECREASE OF 10 
TO 15 
PERCENTAGE 
POINTS 
ABSOLUTE DECREASE OF 
16 PERCENTAGE POINTS 
 
Within radiology 
facility’s normal 
limits 
Continue T + P 
Continue T + P 
Hold T + P and repeat LVEF 
within 3 weeks 
 
1 to 5 percentage 
points below the 
LLN 
Continue T + P 
Hold T + P and repeat 
LVEF within 3 weeks 
Hold T + P and repeat LVEF 
within 3 weeks 
 
 6 percentage 
points below the 
LLN 
Continue T + P 
and repeat LVEF 
within 3 weeks 
Hold T + P and repeat 
LVEF within 3 weeks 
Hold T + P and repeat LVEF 
within 3 weeks 


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T=Trastuzumab 
 
P=Pertuzumab 
 
A repeated LVEF may be assessed by an ECHO or MUGA. 
 
 Rules f or inter pr eting  and applying  “r epeat”  LVEF results: 
 
• 
T+ P must be permanently discontinued when two consecutive “hold” categories occur. 
• 
T + P must be permanently discontinued when three intermittent “hold” categories occur. 
(At the investigator’s discretion, T + P may also be permanently discontinued prior to the 
occurrence of three intermittent “hold” categories.) 
• 
If LVEF is maintained at a “continue and repeat LVEF” or improves from a “hold” to a 
“continue and repeat LVEF” category, an additional ECHO (or MUGA scan) prior to the next 
scheduled LVEF assessment will be at the investigator’s discretion. 
• 
Patient who experiences a significant “asymptomatic” LVEF decline while on trastuzumab + 
pertuzumab which result in permanent discontinuation of T + P will be seen in the 
cardiology clinic. 
• 
If a patient experiences G 3-4 symptomatic congestive heart failure at any time, 
trastuzumab and pertuzumab should be stopped and she/he will be removed from study 
and be seen by a cardiologist. 
 
Note:  If a patient has any temporary or permanent cessation of trastuzumab and pertuzumab 
due to asymptomatic or symptomatic LVEF declines, weekly paclitaxel may be continued as 
planned. 
Diarrhea and Rash Management 
 
Pertuzumab may cause diarrhea and rash.  Below are guidelines in place for management 
of these toxicities as follows: 
 
Pertuzumab Diarrhea and Rash Management 
Diarrhea 
Grade 
Management 
Dose Delay 
1 
Loperamide 
at 1st onset 
None 
2 
Loperamide 
at 1st onset 
None; 
If unacceptable, hold 
pertuzumab < 21 days, 
resume pertuzumab at 
same dose * 
> 3 
Loperamide 
at 1st onset 
Hold pertuzumab + 
paclitaxel < 21 days until < 
G 1, resume pertuzumab at 
same dose and paclitaxel at 
25% dose reduction ** 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  32 of 61 
 
 
 
Rash 
Grade 
Management 
Dose Delay 
1 
None 
None 
2 
minocycline, topical 
tetracycline or clindamycin, 
topical silver sulfadiazine, 
diphenhydramine, oral 
prednisone 
None; 
If unacceptable, hold 
pertuzumab < 21 days, 
resume same dose # 
> 3 
Same as above 
Hold pertuzumab < 21 days 
until < G 1, resume at same 
dose ## 
 
 
Note: Refer to Appendix C for diarrhea and rash management. 
 
* If the patient experiences a G 2 diarrhea that is “unacceptable”, hold pertuzumab for  < 21 days 
and resume at the same dose.  If G 2 diarrhea recurs that is “unacceptable” despite a held dose 
previously for G 2 toxicity, then can hold pertuzumab again for < 21 days and should reduce 
paclitaxel by 25% (80 mg/m2 → 60 mg/m2). Trastuzumab should be continued as planned. There 
is no dose reduction for trastuzumab and pertuzumab. 
 
** If the patient experiences G > 3 diarrhea, hold pertuzumab and paclitaxel for < 21 days until < G 
1 and then resume pertuzumab at the same dose and should reduce paclitaxel by 25% (80 mg/m2 
→ 60 mg/m2).  If > 3 weeks are required for the toxicity to reach to < G 1, then pertuzumab should 
be held permanently and the patient should be taken off the study (The patient may remain on 
paclitaxel and trastuzumab at the physician’s discretion). If G 3 diarrhea recurs upon being re- 
challenged with pertuzumab and paclitaxel (at a reduced dose), then the patient will be removed 
from study. There is no dose reduction for trastuzumab and pertuzumab. 
 
# If the patient experiences a G 2 rash that is “unacceptable”, hold pertuzumab for  < 21 days and 
resume at the same dose.  If G 2 rash recurs that is “unacceptable” despite a held dose previously 
for G 2 toxicity, then can hold pertuzumab again for < 21 days. Trastuzumab and paclitaxel should 
be continued as planned. There is no dose reduction for trastuzumab and pertuzumab. 
 
## If the patient experiences G > 3 rash, hold pertuzumab < 21 days until < G 1 and then resume 
pertuzumab at the same dose.  If > 3 weeks are required for the toxicity to reach to < G 1, then 
pertuzumab should be held permanently and the patient should be taken off the study (The patient 
may remain on paclitaxel and trastuzumab at the physician’s discretion).  If G 3 rash recurs upon 
being re-challenged with pertuzumab, then the patient will be removed from study. There is no 
dose reduction for trastuzumab and pertuzumab. 
 
Note:   If the patient is found to have brain metastasis that requires treatment but is responding to 
this study regimen systemically, she may be allowed to take a break from receiving paclitaxel for 
up to 6 weeks in order to have treatment for brain metastasis (ie: whole brain radiation, stereotactic 
radiation, surgical resection, etc).  It is encouraged that trastuzumab and pertuzumab should be 


Page  33 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
continued every 3 weeks if possible. However, a >3 week delay is allowed from trastuzumab and 
 
 
pertuzumab while the patient is receiving care for brain metastases.As it is not known that 
paclitaxel, trastuzumab, or pertuzumab can cross the blood-brain barrier well, a central nervous 
system progression will not be considered a treatment failure.  This will be the one time that a 
patient may have up to a 6 week break from paclitaxel while undergoing treatment for brain 
metastasis. 
  
 
 
10.0 
EVALUATION DURING TREATMENT/INTERVENTION 
 
• 
Patients will be seen at every cycle of treatment preferably on day 1 of each cycle, while 
receiving paclitaxel.  If there is a schedule conflict, patients may be seen on day 8 or 15. 
Patients who are no longer receiving paclitaxel (i.e. at the 6 month mark) may be seen 
every other  cycle (+/- 3 weeks) of antibody treatment per the physician’s discretion. Each 
evaluation will consist of the following: 
 
▪ 
History and physical examination with vital signs, ECOG performance status. 
 
▪ 
Recording of the adverse events 
 
• 
Investigators will assess the occurrence of AEs and SAEs at all 
patient evaluation time points during the study. All AEs and SAEs 
whether volunteered by the patient, discovered by study personnel 
during questioning, or detected through physical examination, 
laboratory test, or other means will be recorded in the patient’s 
medical record and on the appropriate AE or SAE CRDB page. Each 
recorded AE or SAE will be described by its duration (i.e., start and 
end dates), severity, regulatory seriousness criteria, if applicable, 
suspected relationship to the investigational product, and actions 
taken. Since this trial’s secondary objective is to measure safety and 
tolerability of the intervention by assessing toxicity, suspected 
relationships or attributions of non-hematological adverse events will 
only be collected if assessed as grades ≥ 2, except for the following 
events: rash and diarrhea. AE grading (severity) scale found in the 
NCI CTCAE, Version 4.0 will be used for AE reporting. 
 
▪ 
Labs 
 
• 
CBC prior to each paclitaxel (paclitaxel, trastuzumab, and 
pertuzumab can be given +/- 3 days). A CBC can be completed up to 
3 days prior to the infusion. 
 
• 
Comprehensive profile once per cycle of treatment for patients 
receiving paclitaxel. The patient does not have to wait for the result to 
come back to start treatment on the same day. The result will not 
necessarily be used to guide treatment on the same day but may be 
used to guide subsequent treatments. The specific labs that are used 


Page  34 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
to guide paclitaxel treatment are the AST, ALT, and bilirubin.  On the 
day of each paclitaxel treatment, the AST, ALT, and bilirubin obtained 
within 3 weeks may be used. 
 
• 
Patients who have surpassed the 6 month period and are on antibody 
therapy alone (off chemotherapy) may have CBC and comprehensive 
labs drawn at any frequency per physician’s discretion. This is allowed 
as these labs are not used to dose trastuzumab or pertuzumab. 
 
• 
Patients will have cardiac biomarkers drawn at every other cycle (ie: cycle 1, 3, 5, 7, etc), 
preferably on day 1 (pre- and post- infusion of paclitaxel, trastuzumab, and pertuzumab) of 
every other cycle.  If biomarkers were not done on day 1, these may be drawn on day 8 or 
15 (pre- and post- infusion of paclitaxel).  These biomarkers will be done at every other 
cycle up to 6 time-points. 
 
• 
Patients may have their treatment schedule modified as follows: 
 
▪ 
Patients may have a delay of treatment for up to 3 weeks (for any reason). 
 
▪ 
If there is a delay of > 2 weeks since the last infusion of trastuzumab and 
pertuzumab, then a re-loading of trastuzumab and pertuzumab is advised. 
 
• 
Patients will be assessed radiographically after every 4th cycle +/- 2 weeks (i.e. day 1 of 
cycle 5 ± 2 weeks, day 1 of cycle 9 ± 2 weeks, etc).  Patients who have surpassed the 6 
month period may complete these radiologic assessments every 6 months +/- 1 month 
starting form the most recent radiology scan date. Patients who have surpassed the 6 
month period and have progression will be censored but may have paclitaxel re-initiated; at 
this point the frequency of radiographic assessment is determined by physician’s discretion. 
 
• 
Radiographic assessment will include: 
 
▪ 
CT of chest and abdomen +/- pelvis or MRI of chest/abdomen +/- pelvis (+/- 
1 month) 
 
▪ 
Bone scan and PET are optional (+/- 1 month) 
 
• 
Patients will have an ECHO with strain imaging analysis after every 4th cycle +/- 2 weeks 
(i.e. day 1 of cycle 5 ± 2 weeks, day 1 of cycle 9 ± 2 weeks, etc). Patients who have 
surpassed the 6 month period may complete ECHO with strain imaging analysis every 6 
months +/- 1 month starting from the most recent ECHO scan date. Patients who have 
surpassed the 6 month period and have progression will be censored but may have 
paclitaxel re-initiated; at this point the frequency of ECHO (or MUGA) assessment is 
determined by physician’s discretion. When an ECHO by the GE Vivid 7 or E9 system (GE 
Healthcare, Milwaukee, WI) is not available for strain imaging analysis, then an LVEF by a 
standard ECHO machine per facility may be done. If an ECHO cannot be done, a MUGA 
scan may be done (+/- 1 month). The same modality should be used throughout the study. 
 
Biomarker Evaluations: 


Page  35 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
Troponin 
 
From each patient at every other cycle for up to 6 time-points, five mL of peripheral blood will 
be collected pre- and post-infusion in a green top (heparin) tube for the measurement of TnI. 
For the troponin assay, plasma will be separated from peripheral blood and samples will be 
frozen for analysis and will not be known to the investigator until the patient has completed the 
study. The TnI samples will be evaluated by Dr. Martin Fleisher’s laboratory at MSKCC.   At all 
MSKCC sites, blood samples should be clearly labeled before transfer to Main campus. This 
labeling should include the study identifier (IRB-assigned protocol number), MSKCC-assigned 
patient identifier (once available), test ("troponin") and the time point of sample measurement. 
 
TnI concentrations will be determined by a fluorometric enzyme immunoassay analyzer (Tosoh 
Bioscience, Inc., San Francisco, CA) with a low end sensitivity of 0.06 ng/ml. TnI levels will be 
classified as <0.06 ng/mL (“undetectable”), 0.06-0.31 ng/mL (“minimal elevations”), or >0.31 
ng/mL (“above normal range”). In addition to categorizing TnI values in this way, the absolute 
change (represented by the difference between the baseline value and the maximum value 
observed during follow-up) will be calculated for each patient. 
 
Brain Natriuretic Peptide 
 
From each patient at every other cycle for up to 6 time-points, five mL of peripheral blood will 
be collected pre- and post-infusion into a lavender top (EDTA) tube for measurement of BNP. 
The BNP assay will be performed within 24 hours of blood collection. The BNP samples will be 
evaluated by Dr. Martin Fleisher’s laboratory at MSKCC.  BNP specimens can be refrigerated 
following collection. Samples from MSKCC Regional Network sites will be delivered to the 
MSKCC Main Campus at least once daily per usual Regional practice for preparation and 
frozen storage. At all MSKCC sites, blood samples should be clearly labeled before transfer to 
Main campus. This labeling should include the study identifier (IRB-assigned protocol number), 
MSKCC-assigned patient identifier (once available), test (“BNP”) and the time point of sample 
measurement. 
 
BNP is assayed in the Clinical Chemistry STAT lab. The BNP assay is performed on a Biosite 
Triage analyzer (Biosite, San Diego, California) using fluorescence immunoassay on EDTA 
anticoagulated whole blood.  Average within day imprecision is 8.5% at 71 pg/ml and 11% at 
630 pg/ml.  BNP results less than or equal to 100 pg/ml are representative of normal values in 
patients without CHF. BNP will be classified as ≤100 pg/mL (“within normal range”) or >100 
pg/mL (“above normal range”). In addition to categorizing BNP values in this way, the absolute 
change (represented by the difference between the baseline value and the maximum value 
observed during follow-up) will be calculated for each patient. 
 
Neuregulin 1ß 
 
From each patient at every other cycle for up to 6 time-points, five mL of peripheral blood will 
be collected pre- and post-infusion in a lavender top (EDTA) tube for the measurement NRG- 
1ß.  For the NRG-1ß assay, plasma will be separated from peripheral blood and samples will 
be frozen for analysis and will not be known to the investigator until the patient has completed 


Page  36 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
the study.  A reproducible assay for assessing serum NRG-1ß levels using an indirect 
sandwich ELISA technique has been developed and validated in the Sawyer Lab at Vanderbilt 
University.  The monoclonal capture antibody used in this assay is against a biologically active 
and cardiac-specific peptide sequence, which has been studied extensively by Sawyer et al. 
This peptide has been shown to play an important role in the activation of the ErbB receptor 
and downstream signaling pathways in ventricular myocytes 93. The coefficient of variation (CV) 
of this assay is 5.6-13%. 
 
The first generation form of this assay was used in a pilot study performed by Dr. Sawyer’s 
group which sought to define the effects of exercise on circulating NRG-1ß levels in humans 94. 
This study demonstrated that there was no significant difference in serum NRG-1ß levels pre- 
and post- exercise in healthy human subjects, but these levels were associated with 
cardiopulmonary exercise capacity. 
 
A second generation ELISA assay with lower detection limits has since been developed with 
NRG-1ß being detected in >98% samples tested to date. This assay was used to quantitate 
NRG-1ß from serum samples in 899 subjects with chronic heart failure. 82 NRG-1ß levels were 
detected in all non-heart failure samples and all but 12 heart failure patients.  Extensive 
validation of the second generation form of this assay has been performed. The effects of 
multiple freeze/thaw cycles and the differences between plasma and serum NRG-1ß levels 
have also been assessed.  NRG-1ß is detectable in both serum and plasma with a strong 
correlation (R2=0.91), with plasma levels being 50% higher than serum.  Repeated measures of 
NRG-1ß levels after exposure to multiple freeze/thaw cycles are highly correlated (R2=0.92), 
but decrease 25.7% per freeze/thaw cycle.  Because of these findings, we will use frozen, 
previously unthawed plasma for our study. 
 
A third generation form of this assay has also been developed and validated at the University of 
Pennsylvania Translational Core Lab led by Theodore Mifflin, PhD and Daniel Rader, MD 
under Dr. Ky’s direction and Dr. Sawyer’s collaboration. This assay has lower detection limits 
and an improved coefficient of variation. At all MSKCC sites, blood samples should be clearly 
labeled before transfer to University of Pennsylvania Translational Core Laboratory. This 
labeling should include the study identifier (IRB-assigned protocol number), MSKCC-assigned 
patient identifier (once available), test (“NRG-1ß ”) and the time point of sample measurement. 
 
Note:  As the clinical significance of an elevated TnI, BNP, or NRG-1ß in an asymptomatic 
patient is unknown, the TnI and NRG-1ß samples drawn at various time intervals as described 
previously for each patient will be stored frozen and analyzed but the results will be blinded to 
the treating physician until the end of the study, “not in real time”.  Patients and their treating 
physicians will not have the results in real time and thus, treatment decisions will not be 
affected. The BNP assay will be performed within 24 hours of sample collection, but the results 
will not be released to the treating oncologist until the end of the study, as the significance of an 
elevated BNP in an asymptomatic patient is not known. The results will instead be stored for 
interpretation at the end of the study. 
 
As of A(15), we will no longer be quantifying the relationship between NRG-1ß and incident 
cardiac dysfunction since the incidences of cardiac dysfunction based on the LVEF data have 
been minimal. 


Page  37 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
Echocardiograms (and Strain Imaging Analysis for research purposes): 
 
 
Echocardiograms will be performed every 4th cycle of treatment as defined in the study. 
Patients who have surpassed the 6 month PFS period may complete ECHO with strain imaging 
analysis every 6 months +/- 1 month starting from the most recent ECHO scan date. Strain 
imaging will be analyzed off-line using 2D image loops from the routine echocardiographic 
examination.  The ECHO machine for the strain imaging analysis should be the Vivid 7 or E9 
machine (GE healthcare, Milwaukee, WI).  In addition to being stored in the main ECHO PACS 
system, these studies will also be stored in an external GE workstation which contains the 
software needed to perform the strain imaging analysis. To calculate strain and strain rate, the 
LV myocardium is traced in a click-to-point approach.  Subsequently, the software 
automatically defines an epicardial and midmyocardial line and processes all frames of the 
loop. The myocardium in each of the 3 standard apical views is divided into 6 segments.  The 
software will automatically calculate strain and strain rate for each of the 18 segments plus a 
global value for the entire myocardium. These measurements will be made by a designated 
investigator (Dr. Jennifer Liu) blinded to patient identification, demographics and clinical 
characteristics at the end of the study. When possible any ECHOs done outside of MSKCC 
are requested to be done on the GE Vivid 7 or E9 machine (GE healthcare, Milwaukee, WI), 
and the disc to be sent to Dr. Jennifer Liu for the strain imaging analysis. 
 
Schedule of Activity 
 
Pre- Treatment 
Prior to each 
chemo- therapy 
treatment 4 
Every 
Cycle
6- 
7 
Every other 
cycle 
After 
every 4
th 
cycle 
After Treatment 
Completion 
5 
Medical History 
X (w/i 4 weeks) 
X 
X 
Physical examination 
X (w/i 4 weeks) 
X 
X 
ECOG PS 
X (w/i 4 weeks) 
X 
CBC 
X (w/i 2 weeks) 
X 
X 
Comprehensive Profile 
X (w/i 2 weeks) 
X 
EKG 
X (w/i 4 weeks) 
LVEF 1 
X (w/i 4 weeks) 
X 
Correlative blood- 
work² 
X 
Pregnancy test 
X (w/i 2 weeks) 
Evidence of disease 
evaluation (EOD) 
3 
X (w/i 4 weeks) 
X 
Signed informed 
X (w/i 4 weeks) 


Page  38 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
consent 
Adverse event/toxicity 
assessment 
X 
 
 
 
 
 
1.   LVEF is assessed via an ECHO with strain imaging. When an ECHO by the GE Vivid 7 or E9 system 
(GE Healthcare, Milwaukee, WI) is not available for strain imaging analysis, then an LVEF by a 
standard ECHO machine per facility may be done. If an ECHO cannot be done, a MUGA scan may 
be done. The LVEF will be assessed after every 4th cycle +/- 2 weeks (i.e. day 1 of cycle 5 ± 2 
weeks, day 1 of cycle 9 ± 2 weeks, etc.). Patients who have surpassed the 6 month period may 
complete ECHO or MUGA every 6 months +/- 1 month starting from the most recent scan date. 
 
2.   Correlative bloodwork will consist of TnI, BNP, and NRG-1ß. These will be done pre- and post- 
infusion on day 1 of every other cycle, up to six time points (i.e. Cycle 1, 3, 5, 7, 9, and 11). If day 1 
bloodwork was missed, it can be done on day 8 or 15. 
 
3.   EOD evaluation will consist of a CT of chest and abdomen +/- pelvis or MRI of chest/abdomen +/- 
pelvis. Bone scan and PET are optional. EOD evaluation will be assessed after every 4th cycle (+/- 2 
weeks). Patients who have surpassed the 6 month period may complete these radiologic 
assessments every 6 months +/- 1 month starting from the most recent scan date. 
 
4.   Prior to the first cycle of treatment, a height and weight must be obtained. 
 
5.  After treatment completion, the patient will be seen for routine follow-ups (ie: medical history, 
physical examination) at the discretion of the treating physician. 
 
6.  A comprehensive profile and CBC may be omitted for patients who have reached the 6 month mark 
and are no longer receiving paclitaxel, 
 
7.   Patients who have reached the 6 month mark and are no longer receiving paclitaxel may be seen at 
every other cycle of treatment per the physician’s discretion. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
Trastuzumab (Herceptin®) 
 
 
Infusion-Associated Symptoms. During the first infusion with Herceptin, a symptom complex 
consisting of chills and/or fever is observed in approximately 40% of patients. Other signs 
and/or symptoms may include nausea, vomiting, pain, rigors, headache, cough, dizziness, 
rash, and asthenia. These symptoms are usually mild to moderate in severity, and occur 
infrequently with subsequent Herceptin infusions. These symptoms can be treated with an 
analgesic/antipyretic such as meperidine or paracetamol, or an antihistamine such as 
diphenhydramine. 
 
Serious Infusion-Associated Events. Serious adverse reactions to Herceptin infusion 
including dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation and respiratory distress have been reported infrequently.   In rare cases (4 per 
10,000), these events were associated with a clinical course culminating in a fatal outcome. 


Page  39 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
Serious reactions have been treated with supportive therapy such as oxygen, beta- 
agonists, corticosteroids and withdrawal of Herceptin as indicated. 
 
Hematologic Toxicity.  In the clinical trials, an increased incidence of anemia was observed 
in patients receiving Herceptin plus chemotherapy compared with patients receiving 
chemotherapy alone. The majority of these anemia events were mild or moderate in 
intensity and reversible; none resulted in discontinuation of Herceptin therapy.  In the 
clinical trials, the per-patient incidences of moderate to severe neutropenia and of febrile 
neutropenia were higher in patients receiving Herceptin in combination with 
myelosuppressive chemotherapy as compared to those who received chemotherapy alone. 
In the post marketing setting, deaths due to sepsis in patients with severe neutropenia have 
been reported in patients receiving Herceptin and myelosuppressive chemotherapy, 
although in controlled clinical trials (pre- and post-marketing), the incidence of septic deaths 
was not significantly increased. The pathophysiologic basis for exacerbation of neutropenia 
has not been determined; the effect of Herceptin on the pharmacokinetics of 
chemotherapeutic agents has not been fully evaluated. The observed incidence of leukemia 
among Herceptin-treated patients appears to be consistent with the expected incidence of 
leukemia among patients treated with chemotherapy for metastatic breast cancer. 
Therefore, the contribution of Herceptin to the etiology of acute leukemia or myelodysplastic 
syndrome in these cases is unclear. 
Paclitaxel (Taxol®) 
 
Side-effects include alopecia, myelosuppression, fatigue, neuropathy, arthralgia, myalgia, 
onycholysis, taste changes, amenorrhea, teratogenesis, hypersensitivity (hypotension, 
flushing, chest pain, abdominal or extremity pain, skin reactions, pruritus, dyspnea, 
bronchospasm, and tachycardia), fever, sinus bradycardia, complete heart block, sinus 
tachycardia, premature ventricular beats, ventricular tachycardia, bigeminy, syncope, 
myocardial infarction, hypotension, hypertension, dizziness, visual changes, headaches, 
radiation recall, nausea and vomiting, mouth sores, abdominal pain, diarrhea, typhlitis, 
ischemic colitis, abnormal liver function, pancreatitis, abnormal triglyceride, and seizures. 
 
Pertuzumab 
 
Diarrhea and rash 
 
Although pertuzumab targets HER2, because of its role in heterodimerization with other 
members of the HER family (ie: HER1/EGFR), it may cause toxicities associated with the 
use of EGFR inhibitors. Diarrhea and rash are common events increased with pertuzumab 
given in combination with chemotherapy compared with chemotherapy alone.  Diarrhea has 
been reported in 60-70% of patients treated with pertuzumab and was mostly of grades 1-2. 
The mechanism of diarrhea and rash are unknown, but the nature is similar to that of other 
agents causing HER1 inhibition.  In the event of diarrhea, early intervention with anti- 
diarrhea medication should be considered and patients treated with fluid and electrolyte 
replacement, as clinically indicated.55 
 
Infusion-related Symptoms 
 
Monoclonal antibodies may cause infusion-associated symptoms such as fever, chills, 
hypotension, shortness of breath, skin rash, headache, nausea, and/or vomiting. Serious 
or severe infusion-related symptoms have been rarely observed with 7 patients 
experiencing serious reactions to date [hypersensitivity, fatal ARDS, pulmonary edema, 


Page  40 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
anaphylaxis, dyspnea with hypotension, infusion-related reaction (unsteady on feet, 
headache)].  In pertuzumab single-agent studies, less than 5% of patients experienced 
adverse reactions during pertuzumab infusions. Serious infusion-related reactions with 
pertuzumab have been infrequently reported (< 1%).  Intravenous pertuzumab 
administration should be performed in the setting with emergency equipment and staff who 
re trained to monitor medical situations and respond to medical emergencies.   Patients 
should be monitored during each pertuzumab infusion for any adverse effects, as infusion 
reactions may occur with the first or subsequent doses.  The infusion should be stopped for 
patients who develop dyspnea, clinically significant hypotension, or other clinically 
significant events.  Patients who experience an NCI-CTC grade 4 allergic reaction or acute 
respiratory distress syndrome should not receive additional peruzumab.55 
 
Cardiac Toxicities 
 
Since pertuzumab targets HER2, as with trastuzumab, there is a potential risk of cardiac 
dysfunction, particularly in patients who have received prior anthracycline treatment. 
Cardiac toxicities, predominantly asymptomatic LVEF declines, and 4 cases of cardiac 
failure have been reported in approximately 840 patients with advanced malignant disease 
or early stage HER2 (+) breast cancer treated with pertuzumab. Two of these cases 
occurred in patients with metastatic breast cancer who had received prior anthracyclines 
and two in patients with ovarian cancer.  No clear association between the frequency, 
nature, and severity of pertuzumab-related toxicities and dose level has been observed.55 
 
Patients with significant cardiac disease or baseline LVEF below the institution’s lower limit 
of normal (LLN) should not commence treatment with pertuzumab.  Risk factors for 
pertuzumab-associated cardiac dysfunction are not known at this time. This risk should be 
carefully weighed against the potential benefit in patients who have received prior 
anthracyclines.  Monitoring of the LVEF is advised while patients are receiving pertuzumab. 
If symptomatic LVEF decline develops (NCI-CTC grade 3 or 4), the patient must 
discontinue pertuzumab.  Left ventricular dysfunction, symptomatic or not, should be 
treated and followed according to standard medical practice. 
 
Other Side-effects 
 
Other side-effects of pertuzumab include low blood count and fatigue. 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Patients with measurable or non- measurable lesions are included in this study. Measurable 
lesions are defined as those that can be measured accurately in at least one diameter, that 
is   20 mm using conventional imaging techniques (including incremental CT) or 10 mm 
using spiral CT equipment.  Non- measurable lesions include bony metastases, 
leptomeningeal disease, ascites, pleural/pericardial effusions, inflammatory breast cancer, 
lymphangitis carcinomatosis, and heavily calcified and cystic/necrotic lesions. 
 
Patients will have an evidence of disease evaluation (EOD) evaluation after every 4th cycle 
of study treatment which will consist of CT of chest and abdomen +/- pelvis. Bone scan and 
PET scan are optional. Evaluable patients include all patients who started therapy and for 
whom we are able to assess PFS status at 6 months. Patients who withdraw before 6 


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Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
months for non-toxicity reasons (ie: personal reasons, non-cancer related illness, and non- 
compliance) are considered inevaluable. We do not anticipate a significant early withdrawal 
for non-toxicity reasons.  Patients who discontinue therapy due to toxicity before the 6 
month endpoint are considered evaluable and their progression status at 6 months will be 
assessed during followup. Patients who have surpassed the 6 month period may complete these 
radiologic assessments every 6 months +/- 1 month starting from the most recent scan date. 
 
The primary endpoint is PFS and secondary endpoint will include the response rate using 
the RECIST criteria (version 1.1). The definitions are included as below: 
 
• 
Progression-free survival (PFS) is defined from time from treatment assignment to 
disease progression or death, whichever comes first. 
 
• 
Partial response (PR) is at least a 30% reduction in the sum of longest diameter of 
target lesions 
 
• 
Complete response (CR) is the disappearance of all target lesions. 
 
• 
Stable disease (SD) is neither a PR nor a POD. 
 
• 
Progression of disease (POD) requires a 20% increase in the sum of the longest 
diameters or the appearance of new lesions. 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
• 
1) > 2 dose reductions of paclitaxel 
• 
2) > 3 consecutive weeks of a delay in treatment due to toxicities 
• 
3)  Progressive disease 
• 
4)  Unacceptable toxicity 
• 
5) Intercurrent, non-cancer related illness that prevents continuation of protocol therapy or 
follow-up 
• 
6) Major protocol violation that would render the patient inevaluable for efficacy 
• 
7)  Repeated non-compliance by the patient with protocol requirements 
• 
8)  Changes in the patient’s condition or study drug related toxicity such that, in the opinion 
of the investigator, continued participation in the protocol would compromise patient well- 
being 
• 
9) Withdrawal of patient’s consent for personal reasons 
• 
10) Death 
 
 
Patients removed due to criteria listed in 5, 6, 7, and 9 are considered inevaluable for the 
primary 6 month PFS endpoint. 
 
14.0 
BIOSTATISTICS 
 
This is a single stage phase II trial of paclitaxel given with pertuzumab and 
trastuzumab in patients with metastatic HER2-positive breast cancer.  Patients with 
HER2 (+) breast cancer who have had 0-1 prior treatment in the metastatic setting 
are eligible and will be enrolled. The primary objective of this trial is to determine the 
efficacy of this regimen.  The primary endpoint of this study will be the proportion of 


Page  42 of 61 
Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
patients who are progression free at 6 months or later.  Patients who are considered 
progression-free at 6 months are deemed successes.  Failures are those patients 
who progressed or died before the 6 month mark.  Evaluable patients include all 
patients who started therapy and for whom we are able to assess PFS status at 6 
months.   Patients who withdraw before 6 months for non-toxicity reasons (ie: 
personal reasons, non-cancer related illness, and non-compliance) are considered 
inevaluable.  We do not anticipate a significant early withdrawal for non-toxicity 
reasons.   Patients who discontinue therapy due to toxicity before the 6 month 
endpoint are considered evaluable and their progression status at 6 months will be 
assessed during followup.  Patients will be followed until progression of disease at 
which point further follow-up is not mandated by the study.  There is no minimal time 
on study treatment before patients are considered evaluable. The secondary 
endpoints are response, safety (including cardiac safety) and tolerability.   Serial 
blood  measurements  of  cardiac  markers  (cTnI,  BNP,  and  NRG-1ß)  will  be 
examined.    We  will  also  assess  the  LVEF  at  baseline  and  every  4th   cycle  of 
treatment with an ECHO with a strain imaging analysis.  When an ECHO cannot be 
done, a multi-gated acquisition scan (MUGA) may be done. 
 
A single stage design will be used to evaluate the efficacy of this regimen. We elected a 
target progression-free rate below 50% as the unpromising rate and 65% or higher as the 
promising 6 month progression-free rate.  These target rates are based on data from 
Slamon et al which showed that the combination of paclitaxel and trastuzumab led to a 
median TTP of 7.4 months in patients with untreated HER2 (+) metastatic breast cancer. 
We chose 6 months, as opposed to 7 months, as patients with one prior treatment are 
included.  Based on these proportions, we would need 69 patients, at an alpha level of 5% 
and 80% power for a single stage design. The secondary endpoints will be the safety 
(including cardiac safety) and tolerability and the assessments of biomarkers.  Baselga et al 
reported that in 66 patients treated with trastuzumab and pertuzumab, only 3/66 (4.5%) of 
patients experienced an asymptomatic LVEF decline of > 10% to < 50% and 0/66 (0%) 
patient had symptomatic CHF.57 However, Portera et al reported that in 11 patients treated 
with these 2 antibodies, 2/11 (18%) had asymptomatic LVEF decline of > 10 % to < 50%, 
and 1/11 (9%) patient experienced symptomatic CHF.59   The differences in cardiac events 
(asymptomatic and symptomatic) between the 2 studies could be due to sample sizes and 
variations in patient inclusion criteria.  Nevertheless, in our study we will consider an 
asymptomatic LVEF decline (of > 10% to < 50%) rate of < 20% (or 14 of 69 patients) as 
acceptable, based on the Baselga and Portera studies 57, 59. We will consider a 
symptomatic CHF rate of < 4% as acceptable to be consistent with what has been reported 
in previous trials with trastuzumab alone (symptomatic CHF rates ranging from 2-4%) 95. 
For this study, to be homologous to the large phase III trial, CLEOPATRA, a cardiac event 
is defined as a) “symptomatic” left ventricular systolic dysfunction (LVSD) (deaths and non- 
deaths), b) non-LVSD cardiac death, or c) probable cardiac death.  Other cardiac non-death 
events that do not meet this definition are not counted as a cardiac event (personal 
communications with Dr. Melissa Brammer and Dr. Christina Pelizon for CLEOPATRA). 
For safety, we have built in a stopping rule based on symptomatic cardiac events and 
asymptomatic LVEF declines.  The trial will be closed if:  1) 4 patients experience a cardiac 
event while on study treatment at any point in the study or 2) if 15 patients have an 
asymptomatic LVEF decline (of > 10% to < 50%) at any point while on study.  This 
corresponds to an overall cardiac event (as defined above) rate of 5.8% (4/69) and an 
overall asymptomatic LVEF decline (of > 10% to < 50%) rate of 22% (15/69). 
 
Upon completion of the study, the 6 month PFS rate will be estimated and an exact 
confidence interval will be constructed.  Progression-free survival and median overall 


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IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
survival will also be estimated by the Kaplan-Meier method.  Selected non-hematologic and 
hematologic toxicities will be described by frequency and grade, by each cycle and all 
cycles, with the maximum grade over all cycles used as the summary measure per patient. 
Each of the cardiac markers and LVEF will be examined graphically over the study period. 
Particular attention to the trajectories of the cardiac markers will be given to patients who 
have had significant LVEF decline (defined in section 10.0). We anticipate an accrual rate 
of 2 patients per month over the course of 3 years. Additional patients will be accrued to 
take place of inevaluable patients as necessary.  We expect this early dropout to be a rare 
event, occurring 5% of the time, and will be examined closely as a source for potential bias. 
 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through Friday 
from 8:30am – 5:30pm at 646-735-8000. Registrations must be submitted via the PPR 
Electronic Registration System (http://ppr/). The completed signature page of the written 
consent/RA or verbal script/RA, a completed Eligibility Checklist and other relevant 
documents must be uploaded via the PPR Electronic Registration System 
. 
 
16.0 
DATA MANAGEMENT ISSUES 
 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the 
RSA include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of 
the protocol study team. 
 
The Clinical Research Database (CRDB) will be used for data collection. The data will be 
reported to the institution (IRB) and the sponsor (Roche) as appropriate. 
 
It is estimated that 2 patients will be accrued per month and it will take 3 years to accrue. 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals, protocol 
compliance, eligibility verification, informed consent procedure, data accuracy, and 
completeness of registration data.  Routine data quality reports will be generated to assess 
missing data and inconsistencies. Accrual rates and extent and accuracy of evaluations 
and follow-up will be monitored periodically throughout the study period and potential 
problems will be brought to the attention of the study team for discussion and action. 


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IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
 
 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of  two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center 
were approved by the National Cancer Institute in September 2001. The plans address the 
new policies set forth by the NCI in the document entitled “Policy of the National Cancer 
Institute for Data and Safety Monitoring of Clinical Trials” which can be found at: 
http://www.cancer.gov/clinicaltrials/conducting/dsm-guidelines/page1. The DSM Plans at 
MSKCC were established and are monitored by the Office of Clinical Research. The 
MSKCC Data and Safety Monitoring Plans can be found on the MSKCC Intranet at: 
http://smskpsps9/dept/ocr/OCR%20Website%20Documents/Clinical%20Research%20Qual 
ity%20Assurance%20(CRQA)/MSKCC%20Data%20and%20Safety%20Monitoring%20Plan 
.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality.  There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff 
education on clinical research QA) and departmental procedures for quality control, plus 
there are two institutional committees that are responsible for monitoring the activities of our 
clinical trials programs. The committees: Data and Safety Monitoring Committee (DSMC) 
for Phase I and II clinical trials, and the Data and Safety Monitoring Board (DSMB) for 
Phase III clinical trials, report to the Center’s Research Council and Institutional Review 
Board. 
 
During the protocol development and review process, each protocol will be assessed for its 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH 
sponsored, in-house sponsored, industrial sponsored, NCI cooperative group, etc.) will be 
addressed and the monitoring procedures will be established at the time of protocol 
activation. 
 
16.3 
Regulatory Documentation 
 
Participating sites that are consulting and/or conducting specimen or data analysis should 
submit this protocol to their IRB according to local guidelines. Copies of any site IRB 
correspondence should be forwarded to MSKCC. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Prior to the enrollment of each patient, the risks, benefits and objectives of the study will be 
reviewed with the participant, including a discussion of the possible toxicities and side 
effects. Every effort will be made to keep study records private. Neither the patient's name 
nor anything else that could identify the patient will be used in any reports or publications 
that result from this study. Trained staff at Memorial Hospital, the Food and Drug 
Administration, or the study supporters will be able to review the medical records if 
necessary. The patient may terminate her participation in the study at any time during the 
trial. 
 
17.1 
Privacy 


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MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure 
of protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board (IRB/PB). 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
• 
Death 
• 
A life-threatening adverse event 
• 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• 
A congenital anomaly/birth defect 
• 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an 
SAE. 
  
SAE reporting is required as soon as the participant signs consent.  SAE reporting is 
required for 30-days after the participant’s last investigational treatment or intervention. Any 
events that occur after the 30-day period and that are at least possibly related to protocol 
treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting of Serious 
Adverse Events’, the SAE report must be sent to the IRB within 5 calendar days of the 
event. The IRB requires a Clinical Research Database (CRDB) SAE report be submitted 
electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org. All other reports should be sent to saemskind@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 
 
Data needing to be entered: 


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• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject remains on the study 
• 
If an amendment will need to be made to the protocol and/or consent form 
• 
If the SAE is an Unanticipated Problem 
The PI’s signature and the date it was signed are required on the completed report. 
For IND/IDE protocols: 
The CRDB SAE report should be completed as per above instructions.  If appropriate, the 
report will be forwarded to the FDA by the SAE staff through the IND Office. 
 
 
 
 
17.2.1 Genentech Serious Adverse Event (SAE) Reporting 
All SAE reports must also be forwarded as soon as possible to: 
Genentech Drug Safety 
 
Pertuzumab Safety Monitor 
 
Tele: 1-888-835-2555 
 
Fax:  (650) 225-4682 
  
 
 
Reporting SAEs: 
 
All SAEs that are serious and reasonably or probably related to the use of pertuzumab (this 
applies to both expected and unexpected events) should be recorded on an MSK CRDB 
SAE report and faxed as soon as possible to: 
 
Genentech Drug Safety Contact Line 
 
Tele: 1-888-835-2555 
 
Fax:  (650) 225-4682/ (650) 225-4683 
 
AND: 
 
Study Coordination Center/Principal Investigator: Chau Dang, M.D. 
Contact Information phone: 646-888-4554 fax : 646-888-4555 


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Approval Date: 10-Jan-2018 
Page  47 of 61 
 
 
 
 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or 
current status of the subject for whom and adverse event was reported.  For questions 
regarding SAE reporting, you may contact the Genentech Drug Safety representative noted 
above. 
 
 
Study Drug Relationship: 
 
The investigator will determine which events are associated with the use of study drug. For 
reporting purposes, an AE should be regarded as possibly related to the use of pertuzumab 
if the investigator believes: 
 
• 
There is a clinically plausible time sequence between onset of the AE and pertuzumab 
administration; and/or 
 
• 
There is a biologically plausible mechanism for pertuzumab to cause or contribute to the 
AE; and 
 
The AE cannot be attributed solely to concurrent/underlying illness, 
 
Adverse Event Reporting Definitions: 
 
A serious treatment emergent adverse event (STEAE) is any sign, symptom or medical 
condition that emerges during pertuzumab treatment or during a post-treatment follow-up 
period that (1) was not present at the start of pertuzumab treatment and it is not a chronic 
condition that is part of the patient’s medical history, OR (2) was present at the start of 
pertuzumab treatment or as part of the patient’s medical history but worsened in severity 
and/or frequency during therapy, AND that meets any of the following regulatory serious 
criteria: 
 
• 
Results in death 
• 
Is life-threatening 
• 
Requires or prolongs inpatient hospitalization 
• 
Is disabling 
• 
Is a congenital anomaly/birth defect 
• 
Is medically significant or requires medical or surgical intervention to prevent one of the 
outcomes listed above. 
 
Assessing Causality: 
 
The event should be assessed to decide whether there is a reasonable possibility that 
pertuzumab caused or contributed to an adverse event.  The following general guidance 
may be used. 
 
Yes:    if the temporal relationship of the clinical event to pertuzumab administration makes 
a causal relationship possible, and other drugs, therapeutic interventions or underlying 
conditions do not provide a sufficient explanation for the observed event. 
 
No:      if the temporal relationship of the clinical event to pertuzumab administration makes 
a causal relationship unlikely, or other drugs, therapeutic interventions or underlying 
conditions provide a sufficient explanation for the observed event. 


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For Investigator Sponsored IND Studies, there are some additional reporting 
requirements for the FDA in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug 
Administration (FDA) as expedited IND Safety Reports according to the following guidance 
and timelines: 
 
7 Calendar-Day Telephone or Fax Report: The Sponsor-Investigator is required to notify 
the FDA of any fatal or life-threatening adverse event that is unexpected and assessed by 
the investigator to be possibly related  to the use of the investigational product.  An 
unexpected adverse event is one that is not already described in the pertuzumab Package 
Insert or Investigator Brochure. Such reports are to be telephoned or faxed to the FDA and 
Genentech within 7 calendar days of first learning of the event. 
 
15 Calendar-Day Written Report: The Sponsor-Investigator is also required to notify the 
FDA and all participating investigators, in a written IND Safety Report, of any serious, 
unexpected AE that is considered reasonably or possibly related to the use of 
pertuzumab.  An unexpected adverse event is one that is not already described in the 
Package Insert or Investigator Brochure for pertuzumab. 
 
• 
Written IND Safety Reports should include an Analysis of Similar Events in accordance 
with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning 
similar events should be analyzed and the significance of the new report in light of the 
previous, similar reports commented on. 
 
• 
Written IND safety reports with Analysis of Similar Events are to be submitted the FDA, 
Genentech Drug Safety, and all participating investigators within 15 calendar days of first 
learning of the event. The FDA prefers these reports on a MedWatch 3500 Form but 
alternative formats are acceptable (e.g. summary letter). 
 
 
 
All written IND Safety Reports submitted to the FDA by the Sponsor-Investigator 
must also be faxed to: 
 
Genentech Drug Safety 
Pertuzumab Safety Monitor 
Tele: 1-888-835-2555 
Fax:  (650) 225-4682 
 
 
 
For questions related to safety reporting, contact: 
Genentech Drug Safety 
Pertuzumab Safety Monitor 
 
Tele: 1-888-835-2555 
 
Fax:  (650) 225-4682 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 


Memorial Sloan Kettering Cancer Center
IRB Number: 10-142 A(19) 
Approval Date: 10-Jan-2018 
Page  49 of 61 
 
 
 
Before protocol-specified procedures are carried out, consenting professionals will explain 
full details of the protocol and study procedures as well as the risks involved to participants 
prior to their inclusion in the study. Participants will also be informed that they are free to 
withdraw from the study at any time. All participants must sign an IRB/PB-approved consent 
form indicating their consent to participate. This consent form meets the requirements of the 
Code of Federal Regulations and the Institutional Review Board/Privacy Board of this 
Center. The consent form will include the following: 
 
1.  The nature and objectives, potential risks and benefits of the intended study. 
2.  The length of study and the likely follow-up required. 
3.  Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive 
care for therapeutic studies.) 
4.  The name of the investigator(s) responsible for the protocol. 
5.  The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will 
fully explain the aspects of patient privacy concerning research specific information.  In 
addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 
 
 
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Approval Date: 10-Jan-2018 
Page  50 of 61 
 
 
 
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22. 
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Tedesco KL, Thor AD, Johnson DH, et al. Docetaxel combined with trastuzumab is 
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25.      O’Shaughnessy JA, Vukelja S, Marsland T, et al: Phase II study of trastuzumab plus 
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27. 
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capecitabine in a German multicentre phase II study of pretreated metastatic breast cancer 
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28. 
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38. 
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20. APPENDICES 
 
 
 
Appendix A 
ECOG Performance Scale 
Appendix B 
Hypersensitivity Management 
Appendix C 
Diarrhrea and Rash Management 


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Appendix D 
CYP3A4 Inducers and Inhibitors and CYP2C8 Substrates 


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APPENDIX  A 
 
ECOG PERFORMANCE STATUS SCALE 
 
 
 
Grade 
Description 
0 
Fully active, able to carry out all normal activity without restriction 
(Karnofsky 100) 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out light work (Karnofsky 90-80) 
2 
Ambulatory and capable of all self-care but unable to carry out any work. 
Up and about more than 50% of waking hours (Karnofsky 70-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours (Karnofsky 50-40) 
4 
Completely disabled.  Cannot carry out any self-care. Totally confined to 
bed or chair (Karnofsky 30-20) 
5 
Death 


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APPENDIX B 
 
MANAGEMENT OF ACUTE HYPERSENSITIVITY 
 
Severity of Symptoms 
Treatment Guidelines 
Mild symptoms: localized cutaneous 
reactions such as mild pruritus, flushing, rash 
· 
consider decreasing the rate of infusion until recovery 
from symptoms, stay at bedside and monitor patient 
· 
then, complete taxane infusion at the initial planned rate 
Moderate symptoms: any symptom that is 
not listed above (mild symptoms) or below 
(severe symptoms) such as generalized 
pruritus, flushing, rash, dyspnea, hypotension 
with systolic BP > 80 mm Hg 
· 
interrupt taxane infusion 
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV; monitor patient until 
resolution of symptoms 
· 
resume taxane infusion after recovery of symptoms; 
depending on the physician’s assessment of the 
patient, taxane infusion should be resumed at a slower 
rate, then increased incrementally to the initial planned 
rate, (eg. infuse at an 8 hour rate for 5 minutes, then at 
a 4-h rate for 5 minutes, and then finally, resume at the 
3-h infusion rate) 
· 
depending on the intensity of the reaction observed, 
additional oral or IV premedication with an antihistamine 
should also be given for the next cycle of treatment, and 
the rate of infusion should be decreased initially and 
then increased back to the initial planned rate, (eg. 
infuse at an 8 hour rate for 5 minutes, then at a 4-h rate 
for 5 minutes, and finally, administer at the 3-h infusion 
rate) 
Severe symptoms: any reaction such as 
bronchospasm, generalized urticaria, systolic 
BP  80mm Hg, angioedema 
· 
immediately discontinue taxane infusion 
· 
give diphenhydramine 50 mg IV with or without 
dexamethasone 10 mg IV and/or epinephrine as 
needed; monitor patient until resolution of symptoms 
· 
the same treatment guidelines outlined under moderate 
symptoms (i.e. the third and fourth bullets) should be 
followed. 
Anaphylaxis  (NCI grade 4 reaction) 
· NO FURTHER STUDY DRUG THERAPY 


Page  59 of 61 
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APPENDIX C 
 
 
 
 
Supportive Care Guidelines for Pertuzumab 
 
Although pertuzumab targets HER2, because of its role in hetero-dimerization with other 
members of the HER family (ie: EGFR), it may cause toxicities associated with the use of 
EGFR inhibitors such as diarrhea and rash. 
 
Rash: The following agents may be used: minocycline, topical tetracycline, topical 
clindamycin, topical silver sulfadiazine, diphenhydramine, oral prednisone. 
 
Diarrhea: Loperamide is recommended at the first sign of diarrhea.  The recommended 
dose of loperamide is 4 mg at first onset, followed by 2 mg q 2–4 hr until diarrhea free 
for 12 hr. 
 
 Diarrhea Management Guidelines: 
 
1. Unco mplicated grade 1-2 diarrhea: 
➢Stop all lactose containing products; 
➢Drink 8-10 large glasses of clear liquids a day; 
➢Eat frequent small meals; 
➢Grade 2 diarrhea, consider holding cytotoxic chemotherapy;
➢Administer standard dose of loperamide: 
o Initial dose 4mg followed by 2mg every 4 hours or after every unformed 
stool. 
o We suggest continuation of loperamide until diarrhea free for 12 hours. 
 
 
2.  For grade 3 or 4 diarrhea or grade 1 or 2 with complicating features (severe cramping, 
severe nausea/vomiting, decreased performance status, fever, sepsis, grade 3 or 4 
neutropenia, frank bleeding, dehydration): 
➢   Use intravenous fluids as appropriate, consider hospital admission; 
➢   Use prophylactic antibiotics as needed (example fluoroquinolones), especially if 
diarrhea is persistent beyond 24 hours or there is fever or grade 3-4 neutropenia; 
➢   Hold cytotoxic chemotherapy. 
 
These broad general management principles are recommended to proactively try and 
avoid more serious complications by active management of the diarrhea syndrome. 
 
 
Guidelines such as these should never replace sound clinical judgment. 
Other anti-diarrheal agents are allowed at the physician’s discretion. 
 
 
 
 
APPENDIX D 


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CYP3A4 inducers and inhibitors 
 
 
Drug Class 
Agent 
Wash-out1 
CYP3A4 Inducers 
Antibiotics 
All rifamycin class agents (ie: 
rifampicin, rifabutin, 
rifapentine) 
14 days 
Anticonvulsants 
phenytoin, carbamazepine, 
barbituates (ie: phenobarbital) 
14 days 
Antiretrovirals 
efavirenz, nevirapine 
14 days 
Glucocorticoids 
cortisone (>50 mg), 
hydrocortisone (>40 mg), 
prednisone (>10 mg), 
methylprednisolone (>8 mg), 
dexamethasone (>1.5 mg)2 
14 days 
Other 
St. John’s Wort, modafinil 
14 days 
CYP3A4 Inhibitors 
Antibiotics 
clarithromycin, erythromycin, 
troleandomycin 
7 days 
Antifungals 
itraconazole, ketoconazole, 
fluconazole (>150 mg daily), 
voriconazole 
7 days 
Antiretrovirals, Protease 
Inhibitors 
declaviridine, nelfinavir, 
amprenavir, ritonavir, 
indinavir, saquinavir, 
lopinovir 
7 days 
Calcium channel blockers 
verapamil, diltiazem 
7 days 
Antidepressants 
nefazodone, fluvoxamine 
7 days 
GI agents 
cimetidine, aprepitant 
7 days 
Other 
grapefruit, grapefruit juice, 
7 days 
amiodarone 
6 months 
Miscellaneous 
Antacids 
Mylanta, maalox, tums, 
rennies 
1 hour before and after dosing 
Herbal supplements3 
Ginkgo biloba, kava, grape 
seed, valerian, ginseng, 
echinacea, evening primrose 
oil 
14 days 


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CYP2C8 Substrates:
 
 
 
-Amodiaquine 
 
-Torsemide 
 
Cerivastatin 
 
-Repaglinide 
 
Rosiglitazone