Conditions: Breast Cancer
Keywords: Breast - Female Metastatic HER2+
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and activity of gemcitabine plus trastuzumab and pertuzumab in patients with metastatic human epidermal growth factor receptor 2 (HER2)+ breast cancer who have progressed on at least one prior line of chemotherapy plus HER2 targeted agent such as T-DM1, trastuzumab, or lapatinib.

Detailed description:

Arms:
arm 1: Single arm, non-randomized, open label phase I/II multisite Simon two stage minimax trial. Gemcitabine plus trastuzumab and pertuzumab.

Interventions: intervention 1: Gemcitabine intervention 2: Trastuzumab intervention 3: Pertuzumab
Intervention descriptions: intervention 1: The Phase I trial will start at the recommended phase II dose (RP2D) for gemcitabine but will have a de-escalation dose levels in the event that an unacceptable toxicity requires dose reduction. Dose level 0 = gemcitabine (1200 mg/m2) IV D1,8 q21 days; Dose level -1 = gemcitabine (1000 mg/m\^2) IV D1,8 q21 days; Dose level -2 = gemcitabine (850 mg/m\^2) IV D1,8 q21 days. The RP2D will be the dose level where 0-1 dose limiting toxicities (DLTs) in six patients occur. intervention 2: Trastuzumab will be given using an 8 mg/kg loading dose on cycle one, day one (C1D1), followed by 6 mg/kg IV on subsequent cycles every (q) 21 days. intervention 3: Pertuzumab will be given using an 840 mg IV loading dose on C1D1, followed by 420 mg IV on subsequent cycles q 21 days.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
TITLE: Phase I/IIa Trial of Gemcitabine Plus Trastuzumab and Pertuzumab in 
Previously Treated Metastatic HER2+ Breast Cancer 
NCT02139358 
 
 
Version 1.1 
November 14, 2013 


CONFIDENTIAL 
 
This is a {Institution or Cooperative Group Name} document that 
contains confidential information.  It is intended solely for the recipient 
clinical investigator(s) and must not be disclosed to any other party.  This 
material may be used only for evaluating or conducting clinical 
investigations; any other proposed use requires written consent from 
{Institution or Cooperative Group Name}. 
 
Protocol:  TRASTUZUMAB® and PERTUZUMAB
® Moffitt Cancer Center  
P/IST template 05-2012  {Protocol Number}  
 
280513 
 
PROTOCOL 
STUDY TITLE: 
Phase I/IIa trial of gemcitabine plus 
trastuzumab and pertuzumab in previously 
treated metastatic HER2+ breast cancer 




Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
1/P {Protocol Number} 
 
280513 
 
 
TABLE OF CONTENTS 
1.  INTRODUCTION 
......................................................................................................4  
1.1  Disease  
Background.......................................................................................4  
1.2     HER2 and Breast cancer .................................................................................4 
1.3     Trastuzumab clinical Experience ...................................................................5 
1.4     Pertuzumab clinical Experience .....................................................................7 
1.5  TRASTUZUMAB  
SAFETY................................................................................9  
1.6  PERTUZUMAB  
SAFETY 
..................................................................................9  
1.7  Clinical Pharmacokinetics of Trastuzumab 
................................................10 
1.8  Clinical Pharmacokinetics of PerTUZMAB .................................................11 
1.9  GEMCITABINE  
Background .........................................................................12  
2.  OBJECTIVES.........................................................................................................12  
2.1  Primary  
Objectives........................................................................................13  
2.2  Secondary  
Objectives...................................................................................13  
3.     Study Design........................................................................................................13 
3.1     Description of the Study................................................................................13 
3.2     Rationale For Study Design ..........................................................................15 
3.3     Outcome Measures 
........................................................................................15 
3.3.1      Primary Outcome Measure:...................................................................15 
3.3.2      Secondary Outcome Measures 
.............................................................15 
3.3.3  Ancillary Safety Outcome Measures 
....................................................15 
3.4     Safety Plan......................................................................................................16 
3.4.1 RISK OF LEFT VENTRICULAR DYSFUNCTION ........................................18 
3.4.2     Management of Cardiac Safety ..............................................................19 
3.4.2.1 Metastatic Breast Cancer Protocols ...................................................20 
3.5  Compliance with Laws and Regulations.....................................................20 
4.0     MATERIALS AND METHODS 
............................................................................20 
4.1     Subjects ..........................................................................................................20 
4.1.1     Subject Selection.....................................................................................20 
4.1.2     Inclusion Criteria .....................................................................................20 
4.1.3     Exclusion Criteria 
....................................................................................21 
4.2     Method of Treatment Assignment 
................................................................22 
4.3     STUDY Treatment...........................................................................................22 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
2/P {Protocol Number} 
 
280513 
 
4.3.1  Trastuzumab  
Formulation 
.....................................................................22  
4.3.2  Pertuzumab  
Formulation.......................................................................22  
4.3.3  Trastuzumab Dosage, Preparation, and Storage 
................................23 
4.3.4  Pertuzumab Dosage, Preparation, Administration, and Storage.......24 
4.3.5      Trastuzumab and Pertuzumab Dosage Modification ..........................25 
4.3.6  Trastuzumab and Pertuzumab Overdosage 
........................................25 
4.3.7  Gemcitabine preparation and dosing...................................................25 
4.3.8       GEMCITABINE DOSE REDUCTIONS/DELAYS 
....................................25 
4.4  Concomitant and Excluded THERAPY 
........................................................27 
4.5  Study  
Assessments ......................................................................................28  
4.5.1  Assessments during Treatment ...........................................................28 
4.5.2  Follow-Up  
Assessments........................................................................29  
4.6  Discontinuation of Protocol-Specified Therapy .........................................29 
4.7  Subject  
DISCONTINUATION.........................................................................29  
4.8  Study  
DISCONTINUATION............................................................................29  
4.9  Statistical  
Methods........................................................................................30  
4.9.1  Analysis of the Conduct of the Study ..................................................30 
4.9.2  Analysis of Treatment Group Comparability.......................................30 
4.9.3  Efficacy  
Analysis....................................................................................30  
4.9.4  Safety  
Analysis.......................................................................................31  
4.9.5  Missing  
Data 
...........................................................................................31  
4.9.6  Determination of Sample Size...............................................................31 
4.10  Data Quality Assurance 
................................................................................32 
4.11 CORRELATIVE 
EXPERIMENTS....................................................................32 
4.11.1 Multiparametric flow cytometry for immune profiling............................32 
4.11.2 Measurement of HER2-HER3 dimerization in circulating tumor cells 
using proximity ligation assay 
............................................................................33 
5.  REPORTING OF ADVERSE EVENTS ..................................................................34 
5.1    ASSESSMENT OF SAFETY ..........................................................................34 
5.2    METHODS AND TIMING FOR ASSESSING AND RECORDING SAFETY 
VARIABLES ..............................................................................................................35 
5.3    PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS ..................................................................................................36 
5.4    MedWatch 3500A Reporting Guidelines ....................................................38 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
3/P {Protocol Number} 
 
280513 
 
5.5   Additional Reporting Requirements for IND Holders ................................39 
6.  INVESTIGATOR  
REQUIREMENTS.......................................................................41  
6.1  Study  
Initiation ..............................................................................................41  
6.2  Study  
Completion..........................................................................................41  
6.3  Informed  
Consent..........................................................................................41  
6.4  Institutional Review Board or Ethics Committee Approval.......................41 
6.5  Study  
Monitoring  
Requirements..................................................................42  
6.6  DATA  
COLLECTION 
......................................................................................42  
6.7  Study  
Medication  
Accountability.................................................................42  
6.8  Disclosure of Data.........................................................................................42 
6.9  Retention of Records 
....................................................................................43 
REFERENCES ..............................................................................................................44 
APPENDIX A SAMPLE ORDER SET FOR STUDY THERAPY 
...................................48 
APPENDIX B Response Evaluation Criteria in Solid Tumors (RECIST 1.1 Criteria)
.......................................................................................................................................51 
APPENDIX C National Cancer Institute Common Toxicity Criteria.........................53 
APPENDIX D HFSA Guidelines Recommendations for Pharmacological 
Therapy:Left Ventricular Systolic Dysfunction.........................................................54 
APPENDIX E SAFETY REPORTING FAX COVER SHEET ........................................76 
APPENDIX F (MBC ISTs) Algorithm for Continuation and Discontinuation of 
Pertuzumab and Trastuzumab Based on LVEF Assessments in MBC ISTs 
..........77 
 




















Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
13/P {Protocol Number} 
 
280513 
 
2.1  PRIMARY  
OBJECTIVES  
Phase I: Safety/feasibility of the recommended phase II dosing for gemcitabine 
plus trastuzumab and pertuzumab.  
Phase II: Overall response rate (CR+PR) using RECIST 1.1 with the 
combination of gemcitabine plus trastuzumab and pertuzumab.  
2.2  SECONDARY  
OBJECTIVES  
Phase I and II: Progression free survival (PFS), biomarker and immune based 
correlates as it relates to clinical benefit from the combination 
Phase II: Safety/toxicity of the combination using CTCAE 4.0 
3.       STUDY DESIGN 
Single arm, non-randomized, open label phase I/II multisite Simon two stage 
minimax trial. 
 
3.1  DESCRIPTION OF THE STUDY 
Patients with metastatic HER2+ breast cancer who have progressed on at least 
one prior line of chemotherapy in combination with a HER2 targeting agent (i.e. 
T-DM1, trastuzumab, pertuzumab, or lapatinib) will be enrolled in this phase I/II 
single arm study.  
Screening/baseline testing following consent: 
  Review of clinical records for eligibility criteria 
  History and physical exam 
  Diagnostic quality CT scan of the thorax/abdomen/pelvis 
  Nuclear medicine bone scan should be performed for those with known or 
suspected bone metastases 
  Echocardiogram or MUGA scan 
  Complete metabolic panel and complete blood count with differential 
Patients should have all baseline evaluations completed and initiate study 
treatment within 28 days of signing consent. Routine CT scans that were done 
prior to consent but still fall within the 28 day window prior to the anticipated 
treatment start date may be used provided they are of adequate quality and can 
be reviewed by study site radiologists for measurable disease. Patients should 
have measurable disease on baseline scans and have target lesions selected 
as per RECIST 1.1 criteria (http://www.eortc.be/recist/). Qualified patients will 
then undergo central registration in Moffitt’s Oncore system, the study 
coordinator will be sent a confirmation with treatment assignment via fax or 
email, and then treatment is initiated.   
Phase I portion: 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
14/P {Protocol Number} 
 
280513 
 
The phase I trial will start at the recommended phase 2 dose (RP2D) for 
gemcitabine but will have a de-escalation dose levels in the event that an 
unacceptable toxicity requires dose reduction. 
Dose level 0 = gemcitabine (1200mg/m2) IV D1,8 q21 days 
Dose level -1 = gemcitabine (1000mg/m2) IV D1,8 q21 days 
Dose level -2 = gemcitabine (850mg/m2) IV D1,8 q21 days 
Trastuzumab will be given using an 8mg/kg loading dose on C1D1, followed by 
6mg/kg IV on subsequent cycles q21 days.  
Pertuzumab will be given using an 840mg IV loading dose on C1D1, followed by 
420mg IV on subsequent cycles q21 days.   
There will be no dose adjustments or reductions for either trastuzumab or 
pertuzumab. A sample order sheet is included in Appendix A for each of the 
agents along with the supportive premedications given during administration.  
The phase I trial will use a typical 3+3 design. The RP2D will be the dose level 
where 0-1 dose limiting toxicities (DLTs) in six patients occur. Six patients 
should be treated at the RP2D to acquire sufficient safety data to proceed with 
the phase II portion of the study.  If 2 or more DLTs occur at a given dose level 
then accrual to that dose level is stopped and subsequent patients will be 
enrolled at the dose level below. In the event 2 DLTs occur at the -2 dose level 
then accrual to the trial will be held and discussions with the sponsor will take 
place to determine if there is a feasible protocol amendment that would allow the 
trial to continue or if the trial should be permanently closed. During the phase I 
portion of the study patients should be treated at least 1 week (+/- 2 days) apart 
to allow for a margin of safety. 
Phase I DLT definition: 
The definition of a DLT is any 1st cycle toxicity which meets the following criteria: 
G3 non-hematologic toxicity or G4 hematologic toxicity that is not expected 
with gemcitabine plus trastuzumab and not manageable with routine supportive 
care causing a delay of treatment greater than 3 weeks. 
Phase II Portion: 
The phase II portion of the study can commence as soon as the last patient on 
the phase I completes one cycle of therapy. It will be a single arm, open label, 
non randomized, Simon two stage minimax phase IIa. The first stage of the trial 
will enroll 20 patients. If there are 8 or fewer objective responses out of the first 
20 evaluable patients enrolled then the trial will stop early for futility. If 9 or more 
objective responses are seen in the first 20 evaluable patients, then the second 
stage of the trial consisting of 17 additional evaluable patients will commence. 
Patients will undergo consent, screening, central registration as previously 
described, and start treatment at the RP2D. Patients in the phase II can be 
initiated on treatment concurrently with no delay required between individual 
patients.  


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
15/P {Protocol Number} 
 
280513 
 
Evaluability of patients for endpoints: 
Any patient who receives any dose of the study treatment will be evaluated for 
the safety/toxicity endpoints in the trial. To be considered evaluable for the 
primary efficacy endpoint (ORR) the patient must undergo two treatment cycles 
followed by a response scan. Those un-evaluable for the efficacy endpoint may 
be replaced with approval from the study sponsor. 
3.2  RATIONALE FOR STUDY DESIGN 
The study population is patients with previously treated, metastatic HER2+ 
breast cancer.  The compelling reason for studying this particular population is 
that there is ample evidence that continued targeting of HER2 signaling through 
progression on prior HER2 directed therapy confers clinical benefit (i.e. 
Trastuzumab Beyond Progression study). With the inclusion of newer HER2 
targeted therapies such as first line pertuzumab combination therapy and T-
DM1, there is little data regarding the efficacy of pertuzumab/trastuzumab 
combined with salvage chemotherapy in previously treated patients. This trial 
seeks to provide some clinical information regarding safety and efficacy for 
gemcitabine/pertuzumab/trastuzumab in this patient population.   
3.3 OUTCOME  
MEASURES  
3.3.1  Primary Outcome Measure:  
Phase I: Establishing the recommended phase 2 dose for the combination of 
gemcitabine+trastuzumab+pertuzumab with safety data described using CTCAE 
4.0 terminology. 
Phase II: Objective response rate (CR+PR) using RECIST 1.1 criteria for the 
combination of gemcitabine+trastuzumab+pertuzumab at the recommended 
phase 2 dose. 
3.3.2 Secondary Outcome Measures: 
  Stable disease > 6 months, median progression free survival (in months) 
for all patients evaluable for response  
  Safety/toxicity using CTCAE 4.0 frequency data 
  Exploratory analysis for correlation between clinical outcomes (ORR, 
PFS) and levels of circulating MDSCs (HLA-DR-CD33+), NK cells 
(CD56+), and ratio of CD4+/CD14+HLA-DRlow using multiparametric 
flow cytometry at baseline, weeks 4,7, and 10 
  Exploratory analysis for correlation between clinical outcomes (ORR, 
PFS) and the level of HER2-HER3 dimerization as measured by a 
proximity ligation assay on isolated circulating tumor cells 
 
3.3.3  Ancillary Safety Outcome Measures 
Cardiac safety monitoring by measuring ejection fraction via serial MUGA scans 
during treatment q3 months 
 












  Have not been treated with gemcitabine in the metastatic setting 
  Measurable disease per RECIST 1.1 criteria 
  ECOG performance status 2
 
  Left Ventricular Ejection Fraction (LVEF)   50% at baseline as determined by 
either ECHO or MUGA  
  Adequate bone marrow function as indicated by the following: 
ANC >1500/L  
Platelets 100,000/L 
Hemoglobin >10 g/dL  
  Adequate renal function, as indicated by creatinine 1.5 upper limit of normal 
(ULN) 
  Adequate liver function, as indicated by bilirubin 1.5 ULN, AST or ALT <2 
ULN unless related to metastatic breast cancer to the liver (in which case 
AST/ALT < 5x ULN is allowed). 
  Signed informed consent 
  Adequate birth control in sexually active women of childbearing potential 
 
4.1.3 Exclusion Criteria 
  Active uncontrolled infection or major concurrent illness which in the opinion of 
the investigator would render the patient unsafe to proceed with the study   
  Uncontrolled central nervous system metastases. Treated, non-progressing 
CNS disease (documented by brain MRI) off corticosteroids for at least 1 month 
are eligible 
  Pregnant or lactating women 
  Prior chemotherapy within the last 3 weeks (last 6 weeks for 
nitrosureas/mitomycin) 
  Prior radiation therapy within the last 4 weeks; prior radiation therapy to indicator 
lesion (unless objective disease recurrence or progression within the radiation 
portal has been documented since completion of radiation). 
  Other concomitant active malignancies  
  History of significant cardiac disease, cardiac risk factors or uncontrolled 
arrhythmias 
  Ejection fraction <50% or below the lower limit of the institutional normal range, 
whichever is lower 
Protocol:  Trastuzumaband Pertuzumab Moffitt Cancer Center and Research Institute 
21/P {Protocol Number} 
 
280513 
 
 
  Hypersensitivity to any of the study medications 








Protocol:  Trastuzumaband Pertuzumab Moffitt Cancer Center and Research Institute 
25/P {Protocol Number} 
 
280513 
 
 
period of 30 - 60 minutes.  DO NOT ADMINISTER AS AN IV PUSH OR 
BOLUS.   
When administered with pertuzumab, the recommended initial dose of 
trastuzumab is 8 mg/kg followed every 3 weeks thereafter by a dose of 6 mg/kg.  
If pertuzumab and trastuzumab are being administered concomitantly with 
chemotherapy, monoclonal antibody administration should precede 
chemotherapy administration.  Patients should be observed for fever and chills 
or other infusion-associated symptoms.  If chemotherapy is discontinued during 
the treatment phase, either because of completing a planned number of cycles 
of chemotherapy, or because of chemotherapy related toxicity. 
Trastuzumab and Pertuzumab Infusion Time and Post-Infusion 
Observation Period 
 
Infusion Time 
(minutes) 
Post-Infusion 
Observation 
Period (minutes)
HP Loading 
Doses 
(8 mg/kg and 
840mg)
 First
 
Infusion
 
60
 60
 
HP 
(6mg/kg and 
420mg) q3w 
Subsequent 
Infusions
 30-60 a 
30 a 
 
   
a Only if previous dose was well tolerated. 
 
4.3.5  Trastuzumab and Pertuzumab Dosage Modification 
Dose modification of trastuzumab and pertuzumab is not permitted.   
4.3.6  Trastuzumab and Pertuzumab Overdosage 
There is no experience with overdosage in human clinical trials.   
4.3.7  GEMCITABINE PREPARATION AND DOSING 
Refer to the full prescribing information for gemcitabine to obtain formulation and 
preparation information at 
 The initial dosing of 
the gemcitabine will be the recommended phase 2 dose identified in the phase 1 
portion of the study. 
 
4.3.8 GEMCITABINE DOSE REDUCTIONS/DELAYS 
 
The following dose reduction recommendations for subsequent day 1 dosing are 
described below. These dose reductions are permanent. Two dose reductions 


are allowed while on study. The first table is for hematologic toxicity and the 
second table is for non-hematologic toxicity. Any grade 2 or greater pneumonitis 
due to gemcitabine warrants discontinuation of gemcitabine permanently and 
administration of steroids. 
 
 
 
 
HEMATOLOGIC TOXICITIES 
 
 
 
NON-HEMATOLOGIC TOXICITIES 
 
 
 
Gemcitabine dosage adjustment for hematological toxicity within a cycle of 
treatment is based on the granulocyte and platelet counts taken on day 8 of 
therapy. If marrow suppression is detected, gemcitabine dosage should be 
modified according to guidelines in the table below.   
 
Day 8 Dosage Reduction 
Guidelines for Gemcitabine 
Platelet count 
(x10
6/L)  
% of full dose 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
26/P {Protocol Number} 
 
280513 
 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
27/P {Protocol Number} 
 
280513 
 
Absolute granulocyte count (x 
106/L)  
1000  
And  
100,000  
100  
999-750  
And/Or  
75,000-
99,999  
80  
<750 
And/Or  
<75,000  
Hold  
 
If a day 8 gemcitabine dose is held due to toxicity then that dose will not be 
made up for the remainder of that cycle.  With the exception of pneumonitis as 
described previously, dosing on d8 should be held for any G3-4 non-
hematologic toxicity. Subsequent dosing should follow the same dose 
reductions shown in the table once the toxicity has resolved to a G0-1. In 
addition, physician judgment can be exercised in initiating subsequent cycle 
dose reductions for a grade 2 or less toxicity due to concerns over patient 
tolerance of the chemotherapy. 
 
4.4  CONCOMITANT AND EXCLUDED THERAPY 
All standard anti-emetics, supportive care medications, growth factors such as 
GCSF or pegylated GCSF are permitted while on study treatment. Concomitant 
bisphosphonates or denosumab for bone metastases are permitted if these 
agents were initiated prior to initiating the study therapy and patients are stable 
on these medications. Aspirin, platelet inhibiting agents, and anticoagulants are 
permitted only if they are absolutely medically necessary (i.e. treatment for 
DVTs/PEs or cardiac stents/CAD) and as long as they are held when medically 
indicated due to thrombocytopenia from gemcitabine. No other cytotoxic, 
targeted, or anti-hormonal agents intended to treat the underlying malignancy 
should be administered concurrently with the study treatment. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
28/P {Protocol Number} 
 
280513 
 
 
 
4.5  STUDY  
ASSESSMENTS 
Study Calendar (Showing first 3 cycles): 
 
Pre- 
Study 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
Wk 
12 
Off Studyc 
Trastuzumab and Pertuzumab 
 
A 
 
 
A 
 
 
A 
 
 
A 
 
 
 
Gemcitabine 
 
B 
B 
 
B 
B 
 
B 
B 
 
B 
B 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------X 
 
Physical exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Vital signs 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Performance status 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
CBC w/diff, plts 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Serum chemistrya 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event evaluation 
 
X---------------------------------------------------------------------------------------------X 
X 
Tumor measurements 
X 
Tumor measurements are repeated after every 6 weeks (+/- 3 days).  Documentation 
(radiologic) must be provided for patients removed from study for progressive 
disease. 
X 
Radiologic evaluation 
X 
Radiologic measurements should be performed every  6 weeks (+/- 3 days)  
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or echocardiogram 
(q3 months +/- 1 week) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
CTCs, Immune response 
markers(1
st 3 cycles only) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
A:  Trastuzumab and Pertuzumab  6mg/kg and 420mg IV q21 days, following loading dose on CID1 
B:  Gemcitabine at RP2D on days 1,8 IV q21 days 
a:  Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose,  potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
b:  Serum or urine pregnancy test (sexually active women of childbearing potential). 
c:  Off-study evaluation to be  completed within 30 days of last study dose.   
 
4.5.1  Assessments during Treatment 
The following are recommended evaluations: 
  Complete metabolic panel day 1 of each cycle, complete blood count with 
differential prior to each gemcitabine administration 
  Regular assessment of cardiac function by either MUGA or echocardiography 
q3months +/- 1 week while on treatment. If trastuzumab is discontinued for a 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
29/P {Protocol Number} 
 
280513 
 
decline in LVEF, a repeat measure of LVEF will be obtained in 1 month to 
assess whether the decline has resolved. 
  Radiologic imaging for response assessment should be obtained at baseline 
and after every 6 weeks (+/- 3 days) of study therapy. This includes diagnostic 
CT of thorax/abdomen/pelvis with contrast, and bone scans in patients with 
known or suspected bone metastases.   
4.5.2 Follow-Up Assessments 
Patients would be followed up 30 days after last study therapy, or in the event of 
a study treatment related adverse event until resolution, stabilization, or death. 
Follow up intervals for these adverse events will be as clinically indicated by 
their treating oncologist.  
4.6  DISCONTINUATION OF PROTOCOL-SPECIFIED THERAPY 
Protocol-specified therapy may be discontinued for any of the following reasons: 
 Progressive 
disease 
 Unacceptable 
toxicity 
 Pregnancy 
on 
study 
  Patient non-compliance or election to discontinue therapy (for any reason) 
 Physician’s 
judgment 
  Adverse event causing a dosing delay of greater than 28 days 
 
4.7  SUBJECT  
DISCONTINUATION 
Subjects may be discontinued for any of the reasons outlined in section 4.6. 
Patients experiencing study treatment related adverse events requiring 
discontinuation should be treated as medically indicated by their treating 
oncologist. The patient should be followed until the adverse event has 
stabilized/resolved or death. Patients discontinuing prematurely for non-adverse 
event related issues should be followed up 30 days from the last study 
treatment. Patients who are non-evaluable for the primary endpoint due to 
premature discontinuation can be replaced with approval from the study sponsor 
and IRB (if applicable).  
4.8  STUDY  
DISCONTINUATION  
Genentech Study Center and the Principal Investigator have the right to 
terminate this study at any time.  Reasons for terminating the study may include 
the following: 
  The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects (see early stopping rule 4.8.1) 
  Subject enrollment is unsatisfactory 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
30/P {Protocol Number} 
 
280513 
 
  Data recording are inaccurate or incomplete 
  Study protocol not followed 
4.8.1 Early stopping rule for toxicity: There will be an interim analysis for 
toxicity after the first stage of the phase II trial (20 patients) has completed 
accrual. The study will terminate early for excessive toxicity if >50% of the 
patients experience a study treatment related (probably or definitely) grade 3/4 
toxicity requiring permanent discontinuation of treatment despite appropriate 
supportive care/dose reductions.  
4.9  STATISTICAL  
METHODS  
4.9.1  Analysis of the Conduct of the Study 
All data regarding subject enrollment, patient flow, patient demographics, 
performance status, prior therapy, screening success/failures, number of study 
treatments administered, disposition, and follow up will be captured via eCRFs 
into the Oncore study system. Descriptive statistics will be used to characterize 
the study patients. Patients who receive at least one treatment on study are 
eligible for safety analyses. Patients who receive at least two cycles of therapy 
followed by response scans will be evaluable for the efficacy analyses.  
4.9.2  Analysis of Treatment Group Comparability 
Selected exploratory retrospective subset analyses will be undertaken only 
when possible to evaluate impact of demographics, lines of prior treatment (1 or 
>1), prior pertuzumab exposure, or performance status (0-1 or 2).   
 
4.9.3  Efficacy Analysis  
Primary Endpoints:  
Phase I: Establishing the RP2D of gemcitabine/pertuzumab/trastuzumab  
based on safety/feasibility. Toxicity events will be tabulated and summarized 
for all patients at each dose level using CTCAE 4.0 criteria.  The dose level at 
which 0-1 DLTs occur in six patients (as defined in section 3.1) will be selected 
as the RP2D.   
Phase II: Overall response rate (CR+PR) (ORR) using RECIST 1.1 criteria: 
The 95% confidence interval for the response rate will be calculated based on 
the exact binomial distribution. Those patients in the phase I and phase II 
portions who have undergone at least two cycles of therapy at the RP2D 
followed by a response scan will be evaluable for this primary endpoint.  
Secondary Endpoints: 
Median progression free survival (in months): The time-to-event data will be 
summarized using Kaplan-Meir curve method for all patients who are evaluable 
for the ORR endpoint. 
Clinical benefit rate (CR+PR+SD) using RECIST 1.1 criteria: Defined as 
proportion of patients evaluable for response who attain a complete response, 










Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
35/P {Protocol Number} 
 
280513 
 
  
It results in persistent or significant disability/incapacity (i.e., the AE 
results in substantial disruption of the subject’s ability to conduct normal life 
functions). 
  
It results in a congenital anomaly/birth defect in a neonate/infant born to a 
mother exposed to the IMP. 
  
It is considered a significant medical event by the investigator based on 
medical judgment (e.g., may jeopardize the subject or may require 
medical/surgical intervention to prevent one of the outcomes listed above). 
 
5.2    METHODS AND TIMING FOR ASSESSING AND RECORDING 
SAFETY VARIABLES 
 
The investigator is responsible for ensuring that all AEs and SAEs that are 
observed or reported during the study, are collected and reported to the FDA, 
appropriate IRB(s), and Genentech, Inc. in accordance with CFR 312.32 (IND 
Safety Reports).  
Adverse Event Reporting Period 
The study period during which all AEs and SAEs must be reported begins after 
informed consent is obtained and initiation of study treatment and ends 30 days 
following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier. After this period, investigators 
should only report SAEs that are attributed to prior study treatment. 
Assessment of Adverse Events 
All AEs and SAEs whether volunteered by the subject, discovered by study 
personnel during questioning, or detected through physical examination, 
laboratory test, or other means will be reported appropriately. Each reported AE 
or SAE will be described by its duration (i.e., start and end dates), regulatory 
seriousness criteria if applicable, suspected relationship to the study treatment 
(see following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators 
should apply the following general guideline: 
Yes 
There is a plausible temporal relationship between the onset of the AE and 
administration of the study treatment, and the AE cannot be readily explained by 
the subject’s clinical state, intercurrent illness, or concomitant therapies; and/or 
the AE follows a known pattern of response to the study treatment; and/or the 
AE abates or resolves upon discontinuation of the study treatment or dose 
reduction and, if applicable, reappears upon re-challenge. 
No 
Evidence exists that the AE has an etiology other than the study treatment (e.g., 
preexisting medical condition, underlying disease, intercurrent illness, or 
concomitant medication); and/or the AE has no plausible temporal relationship 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
36/P {Protocol Number} 
 
280513 
 
to study treatment administration (e.g., cancer diagnosed 2 days after first dose 
of study drug). 
 
Expected adverse events are those adverse events that are listed or 
characterized in the Package Insert or current Investigator Brochure.  
 
Unexpected adverse events are those not listed in the Package Insert (P.I.) or 
current Investigator Brochure (I.B.) or not identified. This includes adverse 
events for which the specificity or severity is not consistent with the description 
in the P.I. or I.B. For example, under th
is definition, hepatic necrosis would be 
unexpected if the P.I. or I.B. only referred to elevated hepatic enzymes or 
hepatitis. 
 
5.3    PROCEDURES FOR ELICITING, RECORDING, AND REPORTING 
ADVERSE EVENTS 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject evaluation timepoints 
should be adopted. Examples of non-directive questions include:  
  
“How have you felt since your last clinical visit?” 
  
“Have you had any new or changed health problems since you were last      
here?”  
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs. Avoid colloquialisms and abbreviations. 
a. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases). However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a 
single diagnosis or syndrome at the time of reporting, it is ok to report the 
information that is currently available. If a diagnosis is subsequently established, 
it should be reported as follow-up information. 
b.
 Deaths
 
All deaths that occur during the protocol-specified AE reporting period (see 
Section 5.1.2), regardless of attribution, will be reported to the appropriate 
parties. When recording a death, the event or condition that caused or 
contributed to the fatal outcome should be reported as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at the time 
of reporting, report “Unexplained Death”. 
c.
 Preexisting
 
Medical
 
Conditions
 
A preexisting medical condition is one that is present at the start of the study. 
Such conditions should be reported as medical and surgical history. A 










Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
41/P {Protocol Number} 
 
280513 
 
6.
 INVESTIGATOR
 
REQUIREMENTS
 
6.1  STUDY  
INITIATION  
Before the start of this study, the following documents must be on file with 
Genentech or a Genentech representative: 
  Original U.S. FDA Form 1572 for each site (for all studies conducted under U.S. 
Investigational New Drug [IND] regulations), signed by the Principal Investigator 
The names of any sub-investigators must appear on this form.  Investigators 
must also complete all regulatory documentation as required by local and 
national regulations. 
 Current curriculum vitae of the Principal Investigator 
  Written documentation of IRB approval of protocol 
  A signed Clinical Research Agreement 
6.2  STUDY  
COMPLETION  
The following materials are requested by Genentech when a study is considered 
complete or terminated: 
  Any study report submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. This includes all IND annual reports and the Clinical Study 
Report (final study report). Additionally, any literature articles that are a result of 
the study should be sent to Genentech. Copies of such reports should be mailed 
to the assigned Clinical Operations contact for the study: 
  
 
 
6.3  INFORMED  
CONSENT  
The informed consent document must be signed by the subject or the subject’s 
legally authorized representative before his or her participation in the study.  The 
case history for each subject shall document that informed consent was 
obtained prior to participation in the study.  A copy of the informed consent 
document must be provided to the subject or the subject
's legally authorized 
representative.  If applicable, it will be provided in a certified translation of the 
local language. 
Signed consent forms must remain in each subject’s study file. 
6.4  INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE APPROVAL 
This protocol, the informed consent document, and relevant supporting 
information must be submitted to the IRB for review and must be approved 
before the study is initiated.  The study will be conducted in accordance with 
U.S. FDA, applicable national and local health authorities, and IRB 
requirements. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
42/P {Protocol Number} 
 
280513 
 
The Principal Investigator is responsible for keeping the IRB apprised of the 
progress of the study and of any changes made to the protocol as deemed 
appropriate, but in any case the IRB must be updated at least once a year.  The 
Principal Investigator must also keep the IRB informed of any significant 
adverse events. 
Investigators are required to promptly notify their respective IRB of all adverse 
drug reactions that are both serious and unexpected.  This generally refers to 
serious adverse events that are not already identified in the Investigator 
Brochure and that are considered possibly or probably related to the molecule or 
study drug by the investigator.  Some IRBs may have other specific adverse 
event requirements that investigators are expected to adhere.  Investigators 
must immediately forward to their IRB any written safety report or update 
provided by Genentech (e.g., IND safety report, Investigator Brochure, safety 
amendments and updates, etc.). 
6.5  STUDY  
MONITORING REQUIREMENTS 
The study will be internally monitored according to institutional requirements and 
as stipulated by the study sponsor.  
6.6  DATA  
COLLECTION  
All patient, safety, treatment, response and disposition data will be entered on 
electronic CRF forms within the Oncore trial management system by clinical trial 
coordinators/data specialists trained in its use. Data security will be maintained 
using both software (authorized user accounts with access restrictions) and 
physical measures (systems will be in locked rooms). All efforts should be made 
to enter routine study data within two weeks from the date of the patient 
encounter or study procedure. 
6.7  STUDY MEDICATION ACCOUNTABILITY (IF APPLICABLE) 
If study drug will be provided by Genentech, the recipient will acknowledge 
receipt of the drug by returning the INDRR-1 form indicating shipment content 
and condition.  Damaged supplies will be replaced. 
Accurate records of all study drug dispensed from and returned to the study site 
should be recorded by using the institution’s drug inventory log or the NCI drug 
accountability log. 
All partially used or empty containers should be disposed of at the study site 
according to institutional standard operating procedure.  Return unopened, 
expired, or unused study drug with the Inventory of Returned Clinical Material 
form as directed by Genentech. 
 
6.8  DISCLOSURE OF DATA 
Subject medical information obtained by this study is confidential, and disclosure 
to third parties other than those noted below is prohibited. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
43/P {Protocol Number} 
 
280513 
 
Upon the subject’s permission, medical information may be given to his or her 
personal physician or other appropriate medical personnel responsible for his or 
her welfare. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, 
Genentech, and the IRB for each study site, if appropriate. 
 
6.9  RETENTION OF RECORDS 
U.S. FDA regulations (21 CFR §312.62[c]) require that records and documents 
pertaining to the conduct of this study and the distribution of investigational drug, 
including CRFs, consent forms, laboratory test results, and medication inventory 
records, must be retained by the Principal Investigator for 2 years after 
marketing application approval.  If no application is filed, these records must be 
kept 2 years after the investigation is discontinued and the U.S. FDA and the 
applicable national and local health authorities are notified.  Genentech will 
notify the Principal Investigator of these events. 
For studies conducted outside the United States under a U.S. IND, the Principal 
Investigator must comply with U.S. FDA IND regulations and with the record 
retention policies of the relevant national and local health authorities. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
44/P {Protocol Number} 
 
280513 
 
REFERENCES 
 
Akerley W, Sikov WM, Cummings F, et al. Weekly high-dose paclitaxel in 
metastatic and locally advanced breast cancer: a preliminary report. Semin 
Oncol 1997; 24 (5 Suppl 17):87-90. 
 
Arteaga CL, Winnier AR, Poirier, MC, et al. P185c-erbB-2 signal enhances 
cisplatin-induced cytotoxicity in human breast carcinoma cells : association 
between an oncogenic receptor tyrosine kinase and drug-induced DNA repair. 
Cancer Res 1994; 54:3758-3765. 
 
Baselga J, Norton L, Albanell J, et al. Recombinant humanized anti-HER2 
antibody (Herceptin) enhances the antitumor activity of paclitaxel and 
doxorubicin against HER2/neu overexpressing human breast cancer xenografts. 
Cancer Res 1998; 58:2825-2831. 
 
Baselga J, Gelmon KA, Verma S, et al. Phase II trial of pertuzumab and 
trastuzumab in patients with human epidermal growth factor receptor 2-positive 
metastatic breast cancer that progressed during prior trastuzumab therapy. J 
Clin Oncol 2010;28:1138-1144. 
 
Baselga J, Cortés J, Kim S-B, et al. Pertuzumab plus trastuzumab plus 
docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-119. 
 
Burstein HJ, Kuter I, Campos SM, et al. Clincial activity of trastuzumab and 
vinorelbine in women with HER2-overexpressing metastatic breast cancer. J 
Clin Oncol 2001: 19:2722-2730.  
 
Chevallier B, Fumoleau P, Kerbrat P, et al. Docetaxel is a major cytotoxic drug 
for the treatment of advanced breast cancer : a Phase II trial of the Clinical 
Screening Cooperative Group of the European Organization for Research and 
Treatment of Cancer. J Clin Oncol 1995; 13:314-322.  
Cobleigh M, Vogel CL, Tripathy D, et al.  Multinational study of the efficacy and 
safety of humanized anti-Her2-overexpressing metastatic breast cancer that has 
progressed after chemotherapy for metastatic disease.  J Clin Oncol 1999;17:1-
10. 
Cross M, Dexter TM. Growth factors in development, transformation, and 
tumorigenesis. Cell 1991;64:271–80. 
Di Fiore PP, Pierce JH, Kraus MH, et al. erbB-2 is a potent oncogene when 
overexpressed in NIH-3T3 cells. Science 1987;237:178–82. 
 
Drebin JA, Link VC, Stern DF, et al. Down-modulation of an oncogene protein 
product and reversion of the transformed phenotype by monoclonal antibodies. 
Cell 1985; 41:697-706. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
45/P {Protocol Number} 
 
280513 
 
Drebin JA, Link VC, Greene MI. Monoclonal antibodies specific for the neu 
oncogene product directly mediate anti-tumor effects in vivo. Oncogene 
1988;2:387–94. 
 
Fendly BM, Winget M, Hudziak RM, et al. Characterization of murine 
monoclonal antibodies reactive to either the human epidermal growth factor 
receptor or HER2/neu gene product. Cancer Res 1990;50:1550–8. 
Gelmon K, Arnold A, Verma S, et al. Pharmacokinetics (PK) and safety of 
trastuzumab (Herceptin) when administered every three weeks to women with 
metastatic breast cancer. Oral presentation at the 37th Annual Meeting of the 
American Society of Clinical Oncology, May12-15 in San Francisco, California 
2001.  
 
Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant chemotherapy with 
trastuzumab followed by adjuvant trastuzumab versus neoadjuvant 
chemotherapy alone, in patients with HER2-positive locally advanced breast 
cancer (the NOAH trial): a randomised controlled superiority trial with a parallel 
HER2-negative cohort. Lancet 2010;375:377-384. 
 
Gianni L, Dafni U, Gelber RD, et al. Treatment with trastuzumab for 1 year after 
adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-
year follow-up of a randomised controlled trial. Lancet Oncol.  2011; 12:236-44. 
 
Gianni L, Pienkowski T, Im YH, et al. Efficacy and safety of neoadjuvant 
pertuzumab and trastuzumab in women with locally advanced, inflammatory, or 
early HER2-positive breast cancer (NeoSphere): a randomised multicentre, 
open-label, Phase 2 trial. Lancet Oncol 2012; 13: 25-32  
 
Gustafson, M., Y. Lin, et al. (2013). "Immune monitoring using the predictive 
power of immune profiles." Journal for ImmunoTherapy of Cancer 1(1): 7. 
 
Guy CT, Webster MA, Schaller M,et al. Expression of the neu protooncogene in 
the mammary epithelium of transgenic mice induces metastatic disease. Proc 
Natl Acad Sci USA 1992;89:10,578–82.  
Hancock MC, Langton BC, Chan T, et al. A monoclonal antibody against the c-
erbB-2 protein enhances the cytotoxicity of cis-diamminedichloroplatinum 
against human breast and ovarian tumor cell lines. Cancer Res 1991; 51:4575-
4580. 
 
Heinemann V., Role of Gemcitabine in the Treatment of Advanced and 
Metastatic Breast Cancer Oncology 2003;64:191–206  
 
Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative 
growth factor receptor p185HER2 causes transformation and tumorigenesis of 
NIH-3T3 cells. Proc Natl Acad Sci USA 1987;84:7159–63. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
46/P {Protocol Number} 
 
280513 
 
Hynes NE. Amplification and overexpression of the erbB-2 gene in human 
tumors: its involvement in tumor development, significance as a prognostic 
factor, and potential as a target for cancer therapy. Sem Cancer Biol 1993;4:19–
26. 
Jurianz K, Maslak S, Garcia-Schuler H, et al. Neutralization of complement 
regulatory proteins augments lysis of breast carcinoma cells targeted with 
rhumAb anti-HER2. Immunopharmacology 1999; 42:209-218. 
 
Kallioniemi OP, Kallioniemi A, Kurisu W, et al. ERBB2 amplification in breast 
cancer analyzed by fluorescence in situ hybridization. Proc Natl Acad Sci USA 
1992; 89:5321-5325. 
 
Kuzur ME, Albain KS, Huntington MO, et al. A phase II trial of docetaxel and 
Herceptin in metastatic breast cancer patients overexpressing HER-2. Proc Am 
Soc Clin Oncol 2000; 19:131a. 
 
Lenihan D, Suter T, Brammer M, Neate C, Ross G, Baselga J. Pooled analysis 
of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol. 
2012 Mar;23(3):791-800. Epub 2011 Jun 10. 
 
Leyland-Jones B, Hemmings F, Arnold A, et al. Pharmacokinetics of Herceptin 
administered with paclitaxel every three weeks. Breast Cancer Res Treat 2000; 
64:124. 
 
Nicholson BP, Thor AD, Goldstein LJ, et al. Weekly docetaxel and rhuMAb 
HER2 combination therapy as first- or second-line therapy for metastatic breast 
cancer. Proc Am Soc Clin Oncol 2000; 19:139a. 
 
O’Shaughnessy J. A., Vukelja S., Marsland T., Kimmel G., Ratnam S., and 
Pippen J. E., “Phase II study of trastuzumab plus gemcitabine in chemotherapy-
pretreated patients with metastatic breast cancer,” Clinical Breast Cancer, vol. 5, 
no. 2, pp. 142–147, 2004 
 
Pauletti G, Godolphin W, Press MF, Slamon DJ. Detection and quantitation of 
HER-2/neu gene amplification in human breast cancer archival material using 
fluorescence in situ hybridization. Oncogene1996; 13:63-71. 
 
Pegram MD, Lopez A, Konecny G, Slamon DJ. Trastuzumab and 
chemotherapeutics: drug interactions and synergies. Semin Oncol 2000; 27:21-
25. 
 
Pegram MD, Finn RS, Arzoo K, et al. The effect of her-2/neu overexpression on 
chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. 
Oncogene 1997; 15:537-547. 
 
Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab 
plus adjuvant chemotherapy for operable human epidermal growth factor 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
47/P {Protocol Number} 
 
280513 
 
receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and 
NSABP B-31. J Clin Oncol 2011;29:3366-3373 
 
Pietras RJ, Fendly BM, Chazin VR, et al. Antibody to HER-2/neu receptor blocks 
DNA repair after cisplatin in human breast and ovarian cancer cells. Oncogene 
1994; 9:1829-1838. 
 
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant 
chemotherapy for operable HER2-positive breast cancer. N Engl J Med 
2005;353:1673-1684. 
 
Schneeweiss A, Chia S, Hickish T, et al. Neoadjuvant pertuzumab and 
trastuzumab concurrent or sequential with an anthracycline-containing or 
concurrent with an anthracycline-free standard regimen: a randomized Phase II 
study (TRYPHAENA). Presented at the 34th Annual San Antonio Breast Cancer 
Symposium in San Antonio, TX; December 6-10, 2011. SABCS Oral 
presentation #S5-6. http://www.sabcs.org . 
Seidman AD, Fornier M, Hudis C, et al.  Phase II trial of weekly 1-hour Taxol 
and Herceptin for metastatic breast cancer: toward further exploitation of proven 
synergistic antitumor activity.  Cancer Invest 1999;17(Suppl 1):44-45. 
Seidman AD, Fournier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel 
therapy for metastatic breast cancer with analysis of efficacy by HER2 
immunophenotype and gene amplifcation. J Clin Oncol 2001; 19:2587-2595.  
 
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of 
relapse and survival with amplification of the HER-2/neu oncogene. Science 
1987; 235:177-182. 
 
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-
oncogene in human breast and ovarian cancer. Science 1989; 244:707-712. 
 
Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a 
monoclonal antibody against HER2 for metastatic breast cancer that 
overexpresses HER2. N Engl J Med 2001; 344:783-792. 
 
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive 
breast cancer. N Engl J Med 2011;365:1273-1283. 
 
Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after 
adjuvant chemotherapy in HER2-positive breast cancer: a randomised 
controlled trial. Lancet 2007;369:29-36. 
 
Tripathy D, Slamon D, Leyland-Jones B, et al. Treatment beyond progression in 
the Herceptin pivotal combination chemotherapy trial. Breast Cancer Res Treat 
2000; 64:32. 
 


APPENDIX A SAMPLE ORDER SET FOR STUDY THERAPY 
 
 
 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
48/P {Protocol Number} 
 
280513 
 


 
 
 
 
 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
49/P {Protocol Number} 
 
280513 
 
 


 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
50/P {Protocol Number} 
 
280513 
 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
51/P {Protocol Number} 
 
280513 
 
   APPENDIX B Response Evaluation Criteria in Solid Tumors 
(RECIST 1.1 Criteria) 
 
 
The RECIST 1.1 criteria should be used to assess response to treatment.  Only 
subjects with measurable disease should be entered in the study.  Measurable 
disease is defined as the presence of one lesion that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as 
2.0 cm with conventional techniques (or as 1.0 cm by spiral CT).  Evaluable 
lesions should be followed for the assessment of response.  Non-measurable 
lesions include bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusion, lymphangitic carcinomatosis, abdominal masses that are not confirmed 
by CT, and cystic lesions. 
All measurable lesions, up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  A sum of the longest diameter for all 
target lesions will be calculated and reported as the baseline sum longest 
diameter.  The baseline sum longest diameter will be used as the reference by 
which to characterize the objective tumor response. 
  
Complete response (CR) 
Disappearance of all evidence of tumor for at least two cycles of therapy.  Tumor 
markers must be normal. 
 Partial
 
response
 
At least a 30% decrease in the sum of the longest diameter of target lesions, 
taking a reference the baseline sum longest diameter. 
  
Stable disease (SD)  
Neither sufficient shrinkage to qualify for partial response nor sufficient increase 
to qualify for progressive disease, taking as reference the smallest sum longest 
diameter since the treatment started. 
  
Progressive disease (PD) 
At least a 20% increase in the sum of the longest diameter of target lesions, 
taking as reference the smallest sum longest diameter recorded since the 
beginning of treatment or the appearance of one or more new lesions. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
52/P {Protocol Number} 
 
280513 
 
APPENDIX B (cont’d) 
Response Evaluation Criteria in Solid Tumors (RECIST Criteria) 
 
  
Clinical progressive disease 
Subjects, who in the opinion of the treating physician investigator have had 
a substantial decline in their performance status and have clinical evidence 
of progressive disease may be classified as having progressive disease. 


Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
53/P {Protocol Number} 
 
280513 
 
APPENDIX CNational Cancer Institute Common Toxicity Criteria 
obtained from http://evs.nci.nih.gov/ftp1/CTCAE/About.html 








































 
HFSA Guidelines 
Criteria for NYHA functional classification for chronic heart failure patients, 
functional capacity (130) 
 
CLASS 1   
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, or dyspnea. 
 
CLASS 2   
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea. 
 
CLASS 3   
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation or dyspnea. 
 
CLASS 4   
Unable to carry out any physical activity without discomfort. Symptoms of cardiac 
insufficiency at rest. If any physical activity is undertaken, discomfort is 
increased. 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
73/P {Protocol Number} 
 
280513 
 


 
HFSA Guidelines 
Glossary of Clinical Trials 
 
AVID   
  
  
Antiarrhythmics Versus Implantable Defibrillators 
BEST  
  
  
Beta-blocker Evaluation of Survival Trial 
CAMIAT     
Canadian Amiodarone Myocardial Infarction Arrhythmia Trial 
CAPRIE     
Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events 
CASH   
  
Cardiac Arrest Study Hamburg 
CHF-STAT   
Congestive Heart Failure-Survival Trial of Antiarrhythmic 
Therapy 
 
CHARM   
Candesartan Cilexetil in Heart Failure Assessment of 
Reduction in Mortality and Morbidity 
CIBIS  
  
  
Cardiac Insufficiency BIsoprolol Study 
CIBIS II   
  
Cardiac Insufficiency Bisoprolol Study II 
CIDS    
  
Canadian Implantable Defibrillator Study 
COMET   
  
Carvedilol or Metoprolol European Trial 
CONSENSUS   
Cooperative North Scandinavian Enalapril Survival Study 
CONSENSUS II   Cooperative New Scandinavian Enalapril Survival Study II 
COPERNICUS   
Carvedilol Prospective Randomized Cumulative Survival     
                                Trial 
DEFINITE   
Defibrillators in Nonischemic Cardiomyopathy Treatment 
Evaluation 
DIAMOND   
Danish Investigation of Arrhythmia and Mortality on 
Dofetilide 
DIG
   
 Digitalis
 
Investigation
 
Group
 
ELITE   
  
Evaluation of Losartan In The Elderly 
ELITE II   
  
Losartan Heart Failure Survival Study - ELITE II 
EMIAT   
  
Infarction Amiodarone Trial 
GESICA     
Grupo de Estudio de Sobrevida en Insuficiencia Cardiaca en  
                                Argentina 
  GUSTO 1   
 Global Utilization of Streptokinase and TPA for Occluded    
coronary arteries 
MADIT   
  
Multicenter Automatic Defibrillator Implantation Trial 
MADITII   
  
Multicenter Automatic Defibrillator Implantation Trial II 
  
      
  
Metoprolol in Dilated Cardiomyopathy trial 
MERIT-HF     
Metoprolol CR/XL Randomized Intervention Trial in Heart  
                                Failure 
MOCHA             Multicenter Oral Carvedilol in Heart-failure Assessment 
MTT
   
 Myocarditis
 
Treatment
 
Trial
 
OPTIMALL     
Optimal Therapy in Myocardial Infarction with the 
Angiotensin II   
Antagonist Losartan 
PRECISE   
Prospective Randomized Evaluation of Carvedilol In 
Symptoms and Exercise 
PROVED   
Prospective Randomized study Of Ventricular failure and the 
Efficacy of Digoxin 
RADIANCE   Randomized Assessment of Digoxin on Inhibitors of the  
Angiotensin Converting Enzyme 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
74/P {Protocol Number} 
 
280513 
 


 
RALES     
Randomized Aldactone Evaluation Study 
RESOLVD   
Randomized Evaluation of Strategies for Left Ventricular         
Dysfunction 
SAVE     
Survival And Ventricular Enlargement 
SCD-HeFT   Sudden Cardiac Death in Heart Failure: Trial of prophylactic 
amiodarone versus implantable defibrillator therapy 
SOLVD   
Studies Of Left Ventricular Dysfunction 
SWORD   
Survival With Oral D-sotalol 
ValHeFT   
Valsartan Heart Failure Trial 
VALIANT   
Valsartan in Acute Myocardial Infarction 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
75/P {Protocol Number} 
 
280513 
 




 
Protocol:  Trastuzumab and Pertuzumab Moffitt Cancer Center and Research Institute 
77/P {Protocol Number} 
 
280513 
 
 
APPENDIX F (MBC ISTs) Algorithm for Continuation and Discontinuation of 
Pertuzumab and Trastuzumab Based on LVEF Assessments in MBC ISTs