Clinical trial NCT02445586
Conditions: Breast Cancer
Sponsor: Hoffmann-La Roche
Start date: 2015-08-17; Completion date: 2018-09-26
Enrollment: 52 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 4, single-arm, open-label, multicenter study to assess the safety and efficacy of pertuzumab in combination with trastuzumab and docetaxel for the treatment of participants with human epidermal growth factor receptor 2 (HER2)-positive advanced (locally recurrent, unresectable, or metastatic) breast cancer.

Detailed description:

Arms: arm 1: Participants will receive pertuzumab in combination with trastuzumab and docetaxel every 3 weeks until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first.
Interventions: intervention 1: Docetaxel intervention 2: Pertuzumab intervention 3: Trastuzumab
Intervention descriptions: intervention 1: Participants will receive docetaxel in line with locally approved Prescribing Information. After Cycle 6 (cycle length = 21 days), continuation of docetaxel treatment will be at the discretion of the investigator. Docetaxel will be administered after pertuzumab and trastuzumab. intervention 2: Participants will receive pertuzumab at an initial dose of 840 milligrams (mg) as a 60-minute intravenous infusion on Cycle 1 Day 1 (cycle length = 21 days), followed by every 3 weeks at a dose of 420 mg as a 30 to 60-minute intravenous infusion until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first. intervention 3: Participants will receive trastuzumab at an initial dose of 8 milligrams per kilogram (mg/kg) as a 90-minute intravenous infusion on Cycle 1 Day 1 (cycle length = 21 days), followed by every 3 weeks at a dose of 6 mg/kg as a 30 to 90-minute intravenous infusion until disease progression, unacceptable toxicity, withdrawal of consent or death, whichever occurs first.

Protocol documents:
Prot_000.pdf: 
 
Official Title:  
 
A PHASE IV, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY 
OF PERTUZUMAB (IN COMBINATION WITH TRASTUZUMAB AND 
DOCETAXEL) IN FIRST LINE TREATMENT OF INDIAN PATIENTS 
WITH HER2-POSITIVE ADVANCED (METASTATIC OR LOCALLY 
RECURRENT) BREAST CANCER 
NCT Number: 
NCT02445586 
Document: 
Version & Date:  
PROTOCOL 
Version 1.0: 06-June-2014 
 




Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6June 2014 
2 
 
TABLE OF CONTENTS 
PROTOCOL ACCEPTANCE FORM .............................................................. 7 
PROTOCOL SYNOPSIS ................................................................................ 8 
1. 
BACKGROUND .................................................................................... 16 
1.1 
Background on Breast Cancer ......................................... 17 
1.1.1 
The HER family receptors ................................................ 17 
1.2 
Background on study treatment ....................................... 19 
1.2.1 
Pertuzumab ..................................................................... 19 
1.2.1.1 Nonclinical Studies ......................................................... 19 
1.2.1.2 Clinical Studies ............................................................... 20 
1.2.2 
Trastuzumab .................................................................... 26 
1.2.3 
Docetaxel ......................................................................... 29 
1.3 
Study Rationale and Benefit–Risk 
Assessment ..................................................................... 29 
2. 
OBJECTIVES ........................................................................................ 30 
2.1 
PRIMARY Objectives....................................................... 30 
2.2 
SECONDARY Objectives ................................................ 30 
3. 
STUDY DESIGN ................................................................................... 31 
3.1 
Description of Study ........................................................ 31 
3.1.1 
Overview of Study Design ............................................... 31 
3.1.2 
Data Monitoring Committee ............................................. 32 
3.2 
End of Study .................................................................... 32 
3.3 
Rationale for Study Design .............................................. 32 
3.3.1 
Rationale for Combination Therapy ................................. 32 
3.3.2 
Rationale for Test Product Dosage .................................. 33 
3.3.3 
Rationale for Patient Population ...................................... 33 
3.4 
Outcome Measures ......................................................... 33 
3.4.1 
Primary Outcome Measures ............................................ 33 
3.4.2 
Secondary Outcome Measures ....................................... 33 
4. 
MATERIALS AND METHODS .............................................................. 34 
4.1 
Patients ............................................................................ 34 
4.1.1 
Inclusion Criteria .............................................................. 34 
4.1.2 
Exclusion Criteria ............................................................. 35 
4.2 
Study Treatment .............................................................. 36 
4.2.1 
Formulation, Packaging, and Handling ............................ 36 
4.2.1.1 Pertuzumab .................................................................... 36 
4.2.1.2 Trastuzumab .................................................................. 36 
4.2.1.3 Docetaxel ....................................................................... 37 
4.2.2 
Dosage, Administration, and Compliance ........................ 37 
4.2.2.1 Pertuzumab .................................................................... 37 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6June 2014 
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4.2.2.2 Trastuzumab and Docetaxel .......................................... 38 
4.2.3 
Dose Delays and Modifications ....................................... 38 
4.2.4 
Investigational Medicinal Product 
Accountability ..................................................................................... 38 
4.2.5 
Post-Trial Access to Pertuzumab .................................... 38 
4.3 
Concomitant Therapy ...................................................... 39 
4.3.1 
Permitted Therapy ........................................................... 39 
4.3.2 
Prohibited Therapy .......................................................... 40 
4.4 
Study Assessments ......................................................... 40 
4.4.1 
Description of Study Assessments .................................. 40 
4.4.1.1 Medical History and Demographic Data ......................... 40 
4.4.1.2 Physical Examinations ................................................... 40 
4.4.1.3 Vital Signs ...................................................................... 41 
4.4.1.4 Tumor and Response Evaluations ................................. 41 
4.4.1.5 Other Disease-Specific Assessments ............................ 41 
4.4.1.6 Laboratory Assessments ................................................ 41 
4.4.2 
Timing of Study Assessments ......................................... 42 
4.4.2.1 Screening and Pretreatment Assessments .................... 42 
4.4.2.2 Assessments during Treatment ...................................... 43 
4.4.2.3 Assessments at Post-treatment Safety 
Follow-up ...................................................................................... 43 
4.4.2.4 Assessments at Study Completion/Early 
Termination Visit ........................................................................... 44 
4.4.2.5 Follow-Up Assessments ................................................. 44 
4.4.2.6 Assessments at Unplanned Visits .................................. 44 
4.5 
Patient, Study, and Site Discontinuation .......................... 44 
4.5.1 
Patient Discontinuation .................................................... 44 
4.5.1.1 Discontinuation from Study Drug .................................... 44 
4.5.1.2 Withdrawal from Study ................................................... 45 
4.5.2 
Study and Site Discontinuation ........................................ 45 
5. 
ASSESSMENT OF SAFETY ................................................................. 46 
5.1 
Safety Plan ...................................................................... 46 
5.1.1 
Toxicity Management Guidelines ..................................... 46 
5.1.1.1 Cardiac Safety ................................................................ 46 
5.1.1.2 Infusion-associated reactions, 
Hypersensitivity Reactions and Anaphylaxis ................................ 46 
5.1.1.3 Incomplete Loading Dose ............................................... 47 
5.1.1.4 Risk of Cardiotoxicity with Pertuzumab .......................... 48 
5.1.1.5 Risk of EGFR-Related Toxicities .................................... 48 
5.1.1.6 Respiratory Events ......................................................... 49 
5.1.1.7 Warnings and Precautions for Docetaxel ....................... 49 
5.1.2 
Management of Specific Adverse Events ........................ 49 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6June 2014 
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5.1.3 
Dose Modification and Discontinuation for 
Trastuzumab and Docetaxel .............................................................. 50 
5.2 
Safety Parameters and Definitions .................................. 50 
5.2.1 
Adverse Events ............................................................... 50 
5.2.2 
Serious Adverse Events (Immediately 
Reportable to the Sponsor) ................................................................ 51 
5.2.3 
Non-Serious Adverse Events of Special 
Interest (Immediately Reportable to the Sponsor) ............................. 51 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters .......................................... 52 
5.3.1 
Adverse Event Reporting Period ..................................... 52 
5.3.2 
Eliciting Adverse Event Information ................................. 52 
5.3.3 
Assessment of Severity of Adverse Events ..................... 53 
5.3.4 
Assessment of Causality of Adverse Events ................... 53 
5.3.5 
Procedures for Recording Adverse Events ...................... 54 
5.3.5.1 Diagnosis versus Signs and Symptoms ......................... 54 
5.3.5.2 Adverse Events Occurring Secondary to 
Other Events ................................................................................ 54 
5.3.5.3 Persistent or Recurrent Adverse Events ........................ 55 
5.3.5.4 Abnormal Laboratory Values .......................................... 55 
5.3.5.5 Abnormal Vital Sign Values ............................................ 56 
5.3.5.6 Abnormal Liver Function Tests ....................................... 56 
5.3.5.7 Deaths ............................................................................ 56 
5.3.5.8 Preexisting Medical Conditions ...................................... 57 
5.3.5.9 Lack of Efficacy or Worsening of Breast 
Cancer  ....................................................................................... 57 
5.3.5.10 Hospitalization or Prolonged Hospitalization ................ 57 
5.3.5.11 Overdoses .................................................................... 58 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor .................................................... 58 
5.4.1 
Emergency Medical Contacts .......................................... 59 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Non-Serious Adverse Events of Special 
Interest 
 ........................................................................................ 59 
5.4.3 
Reporting Requirements for Pregnancies ........................ 60 
5.4.3.1 Pregnancies in Female Patients ..................................... 60 
5.4.3.2 Pregnancies in Female Partners of Male 
Patients  ....................................................................................... 60 
5.4.3.3 Abortions ........................................................................ 61 
5.4.3.4 Congenital Anomalies/Birth Defects ............................... 61 
5.5 
Follow-Up of Patients after Adverse Events .................... 61 
5.5.1 
Investigator Follow-Up ..................................................... 61 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6June 2014 
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5.5.2 
Sponsor Follow-Up .......................................................... 61 
5.6 
Post-Study Adverse Events ............................................. 61 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees ........................................................... 62 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ................. 62 
6.1 
Determination of Sample Size ......................................... 63 
6.2 
Summaries of Conduct of Study ...................................... 63 
6.3 
Efficacy Analyses ............................................................ 63 
6.3.1 
Efficacy Endpoints ........................................................... 64 
6.4  
Safety Analyses ............................................................... 64 
6.4.1 
Safety Endpoints ............................................................. 65 
6.5 
Interim Analyses .............................................................. 65 
7. 
DATA COLLECTION AND MANAGEMENT ......................................... 66 
7.1 
Data Quality Assurance ................................................... 66 
7.2 
Electronic Case Report Forms ......................................... 66 
7.3 
Source Data Documentation ............................................ 66 
7.4 
Use of Computerized Systems ........................................ 67 
7.5 
Retention of Records ....................................................... 67 
8. 
ETHICAL CONSIDERATIONS .............................................................. 67 
8.1 
Compliance with Laws and Regulations .......................... 67 
8.2 
Informed Consent ............................................................ 67 
8.3 
Institutional Review Board or 
Ethics Committee ............................................................ 68 
8.4 
Confidentiality .................................................................. 69 
8.5 
Financial Disclosure ........................................................ 69 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ............................................................................... 69 
9.1 
Study Documentation ...................................................... 69 
9.2 
Site Inspections ............................................................... 70 
9.3 
Administrative Structure................................................... 70 
9.4 
Publication of Data and Protection of Trade 
Secrets ............................................................................ 70 
9.5 
Protocol Amendments ..................................................... 70 
10. REFERENCES ..................................................................................... 72 
 
 
 
 
 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6June 2014 
6 
LIST OF TABLES 
Table 5-1 Adverse Event Severity Grading Scale ......................................... 53 
Table 9-1 Study Administrative Structure ..................................................... 70 
 
 
LIST OF APPENDICES 
Appendix 1 Schedule of Assessments ......................................................... 76 
Appendix 2 Eastern Cooperative Oncology Group (ECOG) Performance 
Status .................................................................................... 81 
Appendix 3 RECIST Criteria Version 1.1 ...................................................... 82 
Appendix 4 Algorithm for Continuation and Discontinuation of 
Pertuzumab based on LVEF assessment ............................. 94 
Appendix 5 NYHA Classification of Heart Failure and Left Ventricular 
Systolic Dysfunction NCI-CTCAE Version 4.03 
Grading………………………… ......... …………………………95 
Appendix 6 CTC AE Version 4.03……………......... …………………………..96 
 
 
 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
7 
PROTOCOL ACCEPTANCE FORM 
TITLE: 
A 
PHASE 
IV, 
MULTICENTER, 
OPEN-LABEL, 
SINGLE-ARM 
STUDY 
OF 
PERTUZUMAB 
(IN 
COMBINATION 
WITH 
TRASTUZUMAB 
AND 
DOCETAXEL) IN FIRST LINE TREATMENT OF 
INDIAN 
PATIENTS 
WITH 
HER2-POSITIVE 
ADVANCED 
(METASTATIC 
OR 
LOCALLY 
RECURRENT) BREAST CANCER 
PROTOCOL NUMBER: ML29282 
VERSION NUMBER: 
1.0 dated 6 June 2014 
EUDRACT NUMBER: 
Not applicable 
IND NUMBER: 
Not applicable 
TEST PRODUCT: 
Pertuzumab RO 43-68451 
MEDICAL MONITOR: 
Dr. 
 
SPONSOR: 
Roche Products (India) Pvt. Ltd. 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please return the signed original of this form as instructed by your local study monitor at Roche 
Products (India) Pvt. Ltd. Please retain a copy for your study files. 


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
9 
Target Population 
Patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast 
cancer (locally recurrent, unresectable, or metastatic) who have not previously received 
systemic non-hormonal anticancer therapy in the metastatic setting.  
Patients who have been considered being eligible for pertuzumab (in combination with 
trastuzumab, and docetaxel) therapy by the treating physician as per the prescribing information. 
 
Patients must meet the following criteria for study entry:- 
 
1. Male or female patients aged ≥18 years 
2. Signed written informed consent approved by the relevant Institutional Review Board/Ethics 
Committee,prior to any study procedure   
3. Histologically or cytologically confirmed and documented adenocarcinoma of the breast 
with metastatic or locally recurrent disease not amenable to curative resection; patients with 
measurable and/or non-measurable disease are eligible 
4. Known and documented HER2-positive (defined as either immunohistochemistry [IHC] 3+ 
or in situ hybridization [ISH] positive) as assessed on primary tumor and/or metastatic site 
as determined in a local laboratory that is experienced/certified in HER2-expression testing 
using an accurate and validated assay 
5. Known and documented left ventricular ejection fraction (LVEF) of at least 50% 
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1 
7. A negative serum β-HCG test for women of childbearing potential (premenopausal, or <12 
months of amenorrhea post-menopause, and women who have not undergone surgical 
sterilization [i.e., absence of ovaries and/or uterus]) within 7 days prior to the first dose of 
study treatment with the result available prior to first dosing 
8. For women of childbearing potential and men with partners of childbearing potential, 
agreement to use a highly-effective non-hormonal form of contraception or two effective 
forms of non-hormonal contraception by the patient and/or partner. Contraception use must 
continue for the duration of study treatment and for at least 7 months after the last dose of 
study treatment. Male patients whose partners are pregnant should use condoms for the 
duration of the pregnancy. 
(for women of childbearing potential: agreement to remain abstinent (only if it is in line with 
the preferred and usual lifestyle) or use single or combined non-hormonal contraceptive 
methods that result in a failure rate of <1% per year during the treatment period and for at 
least 7 months after the last dose of study drug) 


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
11 
7. Serious uncontrolled concomitant disease that would contraindicate the use of any drug 
used in this study or that would put the patient at high risk for treatment-related 
complications 
8. Uncontrolled hypertension (systolic >150 mmHg and/or diastolic >100 mmHg) or clinically 
significant (i.e. active and/or requiring medication) cardiovascular disease, including but 
not limited to cerebrovascular accident (CVA)/stroke or myocardial infarction within 
6 months prior to first study medication, unstable angina, CHF of New York Heart 
Association (NYHA) grade II or higher, or serious cardiac arrhythmia requiring medication, 
or other cardiovascular problem that is uncontrolled or is currently controlled with 
medication 
9. Current known infection with HIV, Hepatitis B virus, or Hepatitis C virus 
10. Dyspnea at rest due to complications of advanced malignancy, or other disease 
requiring continuous oxygen therapy 
11. Major surgical procedure or significant traumatic injury within 14 days prior to 1st study 
drug administration (dosing) or anticipation of need for major surgery during the course 
of study treatment. Note: Should surgery be necessary during the course of the study, 
patients should be allowed to recover for a minimum of 14 days prior to subsequent 
pertuzumab and trastuzumab treatment 
12. Known hypersensitivity to any of the study medications or to excipients of recombinant 
human or humanized antibodies 
13. History of receiving any investigational treatment within 28 days prior to 1st study drug 
administration (dosing) and/or concurrent participation in any interventional clinical trial 
14. Pregnant or lactating women 
15. Current clinical or radiographic evidence of central nervous system (CNS) metastases 
16. History of LVEF decline to below 50% during or after prior trastuzumab adjuvant or 
neo-adjuvant therapy 
 
Length of Study 
1. Enrollment period will be of approx. 12 months or till achievement of enrollment target of 
approx. 52 patients 
2. Patients will receive study medication till disease progression or unacceptable toxicity or 
withdrawal of consent or death, whichever occurs first 
 


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alkaline transaminase 
aPTT 
activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC  
Area under the curve 
BUN 
Blood urea nitrogen 
CHF 
Congestive heart failure 
CL 
Clearance 
CNS 
Central nervous system 
CR 
Complete response 
CRO 
Contract research organization 
CT 
Computed tomography 
CTCAE 
Common terminology criteria for adverse events 
CVAD 
Central venous access device 
DDI 
Drug-drug interactions 
DMC 
Data monitoring committee 
DSMB 
Data safety monitoring board 
EC 
Ethics committee 
ECG 
Electrocardiography 
ECOG 
Eastern cooperative oncology group 
eCRF 
electronic case report form 
EDC 
Electronic data capture 
EGFR 
Epidermal growth factor receptor 
ePRO 
electronic Patient-reported outcome 
FDA 
Food and drug administration 
G-CSF 
Granulocyte-colony stimulating factor 
GD 
Gestation day 
HBV 
Hepatitis B virus 
HBcAb 
Hepatitis B core antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HER 
Human epidermal growth factor receptor 
HIPAA 
Health insurance portability and accountability act 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
16 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
ICMR 
Indian Council of Medical Research 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IRF 
Independent review facility 
ISH 
In situ hybridization 
LDH 
Lactate dehydrogenase 
LPLV 
Last patient, last visit 
LVEF 
Left ventricular ejection fraction 
LVSD 
Left ventricular systolic dysfunction 
mBC 
Metastatic breast cancer 
MRI 
Magnetic resonance imaging 
NCI 
National Cancer Institute 
NYHA 
New York Heart Association 
OS 
Overall survival 
ORR 
Overall response rate 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Prescribing information 
PK 
Pharmacokinetic 
PR 
Partial response 
PRO 
Patient-reported outcome 
PTT 
Partial thromboplastin time 
RBC 
Red blood cell 
RCR 
Roche Clinical Repository 
RECIST 
Response evaluation criteria in solid tumours 
SAEs 
Serious adverse events 
SPC 
Summary of product characteristics 
SS 
Steady state 
ULN 
Upper limit of normal 
Vc 
Central volume of distribution 
WBC 
White blood cell 
 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
17 
1. 
`BACKGROUND 
1.1 
BACKGROUND ON BREAST CANCER  
Breast cancer is by far the most frequent cancer among women worldwide with an estimated 
1.38 million new cancer cases diagnosed in 2008 (23% of all cancers), and ranks second overall 
(10.9% of all cancers) (Ferlay et al., 2010). Breast cancer is a cause of concern in developed as 
well as developing regions of the world and India is no exception. Although the overall incidence 
of breast cancer in India is comparatively lower than in western world, the burden remains high. 
Data recorded from urban registries in India showed breast cancer incidence ranging from 19.3 % 
to 27.5% (ICMR 2001-2004).  
A study conducted over 30 years in Mumbai, India showed that the annual rate of breast cancer 
significantly increased during the period 1976 and 2005. The rates of breast cancer among 
women aged 30–64 had risen gradually over the 30-year study period, with the mean increase 
estimated at 1.1% per year, and representing 32% of the female cancer burden in 
2001-2005 (Dhillon et al., 2011). 
Surgery is the main modality of local treatment for breast cancer. Where ever possible isolated 
loco-regional recurrence should be treated with curative intent. If feasible, excision of recurrent 
tumor is recommended. In patients not suitable for local treatment with curative intent (e.g. 
inoperable), systemic therapies remain the mainstay of treatment. Their choice mainly depends 
on tumor biology and previous systemic treatments.  
Less than 10% of breast cancers are metastatic at diagnosis across developed and developing 
nations of the world; of these approximately one-fifth patients survive for five years (Cardoso et 
al., 2012; Hagberg et al., 2013; Barinoff et al., 2013; Lord et al., 2012). In contrast, a higher 
proportion of breast cancer patients, i.e., about 6% to 25% have metastatic disease at 
presentation in India. (Agarwal et al., 2007; Nair et al., 1993) 
In a study from New Delhi, 80% of the patients treated for breast cancer over a period of a 
decade had metastatic disease in the axillary lymph nodes. (Saxena et al., 2005)  
The primary goals of treatment of advance stage cancer are maximizing the patient’s survival and 
preserving quality of life. Treatment options for these patients have become more numerous, with 
the option to use sequential single agents or combination regimens. Additional considerations to 
use therapies directed to specific molecular subtypes of breast cancer also serve to maximize the 
benefit for an individual patient. Several targeted drugs with different molecular pathways have 
been approved for metastatic breast cancer (mBC). 
1.1.1 
The HER family receptors 
The members of human epidermal growth factor receptor (HER) family of receptor tyrosine 
kinases are important mediators of cell growth, survival, and differentiation.  


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
18 
The HER family comprises of four receptors: HER1 (EGFR), HER2, HER3, and HER4. These 
receptors mediate tumor cell growth, survival, and differentiation (Sundaresan et al., 1999; 
Yarden and Sliwkowski, 2001). HER receptors normally exit as inactive monomers. Activation of 
HER receptors occurs following ligand binding, leading to receptor dimerization and cell signaling 
through the P13-kinase/AKT pathway for promotion of tumor cell survival and through the 
mitogen-activated protein kinase (MAPK) pathway for cellular proliferation. 
Although 11 ligands are known to bind to various HER family members, none of these ligands 
binds directly to HER2. Instead, HER2 is frequently activated by forming dimers with another 
HER family receptor, when activated in HER ligand-dependent manner. This ligand-driven 
heterodimerization of HER2 with another HER family member is likely to play an important role in 
neoplastic transformation and/or progression. The HER2-HER3 dimer produces the most potent 
signaling for activation of the P13-kinase/AKT pathway. (Lee-Hoeflich et al., 2008; Olayioye et al., 
2000) 
Overexpression of HER2 in breast cancer has been correlated with high histologic grade, 
increased mitotic activity, p53 mutation, negative estrogen receptor (ER), absence of bcl2, and 
absence of lobular architecture. Despite associations with other known negative prognostic 
factors, HER2 overexpression has been independently associated with poorer disease-free 
survival (DFS) and overall survival (OS) compared with tumors that do not overexpress HER2 
(Pauletti et al. 2000; Ménard et al, 2001)  
The validation of the prognostic significance of HER2 gene amplification and protein 
overexpression in the absence of anti-HER2 targeted therapy is discussed in a review of 107 
published studies involving 39,730 patients, which reported an overall HER2 positivity rate of 22.2% 
(Ross et al., 2009). The HER2 positivity rate in breast cancer varies among Indian studies, i.e., 
from 29% to 43.2% by IHC (Vaidyanathan et al., 2010; Munjal et al., 2009). 
Trastuzumab IV has proven clinical benefits in HER2-positive mBC patients and most importantly 
improved survival. It is currently the standard of care for this patient population. Pertuzumab is 
approved by Food and Drug Administration (FDA) and European Medicinal Agency (EMA) for use 
in combination with trastuzumab and docetaxel in adult patients with HER2-positive mBC, who 
have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease 
(Prescribing Information [PI], 2013; Summary of Product Characteristics [SPC], 2013). In addition, 
pertuzumab in combination with trastuzumab and docetaxel is approved by EMA for use in adult 
patients with locally recurrent unresectable breast cancer, who have not received previous 
anti-HER2 therapy (SPC, 2013). Combination of pertuzumab with trastuzumab and docetaxel has 
been categorized as preferred first-line treatment (Category 1) for HER2-positive recurrent and 
mBC (NCCN Guidelines, 2014). 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
19 
1.2 
BACKGROUND ON STUDY TREATMENT 
1.2.1 
Pertuzumab  
Pertuzumab (rhuMAb 2C4) is a recombinant, humanized immunoglobulin (Ig)G1κ monoclonal 
antibody, which targets HER2 (also known as c-erbB-2), a transmembrane glycoprotein with 
intrinsic tyrosine kinase activity. Pertuzumab is the first in a new class of targeted cancer 
treatments called HER2 dimerization inhibitors. By binding to the subdomain 2 epitope of the 
extracellular domain of HER2, it prevents heterodimerization of HER2 with other members of the 
HER family (HER1, HER3, and HER4). As a result, ligand-activated downstream signaling is 
blocked by pertuzumab. Pertuzumab is also capable of mediating antibody-dependent 
cell-mediated cytotoxicity (ADCC) in cell-based assays. (Cho et al., 2003; Franklin et al., 2004) 
Pertuzumab and trastuzumab bind to distinct epitopes on the HER2 receptor without competing 
with each other, and have complementary mechanisms for disrupting HER2 signaling. This 
results in augmented anti-proliferative activity in vitro and in vivo when pertuzumab and 
trastuzumab are given in combination. 
1.2.1.1 
Nonclinical Studies  
The combination of pertuzumab and trastuzumab has been shown to synergistically inhibit the 
growth of xenografts derived from HER2-overexpressing KPL-4 breast cancer. (Scheuer et al., 
2009) 
The synergistic action of pertuzumab and trastuzumab may be explained by their complementary 
modes of action; while pertuzumab prevents the ligand-activated formation of HER2 heterodimers, 
trastuzumab can block the shedding of HER2 extracellular domain that would result in 
constitutively activated truncated receptors. Trastuzumab is thought to be effective in disrupting 
ligand independent HER2-HER3-PI3K complexes, whilst pertuzumab prevents ligand-induced 
HER2-HER3 dimerization. (Junttila et al., 2009) 
1.2.1.1.1 
Nonclinical Toxicology 
Pertuzumab administered weekly by intravenous injection was generally 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. 
Reproductive toxicology studies have been conducted in cynomolgus monkeys and no adverse 
effects on male and female reproductive organs were observed in repeat-dose toxicity studies of 
up to six months duration.  
In an embryo-fetal development reproductive toxicity study, pertuzumab administered to pregnant 
cynomolgus monkeys, twice weekly, during the period of fetal organogenesis (gestation day [GD] 
19 to 50), at clinically relevant exposure levels, caused a dose related increase in embryo-fetal 
death. In addition, low amniotic fluid volume (oligohydramnios) and microscopic evidence of 
delayed renal development (renal hypoplasia) were observed in all pertuzumab-treated groups.  




Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
21 
WO20024 
Ib 
Advanced 
NSCLC 
Pertuzumab 420 mg 
q3w  
Erlotinib (100,150 
mg/day) 
15 
Completed, 
CSR 
published 
Phase II Non-Randomized, Single-Arm Studies 
BO17929 
II 
HER2 positive 
mBC 
Pertuzumab 420 mg 
q3w Trastuzumab 
(either 2 mg/kg qw 
or 6 mg/kg q3w) 
66 in 
Cohorts 
1 and 2 
29 in 
Cohort 3 
Ongoing, 
(primary 
analysis 
Cohorts 1 & 
2 CSR 
published, 
primary 
analysis 
Cohort 3 
CSR 
published) 
TOC4603g 
II 
NSCLC 
Pertuzumab 420 mg 
q3w 
Erlotinib 150 
mg/day 
41 
Study 
closed Nov 
2011 
Phase II Randomized Studies 
TOC3258g 
II 
Platinum-
resistant ovarian, 
peritoneal or 
fallopian tube 
cancer 
Gemcitabine 800 
mg/m2 ± 
Pertuzumab/ 420 
mg q3w 
Gem + p
er: 65 
Gem: 65 
Completed; 
CSR 
published 
BO17931 
II 
Platinum-
sensitive ovarian 
cancer 
Carboplatin-based 
chemoe ± 
Pertuzumab 420 mg 
q3w 
Pertuzum
ab+ 
chemo: 
75 
chemo: 
74 
Completed, 
published 
WO20697 
(NEOSPHERE) 
II 
HER2-positive 
early breast 
cancer (EBC) 
Arm A: 
trastuzumab, 
docetaxelf 
Arm B: 
trastuzumab, 
docetaxel, 
pertuzumabf 
Arm C: 
trastuzumab, 
pertuzumabf 
Arm D: pertuzumab, 
docetaxelf 
 
Pertuzumab 420 mg 
q3w, 
Trastuzumab 
6mg/kg, 
Docetaxel 75 mg/m2 
to 100 mg/m2 
Arm A: 
107 
Arm B: 
107 
Arm C: 
108 
Arm D: 
94 
Ongoing, 
primary 
analysis 
CSR 
(neoadjuva
nt phase) 
and update 
CSR 
(adjuvant 
phase) 
completed 
MO22324 
(PHEREXA) 
II 
HER2-positive 
mBC 
Pertuzumab 420 mg 
q3w 
Trastuzumab 6 
271 
recruited, 
134 
Ongoing 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
22 
mg/kg q3w 
Arm A (no 
pertuzumab): 
Capecitabine 1250 
mg/m² twice-daily 
for 14 days followed 
by 7 days rest q3w. 
Arm B (with 
pertuzumab): 
Capecitabine 1000 
mg/m² as above 
received 
pertuzum
ab (as of 
7 Nov 
2012) 
BO22280 
(TRYPHAENA) 
II 
HER2-positive 
EBC 
Neoadjuvant: All 
q3w Pertuzumab 
420 mg 
Trastuzumab 6 
mg/kg 
FEC: 5-FU 500 
mg/m2, 
epirubicin 100 
mg/m2 and 
cyclophosphamide 
600 mg/m2 
Carboplatin AUC 6 
Docetaxel 75 mg/m2 
initially, 100 mg/m2 
if no DLT 
(patients on 
carboplatin and 
docetaxel with 
trastuzumab + 
pertuzumab stay on 
75 mg/m2) 
Arm A: 
72 
Arm B: 
75 
Arm C: 
76 
Completed, 
published 
BP27836 
(JOSHUA) 
IIa 
HER2-positive 
adenocarcinoma 
of the stomach or 
gastroesophageal 
junction 
All q3w: 
Pertuzumab 420 mg 
(Arm A) 
or 840 mg (Arm B) 
Trastuzumab 6 
mg/kg 
Capecitabine 1000 
mg/m2 
Cisplatin 80 mg/m2 
Arm A: 
15 
Arm B: 
15 
Ongoing; 
Primary 
analysis for 
PK 
conducted 
(data memo 
available) 
and 
ongoing for 
safety 
Phase III randomized studies 
WO20698/TOC4
129g 
(CLEOPATRA) 
III 
HER2 positive 
mBC 
Pertuzumab or 
placebo plus 
trastuzumab, 
docetaxel: 
Pertuzumab 420 mg 
q3w 
Trastuzumab 6 
mg/kg q3w 
Docetaxel 75 mg/m2 
to 100 mg/m2 
Pertuzum
ab + 
trastuzu
mab + 
docetaxel
: 407 
Placebo 
+ 
trastuzu
mab+ 
docetaxel
Completed, 
published 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
23 
a pertuzumab given q3w – the 420 mg dose is given following an initial 840 mg loading dose, trastuzumab given either as 
2 mg/kg weekly (loading dose: 4 mg/kg) or 6 mg/kg q3w (loading dose 8 mg/kg); 
b “Completed” indicates end of trial (as defined in protocol) has been reached; 
c Japanese studies sponsored by Chugai Pharmaceutical Co Ltd; 
d An extension study (TOC2664g) was initiated to follow up patients from these studies opting to continue pertuzumab 
treatment. Three patients were enrolled before the parent studies closed. This study has been completed; 
e either paclitaxel (175 mg/m2 q3w)/carboplatin (AUC 5/q3w) or gemcitabine (1000 mg/m2 day 1 and day 8 
q3w)/carboplatin (AUC 4/q3w); 
f Arms A-D all receive 5-fluorouracil (600 mg/m2), epirubicin (90 mg/m2), cyclophosphamide (600 mg/m2), and Arm C 
receives docetaxel 75 mg/m2 to 100 mg/m2 in the adjuvant setting  
 
 
1.2.1.3 
Clinical Pharmacokinetics 
Pertuzumab demonstrated linear pharmacokinetics at a dose range of 2-25 mg/kg. The 
population PK (popPK) analysis was done for the concentration data available for 481 patients. 
The median clearance (CL) and half-life of pertuzumab was 0.24 L/day and 18 days respectively. 
The steady state (SS) concentration of pertuzumab was reached after first maintenance dose 
(with an initial dose of 840 mg followed by a maintenance dose of 420 mg). (Prescribing 
Information, US) 
Pertuzumab was administered by intravenous infusion (every 3 weeks) either as a weight-based 
dose (0.5-15 mg/kg) or a fixed dose (420 or 1050 mg). It was reported that weight- and BSA-
based dosing reduced the population variability of C (SS, trough) moderately as compared to 
fixed dosing. (Ng CM et al., 2006)  
The popPK analysis suggested that there were no differences observed based on age, gender, 
and ethnicity (Japanese vs. non-Japanese) in PK parameters. Baseline serum albumin level and 
lean body weight as covariates only exerted a minor influence on PK parameters. Therefore, no 
dose adjustments based on body weight or baseline albumin level are needed. (Prescribing 
Information, US) 
No drug interactions were observed between pertuzumab and trastuzumab. There were no 
relationship between CLcr (27 to 244 mL/min) and pertuzumab exposure was observed. 
(Prescribing Information, US) 
Phase IIl study WO20698/TOC4129g (CLEOPATRA), demonstrated that there is no evidence of 
drug-drug interactions between pertuzumab and trastuzumab, or between pertuzumab and 
docetaxel. (Cortés et al., 2013) 
1.2.1.4 
Efficacy of Pertuzumab 
In Phase III, pivotal study WO20698/TOC4129g (CLEOPATRA; N = 808) in patients with 
previously-untreated HER2-positive mBC, a statistically significant and clinically meaningful 
improvement in progression-free survival (PFS), based on tumor assessments by an independent 
review facility (IRF), was observed in patients treated with pertuzumab (Ptz) + trastuzumab (T) + 
docetaxel (D) (N = 406) compared with those receiving placebo (Pla) + trastuzumab (T) + 
docetaxel (D) (N = 402). PFS was prolonged at the median by 6.1 months and the risk of disease 
progression or death was reduced by 38% (Hazard ratio [HR] = 0.62; 95% CI = 0.51, 0.75; p 
: 397 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
24 
<0.0001) with an improvement in median PFS from 12.4 months to 18.5 months. (Baselga et al., 
2011) 
 
Figure 1-1  Independently Assessed Progression-free Survival Results from CLEOPATRA 
study (Baselga et al., 2011) 
Results of the investigator-assessed PFS analysis were consistent with those observed for IRF-
assessed PFS.  
A second interim analysis of overall survival (OS) (performed one year after the primary analysis 
of efficacy) crossed the predefined stopping boundary for statistical significance (p ≤0.0138), 
demonstrating that treatment with Ptz+T+D significantly improved OS when compared with 
Pla+T+D (HR = 0.66; 95% CI = 0.52, 0.84; p = 0.0008). (Swain et al., 2013) 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
25 
 
Figure 1-2 
Overall Survival – Results from CLEOPATRA study (Swain et al., 2013) 
 
1.2.1.5 
Safety of Pertuzumab 
Safety data are available from 2195 cancer patients treated with pertuzumab in company-
sponsored pertuzumab trials and from an additional 175 patients treated with pertuzumab in 
combination studies with trastuzumab emtansine. (Pertuzumab IB, 2013) 
Overall, data indicate that pertuzumab is well-tolerated as monotherapy and that it can be given 
in combination with trastuzumab and a range of other therapeutic agents with manageable 
additional toxicity. No unexpected toxicities were encountered other than those that are known for 
agents that target the HER family of receptors. Serious or severe infusion-associated symptoms 
have been rarely observed in patients receiving pertuzumab. Low levels of cardiac toxicities, 
predominantly asymptomatic decline in left ventricular ejection fraction (LVEF), have been 
reported. (Lenihan et al., 2011; Portera et al., 2008) 
In the pivotal Phase III CLEOPATRA study, the rates of symptomatic and asymptomatic left 
ventricular systolic dysfunction (LVSD) were not higher in patients receiving Ptz+T+D (1.2%) than 
in those receiving Pla+T+D (1.8%). The safety profile of Ptz+T+D (at the time of clinical cut-off of 
14 May 2012) was generally similar to that of Pla+T+D. The most common adverse event (AE) in 
both arms was alopecia (Pla+T+D [60.6%]) vs. Ptz+T+D [60.8%]) (an AE associated with 
docetaxel), followed by diarrhea (Pla+T+D [48.2%]) vs. Ptz+T+D [68.1%]), neutropenia (Pla+T+D 
[49.7%]) 
vs. 
Ptz+T+D 
[52.9%]), 
nausea 
(Pla+T+D 
[42.4%]) 
vs. 
Ptz+T+D 
[43.9%]), 
fatigue (Pla+T+D [37.4%]) vs. Ptz+T+D [38.0%]) and rash (Pla+T+D [24.0%]) vs. Ptz+T+D 
[36.5%]). (Swain et al., 2013) 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014  
26 
1.2.2 
Trastuzumab  
Trastuzumab is a recombinant humanized anti-HER2 monoclonal antibody that binds specifically 
and with high affinity to the extracellular domain of HER2. Trastuzumab has been shown to inhibit 
the proliferation of human tumor cells overexpressing HER2 both in vitro and in vivo. In vitro, 
trastuzumab-mediated ADCC has been shown to be preferentially exerted on HER2 
overexpressing cancer cells compared with cancer cells that do not overexpress HER2. 
(Sliwkowski et al., 1999) 
The clinical data in breast cancer are derived from more than 10 trials in women with HER2-
overexpressing mBC. Table 1-2 below presents summary of these studies.






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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
32 
3.1.2 
Data Monitoring Committee  
In addition to the final analysis, there will be interim analysis for safety once approximately 50% 
patients complete 6 months investigational medicinal product therapy with further review of 
accumulating safety data every 6 months. 
An iDMC will be formed and composed of 3 members, including a statistician. An iDMC will 
perform the review of this interim analysis of efficacy and safety as described in the iDMC 
Charter. 
3.2 
END OF STUDY  
The end of study is defined as the date when all patients have been followed up for at least 24 
months after the last patient is enrolled; unless they have been lost to follow-up, withdrawn 
consent, or died, or if the study is prematurely terminated by the Sponsor, whichever occurs first. 
3.3 
RATIONALE FOR STUDY DESIGN 
This is the multi-centric, open-labeled, non-randomized post-marketing study, to assess the 
safety and efficacy of pertuzumab in combination with trastuzumab and docetaxel to fulfill Indian 
regulatory requirement. The study design employs standard methods for safety studies in patients 
with cancer. All patients will receive the active treatment. Safety will be carefully evaluated, and 
the type of data collected and the frequency with which patients are monitored will ensure safety 
of the patients. 
3.3.1 
Rationale for Combination Therapy  
The use of the combination of pertuzumab with trastuzumab may be explained by their 
complementary mode of action, while pertuzumab prevents the ligand-activated formation of 
HER2 heterodimers and homodimers, trastuzumab can block the shedding of HER2 extracellular 
domain that would result in constitutively activated truncated receptors. Furthermore, as the two 
antibodies are not competing for the same binding epitope on HER2, their combination may lead 
to a higher antibody load, resulting in increased tumor-cell killing via ADCC.  
Phase III (CLEOPATRA) study has shown a significant efficacy and reasonable safety profile of 
the combination of pertuzumab, with trastuzumab and docetaxel over placebo with trastuzumab 
and docetaxel. Ptz+T+D significantly improved overall survival (OS) compared with Pla+T+D 
(HR = 0.66; 95% CI: 0.52, 0.84; p = 0.0008). The overall safety profile, including the cardiac 
toxicity profile, of the pertuzumab combination regimen was generally comparable with that of the 
placebo-controlled arm, apart from a higher incidence (≥5% difference) of Grade 1-2 diarrhea, 
rash, mucosal inflammation, dry skin and Grade 3-4 febrile neutropenia. (Swain et al., 2013) 
In this study, efficacy, safety, and tolerability of pertuzumab (in combination with trastuzumab and 
docetaxel) will be explored further to gain a better understanding of the use of this combination in 
treatment of Indian patients with HER2-positive advanced breast cancer.  


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
36 
11. Major surgical procedure or significant traumatic injury within 14 days prior to 1st study drug 
administration (dosing) or anticipation of need for major surgery during the course of study 
treatment 
Note: Should surgery be necessary during the course of the study, patients should be 
allowed to recover for a minimum of 14 days prior to subsequent pertuzumab and 
trastuzumab treatment 
12. Known hypersensitivity to any of the study medications or to excipients of recombinant 
human or humanized antibodies 
13. History of receiving any investigational treatment within 28 days prior to 1st study drug 
administration (dosing) and/or concurrent participation in any interventional clinical trial 
14. Pregnant or lactating women 
15. Current clinical or radiographic evidence of central nervous system (CNS) metastases 
16. History of LVEF decline to below 50% during or after prior trastuzumab adjuvant or neo-
adjuvant therapy 
 
4.2 
STUDY TREATMENT  
4.2.1 
Formulation, Packaging, and Handling 
4.2.1.1 
Pertuzumab  
Pertuzumab, the Investigational Medicinal Product (IMP) for the study will be manufactured and 
supplied by the Sponsor.  
Pertuzumab will be provided as a single use formulation containing 30 mg/mL pertuzumab in 
20 mM L-histidine acetate (pH 6.0), 120 mM sucrose and 0.02% polysorbate 20. Each vial will 
contain 420 mg/14.0 mL (30 mg/mL) of pertuzumab.  
Study drug packaging and labeling will be overseen by the Sponsor and will be in accordance 
with the Sponsor’s standards and local regulatory requirements. 
Pertuzumab vials must be shipped at temperature ranging from 2°C to 8°C (36°F to 46°F) and 
should be maintained at this temperature until use. Vials must not be frozen. Vials must be kept in 
outer carton in order to protect from light. Vials must not be shaken. For further details, see the PI. 
Upon arrival of investigational products at the site, site personnel should check them for damage 
and verify proper identity, quantity, integrity of seals, and temperature conditions, any deviations 
or product complaints are to be reported to the Monitor upon discovery. 
4.2.1.2 
Trastuzumab 
Commercial trastuzumab will be provided to the site for intravenous use during this study.  
For further details, see the local PI for trastuzumab. 
 


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
43 
CT or MRI scans performed prior to obtaining informed consent and within 28 days prior to the 
first study medication administration (dosing) may be used; these tests do not need to be 
repeated for screening. In patients with signs and symptoms suggesting CNS involvement or 
other unexplained neurological symptoms, CT or MRI brain scan is to be performed at screening.  
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before randomization. The investigator will maintain a screening log to record 
details of all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Pretreatment tests and evaluations will be performed within 3 days prior to the first study 
medication administration (dosing), after confirmation of other eligibility criteria, unless otherwise 
specified. 
Please see Appendix 1 for the schedule of screening and pretreatment assessments. 
4.4.2.2 
Assessments during Treatment 
All assessments must be performed on the day of the specified visit, unless a time window is 
specified in the schedule of assessments (see Appendix 1). Assessments scheduled on the day 
of study treatment administration should be performed prior to administration of study treatment, 
unless otherwise noted in the schedule of assessments. 
The following assessments must be performed every three treatment cycles: tumor assessment, 
ECOG performance status, and LVEF.  
Samples for hematology and blood chemistry will be collected and submitted to a local laboratory 
within 3 days prior to treatment administration in each cycle; the results must be available prior to 
dosing. 
For women of childbearing potential, serum β-HCG test must be performed within 7 days prior to 
the first dose of study treatment with the result available prior to first dosing. Urine β-HCG test 
must be performed within 7 days prior to every 3rd cycle (with results available prior to treatment), 
at the safety follow-up visit, and at 4 and 7 months after the last dose of study treatment. All 
positive urine pregnancy tests must be confirmed by a serum β HCG test.  
Please see Appendix 1 for the Schedule of Assessments performed during the treatment period. 
4.4.2.3 
Assessments at Post-treatment Safety Follow-up 
Patients will receive study medication until unacceptable toxicity, withdrawal of consent, disease 
progression, or death. All patients will continue to be followed up for 24 months after the last 
patient enrolled in study, unless they have been lost to follow-up, withdrawn consent, or died. 
Patients who discontinue from study treatment will be asked to return to the clinic approximately 
28 days after the last dose of study drug for a follow-up visit. The visit at which response 
assessment shows progressive disease may be used as the post-treatment safety follow-up visit. 


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
46 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
5.1.1 
Toxicity Management Guidelines 
The NCI-CTCAE version 4.03 will be used to grade toxicity. Pertuzumab, trastuzumab, and 
docetaxel will be administered as specified in Section 4.3.2. 
Before starting a new treatment cycle, toxicity must have resolved as specified in the following 
sections. 
Pertuzumab and trastuzumab administration may be delayed to assess or treat AEs such as 
cardiac AEs, myelosuppression, or other events. No dose reduction will be allowed for 
pertuzumab or trastuzumab. 
5.1.1.1 
Cardiac Safety 
All patients must have a baseline LVEF ≥50%. LVEF will be monitored by ECHO or MUGA 
regularly according to the Schedule of Assessments (Appendix 1). If an investigator is concerned 
that an AE may be related to cardiac dysfunction, an additional LVEF measurement should be 
performed. Pertuzumab, trastuzumab, and docetaxel will be discontinued in any patient who 
develops clinical signs and symptoms suggesting CHF, with the diagnosis confirmed by a 
suggestive chest X-ray and a drop in LVEF by ECHO or MUGA. CHF should be treated and 
monitored according to standard medical practice. 
At present, there are inadequate data available to assess the prognostic significance of 
asymptomatic drops of LVEF. However, to ensure the safety of patients in the trial, pertuzumab 
and trastuzumab must be discontinued in all patients, for whom a drop of LVEF to a value lower 
than 40% is documented and confirmed with a repeat assessment within 3 weeks of the first 
assessment, using the same assessment method. For patients whose LVEF drops to values 
lower than 45% (50% is required for entry into the study), the decision to stop or continue study 
treatment is based on the algorithm shown in Appendix 4. The incidence of CHF will also be 
recorded throughout the study. 
See Appendix 5 for details of the NYHA classification and left ventricular systolic dysfunction NCI-
CTCAE version 4.03 grading. 
5.1.1.2 
Infusion-associated Reactions, Hypersensitivity Reactions and 
Anaphylaxis 
Pertuzumab has been associated with infusion associated reactions, such as chills, diarrhea, 
fatigue, headache, nausea, and pyrexia, and with hypersensitivity reactions. Close observation of 
the patient during administration, for 60 minutes after the first infusion and, if well tolerated, for 
30 minutes following subsequent infusions. 
If a significant infusion-associated reaction occurs, the infusion should be slowed down or 
interrupted and appropriate medical therapies should be administered. Patients should be 
evaluated and carefully monitored until complete resolution of signs and symptoms.  


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
48 
If the patient received ≥75% of the loading dose, additional loading is probably not necessary. 
However, the remainder of the loading dose may be given at the investigator's discretion. In such 
a case, the remainder may be given at any time before the next scheduled dose or the patient 
may be given an additional loading dose on Day 22. If, after receiving an incomplete loading dose 
on Day 1, the patient cannot attend the site until Day 22, the patient should receive a second 
loading dose on Day 22. However, every effort should be made to give the remainder of the dose 
prior to Day 22. 
If a dose is delayed (i.e. the time between two sequential infusions is less than 6 weeks), the 
420 mg dose of pertuzumab should be administered. If a dose is missed (i.e., the time between 
two sequential infusions is 6 weeks or more), the initial loading dose of 840 mg pertuzumab 
should be re-administered as a 60-minute infusion followed by cycles of 420 mg administered 
over 30-60 minutes. 
In case of a delay to the administration of study treatments, the schedule of drug administration 
will always refer to the first drug to be administered (i.e., pertuzumab). 
5.1.1.4 
Risk of Cardiotoxicity with Pertuzumab 
Risk factors for pertuzumab-associated cardiac dysfunction are not known at this time, and this 
risk should be carefully weighed against the potential benefit in patients who have received prior 
anthracyclines. During the screening/baseline period, complete medical history information will be 
collected from all patients to explore possible risk factors for treatment - CHF, including all prior 
LVEF assessments. 
Monitoring of LVEF is required while patients are receiving study treatment. If symptomatic left 
ventricular dysfunction develops (NCI-CTCAE version 4.03 Grade 3 or 4) with a drop in LVEF 
consistent with cardiac failure, the patient must discontinue study treatment. Left ventricular 
dysfunction, whether symptomatic or not, should be treated and followed according to standard 
medical practice. 
IB should be referred to for most recent data relating to risk of cardiotoxicity. 
5.1.1.5 
Risk of EGFR-Related Toxicities 
Although pertuzumab targets HER2, because of its role in heterodimerization with other members 
of the HER family (e.g., EGFR), it may cause toxicities associated with the use of EGFR tyrosine 
kinase inhibitors. In the 7-week intravenous and 26-week toxicity studies in cynomolgus monkeys, 
there was a treatment-related increase in the incidence of diarrhea. 
Diarrhea has been observed in patients being treated with pertuzumab in Phase II single-agent 
studies, and in combination therapy studies. For patients experiencing diarrhea, early intervention 
with loperamide should be considered. 
Rash has also been observed with EGFR tyrosine kinase inhibitors. IB should be referred to for 
most recent data relating to risk of EGFR-related toxicities. 


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
59 
Investigators must also comply with local requirements for reporting SAEs to the local health 
authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
 
Medical Monitor (Roche Medical Responsible) Contact Information 
Primary Contact 
Medical Monitor:  
Dr. 
 
Telephone No.:  
  
Mobile Telephone No.:  
  
 
Secondary Contact 
Medical Monitor: 
Dr. 
 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will access 
the Roche Medical Emergency List, escalate emergency medical calls, provide medical 
translation service (if necessary), connect the investigator with a Roche Medical Monitor, and 
track all calls. The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week. Toll-free numbers for the Help Desk and Medical Monitor contact information 
will be distributed to all investigators (see "Protocol Administrative and Contact Information & List 
of Investigators").  
Drug Safety: Contact Information 
To ensure the safety reporting, following contact information will be available to all investigators. 
Telephone No.: +91-9820163752 
Direct: +91-22-3394 1422 
Fax: +91-22-3394 1054 
E-mail: india.drugsafety@roche.com 
 
5.4.2 
Reporting Requirements for Serious Adverse Events and Non-
Serious Adverse Events of Special Interest 
For reports of SAEs and non-serious AEs of special interest, investigators should record all case 
details that can be gathered immediately (i.e., within 24 hours after occurrence or learning of the 
event, as applicable) on the AE eCRF and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to Roche Safety Risk Management by the EDC 
system. 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
60 
In the event that the EDC system is unavailable, a paper SAE/Non-Serious AE of Special Interest 
CRF and Fax Coversheet should be completed and faxed to Roche Safety Risk Management or 
its designee immediately (i.e., no more than 24 hours after occurrence/learning of the event, as 
applicable), using the fax numbers provided to investigators (see "Protocol Administrative and 
Contact Information & List of Investigators"). Once the EDC system is available, all information 
will need to be entered and submitted via the EDC system.  
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 7 months after the last dose of study drug. A 
Pregnancy Report eCRF should be completed by the investigator immediately (i.e., no more than 
24 hours after learning of the pregnancy) and submitted via the EDC system. A pregnancy report 
will automatically be generated and sent to Roche Safety Risk Management. Pregnancy should 
not be recorded on the AE eCRF. The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus. Monitoring of 
the patient should continue until conclusion of the pregnancy. Any SAEs associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the pregnancy, or a 
congenital anomaly/birth defect in the child) should be reported on the AE eCRF.  
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and Pregnancy 
Fax Coversheet should be completed and faxed to Roche Safety Risk Management or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), using the fax 
numbers provided to investigators (see "Protocol Administrative and Contact Information & List of 
Investigators"). 
Roche will collect additional follow-up information at the end of the 1st and 2nd trimester, after 
delivery and at 3, 6, and 12 months of the infant’s life. 
5.4.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 7 months after the last 
dose of study drug. A Pregnancy Report eCRF should be completed by the investigator 
immediately (i.e., no more than 24 hours after learning of the pregnancy) and submitted via the 
EDC system. Attempts should be made to collect and report details of the course and outcome of 
any pregnancy in the partner of a male patient exposed to study drug. The pregnant partner will 
need to sign an Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy. Once the authorization has been signed, the investigator will update 
the Pregnancy Report eCRF with additional information on the course and outcome of the 
pregnancy. An investigator who is contacted by the male patient or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, to support 
an informed decision in cooperation with the treating physician and/or obstetrician. 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
61 
In the event that the EDC system is unavailable, follow reporting instructions provided in Section 
5.4.3.1. 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as an SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the AE eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2).  
5.4.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a male 
patient exposed to study drug should be classified as an SAE, recorded on the AE eCRF, and 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow each AE until the event has resolved to baseline grade or better, 
the event is assessed as stable by the investigator, the patient is lost to follow up, or the patient 
withdraws consent. Every effort should be made to follow all SAEs considered to be related to 
study drug or trial-related procedures until a final outcome can be reported. 
During the study period, resolution of AEs (with dates) should be documented on the AE eCRF 
and in the patient’s medical record to facilitate source data verification. If, after follow-up, return to 
baseline status or stabilization cannot be established, an explanation should be recorded on the 
AE eCRF.  
All pregnancies reported during the study should be followed until pregnancy outcome. If the EDC 
system is not available at the time of pregnancy outcome, follow reporting instructions provided in 
Section 5.4.3.1. 
5.5.2 
Sponsor Follow-Up 
For SAEs, non-serious AEs of special interest, and pregnancies, the Sponsor or a designee may 
follow up by telephone, fax, electronic mail, and/or a monitoring visit to obtain additional case 
details and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports) in order to perform an independent medical assessment of the reported case. 
5.6 
POST-STUDY ADVERSE EVENTS 
At the study completion/early termination visit, the investigator should instruct each patient to 
report to the investigator any subsequent AEs that the patient’s personal physician believes could 
be related to prior study drug treatment or study procedures.  
The investigator should notify the Sponsor of any death, SAE, or other AE of concern occurring at 
any time after a patient has discontinued study participation if the event is believed to be related 


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7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
A contract research organization (CRO) will be responsible for the data management of this study, 
including quality checking of the data. Data entered manually will be collected via EDC using 
eCRFs. Sites will be responsible for data entry into the EDC system. In the event of discrepant 
data, the CRO will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system.  
The Sponsor will perform oversight of the data management of this study. The Sponsor/ designee 
will produce an EDC Study Specification document that describes the quality checking to be 
performed on the data. Laboratory data will be sent directly to the CRO, using the CRO's 
standard procedures to handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail. System 
backups for data stored by the Sponsor/ designee and records retention for the study data will be 
consistent with the Sponsor’s standard procedures. 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed using a Sponsor-designated EDC system. Sites will receive training 
and have access to a manual for appropriate eCRF completion. eCRFs will be submitted 
electronically to the Sponsor and should be handled in accordance with instructions from the 
Sponsor. 
All eCRFs should be completed by designated, trained site staff. eCRFs should be reviewed and 
electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a readable 
format on a compact disc that must be kept with the study records. Acknowledgement of receipt 
of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical protocol data 
(i.e., source data) entered into the eCRFs by authorized site personnel are accurate, complete, 
and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, patient-reported outcomes, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records kept at 
pharmacies, laboratories, and medico-technical departments involved in a clinical trial. 


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Before study initiation, the types of source documents that are to be generated will be clearly 
defined in the Trial Monitoring Plan. This includes any protocol data to be entered directly into the 
eCRFs (i.e., no prior written or electronic record of the data) and considered source data. 
Source documents that are required to verify the validity and completeness of data entered into 
the eCRFs must not be obliterated or destroyed and must be retained per the policy for retention 
of records described in Section 7.6. 
To facilitate source data verification, the investigators and institutions must provide the Sponsor 
direct access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/EC review. The investigational site must also allow inspection by applicable 
health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into an investigational site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve as the 
source document if the system has been validated in accordance with health authority 
requirements pertaining to computerized systems used in clinical research. An acceptable 
computerized data collection system allows preservation of the original entry of data. If original 
data are modified, the system should maintain a viewable audit trail that shows the original data 
as well as the reason for the change, name of the person making the change, and date of the 
change. 
7.5 
RETENTION OF RECORDS 
No records may be disposed of without the written approval of the Sponsor. Written notification 
should be provided to the Sponsor prior to transferring any records to another party or moving 
them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good Clinical 
Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the 
country (India) in which the research is conducted, whichever affords the greater protection to the 
individual. The study will comply with the requirements of the ICH E2A guideline (Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting) and local requirements of 
India.  
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent Forms 
such as Caregiver's Informed Consent Form, if applicable) will be provided to each site. If 
applicable, it will be provided in a certified translation of the local language. The Sponsor or its 
designee must review and approve any proposed deviations from the Sponsor's sample Informed 


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Consent Forms or any alternate consent forms proposed by the site (collectively, the “Consent 
Forms”) before IRB/EC submission. The final IRB/EC-approved Consent Forms must be provided 
to the Sponsor for health authority submission purposes according to local requirements. 
The Consent Forms must be signed and dated by the patient or the patient’s legally authorized 
representative before his or her participation in the study. The case history or clinical records for 
each patient shall document the informed consent process and that written informed consent was 
obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures or when 
new information becomes available that may affect the willingness of the patient to participate.  
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and IRB/EC 
policy) during their participation in the study. For any updated or revised Consent Forms, the case 
history or clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained using the updated/revised Consent Forms for continued 
participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s legally 
authorized representative. All signed and dated Consent Forms must remain in each patient’s 
study file or in the site file and must be available for verification by study monitors at any time. 
The audio-visual recording of discussion between the patient and the study doctor regarding the 
patient’s decision whether to or not to participate in this study will be performed as per regulations. 
This recording should be kept confidential to an extent permissible by law. It may be viewed by 
the investigator or any other person authorized by him, sponsoring company and/or its 
representatives. It may also be viewed by people from regulatory authorities and ethics 
committees to check that the study is being carried out correctly.  
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, and 
relevant supporting information must be submitted to the IRB/EC by the Principal Investigator and 
reviewed and approved by the IRB/EC before the study is initiated. In addition, any patient 
recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of the study 
to the IRB/EC annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC. Investigators are also responsible for promptly informing 
the IRB/EC of any protocol amendments (see Section 9.5). 
In addition to the requirements for reporting all AEs to the Sponsor, investigators must comply 
with requirements for reporting SAEs to the local health authority and IRB/EC. Investigators may 
receive written Investigational New Drug (IND) safety reports or other safety-related 
communications from the Sponsor. Investigators are responsible for ensuring that such reports 


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are reviewed and processed in accordance with health authority requirements and the policies 
and procedures established by their IRB/EC, and archived in the site’s study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. This means that patient names are 
not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may only be disclosed to 
third parties as permitted by the Informed Consent Form (or separate authorization for use and 
disclosure of personal health information) signed by the patient, unless permitted or required by 
law. 
Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by representatives of 
the U.S. FDA and other national and local health authorities, Sponsor monitors, representatives, 
and collaborators, and the IRB/EC for each study site, as appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in accordance 
with local regulations to allow the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate health authorities. Investigators are responsible for 
providing information on financial interests during the course of the study and for 1 year after 
completion of the study (as defined in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented, including but not limited to the protocol, protocol amendments, Informed 
Consent Forms, and documentation of IRB/EC and governmental approval. In addition, at the end 
of the study, the investigator will receive the patient data, which includes an audit trail containing 
a complete record of all changes to data. 
Protocol waivers will not be granted, except in circumstances impacting the clinical subjects’ 
health/ health management 
All protocol waivers will be approved by the Medical Monitor or Medical Director. 
All Protocol violations have to reported to the sponsor and to the institutional ethics committee  


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9.2 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for inspection of 
study data, patients’ medical records, and eCRFs. The investigator will permit national and local 
health authorities, Sponsor monitors, representatives, and collaborators, and the IRBs/ECs to 
inspect facilities and records relevant to this study. 
9.3 
ADMINISTRATIVE STRUCTURE 
Table 9-1 Study Administrative Structure 
Sponsor                 
Roche Products India Pvt. Ltd. 
Clinical Supplies    
Local warehouse, Site Pharmacy, etc., as applicable 
Clinical Laboratory  
Institutional laboratories and/or external laboratories 
Study Monitoring  
Roche Products India Pvt. Ltd., designated CRO, as applicable 
Project Management 
Roche Products India Pvt. Ltd. 
List of Investigators   
List will be included in the clinical trial application dossier to  local 
health authorities 
 
9.4 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the Sponsor prior to submission. 
This allows the Sponsor to protect proprietary information and to provide comments based on 
information from other studies that may not yet be available to the investigator. 
The Sponsor will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter trials only in their entirety and not as individual center data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. Any formal publication of the study in which 
contribution of Sponsor personnel exceeded that of conventional monitoring will be considered as 
a joint publication by the investigator and the appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from the use of 
data from this study will become and remain the exclusive and unburdened property of the 
Sponsor, except where agreed otherwise. 
9.5 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor. Protocol amendments will be 
submitted to the IRB/EC and to regulatory authorities in accordance with local regulatory 
requirements. 


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Approval must be obtained from the IRB/EC and regulatory authorities (as locally required) before 
implementation of any changes, except for changes necessary to eliminate an immediate hazard 
to patients or changes that involve logistical or administrative aspects only (e.g., change in 
Medical Monitor or contact information). 
Changes that involve logistical or administrative aspects only may also be documented via a 
Protocol Clarification Memo alone. 
 
 


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10. 
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hybridization and immunohistochemistry. J Clin Oncol 2000;18:3651-64. 
Pegram M, Forbes JF, Pienkowski T, et al. on behalf of the BCIRG007 Investigators. First overall 
survival analysis of a multicenter phase III randomized trial comparing docetaxel and trastuzumab 
with docetaxel, carboplatin and trastuzumab as first line chemotherapy for patients with 
metastatic breast cancer containing the Her2/neu alteration [abstract]. J Clin Oncol 
2007;25(suppl):6s, 1008. 
Portera CC., Walshe JM, Rosing DR, et al. Cardiac toxicity and efficacy of trastuzumab combined 
with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 
2-positive metastatic breast cancer. Clin Cancer Res 2008;14:2710-6. 
Prescribing Information PERJETA ® (pertuzumab) revised on September 2013, Genentech, Inc. 
South San Francisco, CARoss JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and 
breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist 
2009;14:320-68. 
Saxena S, Rekhi B, Bansal A, et al. Clinico-morphological patterns of breast cancer including 
family history in a New Delhi hospital, India – a cross-sectional study. World J Surg Oncol 
2005;3:67. 


Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
75 
Scheuer W, Friess T, Burtscher H, et al. Strongly enhanced antitumor activity of trastuzumab and 
pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer 
Res 2009;69(24):9330-6. 
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against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 
2001;344:783-92. 
Sliwkowski MX, Lofgren JA, Lewis GD, et al. Non-clinical studies addressing the mechanism of 
action of trastuzumab (Herceptin). Semin Oncol 1999;26(Suppl 12):60-70. 
Summary of Product Characteristics PERJETA ® (pertuzumab) 2013, Roche Registration Limited 
United Kingdom. 
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2. Curr Oncol Rep 1999;1:16-22. 
Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive 
metastatic breast cancer (CLEOPATRA study): overall survival results from a randomized, 
double-blind, placebo-controlled, phase 3 study. Lancet, 2013;14(6):461-71. 
Vaidyanathan K, Kumar P, Reddy CO, et al. ErbB-2 expression and its association with other 
biological parameters of breast cancer among Indian women. Indian J Cancer 2010;47:8-15. 
Vogel C, Cobleigh M, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in 
first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-
26. 
Wardley AM, Pivot X, Morales-Vasquez F, et al. Randomized phase II trial of first-line 
trastuzumab plus docetaxel and capecitabine compared with trastuzumab plus docetaxel in 
HER2-positive metastatic breast cancer. J Clin Oncol 2010;28:976-83. 
Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nature Rev Mol Cell Biol 
2001;2:127–37. 
 
 








Appendix 1  
Schedule of Assessments (cont.) 
Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
79 
6. Documented evidence of HER2 positive status from previous testing is acceptable, otherwise HER2-positive status on fixed tissue blocks from 
the primary tumor (and/or metastatic site, if primary tumor not available) to be assessed locally by IHC and/or ISH according to institutional 
criteria and routine clinical practice. On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
7. A CT or MRI and (if indicated) isotope bone scan (evaluation according to RECIST criteria) should be performed at screening and as clinically 
indicated. Scans at screening should not be older than 28 days prior to first study medication administration. NB: Bone scan, PET scan or plain 
films are not considered adequate imaging techniques to measure bone lesions.  
8. Laboratory Assessment as per routine standard of care must be performed within 3 days (with results available) prior to the administration of 
study medication. Hematology, as per routine standard of care, may include hemoglobin, hematocrit, platelet count, RBC, WBC with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils, other cells). Serum chemistry, as per routine standard of care, may include 
sodium, potassium, calcium, chloride, magnesium, BUN (urea), uric acid, total protein, albumin, ALP, ALAT, ASAT, gamma glutamyl 
transferase (GGT), lactate dehydrogenase (LDH), total bilirubin, creatinine, and blood glucose and calculated creatinine clearance at baseline. 
Coagulation tests will consist of INR and aPTT or PTT). 
9. ECOG PS to be recorded every 3 cycles until PD. 
10. LVEF ≥50% at Screening period to be determined by either ECHO or MUGA scan (with ECHO as the preferred method). The same method of 
LVEF assessment (ECHO or MUGA) must be used for the same patient throughout the study and, to the extent possible, be obtained at the 
same institution. 
11. After informed consent, and prior to dosing, SAEs considered related to a study mandated procedure are reportable. As of cycle 1 all AEs and 
SAEs considered will be collected. AEs and SAEs to be monitored continuously collected and End-of-study visit and to be recorded with 
grading according to NCI-CTCAE, Version 4.03 


Appendix 1  
Schedule of Assessments (cont.) 
Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
80 
12. For women of childbearing potential, serum β-HCG test must be performed within 7 days prior to the first dose of study treatment with the 
result available prior to first dosing. Urine β-HCG test must be performed within 7 days prior to every 3rd cycles (with results available prior to 
treatment), at the safety follow-up visit, and at 4 and 7 months after the last dose of study treatment. If a urine pregnancy test is positive, it 
must be confirmed by a serum pregnancy test. 
13. Overall survival is the time from the date of enrollment to the date of death, regardless of the cause of death. Patients who were alive at the 
time of the analysis will be censored at the date of the last follow-up assessment (two years from last patient enrolled in the study).  
14. All treatment visits within ±3 days of scheduled treatment day; 28 day Safety Follow up visit within ±3 days of the scheduled visit date; 3 
monthly Follow up visits (starting after safety follow-up visit) within ±14 days of the scheduled visit date(s); End of Study visit within ±14 days of 
the scheduled visit date. Tumour assessment ±3 days of planned scheduled visit. At the end of study visit, if patient does not fit into end of 
study definition, then tumour assessment to be done as per institutional criteria and routine clinical practice.  
15. Patients who complete the study or discontinue from the study early will be asked to return to the hospital within 28 days after the last dose of 
study drug for the end-of-study visit. 
 
 
 
 


 
Pertuzumab—Roche Products India Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014   
81 
Appendix 2 
 
Appendix 2 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g. light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
 
As published in: 
Oken, MM, Creech, RH, Tormey, DC, Horton, J, Davis, TE, McFadden, ET, Carbone, PP. Toxicity 
and Response Criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5:649-55.


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Pertuzumab—Roche Products (India) Pvt. Ltd. 
Protocol ML29282, Version 1.0: 6 June 2014 
85 
discussed with the radiologist to determine if substitution of these other approaches is possible 
and, if not, the patient should be considered not evaluable from that point forward. 
Care must be taken in measurement of target lesions on a different modality and interpretation of 
non-target disease or new lesions, since the same lesion may appear to have a different size 
using a new modality. 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. 
Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology: The utilization of these 
techniques for objective tumor evaluation cannot generally be advised. However, these 
techniques can be used to confirm the complete pathological response.  
2.  
Tumor Response Evaluation 
i. 
 Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion, as described above. 
ii. 
 Baseline Documentation of Target and Non-Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline. This means 
that, for instances in which patients have only one or two organ sites involved, a maximum of two 
lesions (one site) and four lesions (two sites), respectively, will be recorded. Other lesions (albeit 
measurable) in those organs will be recorded as non-measurable lesions (even if the size is 
> 10 mm by CT scan).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, but in addition should lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion 
does not lend itself to reproducible measurement, in which circumstance the next largest lesion 
that can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures that may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes that are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥ 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum. The short axis of the node is the diameter normally used by radiologists to judge if a node is 


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VSHFLILHGLQWKHSURWRFRO


 
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CR: Disappearance of all non-target lesions and (if applicable) normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesions and/or (if applicable) 
maintenance of tumor marker level above the normal limits 
PD: Unequivocal progression of existing non-target lesions. The appearance of one or more 
new lesions is also considered progression. 
d. 
Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease. In this setting, to achieve unequivocal 
progression on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease in a magnitude that, even in the presence of SD or PR in target 
disease, the overall tumor burden has increased sufficiently to merit discontinuation of therapy. A 
modest increase in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Patient Has Only Non-Measurable Disease. This circumstance arises in some 
Phase III trials when it is not a criterion of study entry to have measurable disease. The same 
general concepts apply here as noted above; however, in this instance there is no measurable 
disease assessment to factor into the interpretation of an increase in non-measurable disease 
burden. Because worsening in non-target disease cannot be easily quantified (by definition: if all 
lesions are truly non-measurable), a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the 
change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease, that is, an increase in tumor burden representing 
an additional 73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion). Examples include an increase in a pleural effusion from “trace” to “large” or 
an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy.” If unequivocal progression is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial. 
e. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
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identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal, that is, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the patient’s baseline lesions show PR or CR. For example, necrosis of a liver lesion may 
be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-
up evaluation will clarify if it represents truly new disease.  
If repeat scans confirm there is definitely a new lesion, then progression should be declared using 
the date of the initial scan. 
iv. 
Evaluation of Response 
The best overall response is the best response recorded from the start of the study treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a 
response may not be documented until after the end of therapy so protocols should be clear if 
post-treatment assessments are to be considered in determination of best overall response. 
Protocols must specify how any new therapy introduced before progression will affect best 
response designation. The patient’s best overall response assignment will depend on the findings 
of both target and non-target disease and will also take into consideration the appearance of new 
lesions. Specifically, in non-randomized trials where response is the primary endpoint, 
confirmation of PR or CR is needed to deem either one the ‘best overall response’.  
a. 
Time point Response  
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each time point for 
patients who have measurable disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 2 is to be used. 
 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
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Table 1 Time point Response: Patients with Target Lesions 
(with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
 
Table 2 Time point Response: Patients with Non-Target Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a“Non-CR/non-PD” is preferred over “stable disease” for non-target disease since stable disease is 
increasingly used as an endpoint for assessment of efficacy in some trials; thus, assigning “stable disease” 
when no lesions can be measured is not advised. 
 
b. 
Missing Assessments and Inevaluable Designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable at that time point. If only a subset of lesion measurements are made at an assessment, 
usually the case is also considered not evaluable at that time point, unless a convincing argument 
can be made that the contribution of the individual missing lesion(s) would not change the 
assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a patient had a baseline sum of 50 mm with three measured lesions and during the 
study only two lesions were assessed, but those gave a sum of 80 mm, the patient will have 
achieved PD status, regardless of the contribution of the missing lesion.  
If one or more target lesions were not assessed either because the scan was not done or the 
scan could not be assessed because of poor image quality or obstructed view, the response for 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
91 
target lesions should be “unable to assess” since the patient is not evaluable. Similarly, if one or 
more non-target lesions are not assessed, the response for non-target lesions should be “unable 
to assess” except where there is clear progression. Overall response would be “unable to assess” 
if either the target response or the non-target response is “unable to assess” except where this is 
clear evidence of progression, as this equates with the case being not evaluable at that time point. 
c. 
Best Overall Response: All Time Points  
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response 
IS NOT required: Best response in these trials is defined as the best response across all time 
points (for example, a patient who has SD at first assessment, PR at second assessment, and 
PD on last assessment has a best overall response of PR). When SD is believed to be best 
response, it must also meet the protocol specified minimum time from baseline. If the minimum 
time is not met when SD is otherwise the best time point response, the patient’s best response 
depends on the subsequent assessments. For example, a patient who has SD at first 
assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD. The same patient lost to follow-up after the first SD assessment would be 
considered inevaluable. 
Best response determination in trials where confirmation of complete or partial response 
IS required: Complete or partial responses may be claimed only if the criteria for each are met at 
a subsequent time point as specified in the protocol (generally 4 weeks later). In this 
circumstance, the best overall response can be interpreted as in Table 3. 
 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
92 
Table 3 Best Overall Response When Confirmation Is Required 
Overall Response at First Time 
point 
Overall Response at 
Subsequent Time point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD, or PRa 
CR 
SD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
CR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD, provided minimum duration 
for SD was met; otherwise, PD 
PR 
NE 
SD, provided minimum duration 
for SD was met; otherwise, NE 
NE 
NE 
NE 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease. 
aIf a CR is truly met at the first time point, any disease seen at a subsequent time point, even disease 
meeting PR criteria relative to baseline, qualifies as PD at that point (since disease must have reappeared 
after CR). Best response would depend on whether the minimum duration for SD was met. However, 
sometimes CR may be claimed when subsequent scans suggest small lesions were likely still present and in 
fact the patient had PR, not CR, at the first time point. Under these circumstances, the original CR should be 
changed to PR and the best response is PR. 
 
d. 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that patients with CR may 
not have a total sum of “zero” on the CRF.  
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response; it is a reason for stopping study therapy. The objective response status of such 
patients is to be determined by evaluation of target and non-target disease as shown in Table 1, 
2 and 3. 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
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For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still or 
partially present), the primary tumor should also be captured as a target or non-target lesion, as 
appropriate. This is to avoid an incorrect assessment of CR if the primary tumor is still present but 
not evaluated as a target or non-target lesion. 
v. 
Frequency of tumor re-evaluation 
Frequency of tumor re-evaluation while on treatment should be protocol specific and adapted to 
the type and schedule of treatment. After the end of the treatment, the need for repetitive tumor 
evaluations depends on whether the trial has as a goal the response rate or the time to an event 
(progression/death). If ‘time to an event’ (e.g. time to progression, disease-free survival, 
progression-free survival) is the main endpoint of the study, then routine scheduled re-evaluation 
of protocol specified sites of disease is warranted. In randomized comparative trials in particular, 
the scheduled assessments should be performed as identified on a calendar schedule (for 
example: every 6–8 weeks on treatment or every 3–4 months after treatment) and should not be 
affected by delays in therapy, drug holidays or any other events that might lead to imbalance in a 
treatment arm in the timing of disease assessment. 


 
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Protocol ML29282, Version 1.0: 6 June 2014   
94 
Appendix 4 
 
Appendix 4 
Algorithm for Continuation and Discontinuation of Pertuzumab 
based on LVEF assessment 
 
 
 
 
 
 
 
 
 
 
 
LVEF <45% 
LVEF ≥45% 
LVEF <40% 
LVEF 40-45% 
LVEF  
10% points below 
baseline or lower  
LVEF  
Higher than 10% 
points below baseline 
Continue Study 
Treatment 
Hold Study Treatment  
Repeat LVEF in 3 weeks 
Continue Study 
Treatment 
LVEF <40% or 
LVEF 40-45% and 10% points 
below baseline or lower 
LVEF >45% or 
LVEF 40-45% and higher than 
10% points below baseline 
Stop Study 
Treatment 
Resume Study 
Treatment 
LVEF Assessment 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
95 
 
Appendix 5 
NYHA Classification of Heart Failure and Left Ventricular 
Systolic Dysfunction NCI-CTCAE Version 4.03 Grading 
NYHA Classification of Heart Failure 
 
Class I 
Patients with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea or angina pain. 
Class II 
Patients with cardiac disease resulting in slight limitations of physical activity. 
They are comfortable at rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain. 
Class III 
Patients with cardiac disease resulting in marked limitations of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea or anginal pain 
Class IV 
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
angina syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
 
 
Left Ventricular Systolic Dysfunction NCI-CTCAE Version 4.03 Grading 
Grade 
 
3 
Symptomatic due to drop in ejection fraction responsive to 
intervention 
4 
Refractory or poorly controlled heart failure due to drop in 
ejection fraction; intervention such as ventricular assist 
device, intravenous vasopressor support, or heart transplant 
indicated 
5 
Death 
A disorder characterized by failure of the left ventricle to produce adequate output despite an 
increase in distending pressure and in end-diastolic volume. Clinical manifestations may include 
dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and edema. 
 
 


 
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Protocol ML29282, Version 1.0: 6 June 2014 
96 
Appendix 6 
Common Terminology Criteria For Adverse Events (CTCAE) 
Version 4.03 
 
A copy will be provided to each study site 
 
 
 
 
 

SAP_001.pdf: 
 
Official Title:  
 
A PHASE IV, MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY 
OF PERTUZUMAB (IN COMBINATION WITH TRASTUZUMAB AND 
DOCETAXEL) IN FIRST LINE TREATMENT OF INDIAN PATIENTS 
WITH HER2-POSITIVE ADVANCED (METASTATIC OR LOCALLY 
RECURRENT) BREAST CANCER 
NCT Number: 
NCT02445586 
Document: 
Version & Date:  
STATISTICAL ANALYSIS PLAN 
Version 1.0: 20-June-2016 
 


 
 
 
 
 
 
 
 
 20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
Page 1 of 174 
 
 
     STATISTICAL ANALYSIS PLAN 
 
 
PROTOCOL TITLE        : 
A PHASE IV, MULTICENTER, OPEN–LABEL, 
SINGLE-ARM 
STUDY 
OF 
PERTUZUMAB 
(IN COMBINATION WITH TRASTUZUMAB 
AND 
DOCETAXEL) 
IN 
FIRST 
LINE 
TREATMENT OF INDIAN PATIENTS WITH 
HER2-POSITIVE ADVANCED (METASTATIC 
OR 
LOCALLY 
RECURRENT) 
BREAST 
CANCER 
PROTOCOL NO.  
: 
ML29282 
STUDY DRUG 
 
:  
Pertuzumab RO 43-68451 
VERSION NUMBER 
:  
Version 1.0 
IND NUMBER 
 
: 
-- 
EUDRACT Number 
:          -- 
SPONSOR 
 
: 
Roche Products (India) Pvt. Ltd. 
PLAN PREPARED BY 
: 
 
 
 
 
 
 
DATE FINAL 
 
: 
20 Jun 2016 
DATE AMENDED  
: 
NA 








 
 
 
 
 
 
 
 
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STATISTICAL ANALYSIS PLAN AMENDMENT 
RATIONALE 
 
 
 
 
  


 
 
 
 
 
 
 
 
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TABLE OF CONTENT 
1.0 
BACKGROUND .......................................................................................................................... 12 
2.0 
STUDY DESIGN ......................................................................................................................... 12 
2.1 
Protocol Synopsis .................................................................................................. 13 
2.2 
Study Objectives and Endpoints ............................................................................ 13 
2.2.1 
Study Objectives .................................................................................................... 13 
2.2.1.1 
Primary Objective ................................................................................................... 13 
2.2.1.2 
Secondary Objective .............................................................................................. 13 
2.2.2 
Study Endpoints ..................................................................................................... 13 
2.2.2.1 
Safety Endpoints .................................................................................................... 13 
2.2.2.2 
Efficacy Endpoints .................................................................................................. 14 
2.3 
Determination of Sample Size................................................................................ 14 
2.4 
Analysis Timing ...................................................................................................... 14 
3.0 
STUDY CONDUCT ..................................................................................................................... 15 
4.0 
STATISTICAL METHODS .......................................................................................................... 15 
4.1 
Analysis Population ................................................................................................ 16 
4.1.1 
Intent–to-Treat (ITT) population ............................................................................. 16 
4.1.2 
Safety population ................................................................................................... 16 
4.2 
Analysis of Study Conduct ..................................................................................... 16 
4.2.1 
Demographics and Baseline Characteristics ......................................................... 16 
4.3 
Primary And Secondary Analysis ........................................................................... 16 
4.3.1 
Primary Analysis .................................................................................................... 16 
4.3.2 
Secondary Analysis ................................................................................................ 17 
4.4 
Safety Analysis ....................................................................................................... 18 
4.5 
Missing Data .......................................................................................................... 19 
4.6 
Interim Analyses ..................................................................................................... 19 
4.7 
Additional Analyses ................................................................................................ 20 
4.8 
Data Listings .......................................................................................................... 20 
4.9  
Plots and Figures ................................................................................................... 20 
5.0 
REFERENCES ............................................................................................................................ 20 
14.1 DEMOGRAPHICS AND BASELINE CHARACTERISTICS ....................................................... 27 
14.1.1 
Patient Disposition ............................................................................................................. 27 
Table 14.1.1.1  Summary of Inclusion/Exclusion Criteria - All Population (N=XXX) .............. 27 


 
 
 
 
 
 
 
 
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Table 14.1.1.2  Summary of Patient Disposition-All Population (N=XXX) .............................. 28 
Table 14.1.1.3  Summary of Patient Disposition by Site- ITT Population (N=XXX) ............... 30 
Table 14.1.1.4  Summary of Subject Follow-up Rate at each Visit- ITT Population 
(N=XXX) ......................................................................................................... 31 
14.1.2 
Demographic and Baseline Characteristics .................................................................... 32 
Table 14.1.2.1  Summary of Patient Demographics at Screening- ITT Population 
(N=XXX) ......................................................................................................... 32 
Table 14.1.2.2  Summary of Medical History at Screening- ITT Population (N=XXX)............ 34 
Table 14.1.2.3  Summary of Breast Cancer Disease History at Screening- ITT 
Population (N=XXX) ....................................................................................... 35 
Table 14.1.2.4  Summary of Previous Therapy for Breast Cancer at Screening- ITT 
Population (N=XXX) ....................................................................................... 40 
Table 14.1.2.5  Summary of Physical Examination at Screening- ITT Population 
(N=XXX) ......................................................................................................... 42 
Table 14.1.2.6  Summary of Vital Signs at Screening- ITT Population (N=XXX) ................... 45 
Table 14.1.2.7  Summary of Assessment at Screening- ITT Population (N=XXX)................. 47 
Table 14.1.2.8  Summary of Tumor/Disease Assessment at Screening- ITT Population 
(N=XXX) ......................................................................................................... 48 
Table 14.1.2.9  Summary of LVEF and CHF at Screening- ITT Population (N=XXX) ............ 50 
Table 14.1.2.10 Summary of Hematology Test at Screening- ITT Population (N=XXX) ......... 52 
Table 14.1.2.11 Summary of Coagulation Test at Screening- ITT Population (N=XXX) ......... 54 
Table 14.1.2.12 Summary of Serum Chemistry at Screening- ITT Population (N=XXX) ........ 56 
Table 14.1.2.13 Summary of Viral Serology at Screening- ITT Population (N=XXX) .............. 58 
Table 14.1.2.14 Summary of ECOG Performance Status and Reproductive Status at 
Screening- ITT Population (N=XXX) .............................................................. 59 
Table 14.1.2.15 Summary of Serum Pregnancy Test at Screening- ITT Population 
(N=XXX) ......................................................................................................... 60 
Table 14.1.2.16 Summary of Survival Status at Screening- ITT Population (N=XXX) ............ 61 
14.2  
Efficacy Analysis ................................................................................................................ 62 
Table 14.2.1.1  Summary of Evaluation of target lesions as per RECIST Criteria at 
Each Visit- ITT Population (N=XXX) .............................................................. 62 
Table 14.2.1.1.1 Summary of Evaluation of non-target lesions as per RECIST Criteria at 
Each Visit - ITT Population (N=XXX) ............................................................. 64 
Table 14.2.1.1.2 Summary of Overall Response as per RECIST Criteria at Each Visit - 
ITT Population (N=XXX) ................................................................................ 65 
Table 14.2.1.2  Summary of Responder - ITT Population (N=XXX) ....................................... 68 
Table 14.2.1.3  Summary of Best Overall Response - ITT Population (N=XXX).................... 69 
Table 14.2.1.4  Summary of Overall Response Rate (CR+PR) - ITT Population 
(N=XXX) ......................................................................................................... 70 


 
 
 
 
 
 
 
 
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Table 14.2.1.5  Summary of Disease Control (CR+PR+SD) - ITT Population (N=XXX) ........ 71 
Table 14.2.1.6  Summary of Duration of Overall Response - ITT Population (N=XXX) ......... 72 
Table 14.2.1.7  Summary of Duration of Stable Disease - ITT Population (N=XXX) ............. 73 
Table 14.2.1.8  Summary of Progression Free Survival at Each Visit - ITT Population 
(N=XXX) ......................................................................................................... 74 
Table 14.2.1.9  Summary of Progression Free Survival by K-M Analysis - ITT 
Population (N=XXX) ....................................................................................... 76 
Table 14.2.1.10 Summary of Progression Free Survival by K-M Analysis for Disease 
Status - ITT Population (N=XXX) ................................................................... 77 
Table 14.2.1.11 Summary of Progression Free Survival by K-M Analysis for Prior anti-
HER2 treated patients - ITT Population (N=XXX) ......................................... 77 
Table 14.2.1.12 Summary of Progression Free Survival by K-M Analysis for Hormone 
Receptor status - ITT Population (N=XXX) .................................................... 77 
Table 14.2.1.13 Summary of Overall Survival at Each Visit - ITT Population (N=XXX) .......... 78 
Table 14.2.1.14 Summary of Overall Survival by K-M Analysis - ITT Population 
(N=XXX) ......................................................................................................... 80 
Table 14.2.1.15 Summary of Overall Survival by K-M Analysis for Disease Status - ITT 
Population (N=XXX) ....................................................................................... 81 
Table 14.2.1.16 Summary of Overall Survival by K-M Analysis for Prior anti-HER2 
treated patients - ITT Population (N=XXX) .................................................... 81 
Table 14.2.1.17 Summary of Overall Survival by K-M Analysis for Hormone Receptor 
status - ITT Population (N=XXX) ................................................................... 81 
14.3  
Safety Analysis ................................................................................................................... 82 
14.3.1 
Adverse Events ................................................................................................................... 82 
Table 14.3.1.1  Overall Summary of Adverse Events -Safety Population (N=XXX) ............... 82 
Table 14.3.1.1a Overall Summary of Treatment Emergent Adverse Events -Safety 
Population (N=XXX) ....................................................................................... 85 
Table 14.3.1.1b Overall Summary of Non-Treatment Emergent Adverse Events -Safety 
Population (N=XXX) ....................................................................................... 88 
Table 14.3.1.2  Summary of Adverse Events (including subjects reporting SAEs) by 
MedDRA System Organ Class and Preferred Term -Safety Population 
(N=XXX) ......................................................................................................... 91 
Table 14.3.1.2a Summary of Adverse Events (excluding subjects reporting SAEs) by 
MedDRA System Organ Class and Preferred Term -Safety Population 
(N=XXX) ......................................................................................................... 92 
Table 14.3.1.3  Summary of Adverse Events by MedDRA System Organ Class and 
Preferred Term by Intensity -Safety Population (N=XXX) ............................. 93 
Table 14.3.1.4  Summary of Adverse Events by MedDRA System Organ Class and 
Preferred Term by Action Taken -Safety Population (N=XXX) ...................... 95 
Table 14.3.1.5  Summary of Adverse Events by MedDRA System Organ Class and 
Preferred Term by Event Outcome -Safety Population (N=XXX) .................. 97 


 
 
 
 
 
 
 
 
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Table 14.3.1.6  Summary of Assessment during Adverse Event -Safety Population 
(N=XXX) ......................................................................................................... 99 
14.3.2 
Serious Adverse Events................................................................................................... 100 
Table 14.3.2.1  Summary of Serious Adverse Events -Safety Population (N=XXX) ............ 100 
Table 14.3.2.2  Summary of Serious Adverse Events by MedDRA System Organ Class 
and Preferred Term -Safety Population (N=XXX) ........................................ 104 
Table 14.3.2.3  Summary of Adverse Event of Special Interest -Safety Population 
(N=XXX) ....................................................................................................... 105 
14.3.3 
Concomitant Medication .................................................................................................. 109 
Table 14.3.3.1  Summary of Concomitant Medication Assessment -Safety Population 
(N=XXX) ....................................................................................................... 109 
14.3.4 
Vital Signs ......................................................................................................................... 110 
Table 14.3.4.1  Summary of Weight at all visits -Safety Population (N=XXX) ...................... 110 
Table 14.3.4.2  Summary of Vital Signs at different Cycles -Safety Population (N=XXX) .... 111 
Table 14.3.4.3  Summary of Vital Signs at different visits at follow-up Safety Population 
(N=XXX) ....................................................................................................... 113 
14.3.5 Physical Examination ........................................................................................................... 115 
Table 14.3.5.1  Summary of Physical Examination at all visits- Safety Population 
(N=XXX) ....................................................................................................... 115 
14.3.6 Laboratory Assessments ..................................................................................................... 116 
Table 14.3.6.1  Summary of Serum Chemistry at all visits- Safety Population (N=XXX) ..... 116 
Table 14.3.6.2  Summary of Hematology Test at All Visit- Safety Population (N=XXX) ...... 118 
Table 14.3.6.3  Summary of Coagulation Test at All Visits- Safety Population (N=XXX) ..... 120 
Table 14.3.6.4  Summary of Pregnancy Test at different Visits- Safety Population 
(N=XXX) ....................................................................................................... 122 
Table 14.3.6.5  Summary of ECOG at different Visits- Safety Population (N=XXX) ............ 123 
Table 14.3.6.6  Summary of LVEF and CHF at different Visits- Safety Population 
(N=XXX) ....................................................................................................... 124 
Table 14.3.6.7  Summary of LVEF at each visit-Safety Population (N=XXX) ....................... 126 
Table 14.3.6.8  Summary of Target Lesion (Sum of longest diameters) at each visit-
Safety Population (N=XXX) ......................................................................... 130 
Table 14.3.6.9  Summary of Mean Exposure to Study Treatment -Safety Population 
(N=XXX) ....................................................................................................... 134 
1.2 
Figures ............................................................................................................................... 135 
14.2.1 
Figures for Efficacy Analysis .......................................................................................... 135 
Figure 14.2.1.1 K-M Plot for Progression Free Survival by Treatment -ITT Population 
(N=XXX) ....................................................................................................... 135 
Figure 14.2.1.2 K-M Plot for Progression Free Survival by Disease Status -ITT 
Population (N=XXX) ..................................................................................... 135 


 
 
 
 
 
 
 
 
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Figure 14.2.1.3 K-M Plot for Progression Free Survival for Prior anti-HER2 treated 
patients -ITT Population (N=XXX) ............................................................... 135 
Figure 14.2.1.4 K-M Plot for Progression Free Survival for Hormone Receptor Status-
ITT Population (N=XXX) .............................................................................. 135 
Figure 14.2.1.5  Bar Chart for Response Rate Analysis at Each Visit -ITT Population 
(N=XXX) ....................................................................................................... 136 
Figure 14.2.1.6 K-M Plot for Overall Survival by Treatment -ITT Population (N=XXX) ........ 137 
Figure 14.2.1.7 K-M Plot for Overall Survival by Disease Status -ITT Population 
(N=XXX) ....................................................................................................... 137 
Figure 14.2.1.8 K-M Plot for Overall Survival for Prior anti-HER2 treated patients -ITT 
Population (N=XXX) ..................................................................................... 137 
Figure 14.2.1.9 K-M Plot for Overall Survival for Hormone Receptor Status-ITT 
Population (N=XXX) ..................................................................................... 137 
Figure 14.2.1.10 Line Diagram for LVEF over a period of time -Safety Population 
(N=XXX) ....................................................................................................... 138 
1.3 
LISTINGS .................................................................................................................................. 139 
16.2 
Patient Data Listings ........................................................................................................ 139 
Listing 16.2.1  Listing of Patient Discontinuation ................................................................. 139 
Listing 16.2.2.1 Listing of Protocol Deviation -Enrolled Population (N=XXX) ....................... 140 
Listing 16.2.2.2 Listing of Analysis Population Sets –Enrolled Population (N=XXX) ............ 141 
Listing 16.2.3  Listing of Patients who fail to meet Inclusion/Exclusion Criteria -
Enrolled Population (N=XXX) ...................................................................... 142 
16.2.4 
Listing of Demographics.................................................................................................. 143 
Listing 16.2.4.1 Listing of Patient Demographics -ITT Population (N=XXX) ......................... 143 
Listing 16.2.4.2 Listing of Medical History at Screening-ITT Population (N=XXX)................ 144 
Listing 16.2.4.3 Listing of Breast Cancer Disease Therapy at Screening-ITT Population 
(N=XXX) ....................................................................................................... 145 
Listing 16.2.4.4 Listing of Previous Hormone Therapy for Breast Cancer at Screening -
ITT Population (N=XXX) .............................................................................. 147 
Listing 16.2.4.5 Listing of Previous Immunotherapy for Breast Cancer at Screening -
ITT Population (N=XXX) .............................................................................. 148 
Listing 16.2.4.6 Listing of Previous Biologic Therapy for Breast Cancer at Screening -
ITT Population (N=XXX) .............................................................................. 149 
Listing 16.2.4.7 Listing of Previous Radiotherapy for Breast Cancer at Screening -ITT 
Population (N=XXX) ..................................................................................... 150 
Listing 16.2.4.8 Listing of Previous Chemotherapy for Breast Cancer at Screening -ITT 
Population (N=XXX) ..................................................................................... 151 
Listing 16.2.4.9 Listing of Previous Concomitant Therapy Log for Breast Cancer at 
Screening -ITT Population (N=XXX) ............................................................ 152 
16.2.6 
Listing for Efficacy ........................................................................................................... 153 


 
 
 
 
 
 
 
 
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Listing 16.2.6.1 Listing of Tumor/Disease Assessment (Target Lessions) -ITT 
Population (N=XXX) ..................................................................................... 153 
Listing 16.2.6.2 Listing of Tumor/Disease Assessment (Non-Target Lesions) -ITT 
Population (N=XXX) ..................................................................................... 154 
Listing 16.2.6.3 Listing of Tumor/Disease Assessment (New Lesions –Target Lesions 
and Non-target Lesions) -ITT Population (N=XXX) ..................................... 155 
Listing 16.2.6.4 Listing of Survival Status-ITT Population (N=XXX) ..................................... 156 
Listing 16.2.7  Listing of Adverse Event -Safety Population (N=XXX) ................................ 157 
Listing 16.2.7.1 Listing of Serious Adverse Event -Safety Population (N=XXX) ................... 157 
16.2.8 
Lab Test Evaluations ........................................................................................................ 159 
Listing 16.2.8.1 Listing of Hematology -Safety Population (N=XXX) .................................... 160 
Listing 16.2.8.2 Listing of Coagulation Test -Safety Population (N=XXX) ............................ 161 
Listing 16.2.8.3 Listing of Serum Chemistry -Safety Population (N=XXX) ............................ 162 
Listing 16.2.8.4 Listing of Viral Serology -Safety Population (N=XXX) ................................. 163 
Listing 16.2.8.5 Listing of Pregnancy Test -Safety Population (N=XXX) .............................. 164 
Listing 16.2.8.6 Listing of ECOG Performance Status -Safety Population (N=XXX) ............ 165 
Listing 16.2.8.7 Listing of LVEF (Left ventricular ejection fraction) -Safety Population 
(N=XXX) ....................................................................................................... 166 
16.4 
Individual subject data listings ....................................................................................... 167 
Listing 16.4.1  Listing of Vital Signs (All Enrolled Subjects) ................................................ 167 
Listing 16.4.1.1 Listing of Vital Signs -Safety Population (N=XXX) ....................................... 167 
Listing 16.4.1.2 Listing of Vital Signs during infusion of Pertuzumab, Trastuzumab and 
Docetaxel -Safety Population (N=XXX) ....................................................... 168 
Listing 16.4.2  Listing of Physical Examination -Safety Population (N=XXX) ..................... 169 
Listing 16.4.3  Listing of Her-2 Determination, CT/MRI and Isotope Bone Scan -Safety 
Population (N=XXX) ..................................................................................... 170 
Listing 16.4.4  Listing of Study Drug Administration ............................................................ 171 
Listing 16.4.4.1 Listing of Administration of Pertuzumab -Safety Population (N=XXX) ........ 171 
Listing 16.4.4.2 Listing of Administration of Trastuzumab -Safety Population (N=XXX) ....... 172 
Listing 16.4.4.3 Listing of Administration of Docetaxel -Safety Population (N=XXX) ............ 173 
Listing 16.2.4.4 Listing of Concomitant Medications -Safety Population (N=XXX) ............... 174 


 
 
 
 
 
 
 
 
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1.0 
BACKGROUND 
Pertuzumab (rhuMAb 2C4) is a recombinant, humanized immunoglobulin (Ig)G1κ 
monoclonal antibody, which targets HER2 (also known as c-erbB-2), a transmembrane 
glycoprotein with intrinsic tyrosine kinase activity. Pertuzumab and trastuzumab bind to 
distinct epitopes on the HER2 receptor without competing with each other, and have 
complementary mechanisms for disrupting HER2 signaling. This results in augmented anti-
proliferative activity in vitro and in vivo when pertuzumab and trastuzumab are given in 
combination. 
Previously many studies of different phases-Phase I/II/III were done using single-agent and 
combination regimens of Pertuzumab, such as Phase III WO20698/TOC4 129g 
(CLEOPATRA), phase II BP27836 (JOSHUA), Phase II BO22280 (TRYPHAENA) and so on.  
In Phase III, pivotal study WO20698/TOC4129g (CLEOPATRA; N = 808) in patients with 
previously-untreated HER2-positive mBC, a statistically significant and clinically meaningful 
improvement in progression-free survival (PFS), based on tumor assessments by an 
independent review facility (IRF), was observed in patients treated with pertuzumab (Ptz) + 
trastuzumab (T) + docetaxel (D) (N = 406) compared with those receiving placebo (Pla) + 
trastuzumab (T) + docetaxel (D) (N = 402). 
2.0 
STUDY DESIGN  
This is a Phase IV, single-arm, open-label, multicenter study to assess the safety and efficacy 
of pertuzumab in combination with trastuzumab and docetaxel for the treatment of patients 
with HER2-positive advanced (locally recurrent, unresectable, or metastatic) breast cancer. 
Patients must not have received systemic non-hormonal anticancer therapy for their locally 
recurrent, unresectable, or metastatic disease. 
A total of 52 patients will be enrolled over duration of approximately 12 months. 
Pertuzumab, trastuzumab, and docetaxel chemotherapy will be administered in line with the 
Prescribing Information. Docetaxel treatment will be given at least for 6 treatment cycles; 
thereafter decision for continuation of docetaxel treatment will be based on investigator’s 
discretion. 
Patients will receive study medication till disease progression or unacceptable toxicity or 
withdrawal of consent or death, whichever occurs first. 
All patients will be followed-up for at least 2 years after the last patient is enrolled; unless they 
have been lost to follow up, withdrawn consent, or died, or the study has been prematurely 
terminated by the Sponsor. 
Tumor assessments will be conducted every 9 weeks from the day 1 of first treatment cycle, 
i.e., every 3 cycles of monoclonal antibody treatment. Tumor assessments will be conducted 
during the follow-up period until progressive disease (PD) has been established, even if 
treatment has been discontinued due to unacceptable toxicity. 
 


 
 
 
 
 
 
 
 
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2.1 
Protocol Synopsis 
The protocol number is ML29282 titled as “A Phase IV, Multicenter, Open–Label Single-Arm 
Study of Pertuzumab (In Combination with Trastuzumab and Docetaxel) in First Line 
Treatment of Indian Patients with HER2-Positive Advanced (Metastatic or Locally Recurrent) 
Breast Cancer” and the Version is 1.0 amended on 6 June 2014. 
2.2 
Study Objectives and Endpoints 
2.2.1 Study Objectives 
2.2.1.1 
Primary Objective 
The primary objectives of this study are to evaluate safety and are as follows:- 
• 
To evaluate the safety of pertuzumab (in combination with trastuzumab and 
docetaxel) in Indian patients 
• 
To evaluate the tolerability of pertuzumab (in combination with trastuzumab and 
docetaxel) in Indian patients 
2.2.1.2 
Secondary Objective 
The secondary objectives of this study are to evaluate efficacy and are as follows:- 
To evaluate the efficacy of pertuzumab in combination with trastuzumab and docetaxel in 
Indian patients with respect to:- 
• 
Overall response rate (ORR) 
• 
Progression-free survival (PFS) 
• 
Overall survival (OS) 
2.2.2 Study Endpoints 
2.2.2.1 
Safety Endpoints 
The safety endpoints of this study are as follows: 
• 
Incidence and severity by NCI-CTCAE version 4.03 of AEs and SAEs 
• 
Incidence of CHF and/or significant decline in LVEF 


 
 
 
 
 
 
 
 
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• 
Change in LVEF over the course of the study 
• 
Laboratory results abnormalities 
• 
Incidence of AEs leading to discontinuation, modification, or interruption of study 
medication 
• 
Incidence and cause of death due to AEs 
2.2.2.2 
Efficacy Endpoints 
The efficacy endpoints of this study are as follows: 
• 
Overall response rate (ORR) 
• 
Progression-free survival (PFS) 
• 
Overall Survival (OS) 
2.3 
Determination of Sample Size 
A total of approximately 52 patients will be enrolled in this study. 
For the purpose of the estimation of sample size, the incidence of all grade AEs related to 
Pertuzumab in combination with Trastuzumab and Docetaxel was chosen as a safety 
endpoint of primary interest. If the observed incidence of all grade AEs related to Pertuzumab 
in combination with Trastuzumab and Docetaxel is 97.3% and assuming level of significance 
5% and precision 5%, 52 enrolled patients are planned for this study. 
Sample size calculation for estimating proportion: 
 
 
 
 
 
 =
/

∗
∗	


 
Where, 
n=Sample Size 
p=Incidence of AE related to Pertuzumab in combination with Trastuzumab and Docetaxel. 
d=Precision 
/=1.96 for 95% confidence level 
2.4 
Analysis Timing 
All patients will be followed-up for at least 2 years after the last patient is enrolled, unless they 
have been lost to follow up, withdrawn consent, or died, or the study has been prematurely 
terminated by the Sponsor, whichever occurs first. 
There will be two interim analyses for safety and efficacy. The first interim analysis is for 
safety only and will take place after 50% patients have been enrolled and followed for at least 
6 months of Pertuzumab therapy. The second interim analysis includes both safety and 
efficacy components and will take place after approximately 67% of the required deaths have 
been observed.  


 
 
 
 
 
 
 
 
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3.0 
STUDY CONDUCT 
This is a multi-centric, open-labeled, non-randomized post-marketing study, to assess the 
safety and efficacy of Pertuzumab in combination with Trastuzumab and Docetaxel. The 
study design employs standard methods for safety studies in patients with cancer. All patients 
will receive the active treatment. Safety will be carefully evaluated, and the type of data 
collected and the frequency with which patients are monitored will ensure safety of the 
patients. 
The study team will periodically review patient eligibility and CRF data to ensure that the 
study is compliant with Good Clinical Practice. 
The eligible patients for this study are the male or female patients with human epidermal 
growth factor receptor 2 (HER2)-positive advanced breast cancer (locally recurrent, 
unresectable, or metastatic) who have not previously received systemic non-hormonal 
anticancer therapy in the metastatic setting. 
The iDMC will review unblinded summaries of patient accrual, demographics and baseline 
characteristics, patient disposition, and eligibility violations at the interim analyses.  The iDMC 
will alert the Sponsor if there are concerns about the appropriateness of the study population 
based on characteristics of enrolled patients, concerns about eligibility violations, or problems 
with protocol compliance. 
The iDMC or the Study Clinical Scientist may request additional interim safety analyses if 
safety concerns arise. 
An iDMC will be formed and composed of 3 members, including a statistician. An iDMC will 
perform the review of this interim analysis of efficacy and safety and subsequent safety 
reviews as described in the iDMC Charter. 
 
4.0 
STATISTICAL METHODS 
All baseline summaries and efficacy analyses will be based on the intent-to-treat (ITT) 
population. This will be defined as all enrolled patients. All safety summaries and analysis will 
be based on the safety population, defined as all enrolled patients who receive at least one 
dose of study medication. The data will be summarized as: 
• 
Continuous data will be summarized using: n, mean, median, range, standard 
deviation, minimum and maximum. 
• 
Discrete data will be summarized using frequency counts (n) and percentages (%) 
All demography and baseline disease characteristics (collected at either the screening or 
baseline) will be summarized using the ITT population. In order to assess the conduct of the 
study, major protocol violations will be summarized and listed. 
Overall response rate (ORR) 95% confidence intervals will be calculated using Clopper-
Pearson methodology. 
PFS will be analyzed by the Kaplan-Meier (KM) approach. The analysis of PFS will be based 
on the survivor function, which is the probability of remaining event free beyond a certain 
point in time. The survival function will be estimated and summarized using the 25th and 75th 
percentiles, median survival, and a 95% confidence interval (CI) for the median.  
OS will also be analyzed by the Kaplan-Meier (KM) approach. Patients without follow-up 
assessment will be censored at the day of last study medication, and patients with no post-


 
 
 
 
 
 
 
 
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baseline information will be censored at baseline. OS will be summarized using the 25th and 
75th percentiles, median survival, and a 95% confidence interval (CI) for the median. 
4.1 
Analysis Population 
4.1.1 Intent–to-Treat (ITT) population 
Intent-to-Treat (ITT) population is defined as all the patients who are enrolled in the study. 
4.1.2 Safety population 
Safety population will include all those patients who have received at least one dose of study 
medication. 
4.2 
Analysis of Study Conduct 
This is a multi-centric, open-labeled, non-randomized post-marketing study, to assess the 
safety and efficacy of Pertuzumab in combination with Trastuzumab and Docetaxel. The 
study design employs standard methods for safety studies in patients with cancer. All patients 
will receive the active treatment. Safety will be carefully evaluated, and the type of data 
collected and the frequency with which patients are monitored will ensure safety of the 
patients. 
The eligible patients for this study are the male or female patients with human epidermal 
growth factor receptor 2 (HER2)-positive advanced breast cancer (locally recurrent, 
unresectable, or metastatic) who have not previously received systemic non-hormonal 
anticancer therapy in the metastatic setting. 
The analysis for different parameters is described below: 
4.2.1 Demographics and Baseline Characteristics 
Subject demographics include Age, Gender, Race, Ethnicity, Height, and Weight. 
Variables that are measured on a continuous scale, which includes the age, weight, and 
height, BMI of the subject the number of non-missing observations, mean, median, SD, 
minimum, and maximum will be presented and variables that are measured on a categorical 
scale, which include gender, ethnicity the frequency count and percentages will be 
represented.  
Medical/Surgical History includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies including trastuzumab treatment and procedures), 
reproductive status, cardiovascular history, and all medications (e.g., prescription drugs, over-
the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within 28 days prior to the screening visit will be summarized by frequency counts and 
percentages. 
All demography and baseline characteristics (collected at either the screening or baseline) will 
be summarized using the ITT population. 
4.3 
Primary And Secondary Analysis 
4.3.1 Primary Analysis 


 
 
 
 
 
 
 
 
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The primary analyses are on safety and tolerability evaluation of pertuzumab (in combination 
with trastuzumab and docetaxel) in Indian patients. Primary safety and tolerability analysis will 
be summarized for the Safety population. 
 
• 
Incidence and severity of AEs and serious adverse events (SAEs) by National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03 
 
The incidence of AEs and SAEs will be summarized according to the primary system-organ 
class (SOC) and within each SOC, by the Medical Dictionary for Regulatory Activities 
(MedDRA) preferred term. 
 
• The incidence of AEs and SAEs 
• 
Overall 
• 
By TEAEs and Non-TEAEs 
• 
By severity using NCI CTCAE version 4.03 
• 
By relationship to study drug 
• 
By action taken with study drug 
• 
By outcome 
 
Incidences and Severity will be summarized by frequency count and percentages. 95% 
confidence intervals will be calculated using Clopper-Pearson for incidences. 
 
• 
Incidence of CHF will be summarized by frequency count and percentages. 
 
• 
Significant decline in LVEF will be summarized by frequency count and percentages. 
 
• 
Change in LVEF will be summarized by cycle including change from baseline summaries and 
frequency count and percentages. 
 
• 
Laboratory data will be analyzed by the number of non-missing observations, mean, median, 
SD, minimum, and maximum. Shift table will be presented to show the change from baseline 
to different visits. 
 
• 
Incidence of AEs leading to discontinuation, modification or interruption of study 
medication will be summarized by frequency count and percentages. 
 
• 
The incidence and cause of deaths due to AE will be summarized by frequency count and 
percentages. 
 
4.3.2 Secondary Analysis 
Secondary Efficacy variables will be summarized for the intent-to-treat (ITT) population. 
The secondary analyses are on efficacy evaluation of pertuzumab in combination with 
trastuzumab and docetaxel in Indian patients with respect to: 
• 
Overall response rate (ORR) 
Overall response (partial response [PR] plus complete response [CR]) determined by the 
investigator using Response Evaluation Criteria in Solid Tumors (RECIST) criteria).  
The analysis of ORR is based on the best (confirmed) overall response (BOR). Best 
(confirmed) overall response (BOR) is defined as the best response recorded from the 
start of trial treatment until disease progression/recurrence or death. To be assigned a 


 
 
 
 
 
 
 
 
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status of PR or CR (i.e., a responder), changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after 
the criteria for response are first met, i.e., patients need to have two consecutive 
assessments of PR or CR to be a responder. 
 
 
Patients without a post-baseline tumor assessment will be considered to be non-
responders.  
Overall response rate (ORR) 95% confidence intervals will be calculated using Clopper-
Pearson methodology. 
 
• 
Progression-free survival (PFS) 
Progression-free survival (PFS), defined as the time from enrollment to the first 
occurrence of disease progression as determined by the investigator using RECIST 
criteria version 1.1, or death from any cause, whichever occurs first. Patients who have 
not progressed, died or lost to follow up at the time of the analysis will be censored on 
the last visit at which assessment for progression was done (two years after the last 
patient enrolled).  
PFS will be analyzed by the Kaplan-Meier (KM) approach.  
Patients without post baseline tumor assessments will be censored at the time of their 
baseline visit unless death occurs prior to their first scheduled tumor assessment. 
The analysis of PFS will be based on the survivor function, which is the probability of 
remaining event free beyond a certain point in time. The survival function will be 
estimated and summarized using the 25th and 75th percentiles, median survival, and a 
95% confidence interval (CI) for the median.  
• 
Overall Survival (OS) 
Overall survival, defined as the time from the date of enrollment to the date of death, 
regardless of the cause of death. Patients who will be alive at the time of the analysis will 
be censored at the date of the last follow-up assessment (two years from last patient 
enrolled in the study). 
OS will also be analyzed by the Kaplan-Meier (KM) approach.  
Patients without follow-up assessment will be censored at the day of last study 
medication, and patients with no post-baseline information will be censored at baseline. 
OS will be summarized using the 25th and 75th percentiles, median survival, and a 95% 
confidence interval (CI) for the median. 
4.4 
Safety Analysis 
The analysis of safety assessments in this study will include summaries of the following 
categories of safety data collected for each subject. It will be performed on safety population. 
• 
Adverse event 
• 
Concomitant medications  
• 
Physical Examination (PE)  
• 
Vital signs  
• 
Pregnancy test results  
• 
Eastern Cooperative Oncology Group (ECOG) 
• 
Body weight 
 


 
 
 
 
 
 
 
 
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Data for continuous variables will be summarized descriptively using number of subjects (n), 
mean, SD, median, Range (minimum and maximum). Categorical data will be presented by 
number of exposed subjects along with percentage of exposed subjects in the various 
categories of the endpoint.  
 
Adverse Events  
 
AEs and SAEs will be coded by System organ class and preferred term, using the latest 
version 18.1 of MedDRA and will be summarized by frequency count and percentages. 
 
Concomitant Medications  
 
Concomitant medications will be coded by drug class and therapeutic class using the 
WHODD dated 1st Sep 2015 and will be summarized by frequency count and percentages. 
 
Physical Examinations  
 
Physical examination will be summarized for each body system such as head, eyes, ears, 
nose, and throat, and cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems will be summarized by frequency 
count and percentages. 
 
Vital signs  
 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and diastolic 
blood pressure while the patient is in a seated position descriptively using number of subjects 
(n), mean, SD, median, Range (minimum and maximum) for each visit and change from 
screening visit to all visits will also be summarized.  
 
Laboratory Parameters  
 
Laboratory parameters will be summarized for actual values at each visit, and change from 
screening visit to each visit. Actual values for each parameter will also be listed by subject. 
Shift tables for each laboratory parameter will also be prepared to represent the shift from 
screening to end of study. Laboratory data will be summarized as per the descriptive statistics 
mentioned above for numeric data.  
 
ECOG  
 
Score for ECOG test will be summarized using frequency count with number of subjects in a 
particular class along with percentages of subjects. 
4.5 
Missing Data 
No statistical imputation method will be applied for any missing values.  
4.6 
Interim Analyses 
There will be two interim analyses for safety and efficacy. The first interim analysis is for 
safety only and will take place after 50% patients have been enrolled and followed for at least 
6 months of Pertuzumab therapy. The second interim analysis includes both safety and 
efficacy components and will take place after approximately 67% of the required deaths have 
been observed.  


 
 
 
 
 
 
 
 
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An iDMC will be formed and composed of 3 members, including a statistician. An iDMC will 
perform the review of this interim analysis of efficacy and safety and subsequent safety 
reviews as described in the iDMC Charter.  
4.7 
Additional Analyses  
If any additional statistical analyses required during the final analysis, appropriate methods 
will be used, and any changes, including the rationale for use, will be documented via 
Statistical Analysis Plan amendment. Any deviations from the planned analyses or 
prospective amendments to the statistical analysis plan will be documented in the Clinical 
Study Report (CSR). 
4.8 
Data Listings 
All CRF data, as well as any outcomes derived from the data, will be summarised in detailed 
data listings. Patient data listings will be presented for all patients enrolled into the study. 
4.9  
Plots and Figures 
The plots and graphs will be presented to illustrate the analysis of safety and efficacy.  
• 
A K-M plot of survival probability versus time will be generated to see the overall 
survival profile of the patients for the single treatment group. 
• 
A K-M plot of PFS probability versus time will be generated to see the PFS profile of 
the patients for the single treatment group. 
• 
A bar chart will be generated to understand the response rate of patients as per 
RECIST criteria.  
• 
A graph of  LVEF over a period of time for all patients (Including mean and median)  
5.0 
REFERENCES 
1. ICH E3: Structure and content of Clinical Study Reports, November 1995, Committee for 
Proprietary Medicinal Products. 
2. ICH E9: Statistical Principles for Clinical Trials, September 1998, Committee for Proprietary 
Medicinal Products. 
 
 


 
 
 
 
 
 
 
 
 
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Appendix 1 
Protocol Synopsis 


 
 
 
 
 
 
 
 
 
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Appendix 2 
Schedule of Assessments 
 
 
 
 


 
 
 
 
 
 
 
 
 
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Notes: 
1. Signed/dated informed consent in language comprehended by the potential ;clinical trial subject/LAR 
2. Complete medical history and demographics (i.e., age, sex, race, and ethnicity, if applicable) and all medications taken during the last 28 days prior to 
screening visit will be collected. 
3. Current concomitant medication will be recorded at Screening and on an ongoing basis. 


 
 
 
 
 
 
 
 
 
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4. Physical Examination includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems. Record abnormalities observed at baseline on the General Medical History and 
Baseline Conditions eCRF. Record new or worsened clinically significant abnormalities on the AE eCRF. 
5. Vital signs will be assessed before treatment on Day 1 of every treatment cycle (pertuzumab, trastuzumab, and chemotherapy), recorded again after 
infusion during the observation period of each study medication. Vital signs include respiratory rate, pulse rate, and systolic and diastolic blood 
pressure while the patient is in a seated position, and oral or axillary temperature. 
6. Documented evidence of HER2 positive status from previous testing is acceptable, otherwise HER2-positive status on fixed tissue blocks from the 
primary tumor (and/or metastatic site, if primary tumor not available) to be assessed locally by IHC and/or ISH according to institutional criteria and 
routine clinical practice. On treatment days, all assessments should be performed prior to dosing, unless otherwise specified. 
7. A CT or MRI and (if indicated) isotope bone scan (evaluation according to RECIST criteria) should be performed at screening and as clinically 
indicated. Scans at screening should not be older than 28 days prior to first study medication administration. NB: Bone scan, PET scan or plain films 
are not considered adequate imaging techniques to measure bone lesions. 
8. Laboratory Assessment as per routine standard of care must be performed within 3 days (with results available) prior to the administration of study 
medication. Hematology, as per routine standard of care, may include hemoglobin, hematocrit, platelet count, RBC, WBC with differential 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils, other cells). Serum chemistry, as per routine standard of care, may include sodium, 
potassium, calcium, chloride, magnesium, BUN (urea), uric acid, total protein, albumin, ALP, ALAT, ASAT, gamma glutamyl transferase (GGT), 
lactate dehydrogenase (LDH), total bilirubin, creatinine, and blood glucose and calculated creatinine clearance at baseline. Coagulation tests will 
consist of INR and aPTT or PTT). 
9. ECOG PS to be recorded every 3 cycles until PD. 
10. LVEF ≥50% at Screening period to be determined by either ECHO or MUGA scan (with ECHO as the preferred method). The same method of LVEF 
assessment (ECHO or MUGA) must be used for the same patient throughout the study and, to the extent possible, be obtained at the same 
institution. 
11. After informed consent, and prior to dosing, SAEs considered related to a study mandated procedure are reportable. As of cycle 1 all AEs and SAEs 
considered will be collected. AEs and SAEs to be monitored continuously collected and End-of-study visit and to be recorded with grading according 
to NCI-CTCAE, Version 4.03 
12. For women of childbearing potential, serum β-HCG test must be performed within 7 days prior to the first dose of study treatment with the result 
available prior to first dosing. Urine β-HCG test must be performed within 7 days prior to every 3rd cycles (with results available prior to treatment), at 


 
 
 
 
 
 
 
 
 
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the safety follow up visit, and at 4 and 7 months after the last dose of study treatment. If a urine pregnancy test is positive, it must be confirmed by a 
serum pregnancy test. 
13. Overall survival is the time from the date of enrollment to the date of death, regardless of the cause of death. Patients who were alive at the time of 
the analysis will be censored at the date of the last follow-up assessment (two years from last patient enrolled in the study). 
14. All treatment visits within ±3 days of scheduled treatment day; 28 day Safety Follow up visit within ±3 days of the scheduled visit date; 3 monthly 
Follow up visits (starting after safety follow-up visit) within ±14 days of the scheduled visit date(s); End of Study visit within ±14 days of the scheduled 
visit date. Tumour assessment ±3 days of planned scheduled visit. At the end of study visit, if patient does not fit into end of study definition, then 
tumour assessment to be done as per institutional criteria and routine clinical practice. 
15. Patients who complete the study or discontinue from the study early will be asked to return to the hospital within 28 days after the last dose of study 
drug for the end-of-study visit. 
 


 
 
 
 
 
 
 
 
 
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14.1 Demographics and Baseline Characteristics 
14.1.1 
Patient Disposition 
Table 14.1.1.1 
Summary of Inclusion/Exclusion Criteria - All Population (N=XXX) 
Inclusion/Exclusion Criteria, n (%)[1] 
Pertuzumab 
(N=XXX) 
Number of Subjects Screened 
XXX 
Number of Subjects Enrolled [1] 
XX (XX.X %) 
Number of Subjects Enrolled meeting all Inclusion Criteria  
XX (XX.X %) 
Number of Subjects meeting at least one exclusion criteria 
XX (XX.X %) 
 
 
Source: Listing 16.2.3 
 
Note: [1] Percentage will be calculated by taking respective column header count as denominator. 
 
 
General Note:  
 Subjects who are meeting inclusion and exclusion criteria will be considered for eligibility analysis.  
 Subjects who are eligible will be considered to enroll into the study.  


 
 
 
 
 
 
 
 
 
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Table 14.1.1.2 
Summary of Patient Disposition-All Population (N=XXX) 
 
Patient Disposition, n (%) [1] 
Pertuzumab 
(n=xxx) 
Population 
 
   Screened Population 
XX  
   Intent-to-Treat Population 
XX (XX.X %) 
   Safety Population 
XX (XX.X %) 
 
 
Patients  who completed the  protocol 
 
   Yes 
XX (XX.X %) 
   No 
XX (XX.X %) 
 
 
Reason for discontinuation of study treatment  
 
   Withdrawal of Consent 
XX (XX.X %) 
   Any medical condition that the Investigator or Sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study 
XX (XX.X %) 
   Investigator or Sponsor determines it is in the best interest of the 
patient 
XX (XX.X %) 
   Patient Non-compliance 
XX (XX.X %) 
   Death 
      Death due to Disease Progression [2] 
XX (XX.X %) 
XX (XX.X %) 
   Disease Progression 
XX (XX.X %) 
Lost to follow-up 
XX (XX.X %) 
Due to AE 
XX (XX.X %) 
   Other [3] 
XX (XX.X %) 
 
 
Source Data: Listing 16.2.1, 16.2.2.1 and 16.2.2.2 
Note: 
[1] Percentages will be calculated using (N=XXX) of column header group as denominator. 


 
 
 
 
 
 
 
 
 
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[2] Percentages will be calculated using (N=XXX) of Death Count as denominator. 
[3] If the reason is others, then it will be specified. 


 
 
 
 
 
 
 
 
 
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Table 14.1.1.3 
Summary of Patient Disposition by Site- ITT Population (N=XXX) 
 
Site, n (%) [1] 
Pertuzumab 
(N=XX) 
Site 1  
XX (XX.X %) 
Site 2 
XX (XX.X %) 
Site 3 
XX (XX.X %) 
Site 4 
XX (XX.X %) 
Site 5 
XX (XX.X %) 
…… 
…… 
Site n 
XX (XX.X %) 
 
 
Source Data: Listing 16.2.1 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
 
 




 
 
 
 
 
 
 
 
 
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14.1.2 
Demographic and Baseline Characteristics 
Table 14.1.2.1 
Summary of Patient Demographics at Screening- ITT Population (N=XXX) 
 
Demographics 
Statistics / Category, n(%)[1] 
Pertuzumab 
(N=XX) 
Age (years) [2] 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
Missing [3] 
XX (XX.X %) 
 
 
 
Gender 
 
 
 
Male 
XX (XX.X %) 
 
Female 
XX (XX.X %) 
 
Missing [3] 
XX (XX.X %) 
 
 
 
Race 
 
 
 
Asian 
XX (XX.X %) 
 
Others 
XX (XX.X %) 
 
Missing [3] 
XX (XX.X %) 
 
 
 
Ethnicity 
 
 
 
Indian Subcontinent 
XX (XX.X %) 
 
Others 
XX (XX.X %) 
 
Missing [3] 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.4.1 
Note:  
[1]Percentages will be calculated using respective column header group as denominator. 


 
 
 
 
 
 
 
 
 
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[2]If Date of Birth date is given then to calculate the Age by following formula: Age = {[Date of Informed Consent 
signed (Screening Date) – Date of Birth +1] /365.25 
[3]If a particular parameter measurement is not captured, it will be displayed under ‘Missing’ category. 
 
 




 
 
 
 
 
 
 
 
 
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Table 14.1.2.3 
Summary of Breast Cancer Disease History at Screening- ITT Population (N=XXX) 
 
 
Breast Cancer Disease History 
 
Statistics/Category, n (%)[1] 
Pertuzumab 
(N=XX) 
How was breast cancer diagnosed 
 
 
 
Cytologically 
XX (XX.X %) 
 
Histologically 
XX (XX.X %) 
 
Both 
XX (XX.X %) 
 
 
 
Breast cancer stage at initial diagnosis 
 
 
 
I 
XX (XX.X %) 
 
II 
XX (XX.X %) 
 
III 
XX (XX.X %) 
 
IV 
XX (XX.X %) 
 
 
 
History of Primary Tumor 
 
 
Location of Primary Tumor 
 
 
 
Left 
XX (XX.X %) 
 
Right 
XX (XX.X %) 
 
Left and Right 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 
 
 
 
Was the primary tumor 
 
 
 
Unifocal 
XX (XX.X %) 
 
Multifocal 
XX (XX.X %) 
 
Multicentric 
XX (XX.X %) 
 
 
 
Primary tumor size (mm) 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Breast cancer subtype 
 
 


 
 
 
 
 
 
 
 
 
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Infiltrating Ductal Carcinoma 
XX (XX.X %) 
 
Infiltrating Lobular Carcinoma 
XX (XX.X %) 
 
Inflammatory Breast Carcinoma 
XX (XX.X %) 
 
Other 
XX (XX.X %) 
 
 
 
Histological grade 
 
 
 
Well Differentiated 
XX (XX.X %) 
 
Moderately Differentiated 
XX (XX.X %) 
 
Poorly Differentiated 
XX (XX.X %) 
 
Anaplastic 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 
 
 
 
Nuclear grade 
 
 
 
Grade 1 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
 
Grade 4 
XX (XX.X %) 
 
 
 
Estrogen receptor status 
 
 
 
Estrogen Receptor Positive 
XX (XX.X %) 
 
Estrogen Receptor Negative 
XX (XX.X %) 
 
 
 
Progesterone receptor status 
 
 
 
Progesterone Receptor Positive 
XX (XX.X %) 
 
Progesterone Receptor Negative 
XX (XX.X %) 
 
 
 
Breast cancer type 
 
 
 
Operable 
XX (XX.X %) 
 
Locally Advanced Inoperable 
XX (XX.X %) 
 
Inflammatory 
XX (XX.X %) 
 
 
 
Breast Tumor Remnants 
 
 
Microscopic Assessments 
 
 
 
Single Focus(mm) 
 
 
n 
XX 
 
Mean 
XX.X 


 
 
 
 
 
 
 
 
 
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SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
 
Multiple foci Largest 
Diameter(mm) 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
 
Tumour Largest Diameter(mm) 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Macroscopic assessment 
 
 
 
Gross tumor size 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
 
 
 
Pathological staging of breast cancer 
 
 
 
Known 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 
 
 
 
Histology 
 
 
Histological grade 
 
 
 
Well Differentiated 
XX (XX.X %) 
 
Moderately Differentiated 
XX (XX.X %) 
 
Poorly Differentiated 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Anaplastic 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 
 
 
 
Breast cancer subtype 
 
 
 
Ductal 
XX (XX.X %) 
 
Lobular 
XX (XX.X %) 
 
Other 
XX (XX.X %) 
 
 
 
Is DCIS (Ductal carcinoma in situ) present 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Diagnosis of metastatic or Locally recurrent Breast 
Cancer 
 
 
 
Locally Recurrent 
XX (XX.X %) 
 
Metastatic 
XX (XX.X %) 
 
 
 
HER2 Confirmation If Metastatic 
 
 
Method 
 
 
 
Immunohistochemistry (IHC) 
XX (XX.X %) 
 
In situ hybridization (ISH) 
XX (XX.X %) 
 
 
 
Expression Score 
 
 
IHC 
 
 
 
0 
XX (XX.X %) 
 
1+ 
XX (XX.X %) 
 
2+ 
XX (XX.X %) 
 
3+ 
XX (XX.X %) 
ISH 
 
 
 
Negative (Non-Amplified) 
XX (XX.X %) 
 
Positive (Amplified) 
XX (XX.X %) 
 
 
 
Progesterone Receptor Score if Metastatic 
 
 
 
Positive 
XX (XX.X %) 
 
Negative 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Estrogen Receptor Score if Metastatic 
 
 
 
Positive 
XX (XX.X %) 
 
Negative 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 
 
 
 
Any previous therapy for Breast Cancer prior to 
Study 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.4.3 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.4 
Summary of Previous Therapy for Breast Cancer at Screening- ITT Population (N=XXX) 
 
 
Previous Therapy [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Has the patient received any hormone therapy 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
If Yes, Ongoing [2] 
 
XX (XX.X %) 
 
 
 
Has the patient received any Immunotherapy 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
If Yes, Ongoing [3] 
 
XX (XX.X %) 
 
 
 
Has the patient received any Biologic therapy 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
If Yes, Ongoing [4] 
 
XX (XX.X %) 
 
 
 
Has the patient received any Radiotherapy 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
If Yes, Ongoing [5] 
 
XX (XX.X %) 
 
 
 
Has the patient received any chemotherapy 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 


 
 
 
 
 
 
 
 
 
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If Yes, Ongoing [6] 
 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.4.4, 16.2.4.5, 16.2.4.6, 16.2.4.7, 16.2.4.8, and 16.2.4.9 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
[2] Percentages will be calculated using ‘Yes’ category of ‘Patients receiving Hormone Therapy’ as denominator. 
[3] Percentages will be calculated using ‘Yes’ category of ‘Patients receiving Immunotherapy’ as denominator. 
[4] Percentages will be calculated using ‘Yes’ category of ‘Patients receiving Biologic Therapy’ as denominator. 
[5] Percentages will be calculated using ‘Yes’ category of ‘Patients receiving Radiotherapy’ as denominator. 
[6] Percentages will be calculated using ‘Yes’ category of ‘Patients receiving chemotherapy’ as denominator. 
 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.5 
Summary of Physical Examination at Screening- ITT Population (N=XXX) 
 
 
System/Result/Significance [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
General appearance 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Musculoskeletal 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Dermatological 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Gastrointestinal 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
HEENT 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Respiratory 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Cardiovascular 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Genitourinary 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 


 
 
 
 
 
 
 
 
 
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Neurological 
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Other  
 
 
Results 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
Clinical Significance 
 
 
 
NCS 
XX (XX.X %) 
 
CS 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.4.2 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.6 
Summary of Vital Signs at Screening- ITT Population (N=XXX) 
 
 
Vital Signs [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Pulse Rate (rate/min) 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Respiratory Rate (breathes/min) 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Blood Pressure (mm/hg) 
 
 
Systolic 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Diastolic 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Temperature (°C) 
 
 
 
n 
XX 
 
Mean 
XX.X 


 
 
 
 
 
 
 
 
 
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SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Height (cms.) 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Weight (kgs.) 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Source Data: Listing 16.4.1 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.7 
Summary of Assessment at Screening- ITT Population (N=XXX) 
 
 
Assessment [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
HER2 Determination 
 
 
Assessment Performed 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
IHC Result 
0/+ 
XX (XX.X %) 
 
++ 
XX (XX.X %) 
 
+++ 
XX (XX.X %) 
 
 
 
ISH Result 
Negative 
XX (XX.X %) 
 
Positive 
XX (XX.X %) 
 
 
 
CT/MRI 
 
 
Any clinically significant abnormalities 
noted in the CT/MRI 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Isotope Bone Scan 
 
 
Result 
Normal 
XX (XX.X %) 
 
Abnormal 
XX (XX.X %) 
Source Data: Listing 16.4.3 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.8 
Summary of Tumor/Disease Assessment at Screening- ITT Population (N=XXX) 
 
 
Assessment [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Tumor/Disease Assessment 
 
 
Any target lesions 
Yes 
XX (XX.X %) 
No 
XX (XX.X %) 
 
 
 
Lesion measurable 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Reason 
Tumour too large to accurately 
measure 
XX (XX.X %) 
 
Tumour too small to accurately 
measure 
XX (XX.X %) 
 
Other Reason 
XX (XX.X %) 
 
 
 
Target Lesions 
 
 
Sum of longest diameters 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Inflammatory Breast Cancer 
 
 
Erythema 
No 
XX (XX.X %) 
 
Less than 1/3 of breast 
XX (XX.X %) 
 
More than 1/3 of breast 
XX (XX.X %) 
 
 
 
Edema 
No 
XX (XX.X %) 
 
Less than 1/3 of breast 
XX (XX.X %) 
 
More than 1/3 of breast 
XX (XX.X %) 
 


 
 
 
 
 
 
 
 
 
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Are there any non-target(non-measurable) lesions 
Yes 
XX (XX.X %) 
No 
XX (XX.X %) 
 
 
 
Method of Assessment 
CT with Contrast 
XX (XX.X %) 
 
CT without Contrast 
XX (XX.X %) 
 
MRI with Contrast 
XX (XX.X %) 
 
MRI without Contrast 
XX (XX.X %) 
 
Status of Lesion 
Present 
XX (XX.X %) 
 
Absent 
XX (XX.X %) 
 
Unequivocal Progression 
XX (XX.X %) 
 
Screening/Baseline Assessment 
XX (XX.X %) 
Number Of Non-Target Lesions 
Within The Organ 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Source Data: Listing 16.4.3 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.9 
Summary of LVEF and CHF at Screening- ITT Population (N=XXX) 
 
LVEF [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Results (%) 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
LVEF 
 done by 
 
 
 
MUGA 
XX (XX.X %) 
 
Echocardiography 
XX (XX.X %) 
 
 
 
If Echocardiography, method [2] 
 
 
 
Simpson (2-D) 
XX (XX.X %) 
 
Teichholz (M-mode) 
XX (XX.X %) 
 
 
 
LVEF finding 
 
 
 
Normal 
XX (XX.X %) 
 
Abnormal but not clinically 
significant 
XX (XX.X %) 
 
Abnormal and clinically 
significant 
XX (XX.X %) 
 
 
 
Any new cardiac signs and symptoms 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Any worsening cardiac signs and symptoms 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Any signs or symptoms of CHF 
 
 
 
Yes 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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No 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.8.7 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
[2] Percentages should be calculated using count “Echocardiography” of “LVEF done by” as denominator.  


 
 
 
 
 
 
 
 
 
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Table 14.1.2.10 
Summary of Hematology Test at Screening- ITT Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Hemoglobin 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Hematocrit 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Red Blood Cells (RBC) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 




 
 
 
 
 
 
 
 
 
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Table 14.1.2.11 
Summary of Coagulation Test at Screening- ITT Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
International normalization ratio(INR) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Activated Partial Thromboplastin Time (aPTT) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Partial Thromboplastin Time (PTT) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 


 
 
 
 
 
 
 
 
 
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Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.8.2 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
 
 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.12 
Summary of Serum Chemistry at Screening- ITT Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Sodium 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Potassium 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Calcium 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 




 
 
 
 
 
 
 
 
 
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Table 14.1.2.13 
Summary of Viral Serology at Screening- ITT Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
HIV I 
 
 
Result 
Reactive 
XX (XX.X %) 
 
Non-Reactive 
XX (XX.X %) 
 
 
 
HIV II 
 
 
Result 
Reactive 
XX (XX.X %) 
 
Non-Reactive 
XX (XX.X %) 
 
 
 
Hepatitis B surface antigen (HBsAG) 
 
 
Result 
Reactive 
XX (XX.X %) 
 
Non-Reactive 
XX (XX.X %) 
 
 
 
Total Hepatitis B Core antibody (HBcAB) 
 
 
Result 
Reactive 
XX (XX.X %) 
 
Non-Reactive 
XX (XX.X %) 
 
 
 
Hepatitis C Virus (HCV) antibody 
 
 
Result 
Reactive 
XX (XX.X %) 
 
Non-Reactive 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.8.4 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.14 
Summary of ECOG Performance Status and Reproductive Status at Screening- ITT Population (N=XXX) 
 
Status [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
ECOG Performance Status 
 
 
Grade 
0 
XX (XX.X %) 
 
1 
XX (XX.X %) 
 
2 
XX (XX.X %) 
 
3 
XX (XX.X %) 
 
4 
XX (XX.X %) 
 
 
 
Reproductive Status 
 
 
Response 
Childbearing Potential Without Contraceptive Protection 
XX (XX.X %) 
 
Surgically Sterilized 
XX (XX.X %) 
 
Childbearing Potential With Contraceptive Protection 
XX (XX.X %) 
 
Post-Menopausal 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.8.6 
Note: [1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
 
Note: In ECOG Performance Status 
Grade 0= Fully active, able to carry on all pre -disease performance without restriction 
Grade 1= Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, 
e.g., light house work, office work 
Grade 2= Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking 
hours 
Grade 3= Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
Grade 4= Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.15 
Summary of Serum Pregnancy Test at Screening- ITT Population (N=XXX) 
 
Result [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Was Serum Pregnancy Test Done 
 
 
 
Done 
XX (XX.X %) 
 
Not Done 
XX (XX.X %) 
 
Not Applicable 
XX (XX.X %) 
 
 
 
If done, results [2] 
Positive 
XX (XX.X %) 
 
Negative 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.8.5 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
[2] Percentages will be calculated using “Done” category of “Was Serum Pregnancy Test Done” as denominator. 
 


 
 
 
 
 
 
 
 
 
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Table 14.1.2.16 
Summary of Survival Status at Screening- ITT Population (N=XXX) 
 
Status [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Survival Status 
 
 
 
Alive 
XX (XX.X %) 
 
Dead 
XX (XX.X %) 
 
Withdrew Consent 
XX (XX.X %) 
 
 
 
Did patient’s disease progress since the last evaluation 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
Not Known 
XX (XX.X %) 
 
 
 
If Yes, how disease progression was assessed[2] Clinical 
XX (XX.X %) 
 
Radiological 
XX (XX.X %) 
 
Both 
XX (XX.X %) 
 
Others 
XX (XX.X %) 
Source Data: Listing 16.2.6.3 
Note: 
[1] Percentages will be calculated using (N=XX) of corresponding column header group as denominator. 
[2] Percentages will be calculated using “Yes” category of “Did patient’s disease progress since the last 
evaluation” as denominator. 
 


 
 
 
 
 
 
 
 
 
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14.2 Efficacy Analysis 
 
Table 14.2.1.1 
Summary of Evaluation of target lesions as per RECIST Criteria at Each Visit- ITT Population 
(N=XXX) 
Visits, n (%) [1] 
Statistics/Category, n (%) 
Pertuzumab 
(N=XXX) 
Cycle 3 
 
 
CR 
XX (XX.X %) 
 
PR 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
 
Cycle 6 
 
 
 
CR 
XX (XX.X %) 
 
PR 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
Cycle … 
 
 
 
CR 
XX (XX.X %) 
 
PR 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
 
 
 
After 28 Days 
 
 
 
CR 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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PR 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
 
 
 
After 3 Months 
 
 
 
CR 
XX (XX.X %) 
 
PR 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
……… 
……… 
……… 
 
 
 
End of Study 
 
 
 
CR 
XX (XX.X %) 
 
PR 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
 
 
 
Source Data: Listing 16.2.6.1, 16.2.6.2 
Note: 
[1] 
“n” denotes the number of subjects who would have completed X months in study from the date of randomization 
[2] 
Percentage will be calculated taking respective “n” count as denominator. 
 
General Note: 
 Response will be calculated using RECIST 1.1. 
 UA: Unable to assess 
 




 
 
 
 
 
 
 
 
 
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Table 14.2.1.1.2 Summary of Overall Response as per RECIST Criteria at Each Visit - ITT Population (N=XXX) 
Visits, n (%) [1] 
Statistics/Category, n (%) 
Aggressive Disease 
(N=XX) 
 Non-Aggressive Disease 
(N=XX)  
Cycle 3 
 
 
CR 
XX (XX.X %) 
XX (XX.X %) 
PR 
XX (XX.X %) 
XX (XX.X %) 
SD 
XX (XX.X %) 
XX (XX.X %) 
PD 
XX (XX.X %) 
XX (XX.X %) 
UA 
XX (XX.X %) 
XX (XX.X %) 
 
 
Cycle 6 
 
 
CR 
XX (XX.X %) 
XX (XX.X %) 
PR 
XX (XX.X %) 
XX (XX.X %) 
SD 
XX (XX.X %) 
XX (XX.X %) 
PD 
XX (XX.X %) 
XX (XX.X %) 
UA 
XX (XX.X %) 
XX (XX.X %) 
 
 
Cycle … 
 
 
 
 
CR 
XX (XX.X %) 
XX (XX.X %) 
 
PR 
XX (XX.X %) 
XX (XX.X %) 
 
SD 
XX (XX.X %) 
XX (XX.X %) 
 
PD 
XX (XX.X %) 
XX (XX.X %) 
 
UA 
XX (XX.X %) 
XX (XX.X %) 
 
 
 
 
After 28 Days 
 
 
CR 
XX (XX.X %) 
XX (XX.X %) 
PR 
XX (XX.X %) 
XX (XX.X %) 
SD 
XX (XX.X %) 
XX (XX.X %) 






 
 
 
 
 
 
 
 
 
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Table 14.2.1.2 
Summary of Responder - ITT Population (N=XXX) 
Response, n (%) [1] 
Pertuzumab                 95 % CI (Clopper-Pearson) 
(N=XX) 
Responder 
XX (XX.X %)                 XX.X - XX.X 
Non-Responder 
XX (XX.X %)                 XX.X - XX.X 
Note:   
[1] 
Percentage will be calculated taking respective header count as denominator. 
 
General Note: 
 Patients without a post-baseline tumor assessment will be considered to be non-responders. 
 
 
 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.3 
Summary of Best Overall Response - ITT Population (N=XXX) 
Response, n (%) [1] 
Pertuzumab 
(N=XX) 
Complete Response (CR) 
XX (XX.X %) 
Partial Response (PR) 
XX (XX.X %) 
Stable Disease (SD) 
XX (XX.X %) 
Progression Disease (PD) 
XX (XX.X %) 
Unable To Assess(UA) 
XX (XX.X %) 
 Note:   
[1] 
Percentage will be calculated taking respective header count as denominator. 
 
General Note: 
 Best Overall Response will be considered to be the best response, out of all the documented responses, patient 
has given in the entire study period. 
 Patients having response as “UA” will not be included in the analysis. 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.4 
Summary of Overall Response Rate (CR+PR) - ITT Population (N=XXX) 
Response, n (%) [1] 
Pertuzumab 
(N=XX) 
ORR (CR+PR) 
XX (XX.X %) 
Non-ORR (SD+PD) 
XX (XX.X %) 
 
 
 Note:   
[1] 
Percentage will be calculated taking respective header count as denominator. 
 
General Note: 
 Overall response rate will be calculated by considering patients having CR or PR as response. 
 Patients having response as “UA” will not be included in the analysis. 
 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.5 
Summary of Disease Control (CR+PR+SD) - ITT Population (N=XXX) 
Response, n (%) [1] 
Pertuzumab 
(N=XX) 
Disease Control (CR+PR+SD) 
XX (XX.X %) 
Disease Progression (PD) 
XX (XX.X %) 
 
 
 Note:   
[1] 
Percentage will be calculated taking respective header count as denominator. 
 
General Note: 
 Patients not having disease progression will be considered under disease control category. 
 Patients having response as “UA” will not be included in the analysis. 
 
 
 
 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.6 
Summary of Duration of Overall Response - ITT Population (N=XXX) 
Statistics 
Pertuzumab 
(N=XXX) 
n 
XX 
Mean 
X.XX 
SD 
X.XX 
Median 
X.XX 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
Source Data: Listing 16.2.2.1 and 16.2.6.2 
 
General Note: 
 The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever 
is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking 
as reference for progressive disease the smallest measurements recorded since the treatment started). 
 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.7 
Summary of Duration of Stable Disease - ITT Population (N=XXX) 
Statistics 
Pertuzumab 
(N=XXX) 
n 
XX 
Mean 
X.XX 
SD 
X.XX 
Median 
X.XX 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
Source Data: Listing 16.2.6.1 and 16.2.6.2 
 
General Note: 
 Duration of stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started. 
 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.8 
Summary of Progression Free Survival at Each Visit - ITT Population (N=XXX) 
Visits 
Category, n (%) [1] 
Pertuzumab 
(N=XXX) 
Cycle 3 
 
 
n 
XX 
 
Progression Free Patients 
XX (XX.X %) 
 
Cycle 6 
 
 
n 
XX 
 
Progression Free Patients 
XX (XX.X %) 
 
Cycle … 
 
 
 
n 
XX 
 
Progression Free Patients 
XX (XX.X %) 
 
 
 
After 28 Days 
 
 
n 
XX 
 
Progression Free Patients 
XX (XX.X %) 
 
After 3 Months 
 
 
n 
XX 
 
Progression Free Patients 
XX (XX.X %) 
……… 
……… 
……… 
 
End of Study 
 
 
n 
XX 
 
Progression Free Patients 
XX (XX.X %) 
 




 
 
 
 
 
 
 
 
 
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Table 14.2.1.9 
Summary of Progression Free Survival by K-M Analysis - ITT Population (N=XXX) 
Category, n (%) [1] 
Pertuzumab 
(N=XX) 
Number (%) of Patients having Progression/death  
XX (XX.X %) 
Number (%) of censored Patients 
XX (XX.X %) 
Median duration of Progression Free Survival (95 % CI) [2] 
XX.X (XX.XX : XX.XX) 
Probability of progression free survival 
Cycle 3 
X.XXXX 
Cycle 6 
X.XXXX 
Cycle … 
X.XXXX 
After 28 Days 
X.XXXX 
After 3 Months 
X.XXXX 
……… 
……… 
End of the study 
X.XXXX 
 
 
Source Data: Listing 16.2.6.1 and 16.2.6.2 
Note: 
[1] 
Percentage will be calculated taking respective column header group count as denominator. 
[2] 
The median duration of progression free survival will be estimated by Kaplan-Meier method and also 90% 
 
confidence interval will be calculated for the median duration of progression free survival. 
General Note: 
 Events are the documented progression or death due to any cause. 
 Censoring: Subjects without occurrence of progression or death during study period, drop outs and lost-to-follow 
up subjects are censored at the time of last follow-up visit. 
 
Programming Note: 


 
 
 
 
 
 
 
 
 
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 The duration will be considered as difference between first drug administration to date of documented progression 
or death due to any cause. 
 The probability of survival at any visit will be derived by the “OUTSERVE =” option of PROC LIFETEST. The 
probability from Survival Distribution Function in dataset derived by “OUTSERVE =” option will be represented at 
each specified time point. 
 The same table will include the analysis for the remaining available cycle after cycle 6 and after every 3 months 
follow-up visits. 
 Same mock-up will be used to generate the table for Aggressive vs. Non-aggressive by specifying “Disease Status” 
as STRATA in PROC LIFETEST with change in table number and table title as: 
 
Table 14.2.1.10 
Summary of Progression Free Survival by K-M Analysis for Disease Status - ITT Population 
(N=XXX) 
 
 Same mock-up will be used to generate the table for treatment only for those patients who have prior anti-HER2 
treated patients and Hormone Receptor Status with change in table number and table title as: 
 
Table 14.2.1.11 
Summary of Progression Free Survival by K-M Analysis for Prior anti-HER2 treated patients - 
ITT Population (N=XXX) 
Table 14.2.1.12 
Summary of Progression Free Survival by K-M Analysis for Hormone Receptor status - ITT Population 
(N=XXX) 


 
 
 
 
 
 
 
 
 
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Table 14.2.1.13 
Summary of Overall Survival at Each Visit - ITT Population (N=XXX) 
 
Visits 
Category, n (%) [1] 
Pertuzumab 
(N=XXX) 
Cycle 3 
 
 
n 
XX 
 
Alive Patients 
XX (XX.X %) 
 
Cycle 6 
 
 
n 
XX 
 
Alive Patients 
XX (XX.X %) 
 
Cycle … 
 
 
 
n 
XX 
 
Alive Patients 
XX (XX.X %) 
 
 
 
After 28 Days of last dose 
 
 
n 
XX 
 
Alive Patients 
XX (XX.X %) 
 
After 3 Months  
 
 
n 
XX 
 
Alive Patients 
XX (XX.X %) 
After 6 Months  
 
 
n 
XX 
 
Alive Patients 
XX (XX.X %) 
 
 
 
 
 
 
……… 
……… 
……… 
 




 
 
 
 
 
 
 
 
 
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Table 14.2.1.14 
Summary of Overall Survival by K-M Analysis - ITT Population (N=XXX) 
 
Category, n (%) [1] 
Pertuzumab 
(N=XX) 
Number (%) of Patients having death 
XX (XX.X %) 
Number (%) of censored Patients 
XX (XX.X %) 
Median duration of Overall Survival (90 % CI) [2] 
XX.X (XX.XX : XX.XX) 
Probability of overall survival 
Cycle 3 
0.XXXX 
Cycle 6 
0.XXXX 
Cycle … 
0.XXXX 
After 28 Days 
0.XXXX 
After 3 Months 
0.XXXX 
……… 
……… 
End of the study 
0.XXXX 
 
 
Source Data: Listing 16.2.6.1 
 
Note: 
[1] 
Percentage will be calculated taking respective column header group count as denominator. 
[2] 
The median duration of overall survival will be estimated by Kaplan-Meier method and also 90% confidence 
interval will be calculated for the median duration of overall survival. 
 
General Note: 
 Events are the documented death of the patient due to any cause. 
 Censoring: Subjects without occurrence of death during study period, drop outs and lost-to-follow up subjects are 
censored at the time of last follow-up visit. 
Programming Note: 


 
 
 
 
 
 
 
 
 
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 The same table will include the analysis for the remaining available cycle after cycle 6 and after every 3 months 
follow-up visits. 
 The duration will be considered as difference between first drug administrations to date of documented death of 
any patient. 
 The probability of survival at any visit will be derived by the “OUTSERVE =” option of PROC LIFETEST. The 
probability from Survival Distribution Function in dataset derived by “OUTSERVE =” option will be represented at 
each specified time point. 
 Same mock-up will be used to generate the table for Aggressive vs. Non-aggressive by specifying “Disease Status” 
as STRATA in PROC LIFETEST with change in table number and table title as: 
Table 14.2.1.15 
Summary of Overall Survival by K-M Analysis for Disease Status - ITT Population (N=XXX) 
 
 Same mock-up will be used to generate the table for treatment only for those patients who have prior anti-HER2 
treated patients and Hormone Receptor Status with change in table number and table title as: 
 
Table 14.2.1.16 
Summary of Overall Survival by K-M Analysis for Prior anti-HER2 treated patients - ITT 
Population (N=XXX) 
Table 14.2.1.17 
Summary of Overall Survival by K-M Analysis for Hormone Receptor status - ITT Population (N=XXX) 


 
 
 
 
 
 
 
 
 
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14.3 Safety Analysis 
14.3.1 
Adverse Events 
Table 14.3.1.1 
Overall Summary of Adverse Events -Safety Population (N=XXX) 
 
Pertuzumab 
(N=XXX) 
Total Number of AEs Reported 
XX  
 
 
Subjects Reporting Any AEs [1] 
XX (XX.X %) 
 
Subjects Reporting 1 AE 
XX (XX.X %) 
 
Subjects Reporting >1 AE 
XX (XX.X %) 
 
 
Subjects Reporting No AEs [1] 
XX (XX.X %) 
 
 
Number of AEs with Intensity (NCI -CTCAE v4.03): [2] 
 
 
Grade 1 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of AEs with Relationship to Pertuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AEs with Relationship to Trastuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AEs with Relationship to Docetaxel:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AEs by Action taken:[2] 
 


 
 
 
 
 
 
 
 
 
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No action taken 
XX (XX.X %) 
 
Infusion Slow Down 
XX (XX.X %) 
 
Infusion Interrupted 
XX (XX.X %) 
Appropriate Medical Therapies Administered 
XX (XX.X %) 
 
 
Number of AEs by Event Outcome:[2] 
 
 
Resolved No-Sequelae 
XX (XX.X %) 
 
Resolved-with Sequelae 
XX (XX.X %) 
 
Unresolved 
XX (XX.X %) 
 
Death 
XX (XX.X %) 
 
 
Number of AEs by Chemotherapy Adjustment:[2] 
 
 
None 
XX (XX.X %) 
 
Dosage Modified/including interruptions 
XX (XX.X %) 
 
Discontinued 
XX (XX.X %) 
 
 
Number of AEs of suspected cardiac origin:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AEs symptomatic of left ventricular systolic dysfunction:[2] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
Number of AEs with NYHA Class [2] 
 
 
I 
XX (XX.X %) 
 
II 
XX (XX.X %) 
 
III 
XX (XX.X %) 
IV 
XX (XX.X %) 
 
 
Number of AEs with LVEF decreases:[2] 
 
 
Yes 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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No 
XX (XX.X %) 
 
 
Subjects Reporting AEs Leading to Withdraw [1] 
XX (XX.X %) 
 
 
Subjects Reporting Serious AEs [1] 
XX (XX.X %) 
 
Subjects Reporting Death 
XX (XX.X %) 
 
 
Subjects Reporting AESIs [1] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
Source Data: Listing 16.2.7 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of AEs Reported’ in corresponding treatment group 
as denominator. 
 
General Note: 
 Adverse events are coded using MedDRA version 18.1 or later. 
 AEs: Adverse Events 
 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.1a 
Overall Summary of Treatment Emergent Adverse Events -Safety Population (N=XXX) 
 
Pertuzumab 
(N=XXX) 
Total Number of TEAEs Reported 
XX  
 
 
Subjects Reporting Any TEAEs [1] 
XX (XX.X %) 
 
Subjects Reporting 1 TEAE 
XX (XX.X %) 
 
Subjects Reporting >1 TEAE 
XX (XX.X %) 
 
 
Subjects Reporting No TEAEs [1] 
XX (XX.X %) 
 
 
Number of TEAEs with Intensity (NCI -CTCAE v4.03): [2] 
 
 
Grade 1 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of TEAEs with Relationship to Pertuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of TEAEs with Relationship to Trastuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of TEAEs with Relationship to Docetaxel:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of TEAEs by Action taken:[2] 
 
No action taken 
XX (XX.X %) 
 
Infusion Slow Down 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Infusion Interrupted 
XX (XX.X %) 
Appropriate Medical Therapies Administered 
XX (XX.X %) 
 
 
Number of TEAEs by Event Outcome:[2] 
 
 
Resolved No-Sequelae 
XX (XX.X %) 
 
Resolved-with Sequelae 
XX (XX.X %) 
 
Unresolved 
XX (XX.X %) 
 
Death 
XX (XX.X %) 
 
 
Number of TEAEs by Chemotherapy Adjustment:[2] 
 
 
None 
XX (XX.X %) 
 
Dosage Modified/including interruptions 
XX (XX.X %) 
 
Discontinued 
XX (XX.X %) 
 
 
Number of TEAEs of suspected cardiac origin:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of TEAEs symptomatic of left ventricular systolic dysfunction:[2] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
Number of TEAEs with NYHA Class [2] 
 
 
I 
XX (XX.X %) 
 
II 
XX (XX.X %) 
 
III 
XX (XX.X %) 
IV 
XX (XX.X %) 
 
 
Number of TEAEs with LVEF decreases:[2] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 


 
 
 
 
 
 
 
 
 
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Subjects Reporting TEAEs Leading to Withdraw [1] 
XX (XX.X %) 
 
 
Subjects Reporting Serious TEAEs [1] 
XX (XX.X %) 
 
Subjects Reporting Death 
XX (XX.X %) 
 
 
Subjects Reporting AESIs [1] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
Source Data: Listing 16.2.7 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of TEAEs Reported’ in corresponding treatment 
group as denominator. 
 
General Note: 
 Adverse events will be coded using MedDRA version 18.1 or later. 
 TEAEs: Treatment Emergent Adverse Events 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.1b 
Overall Summary of Non-Treatment Emergent Adverse Events -Safety Population (N=XXX) 
 
Pertuzumab 
(N=XXX) 
Total Number of non-TEAEs Reported 
XX  
 
 
Subjects Reporting Any non-TEAEs [1] 
XX (XX.X %) 
 
Subjects Reporting 1 non-TEAE 
XX (XX.X %) 
 
Subjects Reporting >1 non-TEAE 
XX (XX.X %) 
 
 
Subjects Reporting No non-TEAEs [1] 
XX (XX.X %) 
 
 
Number of non-TEAEs with Intensity (NCI -CTCAE v4.03): [2] 
 
 
Grade 1 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of non-TEAEs with Relationship to Pertuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of non-TEAEs with Relationship to Trastuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of non-TEAEs with Relationship to Docetaxel:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of non-TEAEs by Action taken:[2] 
 
No action taken 
XX (XX.X %) 
 
Infusion Slow Down 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Infusion Interrupted 
XX (XX.X %) 
Appropriate Medical Therapies Administered 
XX (XX.X %) 
 
 
Number of non-TEAEs by Event Outcome:[2] 
 
 
Resolved No-Sequelae 
XX (XX.X %) 
 
Resolved-with Sequelae 
XX (XX.X %) 
 
Unresolved 
XX (XX.X %) 
 
Death 
XX (XX.X %) 
 
 
 
 
Number of non-TEAEs by Chemotherapy Adjustment:[2] 
 
 
None 
XX (XX.X %) 
 
Dosage Modified/including interruptions 
XX (XX.X %) 
 
Discontinued 
XX (XX.X %) 
 
 
Number of non-TEAEs of suspected cardiac origin:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of non-TEAEs symptomatic of left ventricular systolic dysfunction:[2] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
Number of non-TEAEs with NYHA Class [2] 
 
 
I 
XX (XX.X %) 
 
II 
XX (XX.X %) 
 
III 
XX (XX.X %) 
IV 
XX (XX.X %) 
 
 
Number of non-TEAEs with LVEF decreases:[2] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Subjects Reporting non-TEAEs Leading to Withdraw [1] 
XX (XX.X %) 
 
 
Subjects Reporting Serious non-TEAEs [1] 
XX (XX.X %) 
 
Subjects Reporting Death 
XX (XX.X %) 
 
 
Subjects Reporting AESIs [1] 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
Source Data: Listing 16.2.7 
Note: 
[1] Percentage will be calculated by taking respective column header group count as denominator. 
[2] Percentage will be calculated by taking count of ‘Total Number of non TEAEs Reported’ in corresponding treatment 
group as denominator. 
 
General Note: 
 Non Treatment Emergent Adverse events will be coded using MedDRA version 18.1 or later. 
 Non TEAEs: Non Treatment Emergent Adverse events 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.2 
Summary of Adverse Events (including subjects reporting SAEs) by MedDRA System Organ Class and 
Preferred Term -Safety Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Pertuzumab 
(N=XXX) 
Total number of subjects with at least one Adverse Events(including subjects 
reporting SAEs) 
XX (XX.X %) 
Total number of Adverse Events 
XX 
 
 
System Organ Class 1  
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) [XX] 
 
Preferred Term 2 
XX (XX.X %) [XX] 
 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) [XX] 
 
Preferred Term 2  
XX (XX.X %) [XX] 
…………… 
……………… 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage will be calculated by taking respective column header group count as denominator. 
 
General Note: 
 Adverse events will be coded using MedDRA version 18.1 or later 
 All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 
 Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.2a 
Summary of Adverse Events (excluding subjects reporting SAEs) by MedDRA System Organ Class and 
Preferred Term -Safety Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Pertuzumab 
(N=XXX) 
Total number of subjects with at least one Adverse Events(excluding subjects 
reporting SAEs) 
XX (XX.X %) 
Total number of Adverse Events 
XX 
 
 
System Organ Class 1  
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) [XX] 
 
Preferred Term 2 
XX (XX.X %) [XX] 
 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) [XX] 
 
Preferred Term 2  
XX (XX.X %) [XX] 
…………… 
……………… 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage will be calculated by taking respective column header group count as denominator. 
 
General Note: 
 Adverse events will be coded using MedDRA version 18.1 or later 
 All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 
 Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.3 
Summary of Adverse Events by MedDRA System Organ Class and Preferred Term by Intensity -Safety 
Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Intensity 
Pertuzumab 
(N=XXX) 
Total number of subjects with 
at least one Adverse Events 
 
XX (XX.X %) 
Total number of Adverse Events 
 
XX 
 
 
 
System Organ Class 1 
 
XX (XX.X %) 
Preferred Term 1 
 
XX (XX.X %) [XX] 
 
Grade 1 
XX (XX.X %) [XX] 
 
Grade 2 
XX (XX.X %) [XX] 
 
Grade 3 
XX (XX.X %) [XX] 
 
Grade 4 
XX (XX.X %) [XX] 
 
Grade 5 
XX (XX.X %) [XX] 
 
 
 
Preferred Term 2 
 
XX (XX.X %) [XX] 
 
Grade 1 
XX (XX.X %) [XX] 
 
Grade 2 
XX (XX.X %) [XX] 
 
Grade 3 
XX (XX.X %) [XX] 
 
Grade 4 
XX (XX.X %) [XX] 
 
Grade 5 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage will be calculated by taking respective column header group count as denominator 
General Note: 
 Adverse events will be coded using MedDRA version 18.1 or later 
 All Adverse events are presented as: number of subjects (percent of subjects) [number of events]. 


 
 
 
 
 
 
 
 
 
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 Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 
 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.4 
Summary of Adverse Events by MedDRA System Organ Class and Preferred Term by Action Taken -Safety 
Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Action Taken 
Pertuzumab 
(N=XXX) 
Total number of subjects with  
at least one Adverse Events  
 
XX (XX.X %) 
Total number of Adverse Events 
 
XX 
 
 
 
System Organ Class 1  
 
XX (XX.X %) 
Preferred Term 1 
 
XX (XX.X %) [XX] 
 
No action taken 
XX (XX.X %) [XX] 
 
Infusion Slow Down 
XX (XX.X %) [XX] 
 
Infusion Interrupted 
XX (XX.X %) [XX] 
 
Appropriate Medical Therapies 
Administered 
XX (XX.X %) [XX] 
 
 
 
Preferred Term 2 
 
XX (XX.X %) [XX] 
 
No action taken 
XX (XX.X %) [XX] 
 
Infusion Slow Down 
XX (XX.X %) [XX] 
 
Infusion Interrupted 
XX (XX.X %) [XX] 
 
Appropriate Medical Therapies 
Administered 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage should be calculated by taking respective column header group count as denominator. 
 
General Note: 
 Adverse events will be coded using MedDRA version 18.1 or later 


 
 
 
 
 
 
 
 
 
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 All Adverse events will be presented as: number of subjects (percent of subjects) [number of events]. 
 Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.5 
Summary of Adverse Events by MedDRA System Organ Class and Preferred Term by Event Outcome -Safety 
Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Event Outcome 
Pertuzumab 
(N=XXX) 
Total number of subjects with  
at least one Adverse Events  
 
XX (XX.X %) 
Total number of Adverse Events 
 
XX 
 
 
 
System Organ Class 1  
 
XX (XX.X %) 
Preferred Term 1 
 
XX (XX.X %) [XX] 
 
Resolved No-Sequelae 
XX (XX.X %) [XX] 
 
Resolved-with Sequelae 
XX (XX.X %) [XX] 
 
Unresolved 
XX (XX.X %) [XX] 
 
Death 
XX (XX.X %) [XX] 
 
 
 
Preferred Term 2 
 
XX (XX.X %) [XX] 
 
Resolved No-Sequelae 
XX (XX.X %) [XX] 
 
Resolved-with Sequelae 
XX (XX.X %) [XX] 
 
Unresolved 
XX (XX.X %) [XX] 
 
Death 
XX (XX.X %) [XX] 
…………… 
……………… 
……………… 
 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage will be calculated by taking respective column header group count as denominator. 
 
General Note: 
 Adverse events will be coded using MedDRA version 18.1 or later 


 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
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 All Adverse events will be presented as: number of subjects (percent of subjects) [number of events]. 
 Subjects may have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
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Table 14.3.1.6 
Summary of Assessment during Adverse Event -Safety Population (N=XXX) 
Assessment [1] 
Category n (%) [1] 
Pertuzumab 
(N=XXX) 
Chemotherapy adjustment 
 
 
None 
XX (XX.X %) 
 
Dosage modified/including interruptions 
XX (XX.X %) 
 
Discontinued 
XX (XX.X %) 
 
 
Is Event symptomatic of left 
ventricular systolic dysfunction 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
NYHA Class 
 
 
 
I 
XX (XX.X %) 
 
II 
XX (XX.X %) 
 
III 
XX (XX.X %) 
 
IV 
XX (XX.X %) 
 
 
 
LVEF decrease 
 
 
 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Source Data Listings: 16.2.7 
Note:  
[1] 
Respective column header group count will be used as denominator in percentage calculation. 
 


 
 
 
 
 
 
 
 
 
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14.3.2 
Serious Adverse Events 
Table 14.3.2.1 
Summary of Serious Adverse Events -Safety Population (N=XXX) 
 
Pertuzumab 
(N=XXX) 
Total Number of SAEs Reported 
XX  
 
 
Subjects Reporting Any SAEs [1] 
XX (XX.X %) 
 
Subjects Reporting 1 SAEs 
XX (XX.X %) 
 
Subjects Reporting >1 SAEs 
XX (XX.X %) 
 
 
Subjects Reporting No SAEs [1] 
XX (XX.X %) 
 
 
Number of SAEs with Intensity (Initial NCI -CTCAE v4.03): [2] 
 
 
Grade 1 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of SAEs with Intensity ( Most Extreme NCI -CTCAE v4.03): [2] 
 
Grade 1 
XX (XX.X %) 
Grade 2 
XX (XX.X %) 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of SAEs with Intensity Scale (Initial Intensity) [2] 
 
Mild 
XX (XX.X %) 
Moderate 
XX (XX.X %) 
Severe 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Number of SAEs with Intensity Scale (Most Extreme Intensity) [2] 
 
Mild 
XX (XX.X %) 
Moderate 
XX (XX.X %) 
Severe 
XX (XX.X %) 
 
 
Number of SAEs with Relationship to Pertuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of SAEs with Relationship to Trastuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of SAEs with Relationship to Docetaxel:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of SAEs by Suspect Cause:[2] 
 
Caused by drug 
XX (XX.X %) 
Disease under study 
XX (XX.X %) 
Medical History or Concurrent Illness 
XX (XX.X %) 
Concomitant Medication 
XX (XX.X %) 
Protocol Related Procedure 
XX (XX.X %) 
Others 
XX (XX.X %) 
 
 
Number of SAEs by Action taken:[2] 
 
Infusion of Pertuzumab Reduced 
XX (XX.X %) 
 
Infusion of Pertuzumab Temporarily Interrupted 
XX (XX.X %) 
 
Infusion of Pertuzumab Permanently Discontinued 
XX (XX.X %) 
Infusion of Trastuzumab Reduced 
XX (XX.X %) 
Infusion of Trastuzumab Reduced 
XX (XX.X %) 
Infusion of Trastuzumab Temporarily Interrupted 
XX (XX.X %) 
Infusion of Trastuzumab Permanently Discontinued 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Infusion of Docetaxel Reduced 
XX (XX.X %) 
Infusion of Docetaxel Temporarily Interrupted 
XX (XX.X %) 
Infusion of Docetaxel Permanently Discontinued 
XX (XX.X %) 
 
 
Number of SAEs by Event Outcome:[2] 
 
 
Fatal 
XX (XX.X %) 
 
Recovered/Resolved 
XX (XX.X %) 
 
Recovered/Resolved-with Sequelae 
XX (XX.X %) 
 
Recovering/Resolving 
XX (XX.X %) 
Not recovered/Not resolved 
XX (XX.X %) 
Unknown 
XX (XX.X %) 
 
 
Number of SAEs by Reasons:[2] 
 
Results in death 
XX (XX.X %) 
Life-threatening 
XX (XX.X %) 
Requires in patient hospitalization 
XX (XX.X %) 
Requires prolongation of existing hospitalization 
XX (XX.X %) 
Persistent or significant disability / incapacity 
XX (XX.X %) 
Congenital anomaly / birth defect 
XX (XX.X %) 
Medically Significant 
XX (XX.X %) 
 
 
Subjects Reporting SAEs Leading to Withdraw [1] 
XX (XX.X %) 
 
 
Subjects Reporting Serious SAEs [1] 
XX (XX.X %) 
Subjects Reporting Death 
XX (XX.X %) 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage should be calculated by taking respective column header group count as denominator. 
General Note: 


 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 103 of 174 
 
 Serious Adverse events will be coded using MedDRA version 18.1 or later 
 All Serious Adverse events will be presented as: number of subjects (percent of subjects). 
 Subjects might have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 


 
 
 
 
 
 
 
 
 
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Table 14.3.2.2 
Summary of Serious Adverse Events by MedDRA System Organ Class and Preferred Term -Safety 
Population (N=XXX) 
System Organ Class/Preferred Term, n (%) [1] 
Pertuzumab 
(N=XXX) 
Total number of subjects with at  
Least one serious adverse events  
XX (XX.X %) 
Total number of serious adverse events 
XX 
 
 
System Organ Class 1  
XX (XX.X %) 
 
Preferred Term 1 
XX (XX.X %) [XX] 
 
Preferred Term 2 
XX (XX.X %) [XX] 
 
…………… 
…………… 
System Organ Class 2  
XX (XX.X %) 
 
Preferred Term 1  
XX (XX.X %) [XX] 
 
Preferred Term 2  
XX (XX.X %) [XX] 
 
…………… 
…………… 
 
 
Source Data: Listing 16.2.7 
 
Note:  
[1] 
Percentage should be calculated by taking respective column header group count as denominator. 
General Note: 
 Serious Adverse events will be coded using MedDRA version 18.1 or later 
 All Serious Adverse events will be presented as: number of subjects (percent of subjects) [number of events]. 
 Subjects might have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 


 
 
 
 
 
 
 
 
 
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Table 14.3.2.3 
Summary of Adverse Event of Special Interest -Safety Population (N=XXX) 
 
Pertuzumab 
(N=XXX) 
Total Number of AESIs Reported 
XX  
 
 
Subjects Reporting Any AESIs [1] 
XX (XX.X %) 
 
Subjects Reporting 1 AESIs 
XX (XX.X %) 
 
Subjects Reporting >1 AESIs 
XX (XX.X %) 
 
 
Subjects Reporting No AESIs [1] 
XX (XX.X %) 
 
 
Number of AESIs with Intensity ( Initial NCI -CTCAE v4.03): [2] 
 
 
Grade 1 
XX (XX.X %) 
 
Grade 2 
XX (XX.X %) 
 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of AESIs with Intensity ( Most Extreme NCI -CTCAE v4.03): [2] 
 
Grade 1 
XX (XX.X %) 
Grade 2 
XX (XX.X %) 
Grade 3 
XX (XX.X %) 
Grade 4 
XX (XX.X %) 
Grade 5 
XX (XX.X %) 
 
 
Number of AESIs with Intensity Scale (Initial Intensity) [2] 
 
Mild 
XX (XX.X %) 
Moderate 
XX (XX.X %) 
Severe 
XX (XX.X %) 
 
 


 
 
 
 
 
 
 
 
 
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Number of AESIs with Intensity Scale (Most Extreme Intensity) [2] 
 
Mild 
XX (XX.X %) 
Moderate 
XX (XX.X %) 
Severe 
XX (XX.X %) 
 
 
 
 
Number of AESIs with Relationship to Pertuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AESIs with Relationship to Trastuzumab:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AESIs with Relationship to Docetaxel:[2] 
 
 
Yes 
XX (XX.X %) 
 
 
Number of AESIs by Suspect Cause:[2] 
 
Caused by drug 
XX (XX.X %) 
 Disease under study 
XX (XX.X %) 
 Medical History or Concurrent Illness 
XX (XX.X %) 
Concomitant Medication 
XX (XX.X %) 
Protocol Related Procedure 
XX (XX.X %) 
Others 
XX (XX.X %) 
 
 
Number of AESIs by Action taken:[2] 
 
 
Infusion of Pertuzumab Reduced 
XX (XX.X %) 
 
Infusion of Pertuzumab Temporarily Interrupted 
XX (XX.X %) 
Infusion of Pertuzumab Permanently Discontinued 
XX (XX.X %) 
Infusion of Trastuzumab Reduced 
XX (XX.X %) 
Infusion of Trastuzumab Temporarily Interrupted 
XX (XX.X %) 
Infusion of Trastuzumab Permanently Discontinued 
XX (XX.X %) 
Infusion of Docetaxel Reduced 
XX (XX.X %) 


 
 
 
 
 
 
 
 
 
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Infusion of Docetaxel Temporarily Interrupted 
XX (XX.X %) 
Infusion of Docetaxel Permanently Discontinued 
XX (XX.X %) 
 
 
Number of AESIs by Event Outcome:[2] 
 
 
Fatal 
XX (XX.X %) 
Recovered/Resolved 
XX (XX.X %) 
 
Recovered/Resolved-with Sequelae 
XX (XX.X %) 
Recovering/Resolving 
XX (XX.X %) 
 
Not recovered/Not resolved 
XX (XX.X %) 
 
Unknown 
XX (XX.X %) 
 
 
Number of AESIs by Reasons:[2] 
 
Results in death 
XX (XX.X %) 
Life-threatening 
XX (XX.X %) 
Requires in patient hospitalization 
XX (XX.X %) 
Requires prolongation of existing hospitalization 
XX (XX.X %) 
Persistent or significant disability / incapacity 
XX (XX.X %) 
Congenital anomaly / birth defect 
XX (XX.X %) 
Medically Significant 
XX (XX.X %) 
 
 
Subjects Reporting AESIs Leading to Withdraw [1] 
XX (XX.X %) 
 
 
Subjects Reporting AESIs[1] 
XX (XX.X %) 
Subjects Reporting Death 
XX (XX.X %) 
 
 
 
Note:  
[1] 
Percentage should be calculated by taking respective column header group count as denominator. 
General Note: 
 Adverse events of special interest (AESIs) will be coded using MedDRA version 18.1 or later 


 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 108 of 174 
 
 All Adverse events of special interest (AESIs) will will be presented as: number of subjects (percent of 
subjects). 
 Subjects might have reported more than one event per system organ class or preferred term. Subjects will be only 
counted once for each system organ class or preferred term. 


 
 
 
 
 
 
 
 
 
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Page 109 of 174 
 
14.3.3 
Concomitant Medication 
Table 14.3.3.1 
Summary of Concomitant Medication Assessment -Safety Population (N=XXX) 
 
Therapeutic Class, n (%) [1] 
Generic name, n (%) [2] 
Pertuzumab(N=XXX) 
Count of Ongoing [3] 
Therapeutic  Class 1 
 
XX (XX.X %) 
 
 
Generic Name 1 
XX (XX.X %) 
XX (XX.X %) 
 
Generic Name 2 
XX (XX.X %) 
XX (XX.X %) 
 
Generic Name 3 
XX (XX.X %) 
XX (XX.X %) 
 
…………………… 
…………………………         
………………………… 
 
 
 
 
Source Data: Listing  
Note:  
[1] 
Percentages of Therapeutic class will be calculated from respective column header group count as denominator 
in percentage calculation. 
[2] 
Percentages of Generic Name will be calculated from Respective Class counts. 
[3] 
Percentages of Count of Ongoing will be calculated from respective generic name counts. 
 
 
 
 




 
 
 
 
 
 
 
 
 
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Table 14.3.4.2  
Summary of Vital Signs at different Cycles -Safety Population (N=XXX) 
 
Vital Signs 
Statistics 
Infusion of Pertuzumab 
Infusion of Trastuzumab 
Infusion of Docetaxel 
Prior 
After 
Prior 
After 
Prior 
After 
 
 
 
 
 
 
 
 
Cycle 1 
 
 
 
 
 
 
 
Pulse Rate 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) (XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
Respiratory 
rate 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) (XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 
Blood 
Pressure(mmH
g) 
 
 
 
 
 
 
 
Systolic 
 
 
 
 
 
 
 
 
n 
XX 
XX 
XX 
XX 
XX 
XX 
 
Mean 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
SD 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
XX.XX 
 
Median 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) (XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
Missing [1] 
XX 
XX 
XX 
XX 
XX 
XX 
 
 
 
 
 
 
 
 




 
 
 
 
 
 
 
 
 
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Table 14.3.4.3  
Summary of Vital Signs at different visits at follow-up Safety Population (N=XXX) 
Vital Signs 
Statistics 
Pertuzumab 
(N=XXX) 
 
 
 
After 28 Days 
 
 
Pulse Rate 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
 
Missing [1] 
XX 
 
 
 
Respiratory rate 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
 
Missing [1] 
XX 
 
 
 
Blood Pressure(mmHg) 
 
 
Systolic 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min: Max) 
(XX.X:XX.X) 
 
Missing [1] 
XX 
 
 
 
Diastolic 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 






 
 
 
 
 
 
 
 
 
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14.3.6 Laboratory Assessments 
Table 14.3.6.1 
Summary of Serum Chemistry at all visits- Safety Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Cycle 1 
 
 
Sodium 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Potassium 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Calcium 
 
 
Result 
n 
XX 




 
 
 
 
 
 
 
 
 
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Table 14.3.6.2 
Summary of Hematology Test at All Visit- Safety Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Cycle 1 
 
 
Hemoglobin 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Hematocrit 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Red Blood Cells (RBC) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 




 
 
 
 
 
 
 
 
 
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Table 14.3.6.3 
Summary of Coagulation Test at All Visits- Safety Population (N=XXX) 
 
Test [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Cycle 1 
 
 
International normalization ratio(INR) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Activated Partial Thromboplastin Time (aPTT) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
Out of Range 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Clinically Significant 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Partial Thromboplastin Time (PTT) 
 
 
Result 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 








 
 
 
 
 
 
 
 
 
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 Table 14.3.6.6 
Summary of LVEF and CHF at different Visits- Safety Population (N=XXX) 
 
 
LVEF [1] 
 
Statistics/Category, n (%) 
Pertuzumab 
(N=XX) 
Cycle 3 
 
 
Results (%) 
 
 
 
n 
XX 
 
Mean 
XX.X 
 
SD 
XX.XX 
 
Median 
XX.X 
 
Range(Min:Max) 
(XX.X:XX.X) 
 
 
 
LVEF done by 
 
 
 
MUGA 
XX (XX.X %) 
 
Echocardiography 
XX (XX.X %) 
 
 
 
If Echocardiography, method 
 
 
 
Simpson (2-D) 
XX (XX.X %) 
 
Teichholz (M-mode) 
XX (XX.X %) 
 
 
 
LVEF finding 
 
 
 
Normal 
XX (XX.X %) 
 
Abnormal but not clinically 
significant 
XX (XX.X %) 
 
Abnormal and clinically 
significant 
XX (XX.X %) 
 
 
 
Any new cardiac signs and symptoms 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 
Any worsening cardiac signs and symptoms 
Yes 
XX (XX.X %) 
 
No 
XX (XX.X %) 
 
 
 




 
 
 
 
 
 
 
 
 
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Table 14.3.6.7 
Summary of LVEF at each visit-Safety Population (N=XXX) 
 
Visits, n (%) [1] 
Statistics/Category 
Pertuzumab 
(N=XXX) 
Baseline 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
Cycle 3 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from baseline to Cycle 3 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Cycle 6 
 
 
 
n 
XX 
 
Mean 
X.XX 


 
 
 
 
 
 
 
 
 
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SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to Cycle 6 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
………… 
………… 
………… 
 
 
 
 
 
 
After 28 days 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to After 28 Days 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
After 3 months 
 
 
 
n 
XX 


 
 
 
 
 
 
 
 
 
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Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to After 3 months 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
After 6 months 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to After 6 months 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
………… 
………… 
………… 
Source Data: Listing 16.2.8.7 




 
 
 
 
 
 
 
 
 
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Table 14.3.6.8 
Summary of Target Lesion (Sum of longest diameters) at each visit-Safety Population (N=XXX) 
 
Visits, n (%) [1] 
Statistics/Category 
Pertuzumab 
(N=XXX) 
Baseline 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
Cycle 3 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from baseline to Cycle 3 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Cycle 6 
 
 
 
n 
XX 
 
Mean 
X.XX 


 
 
 
 
 
 
 
 
 
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SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to Cycle 6 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
………… 
………… 
………… 
 
 
 
 
 
 
After 28 days 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to After 28 Days 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
After 3 months 
 
 
 
n 
XX 


 
 
 
 
 
 
 
 
 
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Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to After 3 months 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
After 6 months 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
Change from Baseline to After 6 months 
 
 
 
n 
XX 
 
Mean 
X.XX 
 
SD 
X.XX 
 
Median 
X.XX 
 
Range (Min.: Max.) 
(XX.XX:XX.XX) 
 
 
 
………… 
………… 
………… 
Source Data: Listing 16.2.6.1 




 
 
 
 
 
 
 
 
 
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Table 14.3.6.9 
Summary of Mean Exposure to Study Treatment -Safety Population (N=XXX) 
Cycle, n (%) [1] 
Pertuzumab 
(N=XX) 
Trastuzumab 
(N=XX) 
Docetaxel 
(N=XX) 
Length of Cycle 
 
 
 
n 
XX 
XX 
XX 
Mean 
XX.X 
XX.X 
XX.X 
SD 
XX.XX 
XX.XX 
XX.XX 
Median 
XX.X 
XX.X 
XX.X 
Range(Min:Max) 
(XX.X:XX.X) 
(XX.X:XX.X) 
(XX.X:XX.X) 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
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1.2 
Figures 
14.2.1 
Figures for Efficacy Analysis 
Figure 14.2.1.1 
K-M Plot for Progression Free Survival by Treatment -ITT Population (N=XXX) 
K-M Plot 
A step diagram of K-M analysis will be generated where X-axis will represent Time 
(Days) and Y-axis will represent Progression Free survival probability 
Source Data: Table 14.2.1.9 
Programming Note: 
 Same analysis figure will be prepared for the ITT Population with an appropriate change in title and figure no.: 
Figure 14.2.1.2 
K-M Plot for Progression Free Survival by Disease Status -ITT Population (N=XXX) 
 
Figure 14.2.1.3 
K-M Plot for Progression Free Survival for Prior anti-HER2 treated patients -ITT Population 
(N=XXX) 
 
Figure 14.2.1.4 
K-M Plot for Progression Free Survival for Hormone Receptor Status-ITT Population (N=XXX) 
  


 
 
 
 
 
 
 
 
 
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Figure 14.2.1.5  Bar Chart for Response Rate Analysis at Each Visit -ITT Population (N=XXX) 
Bar chart 
A multiple bar-chart will be generated to represent the response rate at each visit 
where X-axis will represent all the visits along with all the categories of response 
and Y-axis will represent percentage of patients. 
Source Data: Table 14.2.1.1 
 


 
 
 
 
 
 
 
 
 
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Figure 14.2.1.6 
K-M Plot for Overall Survival by Treatment -ITT Population (N=XXX) 
K-M Plot 
A step diagram of K-M analysis will be generated where X-axis will represent Time 
(Days) and Y-axis will represent overall survival probability 
Source Data: Table 14.2.1.14 
 
Programming Note: 
 Same analysis figure will be prepared for the ITT Population with an appropriate change in title and figure no.: 
 
Figure 14.2.1.7 
K-M Plot for Overall Survival by Disease Status -ITT Population (N=XXX) 
 
Figure 14.2.1.8 
K-M Plot for Overall Survival for Prior anti-HER2 treated patients -ITT Population (N=XXX) 
 
Figure 14.2.1.9 
K-M Plot for Overall Survival for Hormone Receptor Status-ITT Population (N=XXX) 
  


 
 
 
 
 
 
 
 
 
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Figure 14.2.1.10 Line Diagram for LVEF over a period of time -Safety Population (N=XXX) 
Line Diagram for Mean and 
Median 
Two line diagram for LVEF will be generated where X-axis will represent Time (Days) 
and Y-axis will represent Mean and Median respectively for both the line diagram. 
Source Data: Table 14.3.6.7 
 
 
 
 
 
 
  


 
 
 
 
 
 
 
 
 
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1.3 
LISTINGS 
16.2 Patient Data Listings 
Listing 16.2.1 
Listing of Patient Discontinuation 
Site ID/ 
Subject 
No. 
Age/Sex 
The patient 
completed 
the protocol 
If Yes, Date 
of Completion 
If No, Date of 
Discontinuation 
The primary 
reason for pre-
mature 
discontinuation 
If reason 
is death, 
mention 
date 
Death 
Due to 
Disease 
Progres
sion 
If 
other 
reason, 
specify 
NN/XXXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
DDMMMYYYY 
XXXX 
DDMMMYYYY 
Yes/No 
XXXX 
NN/XXXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
DDMMMYYYY 
XXXX 
DDMMMYYYY 
Yes/No 
XXXX 
NN/XXXX 
NN/XXX 
Yes/No 
DDMMMYYYY 
DDMMMYYYY 
XXXX 
DDMMMYYYY 
Yes/No 
XXXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.2.1 Listing of Protocol Deviation -Enrolled Population (N=XXX) 
Site No./ Subject 
No. 
Age/ Gender 
Date 
Reason of Deviation 
Comments 
XXX/NNN 
NN/XXX 
DDMMMYYYY 
XXXXXXX 
XXX 
XXX/NNN 
NN/XXX 
DDMMMYYYY 
XXXXXXX 
XXX 
XXX/NNN 
NN/XXX 
DDMMMYYYY 
XXXXXXX 
XXX 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.2.2 Listing of Analysis Population Sets –Enrolled Population (N=XXX) 
Site No./ 
Subject No. 
Age/Gender 
Efficacy Population 
Safety Population 
XXX/NNN 
NN/XXX 
Yes/No 
Yes/No 
XXX/NNN 
NN/XXX 
Yes/No 
Yes/No 
XXX/NNN 
NN/XXX 
Yes/No 
Yes/No 
… 
… 
… 
… 


 
 
 
 
 
 
 
 
 
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Listing 16.2.3 
Listing of Patients who fail to meet Inclusion/Exclusion Criteria -Enrolled Population (N=XXX) 
 
Site ID/ 
Subject 
No. 
Age/Sex 
Date of 
Informed 
Consent 
All Inclusion and 
Exclusion criteria met 
If No, Inclusion 
Criteria Number(s) 
All Exclusion 
criteria Satisfied  
If no, Exclusion 
criteria number(s) 
NN/XXXX 
NN/XXX 
DDMMMYYYY 
Yes/No/NA 
NN 
NN 
NN 
NN/XXXX 
NN/XXX 
DDMMMYYYY 
Yes/No/NA 
NN 
NN 
NN 
NN/XXXX 
NN/XXX 
DDMMMYYYY 
Yes/No/NA 
NN 
NN 
NN 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
 
 
 
 
 
 
 
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 16.2.4 
Listing of Demographics 
Listing 16.2.4.1 Listing of Patient Demographics -ITT Population (N=XXX) 
 
Site ID/ Subject No. 
Age 
Date of Visit 
Sex 
Date of Birth 
Race 
Ethnicity 
NN/XXXX 
NN 
DDMMMYYYY 
Male/Female 
DDMMMYYYY 
XXX 
XXX 
NN/XXXX 
NN 
DDMMMYYYY 
Male/Female 
DDMMMYYYY 
XXX 
XXX 
NN/XXXX 
NN 
DDMMMYYYY 
Male/Female 
DDMMMYYYY 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.2 Listing of Medical History at Screening-ITT Population (N=XXX) 
 
Site ID/ Subject No. 
Age/Sex 
Medical 
History 
Start date 
Stop Date 
Ongoing 
Is the subject 
on Medications 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
Yes/No 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
Yes/No 
NN/XXX  
NN/XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.3 Listing of Breast Cancer Disease Therapy at Screening-ITT Population (N=XXX) 
 
Site 
ID/ 
Subje
ct 
No. 
Age/S
ex 
Date of 
initial 
histological 
or 
cytological 
diagnosis 
Breast 
cancer 
diagno
sed 
BC 
stage 
at 
initial 
Diagnos
is 
Locatio
n of 
Primary 
Tumor 
Was 
the 
prim
ary 
tumo
r 
Prim
ary 
tumo
r 
size 
Breast 
cancer 
subtype 
Histolo
gical 
grade 
Nucl
ear 
grad
e 
Estro
gen 
recep
tor 
statu
s 
Progeste
rone 
receptor 
status 
Brea
st 
canc
er 
type 
NN/XX
X 
NN/XX
X 
DDMMMYYYY 
XXX 
NN 
XXX 
XXX 
NN.N 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN/XX
X 
NN/XX
X 
DDMMMYYYY 
XXX 
NN 
XXX 
XXX 
NN.N 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN/XX
X 
NN/XX
X 
DDMMMYYYY 
XXX 
NN 
XXX 
XXX 
NN.N 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 
 


 
 
 
 
 
 
 
 
 
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Date of 
Primary 
surgery 
Date 
of 
pathol
ogical 
Assess
ment 
Breast tumor remnants 
Histo
logic
al 
grade 
Brea
st 
canc
er 
subt
ype 
DCIS 
present 
Date of 
Diagnosis 
of 
Metastati
c or 
Locally 
Recurrent 
Disease 
Diagnos
is of 
metasta
tic or 
Locally 
recurre
nt BC 
Date of 
Last 
Recurrence 
Microscopic 
assessment 
Macroscopic 
assessment 
Type of 
Tumor 
Diameter 
of Tumor 
Gross 
tumor 
size 
Pathological 
staging of 
BC 
DDMMMYY
YY 
DDMMMY
YYY 
XXX 
NN.N 
NN.N 
NN 
XXX 
XXX 
Yes/No 
DDMMMYYYY 
XXX 
DDMMMYYYY 
DDMMMYY
YY 
DDMMMY
YYY 
XXX 
NN.N 
NN.N 
NN 
XXX 
XXX 
Yes/No 
DDMMMYYYY 
XXX 
DDMMMYYYY 
DDMMMYY
YY 
DDMMMY
YYY 
XXX 
NN.N 
NN.N 
NN 
XXX 
XXX 
Yes/No 
DDMMMYYYY 
XXX 
DDMMMYYYY 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
Date of HER2 
Confirmation If 
Metastatic 
Method 
IHC 
Score 
ISH 
Negative/Positive 
Progesterone 
Receptor Score if 
Metastatic 
Estrogen Receptor 
Score if 
Metastatic 
Any previous 
therapy for BC 
prior to Study 
DDMMMYYYY 
IHC/ISH 
NN 
XXX 
XXX 
XXX 
Yes/No 
DDMMMYYYY 
IHC/ISH 
NN 
XXX 
XXX 
XXX 
Yes/No 
DDMMMYYYY 
IHC/ISH 
NN 
XXX 
XXX 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.4 Listing of Previous Hormone Therapy for Breast Cancer at Screening -ITT Population (N=XXX) 
 
Site ID/ 
Subject No. 
Age/Sex 
Has the patient 
received any 
hormone therapy 
Name of 
Treatment 
Total Dose 
Per Cycle 
Unit Route 
Start 
date 
End date 
Ongoing 
at 
Screening 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.5 Listing of Previous Immunotherapy for Breast Cancer at Screening -ITT Population (N=XXX) 
 
Site ID/ 
Subject 
No. 
Age/Sex 
Has the patient received 
any Immunotherapy 
Name of 
Treatment 
Total 
Dose Per 
Cycle 
Unit Route 
Start 
date 
End date 
Ongoing 
at 
Screening 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.6 Listing of Previous Biologic Therapy for Breast Cancer at Screening -ITT Population (N=XXX) 
 
Site ID/ 
Subject No. 
Age/Sex 
Has the patient 
received any 
Biologic Therapy 
Name of 
Treatment 
Total 
Dose 
Per 
Cycle 
Unit Route 
Start 
date 
End date 
Ongoing 
at 
Screening 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.7 Listing of Previous Radiotherapy for Breast Cancer at Screening -ITT Population (N=XXX) 
 
Site ID/ 
Subject 
No. 
Age/Sex 
Has the patient 
received any 
Radiotherapy 
Locati
on 
Specify 
locatio
n if 
other 
Tota
l 
Dose 
Unit 
Reason for 
administratio
n 
Start 
date 
End date 
Ongoing 
at 
Screening 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.8 Listing of Previous Chemotherapy for Breast Cancer at Screening -ITT Population (N=XXX) 
 
Site ID/ 
Subject 
No. 
Age/Sex 
Has the 
patient 
received any 
Radiotherapy 
Name of 
Drug 
Treatment 
If 
Anthracycline 
Number 
Cycle Unit Method 
Start 
date 
End date 
Ongoing 
at 
Screening 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
Yes/No 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.4.9 Listing of Previous Concomitant Therapy Log for Breast Cancer at Screening -ITT Population (N=XXX) 
 
Site ID/ 
Subject No. 
Age/Sex 
Generic Name  
Indication 
Start date 
End date 
Ongoing at 
Screening 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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16.2.6 
Listing for Efficacy  
Listing 16.2.6.1 Listing of Tumor/Disease Assessment (Target Lessions) -ITT Population (N=XXX) 
Site 
ID/ 
Subjec
t No. 
Age/Se
x 
Visi
t 
Date of 
assessme
nt 
Are 
there 
any 
target 
lesion
s 
Was 
lesion 
measurab
le 
Reaso
n 
Code 
of 
Orga
n 
site 
Locati
on of 
lesion 
How 
assess
ed 
Statu
s of 
Lesio
n 
Siz
e 
(mm
) 
Sum of 
longest 
diamete
rs 
Inflammatory 
Breast Cancer 
Erythe
ma 
Edema 
NN/XXX NN/XXX 
XXX 
DDMMMYYY
Y 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
NN 
NN/XXX NN/XX
X 
NN/XXX NN/XXX 
XXX 
DDMMMYYY
Y 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
NN 
NN/XXX NN/XX
X 
NN/XXX NN/XXX 
XXX 
DDMMMYYY
Y 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
NN 
NN/XXX NN/XX
X 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.6.2 Listing of Tumor/Disease Assessment (Non-Target Lesions) -ITT Population (N=XXX) 
Site ID/ 
Subject 
No. 
Age/Sex Visit 
Date of 
assessment 
Are there 
any non-
target 
lesions 
Method of 
Assessment 
Status 
of 
Lesion 
Code 
of 
Organ 
site 
If 
other 
organ 
site 
Number Of Non-Target 
Lesions 
Within The Organ 
Single 
Lesion 
Multiple 
Lesions 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
NN 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
NN 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
XXX 
NN 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.6.3 Listing of Tumor/Disease Assessment (New Lesions –Target Lesions and Non-target Lesions) -ITT 
Population (N=XXX) 
Site ID/ 
Subject No. 
Age/Sex 
Visit 
Date of 
assessment 
Are there any 
new lesions 
Evaluation 
(Response) of 
Target Lesions 
Evaluation 
(Response) of 
Non-Target 
Lesions  
Overall 
Response 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
NN/XXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 


 
 
 
 
 
 
 
 
 
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Listing 16.2.6.4 Listing of Survival Status-ITT Population (N=XXX) 
Site ID/ 
Subject 
No. 
Age/Sex 
Visit 
Survival Status 
Did patient’s 
disease progress 
since the last 
evaluation 
If Yes 
If No 
If 
Not 
known 
Status 
(Alive/Dead/ 
Withdrew 
consent) 
Date of 
the 
status 
Date of 
Progressiv
e disease 
How 
disease 
progressio
n Was 
assessed 
Date of 
most 
recent 
tumor 
assessment 
Speci
fy 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
Yes/No/Not Known 
DDMMMYYYY 
XXX 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
Yes/No/Not Known 
DDMMMYYYY 
XXX 
DDMMMYYYY 
XXX 
NN/XXX 
NN/XXX 
XXX 
XXX 
DDMMMYYYY 
Yes/No/Not Known 
DDMMMYYYY 
XXX 
DDMMMYYYY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Listing 16.2.7 
Listing of Adverse Event -Safety Population (N=XXX) 
Site 
No./ 
Subject 
No. 
Age/ 
Gender Visit 
AE 
Reported SOC Preferred 
Term 
Event 
Onset 
Date 
Is this event 
considered as 
a related to 
Pertuzumab  
Is this 
event 
considered 
as a 
related to 
Trastuzumab 
Is this 
event 
related 
to 
Docetaxel 
Serious 
AE 
Is this 
an 
Adverse 
Event of 
Special 
Interest 
(AESI) 
XXX/NNN NN/XXX 
XXX 
Yes/No 
XXX 
XXX 
XXX 
DDMMYYYY 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
XXX/NNN NN/XXX 
XXX 
Yes/No 
XXX 
XXX 
XXX 
DDMMYYYY 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
XXX/NNN NN/XXX 
XXX 
Yes/No 
XXX 
XXX 
XXX 
DDMMYYYY 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
 
 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 158 of 174 
 
Act
ion 
Tak
en 
Intensit
y 
(NCI -
CTCAE 
v4.0) 
Chemother
apy 
adjustmen
t 
Treatm
ent 
given 
for 
this 
event 
Advers
e 
events 
of 
suspec
ted 
cardia
c 
origin 
Is this 
event 
symptomatic 
of left 
ventricular 
systolic 
dysfunction 
If 
Yes
, 
NYH
A 
Cla
ss 
LVEF 
decrea
se 
If not 
advers
e 
event 
of 
suspec
ted 
cardia
c 
origin
, 
specif
y 
other 
cause 
Is there 
a 
reasonabl
e 
suspected 
causal 
relations
hip to 
study 
medicatio
n 
If Yes, 
mention 
study 
medicat
ion 
Outco
me 
Date 
Event 
Resolv
ed 
Commen
ts on 
AE 
XXX 
XXX 
XXX 
Yes/No Yes/No 
Yes/No 
XXX Yes/No 
XXX 
Yes/No 
XXX 
XXX 
DDMMYY
YY 
XXX 
XXX 
XXX 
XXX 
Yes/No Yes/No 
Yes/No 
XXX Yes/No 
XXX 
Yes/No 
XXX 
XXX 
DDMMYY
YY 
XXX 
XXX 
XXX 
XXX 
Yes/No Yes/No 
Yes/No 
XXX Yes/No 
XXX 
Yes/No 
XXX 
XXX 
DDMMYY
YY 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
  


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 159 of 174 
 
Listing 16.2.7.1 Listing of Serious Adverse Event -Safety Population (N=XXX) 
Site 
No./ 
Subject 
No. 
Age/ 
Gender Visit 
AE 
Reported SOC Preferred 
Term 
Event 
Onset 
Date 
Date event 
became 
serious 
Study Drug 
Causality 
Study 
Drug 
Other 
Suspect 
Causes 
Cause of 
Seriousness 
of event 
XXX/NNN NN/XXX 
XXX 
Yes/No 
XXX 
XXX 
XXX 
DDMMYYYY 
DDMMYYYY 
Yes/No 
XXX 
XXX 
XXX 
XXX/NNN NN/XXX 
XXX 
Yes/No 
XXX 
XXX 
XXX 
DDMMYYYY 
DDMMYYYY 
Yes/No 
XXX 
XXX 
XXX 
XXX/NNN NN/XXX 
XXX 
Yes/No 
XXX 
XXX 
XXX 
DDMMYYYY 
DDMMYYYY 
Yes/No 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
… 
… 
… 
 
SAE/AE
SI 
outcom
e 
Date 
AE 
Initial 
Intensit
y 
AE most 
extreme 
intensit
y 
AE 
initia
l NCI-
CTCAE 
grade 
AE 
most 
extrem
e NCI-
CTCAE 
grade 
Action 
taken 
with 
Pertuzuma
b 
Date of 
Action 
taken 
with 
Pertuzuma
b 
Action 
taken with 
Trastuzuma
b 
Date of 
Action 
taken with 
Trastuzuma
b 
Action 
taken 
with 
Docetaxe
l 
Date of 
Action 
taken 
with 
Docetaxe
l 
XXX 
DDMMYYYY 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
XXX 
XXX 
XXX 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
XXX 
DDMMYYYY 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 160 of 174 
 
16.2.8 
Lab Test Evaluations 
Listing 16.2.8.1 Listing of Hematology -Safety Population (N=XXX) 
 
Site ID/ 
Subject  
No. 
Age/Sex 
Visit 
Date of 
Collection 
Test 
Results 
Out of 
Range 
Units 
Clinically 
Significant 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 161 of 174 
 
Listing 16.2.8.2 Listing of Coagulation Test -Safety Population (N=XXX) 
 
Site ID/ 
Subject  
No. 
Age/Sex 
Visit 
Date of 
Collection 
Test 
NA 
Results 
Units 
Out of 
Range 
Clinically 
Significant 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
Yes/No 
XXX 
XXX 
Yes/No 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
Yes/No 
XXX 
XXX 
Yes/No 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
Yes/No 
XXX 
XXX 
Yes/No 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 162 of 174 
 
Listing 16.2.8.3 Listing of Serum Chemistry -Safety Population (N=XXX) 
 
Site ID/ 
Subject  No. 
Age/Sex 
Visit 
Date of Collection 
Test 
Results 
Out of Range 
Units 
Clinically 
Significant 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
Yes/No 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 163 of 174 
 
Listing 16.2.8.4 Listing of Viral Serology -Safety Population (N=XXX) 
 
Site ID/ Subject  
No. 
Age/Sex 
Visit 
Date of Collection 
Test 
Results 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 164 of 174 
 
Listing 16.2.8.5 Listing of Pregnancy Test -Safety Population (N=XXX) 
 
Site 
ID/ 
Subject 
No. 
Age/Sex Visit Reproductive 
Status 
Pregnancy 
Test Done 
If Done 
If Urinary 
positive 
If Pregnancy 
test Not 
done, specify 
reason 
Date of 
pregnancy 
test 
Method 
(Serum/Urine) Results 
Date of 
serum 
pregnancy 
test 
Results 
NN/XXXX NN/XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
NN/XXXX NN/XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
NN/XXXX NN/XXX 
XXX 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
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Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 165 of 174 
 
Listing 16.2.8.6 Listing of ECOG Performance Status -Safety Population (N=XXX) 
 
Site ID/ Subject  No. 
Age/Sex 
Visit 
Response 
Grade 
ECOG 
NN/XXXX 
NN/XXX 
XXX 
XXX 
NN 
XXX 
NN/XXXX 
NN/XXX 
XXX 
XXX 
NN 
XXX 
NN/XXXX 
NN/XXX 
XXX 
XXX 
NN 
XXX 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 166 of 174 
 
Listing 16.2.8.7 Listing of LVEF (Left ventricular ejection fraction) -Safety Population (N=XXX) 
 
Site 
ID/ 
Subject  
No. 
Age/Sex Visit 
Date of 
Assessment Result 
By 
If 
Echocardiography
, specify 
calculation 
method 
LVEF 
finding 
Any new 
cardiac 
signs and 
symptoms 
Any worsening 
cardiac signs 
and symptoms 
(since 
screening) 
Any 
signs or 
symptoms 
of CHF 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
Yes/No 
Yes/No 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
Yes/No 
Yes/No 
Yes/No 
NN/XXXX 
NN/XXX 
XXX 
DDMMMYYYY 
XXX 
XXX 
XXX 
XXX 
Yes/No 
Yes/No 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 167 of 174 
 
16.4 Individual subject data listings 
Listing 16.4.1 
Listing of Vital Signs (All Enrolled Subjects) 
Listing 16.4.1.1 Listing of Vital Signs -Safety Population (N=XXX) 
 
Site ID/ 
Subject  
No. 
Age/Sex 
Visit 
Weight 
Pulse Rate 
Respiratory 
Rate 
Blood Pressure 
Temperature 
Systolic 
Diastolic 
NN/XXXX 
NN/XXX 
XXX 
NN 
NN 
NN 
NN 
NN 
NN 
NN/XXXX 
NN/XXX 
XXX 
NN 
NN 
NN 
NN 
NN 
NN 
NN/XXXX 
NN/XXX 
XXX 
NN 
NN 
NN 
NN 
NN 
NN 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 




 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 169 of 174 
 
Listing 16.4.2 
Listing of Physical Examination -Safety Population (N=XXX) 
Site 
No./ 
Subject 
No. 
Age/ 
Gender Visit 
Physical 
Examination 
Performed 
Date of 
Physical 
Examination 
If No, 
Reason 
Body 
System
/Site 
Results 
If 
abnormal
,specify 
Clinical 
Significan
ce 
XXX/NNN NN/XXX 
XXX 
Yes/No 
DDMMYYYY 
XXXX 
XXXX 
Normal/Abnormal/Not Done 
XXX 
Yes/No 
XXX/NNN NN/XXX 
XXX 
Yes/No 
DDMMYYYY 
XXXX 
XXXX 
Normal/Abnormal/Not Done 
XXX 
Yes/No 
XXX/NNN NN/XXX 
XXX 
Yes/No 
DDMMYYYY 
XXXX 
XXXX 
Normal/Abnormal/Not Done 
XXX 
Yes/No 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 170 of 174 
 
Listing 16.4.3 
Listing of Her-2 Determination, CT/MRI and Isotope Bone Scan -Safety Population (N=XXX) 
 
Site 
No./ 
Subje
ct 
No. 
Age/ 
Gend
er 
Vis
it 
Her-2 Determination 
CT/MRI 
Isotope Bone Scan 
Assessm
ent 
perform
ed 
Sample 
collect
ion 
date 
Immunoh
istoche
mistry 
(IHC) 
Result 
In situ 
hybridiza
tion 
(ISH) 
Result 
Date 
CT/MRI 
performed 
clinica
lly 
signifi
cant 
If 
Yes, 
specif
y 
Date 
isotope 
bone scan 
performed 
Result 
(Normal/Abno
rmal) 
If Yes 
abnorm
al, 
specif
y 
XXX/N
NN 
NN/X
XX 
XXX 
Yes/No 
DDMMYYY
Y 
XXXX 
XXXX 
DDMMYYYY 
Yes/No 
XXXX 
DDMMYYYY 
XXXX 
XXXX 
XXX/N
NN 
NN/X
XX 
XXX 
Yes/No 
DDMMYYY
Y 
XXXX 
XXXX 
DDMMYYYY 
Yes/No 
XXXX 
DDMMYYYY 
XXXX 
XXXX 
XXX/N
NN 
NN/X
XX 
XXX 
Yes/No 
DDMMYYY
Y 
XXXX 
XXXX 
DDMMYYYY 
Yes/No 
XXXX 
DDMMYYYY 
XXXX 
XXXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 171 of 174 
 
Listing 16.4.4 
Listing of Study Drug Administration  
Listing 16.4.4.1 Listing of Administration of Pertuzumab -Safety Population (N=XXX) 
 
Site 
No./Subje
ct No. 
Age/Gende
r 
Cycle 
No. 
Date of 
Dose 
Batc
h 
No. 
Start 
Time 
Final 
Stop 
Time 
Planne
d Dose 
Total 
Dose 
Receiv
ed 
Total 
Volume 
Receive
d 
Reasons, 
if 
scheduled 
infusion 
was 
delayed, 
interrupte
d or the 
dose 
modified 
If 
other 
reason
, 
specif
y 
Batches used 
for this 
administratio
n 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NNN 
NN:NN 
NN:NN 
NNN 
NNN 
NNN 
XXX 
XXX 
XXX 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NNN 
NN:NN 
NN:NN 
NNN 
NNN 
NNN 
XXX 
XXX 
XXX 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NNN 
NN:NN 
NN:NN 
NNN 
NNN 
NNN 
XXX 
XXX 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 172 of 174 
 
Listing 16.4.4.2 Listing of Administration of Trastuzumab -Safety Population (N=XXX) 
 
Site 
No./Subject 
No. 
Age/Gender Cycle 
No. 
Date of 
Dose 
Time of 
Dose 
Total 
Dose 
Received 
Route 
Reasons, if scheduled infusion was 
delayed, interrupted or the dose 
modified 
If other 
reason, 
specify 
Adverse Event 
Other 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NN:NN 
NNN 
XXX 
Yes/No 
Yes/No 
XXX 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NN:NN 
NNN 
XXX 
Yes/No 
Yes/No 
XXX 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NN:NN 
NNN 
XXX 
Yes/No 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 173 of 174 
 
Listing 16.4.4.3 Listing of Administration of Docetaxel -Safety Population (N=XXX) 
 
Site 
No./Subject 
No. 
Age/Gender Cycle 
No. 
Date of 
Dose 
Time of 
Dose 
Total 
Dose 
Received 
Route 
Reasons, if scheduled infusion was 
delayed, interrupted or the dose 
modified 
If other 
reason, 
specify 
Adverse Event 
Other 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NN:NN 
NNN 
XXX 
Yes/No 
Yes/No 
XXX 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NN:NN 
NNN 
XXX 
Yes/No 
Yes/No 
XXX 
XXX/NNN 
NN/XXX 
XXX 
DDMMYYYY 
NN:NN 
NNN 
XXX 
Yes/No 
Yes/No 
XXX 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
 


 
 
 
 
 
 
 
 
 
20 Jun 2016 
Confidential and Proprietary to Roche Products (India) Pvt. Ltd. 
 
  
Statistical Analysis Plan (ML29282) 
 
 
 
 
 
 
 
 
 
Page 174 of 174 
 
Listing 16.2.4.4 Listing of Concomitant Medications -Safety Population (N=XXX) 
 
Site ID/ Subject  
No. 
Age/Sex 
Medication 
(Generic 
Name) 
Class of 
Medication[1] 
Indication 
Regimen 
Dose(per 
day) 
NN/XXXX 
NN/XXX 
XXXX 
XXXX 
XXXX 
XXX 
NN 
NN/XXXX 
NN/XXX 
XXXX 
XXXX 
XXXX 
XXX 
NN 
NN/XXXX 
NN/XXX 
XXXX 
XXXX 
XXXX 
XXX 
NN 
… 
… 
… 
… 
… 
… 
… 
 
 
 
Unit 
Frequency 
Route[2] 
Date 
started 
Date 
stopped 
Ongoing 
XXX 
XXX 
XXXXX 
DDMMMYYYY 
DDMMMYYYY 
Yes/No 
XXX 
XXX 
XXXXX 
DDMMMYYYY 
DDMMMYYYY 
Yes/No 
XXX 
XXX 
XXXXX 
DDMMMYYYY 
DDMMMYYYY 
Yes/No 
… 
… 
… 
… 
… 
…