Conditions: Breast Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1846
Healthy volunteers: no

Brief summary:
This two-arm, randomized, open-label, multicenter study will evaluate the efficacy and safety of trastuzumab emtansine in combination with pertuzumab versus trastuzumab in combination with pertuzumab and a taxane as adjuvant therapy in participants with human epidermal growth (HER) factor 2 (HER2)-positive primary invasive breast cancer. Following surgery and anthracycline-based chemotherapy, participants will receive either trastuzumab emtansine at a dose of 3.6 milligrams per kilogram (mg/kg) and pertuzumab at a dose of 420 milligrams (mg) intravenously (IV) every 3 weeks (q3w) or trastuzumab at a dose of 6 mg/kg and pertuzumab at a dose of 420 mg IV q3w in combination with a taxane.

Detailed description:

Arms:
arm 1: Trastuzumab and pertuzumab will be administered concurrently for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) with the taxane (docetaxel or paclitaxel) component of chemotherapy following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy. arm 2: Trastuzumab emtansine and pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles \[1 Cycle = 21 days\]) following anthracycline \[5 fluorouracil, epirubicin, and cyclophosphamide (FEC) or epirubicin and cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC)\] based chemotherapy.

Interventions: intervention 1: Trastuzumab Emtansine intervention 2: Trastuzumab intervention 3: Pertuzumab intervention 4: Paclitaxel intervention 5: Epirubicin intervention 6: Doxorubicin intervention 7: Docetaxel intervention 8: Cyclophosphamide intervention 9: 5-Fluorouracil
Intervention descriptions: intervention 1: Trastuzumab emtansine IV infusion (duration 90 minutes) will be administered at 3.6 mg/kg q3w for up to 18 cycles (1 cycle = 21 days). intervention 2: Trastuzumab IV infusion (duration 90 minutes) will be administered at 8 mg/kg loading dose followed by 6 mg/kg IV q3w for up to 18 cycles (1 cycle = 21 days). intervention 3: Pertuzumab infusion (duration 60 minutes) will be administered at 840 mg loading dose followed by 420 mg IV q3w for up to 18 cycles (1 cycle = 21 days). intervention 4: IV infusion of paclitaxel 80 mg/m\^2 once weekly may be administered concurrently with trastuzumab in combination with pertuzumab for 12 weeks. intervention 5: 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using epirubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. intervention 6: 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using doxorubicin may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. intervention 7: IV infusion either docetaxel every 3 weeks (q3w) (at 100 milligram per square meter \[mg/m\^2\] for 3 cycles (1 cycle = 21 days); at 75 mg/m2 for 4 cycles; or start at 75 mg/m\^2 in the first cycle and escalate to 100 mg/m\^2 if no dose limiting toxicity occurs, for a total of 3 cycles at minimum) may be administered concurrently with trastuzumab in combination with pertuzumab. intervention 8: 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using cyclophosphamide (FEC) may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines. intervention 9: 3 to 4 cycles (1 cycle = 21 days) of standard of care anthracycline-based chemotherapy using 5-fluorouracil, may be administered in both Arms 1 and 2 as per discretion of the investigator and local prescribing information/institutional guidelines.

Protocol document:
Prot_000.pdf: 
 
Official Title: 
 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
TRIAL COMPARING TRASTUZUMAB PLUS PERTUZUMAB 
PLUS A TAXANE FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB 
FOLLOWING ANTHRACYCLINES AS ADJUVANT THERAPY 
IN PATIENTS WITH OPERABLE HER2-POSITIVE PRIMARY 
BREAST CANCER 
NCT Number: 
NCT01966471   
Document Date: 
Protocol Version 3: 30-July-2015 
 
 
 


 
Title
30-Jul-2015 17:56:09
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
PROTOCOL 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
PHASE III TRIAL COMPARING TRASTUZUMAB 
PLUS PERTUZUMAB PLUS A TAXANE 
FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB 
FOLLOWING ANTHRACYCLINES AS ADJUVANT 
THERAPY IN PATIENTS WITH OPERABLE 
HER2-POSITIVE PRIMARY BREAST CANCER 
PROTOCOL NUMBER: 
BO28407 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-004902-82 
IND NUMBER: 
71072 
TEST PRODUCTS: 
Trastuzumab Emtansine (RO5304020) and 
Pertuzumab (RO4368451) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  7 October 2013 
DATE AMENDED: 
Version 2:  16 June 2014 
Version 3:  See electronic date stamp below. 
 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
 
2 
PROTOCOL AMENDMENT, VERSION 3: 
RATIONALE 
Protocol BO28407 has been amended in light of new data from the Phase III study 
TDM4788g/BO22589 (MARIANNE) in metastatic breast cancer, in which efficacy (PFS) 
of trastuzumab emtansine with and without pertuzumab was shown to be non-inferior to 
trastuzumab+taxane, with improvements in tolerability and quality of life (QoL); however 
neither of the trastuzumab emtansine-containing regimens showed PFS superiority over 
taxane plus trastuzumab.  Further, in the early breast cancer (EBC) study (WGS-
ADAPT), a planned interim analysis of pathological complete response (pCR) (ypT0/is, 
ypN0) rates after neoadjuvant trastuzumab emtansine with or without endocrine therapy 
as treatment of ER+, HER2 breast cancer was highly promising.  These preliminary pCR 
rates observed are substantially higher than those seen with previous studies evaluating 
trastuzumab+endocrine therapy or chemotherapy + trastuzumab ± pertuzumab as 
treatment of ER+, HER2+ EBC.  These data, together with those from 
Study TDM4997g/BO25734 (TH3RESA), TDM4370g/BO21977 (EMILIA), TDM4450g, 
and TDM4874g/BO22857 support continuation of the BO28407 study with the following 
key protocol modifications:  
• 
Sample size reduction:  In light of the MARIANNE study results, it is assumed that 
the likelihood of this study meeting its primary efficacy endpoint for superiority has 
decreased.  To address this updated assessment of potential study outcome sample 
size was reduced while maintaining statistical validity of the study in addressing its 
primary endpoint.  Section 3.3.2.3 (Rationale for Sample Size Reduction) was 
added to detail the reasons for this study design modification.   
o Since the study enrollment is stopped earlier than planned, the capping of 
enrollment that was prespecified in Protocol Versions 1 and 2 will not be 
implemented, and thus Section 3.3.2.1 (Rationale for Capping Subgroup 
Enrollment) has been updated.  Relevant protocol sections have also 
been updated to reflect this change accordingly (Sections 3.1, 4.1, 4.1.1, 
6.1) 
• 
The study rationale, background information and benefit-risk assessment sections 
have been updated considering new data for trastuzumab emtansine 
(Sections 1.2.1, 1.3.1 and 1.3.2).  In addition, the Rationale for Adjuvant Regimens 
and Duration of Therapy (Section 3.3.4) was updated to reflect the impact of new 
data on the rationale for adjuvant regimens. 
 
Additional changes to the protocol, by topic, are as follows: 
1. Provision of updated clinical data 
In order to provide a better overview of benefit-risk, in light if all new data, the following 
sections were updated: 
• 
Background section 1.2.1.1.1 (Single-agent studies) have been updated to provide 
latest data for Study TDM4997g/BO25734  


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
 
3 
• 
Background section 1.2.1.1.2 (Combination studies) have been updated to provide 
latest data for Study TDM4788g/BO22589 (MARIANNE) 
• 
Background section 1.2.1.2 (Trastuzumab emtansine clinical experience in EBC) 
have been updated to include Study BO28408 and to provide latest data for Studies 
TDM4874g/BO22857, BP22572, and BO27938. 
• 
Background section 1.2.1.3 (Pooled safety analysis of single-agent trastuzumab 
emtansine) and Table 1 have been updated to provide changes with the latest data 
cut as of 31 July 2012. 
• 
Background section 1.2.2.1 (Pertuzumab clinical experience in MBC) has been 
updated to provide latest data for WO20698/TOC4129g (CLEOPATRA) 
• 
Background section 1.2.2.2 (Pertuzumab clinical experience in EBC) has been 
updated to provide latest data for WO20697 (NEOSPHERE), and BO25126 
(APHINITY).  
• 
Pooled safety analysis of trastuzumab emtansine in combination with pertuzumab 
(Section 1.2.3) and Table 4 have been updated to provide changes with the latest 
data cut as of 30 September 2013. 
 
2. Patient Reorted Outcomes 
• 
Patient-Reported Outcomes has been updated to include additional analyses to 
assess the patient experience with therapy (Section 6.6) 
 
3. Safety Reporting Updates 
• 
The following changes were made, to align with most recent data or guidance 
• 
The section on persistent or recurrent adverse events (Section 5.3.5.3) was updated 
per new template to include information regarding Adverse Event Intensity or Grade 
Changes eCRF. 
• 
Emergency medical contacts (Section 5.4.1) have been updated to reflect personnel 
changes. 
• 
Reporting requirements for pregnancies have been updated to align with the 
Herceptin, Perjeta, and Kadcyla Global Enhancement Pharmacovigilance 
Pregnancy Program (Section 5.4.3.2). 
 
4. Futility Analysis 
• 
Section 6.8.1 (interim analysis) has been updated to indicate the potential for a 
futility analysis to evaluate lack of superiority for the treatment arm of trastuzumab 
emtansine + pertuzumab following anthracyclines that will be further detailed in the 
Statistical Analysis Plan.  
 
5. Effective contracption 
• 
Intrauterine device (IUD) was recognized as highly effective contraception.  Highly 
effective contraception is defined as a method of birth control that results in a very 
low failure rate (i.e., less than 1% per year) when used consistently and correctly 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
 
4 
(theoretical effectiveness).  Per the new World Health Organization data, IUD should 
be categorized as a highly effective method as it has a failure rate of less than 1% 
per year with either theoretical use or typical use (Appendix 10). 
 
Additional minor changes have been made to improve clarity and consistency and to 
reflect current recommendations.  Substantive new information appears in italics. 


Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
5 
PROTOCOL AMENDMENT, VERSION 3: 
SUMMARY OF CHANGES 
GLOBAL CHANGES 
A total of 2500Approximately 1850 patients will are anticipated to be enrolled at 
approximately 350 sites worldwide. 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.2.1.1.1:  Single-Agent Studies 
Study TDM4997g/BO25734 (TH3RESA) is a Phase III study to evaluate efficacy of 
trastuzumab emtansine versus Treatment of Physician’s Choice (TPC) in patients who 
received at least two prior regimens of HER2-directed therapies, including trastuzumab 
and lapatinib, in the metastatic or unresectable locally advanced/recurrent setting.  
Co-primary efficacy endpoints were PFS per investigator assessment and OS.  There 
were 404 patients who received trastuzumab emtansine as their planned treatment, and 
198 patients who received TPC.  Patients receiving trastuzumab emtansine had a 
47.2% reduction in the risk of disease progression or death.  Median PFS was 3.3 
months in the TPC arm and 6.2 months in the trastuzumab emtansine arm (HR = 0.528; 
95% CI: 0.422, 0.661; p < 0.0001).  There was a strong positive trend in OS in favor of 
trastuzumab emtansine at the first interim analysis.  Patients receiving trastuzumab 
emtansine had a 44.8% reduction in the risk of death (HR = 0.552; 95% CI: 0.369, 
0.826; p = 0.0034) compared with patients receiving TPC; however, this result did not 
cross the pre-specified O’Brien-Fleming stopping boundary of HR < 0.363 
(p < 0.0000013).  Patients receiving trastuzumab emtansine also showed a consistent 
treatment benefit compared with the subgroup of TPC patients receiving a 
trastuzumab-containing regimen (74.7% of the intent-to-treat [ITT] population).  
Numerically fewer patients receiving trastuzumab emtansine than those receiving TPC 
had Grade  ≥ 3 AEs (39.0% vs. 46.2%) or AEs leading to dose reduction (12.4% vs. 
20.7%).  The incidence of SAEs (24.1% vs. 22.3%) and of AEs leading to treatment 
discontinuation of any component of therapy (11.7% vs. 10.9%) are similar between 
treatment arms.  Across the majority of the most commonly affected body systems, 
patients receiving trastuzumab emtansine reported more AEs compared with those 
receiving TPC.  However, the higher frequency of events seen for trastuzumab 
emtansine was driven by Grade 1−2 AEs. 
The patient-reported outcome (PRO) measures including “time to pain symptom 
progression” were utilized to evaluate QoL.  The time to pain symptom progression was 
similar different between the two treatment arms (HR = 1.115; 95% CI: 0.819, 1.517). 
SECTION 1.2.1.1.2:  Combination Studies 
A total of 1095 patients were enrolled in this study.  


 
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Efficacy and safety data were recently described (Ellis et al. 2015).  For the primary 
endpoint of PFS based on independent review facility (IRF) assessment, both 
trastuzumab emtansine + placebo and trastuzumab emtansine + pertuzumab were 
non-inferior to trastuzumab + taxane:  the upper bounds of the 97.5% CIs for the 
stratified HRs were below the pre-specified non-inferiority margin of HR 1.1765:  1.13 
for trastuzumab emtansine + placebo (HR = 0.91; 97.5% CI: 0.73, 1.13) and 1.08 for 
trastuzumab emtansine + pertuzumab (HR = 0.87; 97.5% CI: 0.69, 1.08), each versus 
trastuzumab + taxane.  The addition of pertuzumab to trastuzumab emtansine did not 
result in a statistically significant increase in PFS in the ITT population.  Median PFS 
was 13.7 months for trastuzumab + taxane, 14.1 months for trastuzumab 
emtansine + placebo and 15.2 months for trastuzumab emtansine + pertuzumab. 
The safety profile of trastuzumab emtansine as a single agent or in combination with 
pertuzumab was consistent with prior experience, with no new safety signals identified 
compared with those already known for these study drugs.  Trastuzumab emtansine as a 
single agent or in combination with pertuzumab was more tolerable than 
trastuzumab + taxane, with respect to a numerical lower incidence and/or severity of 
certain clinically important and/or symptomatic toxicities, fewer Grade ≥ 3 AEs and 
fewer AEs leading to treatment discontinuation (Ellis et al. 2015). 
As of July 2013, unblinded safety and efficacy data were not available to the Sponsor, 
but the independent Data Monitoring Committee (iDMC), which reviews data from the 
trial on a quarterly basis, had thus far recommended that the study continue as planned. 
SECTION 1.2.1.2:  Trastuzumab Emtansine Clinical Experience in Early 
Breast Cancer 
As of 22 April 2013, a total of 148 patients had received trastuzumab emtansine.  NThe 
final analysis (clinical cut off 12 June 2013) indicated that there were no prespecified 
cardiac events occurred (95% CI: 0.00%, 2.45%), and there were no reports of 
symptomatic left ventricular systolic dysfunction (LVSD) or heart failure.  One patient 
discontinued trastuzumab emtansine due to asymptomatic left ventricular ejection 
fraction (LVEF) decline.  Overall, 123 (83.1%) patients completed the planned course of 
trastuzumab emtansine treatment, 119 (80.4%) of whom had no dose reduction.  Twenty 
patients (13.5%) had adverse events leading to trastuzumab emtansine discontinuation:  
in 11 of these patients, the adverse events were laboratory abnormalities requiring 
discontinuation (none were Grade 4), and in 9 patients, discontinuation was because of 
symptomatic adverse events (2 were Grade 3 [fatigue, joint crepitation]; none were 
Grade 4).  Of the 148 patients, 32.4% had Grade 3 trastuzumab emtansine−related 
adverse events and 2.7% had Grade 4 trastuzumab emtansine−related adverse events 
(1 patient each:  febrile neutropenia and pancytopenia, atrial fibrillation, decreased 
platelet count, and hypokalemia); no deaths occurred.  The adverse events observed to 
date are consistent with the known safety profile of trastuzumab emtansine.  There were 
no cases of portal hypertension/nodular regenerative hyperplasia (NRH) reported.  For 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
7 
additional safety details for this study, please refer to the trastuzumab emtansine 
Investigator’s Brochure. 
In the MBC population (n = 25), the ORR was 80.0% (95% CI: 59.3, 93.2).  In the 
overall LABC population (n = 73), the pCR rate was 60.3% (95% CI: 48.1, 71.5).  In 
LABC patients receiving trastuzumab emtansine + docetaxel (n = 40), the pCR rate was 
60.0%, and in those receiving trastuzumab emtansine + docetaxel + pertuzumab (n = 33), 
it was 60.6%. 
Study WSG-ADAPT is a Phase II study evaluating trastuzumab emtansine with or 
without endocrine therapy in comparison to trastuzumab + endocrine therapy as 
neoadjuvant treatment in HER2+/HR+ EBC patients.  After 4 cycles of either 
neoadjuvant trastuzumab + endocrine therapy or neoadjuvant trastuzumab emtansine 
with or without endocrine therapy, patients underwent definitive breast surgery with 
total pCR serving as the primary endpoint.  Notable therapeutic activity was observed 
at the planned interim analysis (January 2015) among 130 patients.  Total pCR 
(ypT0/is, ypN0) rates after 4 cycles of neoadjuvant trastuzumab + endocrine therapy, 
trastuzumab emtansine + endocrine therapy, or trastuzumab emtansine alone were 
6.7%, 45.8%, and 40.5%, respectively (Harbeck et al. 2015). 
Study BO27938 (KATHERINE) is a randomized, multinational, multicenter, open-label 
Phase III study, evaluating adjuvant treatment with trastuzumab emtansine compared 
with trastuzumab in patients with EBC who have not achieved a pCR following 
neoadjuvant treatment with chemotherapy and trastuzumab.  The primary objective of 
this trial, which started in April 2013, is to compare invasive disease−free survival (IDFS) 
between treatment arms.  As of 11 May 2015, unblinded safety and efficacy data were 
not available to the Sponsor, but the independent Data Monitoring Committee (iDMC), 
which reviews data from the trial, had thus far recommended that the study continue as 
planned. 
Study BO28408/TRIO021 (KRISTINE) is a randomized, multicenter, open-label Phase 
III study, evaluating neoadjuvant treatment with trastuzumab emtansine + pertuzumab 
compared with chemotherapy + trastuzumab and pertuzumab in patients with EBC.  
The primary objective of this trial, which started in June 2014, is to compare the pCR 
rate (ypT0/is, ypN0) using local evaluation between treatment arms.   
SECTION 1.2.1.3:  Pooled Safety Analysis of Single-Agent Trastuzumab 
Emtansine 
Pooled safety data are available for 884 patients with MBC treated with single-agent 
trastuzumab emtansine at a dose of 3.6 mg/kg q3w.  The most common adverse events 
associated with single-agent trastuzumab emtansine (in ≥ 25% of patients) were fatigue 
(46.346.4%), nausea (42.943.0%), thrombocytopenia (32.129.6%), headache 
(29.229.4%), and constipation (26.45%).  Most of these events were Grade 1 or 2 in 
intensity.  The most common Grade ≥ 3 adverse events (occurring in > 2% of patients) 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
8 
were thrombocytopenia (1110.7%), increased AST (4.3%), fatigue (3.2%), increased 
ALT (3.1%), hypokalemia (2.9%), and anemia (2.79%).  Fifty eightSixty-two patients 
(6.67.0%) experienced adverse events that resulted in their trastuzumab emtansine 
treatment being discontinued:  The most common adverse events leading to 
discontinuation were blood and lymphatic system disorders (primarily thrombocytopenia 
[1.5%]) and investigations system organ classes (SOCs) (increased AST [0.8%] and 
increased ALT [0.5%]). 
Selected aAdverse events of special interest for all patients include hepatotoxicity, 
peripheral neuropathy, thrombocytopenia, infusion-related reactions 
(IRR)/hypersensitivity, cardiac dysfunction, and pneumonitis.   
SECTION 1.2.2.1:  Pertuzumab Clinical Experience in MBC 
The primary endpoint of this randomized trial was PFS as assessed by an IRF.  The 
randomized trial demonstrated a statistically significant improvement in IRF-assessed 
PFS in the pertuzumab-treated group compared with the placebo-treated group 
(HR = 0.62 [95% CI: 0.51, 0.75]; p < 0.0001) and an increase in median PFS of 
6.1 months (median PFS of 18.5 months in the pertuzumab-treated group vs. 
12.4 months in the placebo-treated group) (Baselga et al. 2012c).  The final analysis of 
OS took place when 389 deaths had occurred, after a median follow-up of 50 months.  
Despite crossover, OS benefit in favor of the pertuzumab-treated group was maintained 
(HR = 0.68; 95% CI: 0.56, 0.84; p = 0.0002).  The median OS was longer by 15.7 
months in the pertuzumab-treated group (median 56.5 months) compared to the 
placebo-treated group (median 40.7 months) (Swain et al. 2015). 
SECTION 1.2.2.2:  Pertuzumab Clinical Experience in Early Breast Cancer 
Results from the post-treatment follow-up period (up to the third clinical cutoff of 
12 July 2013) showed that there were no clinically relevant, long-term toxicities. 
Five-year pre-planned analyses of pertuzumab in combination with trastuzumab and 
docetaxel compared with trastuzumab and docetaxel showed 81% and 82% PFS (similar 
to event-free survival) and 88% and 84% DFS rate, respectively.  These analyses 
showed that these results are consistent with breast pCR results and shows long-term 
benefits of adding pertuzumab to trastuzumab and docetaxel as neoadjuvant therapy 
(Gianni et al. 2015). 
SECTION 1.2.3:  Pooled Safety Analysis of Trastuzumab Emtansine in 
Combination with Pertuzumab 
Pooled safety data are available for 87 patients treated with trastuzumab emtansine and 
pertuzumab (Studies TDM4373g/BO22495 [n = 67] and TDM4688g [n = 20]; including 
follow-up data for any patients continuing to receive treatment in the extension study 
[TDM4529g/BO25430]).  The most common adverse events of any grade (in ≥ 20% of 
patients) were fatigue (52.9%), nausea (42.5%), diarrhea (354.65%), cough (33.3%), 
decreased appetite (31%), thrombocytopenia (27.6%), constipation (26.4%), vomiting 


 
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9 
(2627.46%), pyrexia (26.4%), increased AST (26.4%), chills (25.3%), epistaxis 
(2425.13%), increased ALT (23%), headache (23%), dyspnea (23%), dysgeusia (20.7%), 
and rash (210.78%), with most of these events being Grade 1 or 2.  The most common 
Grade ≥ 3 adverse events (occurring in > 2 patients [2.5%]) were fatigue (11.5%), 
thrombocytopenia (10.3%), fatigue (10.3%), increased AST (9.2%), dyspnea (8.09.2%), 
increased ALT (6.9%), anemia (5.7%), cellulitis (4.6%), peripheral sensory neuropathy 
(4.6%), pleural effusion (3.4%), hypokalemia (3.4%), and pneumonia (3.4%). 
Adverse Selected adverse events of relevance to trastuzumab emtansine of special 
interest for all patients include hepatotoxicity, peripheral neuropathy, thrombocytopenia, 
infusion reactions, cardiac dysfunction, and pneumonitis.  Table 4 provides an overview 
of these adverse events. 
SECTION 1.3.1:  Study Rationale 
The highly potent chemotherapeutic agent DM1 should complement the HER2 signaling 
pathway inhibition caused by the combination of trastuzumab and pertuzumab.  
Furthermore, DM1 may provide higher dose intensity and longer duration when delivered 
as a HER2-targeted chemotherapy with potentially less systemic toxicity compared with 
conventional chemotherapy.  Therefore, trastuzumab emtansine should substantially 
may reduce the risk of recurrence and increase the likelihood of DFS in HER2-positive 
EBC, with an acceptable safety profile compared with the current or anticipated future 
SoC. 
The Phase III EMILIA study demonstrated improved efficacy (PFS and OS), with a 
favorable safety profile and QoL, with trastuzumab emtansine as a single agent 
compared with lapatinib plus capecitabine in patients with recurrent/metastatic 
HER2-positive breast cancer who have previously received taxanes and trastuzumab.  
Furthermore, this benefit was seen both in patients treated as first-line therapy for 
MBC who had progressed early as well as those who received therapy in second line and 
later (Section 1.2.1.1.1; Blackwell et al. 2012; Verma et al. 2012). 
The Phase III TH3RESA study also showed improved efficacy in PFS and a trend for 
OS benefit at the first interim analysis, with a favorable safety profile for single-agent 
trastuzumab emtansine compared with TPC in patients who received at least two prior 
regimens of HER2-directed therapies, including trastuzumab and lapatinib, in the 
metastatic or unresectable locally advanced/recurrent setting (Section 1.2.1.1.1; 
Krop et al. 2014). 
A randomized Phase II study, TDM4450g/BO21976 (Section 1.2.1.1.1), demonstrated 
improvements in PFS, safety, and QoL with trastuzumab emtansine compared with 
trastuzumab combined with docetaxel in the first-line recurrent/metastatic setting 
(Hurvitz et al. 2013).   


 
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The Phase III MARIANNE study demonstrated that trastuzumab emtansine as single 
agent or in combination with pertuzumab were non-inferior to taxane + trastuzumab 
with respect to PFS as assessed by independent review, with numerical improvements 
in tolerability and QoL; however, neither of the trastuzumab emtansine-containing 
arms showed superiority over taxane plus trastuzumab (Section 1.2.1.1.2; 
Ellis et al. 2015). 
These results, taken in context with the totality of data from all the MBC studies 
described above, demonstrated the therapeutic potential of trastuzumab emtansine, as 
an ADC, to improve or at least provide similar benefit and decrease safety risk 
compared with trastuzumab or lapatinib plus a concurrent systemic 
chemotherapy/taxane in the MBC setting.  
In Study TDM4874g/BO22857, trastuzumab emtansine following anthracycline-based 
chemotherapy showed acceptable safety as neoadjuvant and/or adjuvant treatment in 
HER2-positive early-stage breast cancer.  Furthermore, clinical activity in the 
neoadjuvant setting (pCR [ypT0/is, ypN0] rate of 56%) was also demonstrated 
(Section 1.2.1.2).   
In the WSG-ADAPT Study MO23078 (Section 1.2.1.2), a planned interim analysis 
demonstrated clinically meaningful pCR (ypT0/is, ypN0) rates ( > 40%) in 
HER2+/HR+ EBC patients treated with 4 cycles of neoadjuvant trastuzumab emtansine 
alone or with endocrine therapy, versus a pCR rate of 6.7% treated with 
trastuzumab + endocrine therapy.  These interim pCR results observed in the WGS-
ADAPT trial are among the highest reported for ER+, HER2+ EBC and are an 
improvement over the previously reported 22% total pCR rate observed with 4 cycles of 
docetaxel, trastuzumab, and pertuzumab in subset of patients with ER+ breast cancer 
treated in the WO20697 (NEOSPHERE) study (Gianni et al. 2012).  With the 
acknowledged caveats regarding cross trial comparisons, these promising pCR data 
from the TDM4874g/BO22857 and WSG-ADAPT studies indicate that trastuzumab 
emtansine is an active agent in HER2-positive EBC, regardless of hormonal receptor 
status, and further supported developing trastuzumab emtansine + pertuzumab as a 
treatment option for the EBC population.  
Synergy has been demonstrated in the nonclinical setting between trastuzumab 
emtansine and pertuzumab.  Studies with three HER2-positive mouse xenograft models 
in vivo consistently showed enhanced anti-tumor activity when trastuzumab emtansine 
was administered in combination with pertuzumab compared with trastuzumab 
emtansine administered as a single agent.  Furthermore, the combination of 
trastuzumab emtansine and pertuzumab has shown clinical activity and acceptable 
tolerability in patients with recurrent LABC/MBC in the Phase Ib/II Studies 
TDM4373g/BO22495 and TDM4688g (see details in Section 1.2.1.1.2 and Section 1.2.3).  


 
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In MARIANNE, no clinically or statistically significant synergy between trastuzumab 
emtansine and pertuzumab was observed in the ITT population.  Uncertainties exist 
regarding the translation of results of MBC trials where equivalent or inferior outcomes 
are observed into results of adjuvant studies due to differences in tumor biology (e.g., 
less intratumor heterogeneity in EBC due to temporal variaions in cancer evolution, 
bulky disease in MBC vs. microscopic disease in the adjuvant setting, and the 
hypothesized potential pre-existing suppression of anti-cancer immunoresponse in the 
metastatic tumor microenvironment), study endpoints (imaging based PFS vs. IDFS), 
as well as the mechanism of action of trastuzumab emtansine and pertuzumab (e.g., 
potential MOA as immunotherapy) (Liakou et al. 2007; Stagg et al. 2011; 
Loi et al 2013; Apolo et al. 2014; Bianchini et al. 2014; Perez et al. 2015).  As an 
example, the Phase III study comparing docetaxel, doxorubicin, and cyclophosphamide 
(TAC) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as the first-line 
chemotherapy for MBC patients demonstrated similar time to tumor progression 
(HR = 1.0380; p = 0.51) (Mackey et al. 2002).  However, it was reported in the 
BCIRG001 study that adjuvant TAC showed improved DFS rates compared to FAC 
(HR = 0.72, p = 0.0020) (Mackey et al. 2013).  Therefore, the lack of clinically 
meaningful synergy between trastuzumab emtansine and pertuzumab in the MBC 
setting may not be of full predictive value on whether there would be a potential 
synergy between trastuzumab emtansine and pertuzumab in the adjuvant setting.  
In the adjuvant setting, it may be of particular clinical importance to eEvaluatinge 
trastuzumab emtansine without concurrent taxane, which may can utilize the full 
potential of this ADC in efficacy and safety improvement or demonstrating numerically 
equivalent efficacy with better tolerability or different safety profile in EBC and avoid 
compromised safety and dose intensity observed in Studies TDM4652g and BP22572 
(Section 1.2.1).  The combination of trastuzumab emtansine and pertuzumab without a 
taxane will therefore be compared with trastuzumab and pertuzumab plus taxane in this 
study.  The goal is to assess whether trastuzumab emtansine−based adjuvant regimens 
will significantly improve the benefit-risk outcome of high-risk patients with HER2-
positive EBC.  This study question remains clinically and scientifically important since 
MARIANNE results in the MBC setting may not fully predict the outcome of the 
combination of trastuzumab emtansine and pertuzumab in the adjuvant setting.  
Further rationales for the study design and study design changes can be found in 
Section 3.3. 
SECTION 1.3.2:  Benefit-Risk Assessment 
Trastuzumab emtansine has shown a favorable benefit-risk profile in patients whose 
disease has progressed after prior HER2-directed therapies for MBC (Krop et al. 2014), 
Blackwell et al. 2012, Verma et al. 2012).  Trastuzumab emtansine also appears to have 
an acceptable or favorable benefit-risk profile in patients who have not received prior 
chemotherapy for metastatic disease, including patients who have previously received 
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emtansine monotherapy has demonstrated a favorable or tolerable toxicity profile across 
studies conducted to date in patients with breast cancer, including a Phase II cardiac 
safety study of trastuzumab emtansine in patients with EBC (Study TDM4874g/BO22857, 
see Section 1.2.1.2) and the WSG-ADAPT Study, see Section 1.2.1.2).  Furthermore, 
Studies TDM4874g and WSG-ADAPT indicate that trastuzumab emtansine is an 
active agent in HER2-positive EBC, regardless of hormonal receptor status. 
Although initial safety data to date involving trastuzumab emtansine in previously 
untreated patients in both the adjuvant (Dang et al. 2012) and the metastatic setting 
(Hurvitz et al. 2013; Ellis et al. 2015) appear acceptable, the long-term safety of 
trastuzumab emtansine in the EBC setting is not fully known.  A safety plan for this study, 
including appropriate eligibility criteria, dose modification guidelines, interim safety 
analyses for overall deaths and hepatic events defined as confirmed Hy’s law cases, and 
regular monitoring of accumulating patient safety data by an iDMC, has been put into 
place to minimize any potential risk in the trial patient population.  Furthermore, iDMC 
recommendations and/or available safety and efficacy data from Study MARIANNE 
(TDM4788g/BO22589; see Section 1.2.1.1.2) have been provided to the iDMC; and 
iDMC recommendations and available safety and efficacy data from and 
Study BO25126 (APHINITY; see Section 1.2.2.2) will be available provided as applicable 
to the iDMC for consideration during the conduct of Study BO28407.   
The combination of trastuzumab emtansine and pertuzumab following systemic 
anthracyclines has the potential to further significantly improve the efficacy outcome in 
high-risk patients with HER2-positive EBC.  The totality of data regarding trastuzumab 
emtansine and pertuzumab (see Sections 1.2.1, 1.2.2, and 1.3.1), support that the 
experimental arm (trastuzumab emtansine and pertuzumab following anthracyclines) 
in this study is highly likely to demonstrate a risk/benefit profile at least equivalent to 
the current anthracycline-trastuzumab based adjuvant SoC for patients with 
HER2-positive EBC.  Specifically, the efficacy in MARIANNE is at least equivalent to 
taxane and trastuzumabin the MBC setting with AE profile that may be more tolerable 
than taxane and trastuzumab which is the current EBC adjuvant SoC. In addition the 
interim data from WGS-ADAPT demonstrated clinically meaningful pCR rates ( > 
40%) with single agent trastuzumab emtansine, which is better than or comparable to 
pCR rates achieved with trastuzumab containing regimens with concurrent systemic 
chemotherapy in the EBC setting. (Harback et al, 2015). 
Toxicities observed in studies with combination of trastuzumab emtansine and 
pertuzumab appear to be manageable, on the basis of final Phase II study results 
(TDM4373g/BO22495 and TDM4688g) and iDMC recommendations to continue the 
Phase III MARIANNE Study TDM4788g/BO22589.  On the basis of available data, the 
safety of trastuzumab emtansine when combined with pertuzumab appears consistent 
with the known toxicity profiles of each drug as a single agent (see Section 1.2.3).  
MARIANNE data suggested that the combination of trastuzumab emtansine and 


 
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pertuzumab may be more tolerable than trastuzumab + taxane, which may be of 
particular importance to the EBC population(see Sections 1.2.1, 1.2.2, and 1.3.1).  
Overall, cConsidering the known tolerable safety profiles of these study drugs, the 
totality of efficacy data in the MBC and EBC settings, a potential better efficacy 
outcome of the combination of trastuzumab emtansine and pertuzumab in the adjuvant 
setting compared to the MBC setting due to the long treatment duration of additional 
HER2 targeted DM1 and biology differeneces between EBC and MBC (see Section 1.3.1 
for more details), and the known benefit-risk for the current 
anthracycline-trastuzumab−based adjuvant SOC, it is anticipated that the combination 
regimens in this study will have a manageable safety profile and has an acceptable 
benefit-risk assessment for the conduct of the study.  It is important and justified to 
evaluate the benefit-risk of trastuzumab emtansine plus pertuzumab following 
anthracyclines, compared with the anticipated new SOC 
(taxane + trastuzumab + pertuzumab following anthracyclines), in the adjuvant clinical 
trial setting. 
SECTION 3.3.1:  Rationale for Test Product Dosage 
The dose of 3.6 mg/kg of trastuzumab emtansine has been combined with pertuzumab 
(loading dose of 840 mg with a subsequent dose of 420 mg) q3w in the Phase I/II 
Studies TDM4373g/BO22495 and TDM4688g and in the Phase III 
Study TDM4788g/BO22589 (MARIANNE).  Toxicities in these studies appear to be 
manageable/tolerable, on the basis of final study results (Studies TDM4373g/BO22495,  
and TDM4688g, and) and available study data and iDMC recommendations to continue 
Study TDM4788g/BO22589) (see details in Section 1.2.1.1). 
SECTION 3.3.2.1:  Rationale for Capping Subgroup Enrollment 
The capping as of Protocol Version 2 will not be implemented since the study 
enrollment is stopped earlier than planned.  Therefore, the planned proportion of node-
positive patients with one to three nodes and/or node-negative patients may not be 
achieved as described above. 
SECTION 3.3.2.3:  Rationale for Sample Size Reduction 
The MARIANNE study results (see Section 1.2.1.1.1) have further informed the 
assumptions that drove the original study design (i.e., trastuzumab emtansine improves 
both PFS and safety and a synergy between trastuzumab emtansine and pertuzumab 
will be demonstrated clinically in the first-line MBC setting).  Therefore, the likelihood 
of this study meeting its primary efficacy endpoint for superiority has decreased.  A 
sample size reduction is warranted to mitigate the risk of this study not meeting its 
primary efficacy endpoint.  However, due to the uncertainty of translating MBC results 
to the adjuvant setting (see details in Section 1.3.1), the study question of whether the 
regimen of trastuzumab emtansine in combination with pertuzumab following 
anthracyclines may be superior to the regimen of trastuzumab in combination with a 
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unanswered and is of clinical/scientific importance.  With a sample size reduction from 
2500 to approximately 1850 patients, the study objectives can still be adequately 
addressed with the original statistical power and validity with the prolonged analyses 
timing (see Table 19 in Section 6.1).  
SECTION 3.3.4:  Rationale for Adjuvant Regimens and Duration of Therapy 
Proof of concept has been established in the randomized MBC Studies 
TDM4450g/BO21976, and TDM4370g/BO21977 (EMILIA), and TDM4997g/BO25734 
(TH3RESA) that trastuzumab emtansine as a single agent can improve efficacy and 
safety compared with a combination of a HER2-directed agent and traditional 
chemotherapy.  The TDM4788g/BO22589 (MARIANNE) study supports trastuzumab 
emtansine+ pertuzumab as a non-inferior regimen to trastuzumab + taxane, with a more 
tolerable safety profile in the first-line MBC setting.  In addition, the pCR rates 
observed in the single-arm Study TDM4874g/BO22857 and WGS-ADAPT Study 
MO23078 suggest robust clinical activity of trastuzumab emtansine in EBC.  
Furthermore, a meta-analysis (EBCTCG 2013) of long-term outcome among 
100,000 patients with EBC in 123 randomized trials has shown that in trials adding four 
cycles of taxane to a fixed anthracycline-based control regimen, extending treatment 
duration, mortality due to breast cancer was reduced (RR = 0.86, SE = 0.04, two-sided 
significance p = 0.0005).  However, in trials with four such extra cycles of taxane, 
counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling 
non-taxane dosage, there was no significant difference (RR = 0.94, SE = 0.06, two-sided 
significance p = 0.33).  On the basis of this analysis, the totality of data for trastuzumab 
emtansine and/or pertuzumab in the MBC and EBC setting, and the uncertainties 
regarding the translation of results of trastuzumab emtansine plus pertuzumab in the 
MARIANNE study into results of this combination in this adjuvant study, it is 
anticipated that 1 year of trastuzumab emtansine + pertuzumab, with the HER2-targeted 
chemotherapeutic agent DM1 (i.e., with higher dose intensity and longer duration than 
four cycles of concurrent taxane) will provide risk reduction that is the same as or better 
than that provided by the four cycles of concurrent taxane and 14 cycles of 
trastuzumab + pertuzumab in the control arm.  Therefore, this study will evaluate 
whether trastuzumab emtansine without concurrent taxane as a replacement for 
trastuzumab plus taxane, in combination with pertuzumab following anthracyclines, can 
provide an improved benefit-risk ratio in high-risk patients with HER2-positive EBC.  
Systemic anthracyclines will mitigate potential efficacy risk due to intratumor 
heterogeneity.  The cardiac safety of both pertuzumab and trastuzumab emtansine 
following anthracycline-based regimens appears acceptable to date on the basis of data 
from Study BO22280 (TRYPHAENA; see Section 1.2.2.2) and 
Study TDM4874g/BO22857 EBC safety study; (MARIANNE; see 
Section1.2.1.1.1 1.2.1.1.2).   


 
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SECTION 3.4.3:  Patient-Reported Outcome Measures 
• 
Time from first HER2-targeted treatment, ± a taxane, to clinically meaningful 
deterioration in the worsening of global health status/QoL and functional (physical, 
role, and cognitive) (subscales of the QLQ-C30).  The event of worsening of global 
health status/QoL for a given patient is defined as a decrease in baseline mean 
score by 10 points or more at two consecutive timepoints after initiation of HER2
directed therapy, plus a taxane.  A 10-point or greater change in mean score is 
defined as being a “moderate” to “very much” and perceived an important change 
from the patient’s perspective (Osoba et al. 1998).  Deterioration in function will 
be assessed using the published corresponding MIDs by Cocks et al. (2011). 
 
SECTION 4.1.1:  Inclusion Criteria 
• 
Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 7th edition):  Patients 
must have had sentinel lymph node biopsy (SLNB) and/or axillary lymph node 
dissection for evaluation of pathologic nodal status (minimum requirements for 
patients undergoing SLNB are provided in Section 4.4.1).  Pathological classification 
of regional lymph node micrometastases (tumor deposits > 0.2 mm and ≤ 2 mm) is 
considered to be pN1, and isolated tumor cells are considered to be pN0.  
Eligible patients must have one of the following: 
Node-positive disease (pN ≥ 1), any tumor size except T0, and any hormonal 
receptor status 
Enrollment of patients with 1−3 nodes will was planned to be limited to no 
more than 50% of the total number of randomized patients.  However, no 
formal capping of enrollment will be implemented (see Section 3.3.2.1 for 
details). 
There is no prespecified limit for the enrollment of patients with ≥ 4 nodes. 
Node-negative disease (pN0) with pathologic tumor size > 2.0 cm by standard 
local assessment AND negative for ER and PR as determined by a central 
pathology laboratory 
Enrollment of patients with node-negative disease was planned to will be 
limited to no more than 10% of the total number of randomized patients.  
However, no formal capping of enrollment will not be implemented (see 
Section 3.3.2.1 for details). 
• 
Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is 
required.  This includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B 
core antibody (HBcAb) in addition to HCV antibody testing.  The most recent 
serologic testing must have occurred within 3 months prior to randomization.  If such 
testing has not been done, it must be performed during screening.  
Patients who have positive HBV or HCV serologies without known active 
disease must meet the eligibility criteria for ALT, AST, total bilirubin (TBILI), INR, 
activated partial thromboplastine time (aPTT), and alkaline phosphatase (ALP) 
on at least two consecutive occasions, separated by at least 1 week, within the 


 
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30-day screening period.  The second of these evaluations must be performed 
within 3 days prior to the first administration of study drug.  Note:  positive 
serology markers that indicate immunity will not be considered as clinically 
meaningful positive serology to trigger these tests.  
 
SECTION 4.3.2.2.1:  Trastuzumab plus Pertuzumab plus Taxane Treatment 
(Arm 1) 
Trastuzumab will be given at a loading dose of 8 mg/kg and pertuzumab at 840 mg.  For 
subsequent cycles, trastuzumab will be given as a maintenance dose of 6 mg/kg and 
pertuzumab at 420 mg q3w.  The dose of trastuzumab does not need to be recalculated 
unless the body weight has changed by ±10% or greater from baseline.  Dose must be 
readjusted for ± 10% or greater weight change based on the previous weight used for 
dose recalculation.  The Investigator may choose to re-calculate dose at every cycle 
using actual weight at that time according to their local practice.  If the patient misses 
a dose of trastuzumab for any cycle (i.e., the two sequential administration times are 6 
weeks or more apart), a re-loading dose of 8 mg/kg of trastuzumab should be given.  If 
the patient misses a dose of pertuzumab for any cycle and the time between doses is 6 
weeks or more, a re-loading dose of pertuzumab (840 mg) should be given.  Re-loading 
of doses for trastuzumab per local prescribing information may be followed.  Patients 
who experience trastuzumab or pertuzumab infusion−related symptoms may be pre-
medicated with paracetamol and anti-histamines for subsequent infusions.   
SECTION 4.3.2.2.2:  Trastuzumab Emtansine plus Pertuzumab Treatment 
(Arm 2) 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion in 
combination with pertuzumab at an initial loading dose of 840 mg IV followed by a 
maintenance dose of 420 mg IV q3w.  The dose of trastuzumab emtansine does not 
need to be recalculated unless the body weight has changed by ± 10% or greater from 
baseline.  Dose must be readjusted for ± 10% or greater weight change based on 
the previous weight used for dose recalculation.  The Investigator may choose to re-
calculate dose at every cycle using actual weight at that time according to local practice.  
If the patient misses a dose of pertuzumab for any cycle and the time between doses is 
6 weeks or more, a re-loading dose of pertuzumab (840 mg) should be given.  Patients 
who experience pertuzumab infusion−related symptoms may be pre-medicated with 
paracetamol and anti-histamines for subsequent infusions.   
SECTION 4.7.1.2:  Physical Examinations 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations focusing on organ systems related to adverse events or disease should be 
performed.  Weight is to be measured on Day 1 of the specified cycles and compared 
with baseline.  If ± 10% or greater variation occurs, then study treatment doses will be 
recalculated.  Dose must be readjusted for ± 10% or greater weight change based on 
the previous weight used for dose recalculation.  The investigator may choose to 
re-calculate dose at every cycle using actual weight at that time according to local 


 
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practice.  For anthracyclines and taxanes, local standards for dose calculations will be 
followed. 
SECTION 4.7.1.8:  Patient-Reported Outcomes 
The EORTC QLQ-BR23 breast cancer module was first validated for use in 1995, uses a 
recall period of ”the past week,“ and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment; 
Sprangers et al. 1998).  As peripheral neuropathy (1 item), joint/muscle pain (1 item), 
and skin problems (2 items) are key symptoms of therapy not assessed by currently 
available tools, validated items from the EORTC Item Bank will be added to assess the 
presence and bothersomeness of these treatment-related side effects.  Data analysis 
will be performed on the final modified BR23 data set outside of the protocol in parallel 
with the final data analysis to confirm the psychometric properties of the modified 
instrument and will be reported along with the clinical trial results.  Scale scores can be 
obtained for each of the multi-item and single-item scales by using a linear 
transformation for standardization of the calculated raw score.   
SECTION 5.2.3:  Non Serious Adverse Events of Special Interest 
(Immediately Reportable to the Sponsor) 
Non serious AEs of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  AEs of special interest for this study include the 
following: 
SECTION 5.3.5.3:  Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity of the event should be recorded, and the severity should be 
updated to reflect the most extreme severity any time the event worsens.  If the event 
becomes serious, the Adverse Event eCRF should be updated to reflect this.The initial 
severity (intensity or grade) of the event should be recorded at the time the event is first 
reported.  If a persistent adverse event becomes more severe, then the most extreme 
severity should also be recorded on the Adverse Event eCRF.  Details regarding any 
increases in severity should be captured on the Adverse Event Intensity or Grade 
Changes eCRF.  If the event becomes serious, then it should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning that the event became serious; 
see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be 
updated by changing the event from “non-serious” to “serious,” providing the date that 
the event became serious, and completing all data fields related to SAEs. 
SECTION 5.4:  IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
• 
Non serious AEs of special interest 
 


 
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SECTION 5.4.1:  Emergency Medical Contacts 
Alternate Medical Monitor Contact Information for All Sites: 
Medical Monitor: 
, M.D., M.S. 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
SECTION 5.4.3.2:  Pregnancies in Female Partners of Male Patients 
Additional information on any trastuzumab, pertuzumab, or and trastuzumab 
emtansine−exposed pregnancy and infant will be requested by Roche Drug Safety at 
specific timepoints (i.e., after having received the initial report, at the end of the second 
trimester, 2 weeks after the expected date of delievery, and at 3, 6, and 12 months of the 
infant’s life.) 
SECTION 6:  STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The statistical considerations and analysis plan are summarized below.  Further details 
of the analyses will be described in the Statistical Analysis Plan (SAP) as part of the 
Data Analysis Plan (DAP).  The SAP overrides the analyses as described in the study 
protocol, as applicable. 
SECTION 6.1: DETERMINATION OF SAMPLE SIZE 
The IDFS analysis is powered at 82.25% at 80% for the node-positive subpopulation.  
Additionally, the IDFS analysis with the assumptions stated below is powered at 
8382.5% for the overall protocol-defined population.  It is assumed that the overall 
protocol-defined population has approximately 10% more patients and 6% more IDFS 
events than the node-positive subpopulation.  These percentages were observed in the 
BCIRG 006 (Slamon et al. 2006, 2009, 2011) trial after subsetting for the respective 
populations in this study.  
To detect a target HR of 0.64 in IDFS in the overall protocol-defined population and the 
node-positive subpopulation, approximately 171 and 160 IDFS events will be required to 
achieve 8382.5% and 80% power, respectively, in the two populations, at a two-sided 
significance level of 5% using a log-rank test.  Approximately 1850 and 1665 2500 and 
2250 patients will be enrolled in the overall protocol-defined population and 
node-positive subpopulation, respectively, including a dropout/ineligibility rate of 8% for 
both arms as estimated from previous trials in this setting.   The assumed 3-year IDFS 
rate for the control arms for both the populations were based on the IDFS rate from the 
BCIRG 006 data for the proposed populations and the assumed target HR from Study 
BO25126.  The six piecewise Kaplan-Meier estimates of the IDFS function in the control 
group for the overall protocol-defined population and the node-positive subpopulation 
were 99.6% and 99.5% during the first 6 months, 98.2% and 98.0% during the second 
6 months, 93.7% and 93.1% during Year 2, 89.5% and 89.1% during Year 3, 87.7% and 
87.1% during Year 4, and 86.2% and 85.5% during Year 5.  With the assumed target HR 
of 0.64, the estimated 3-year IDFS rate for the experimental arms in each of the two 
populations is shown in Table 19. 


 
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After a 1 year ramp up period, it is estimated that the monthly accrual of patients per site 
will build to a peak rate of 0.41.  A total of approximately 1850 patients are anticipated 
to be enrolled.  The study is expected to be fully enrolled approximately 24 17 months 
after FPI.  The final IDFS analysis will be performed after at least 172 160 events have 
occurred in the node-positive subpopulation and approximately 183 171 events have 
occurred in the overall protocol-defined population, which is projected to be 
approximately 47 57 months after FPI.   
The sample size calculations are performed using EAST v65.4 software (Cytel Inc.). 
SECTION 6.6:  PATIENT-REPORTED OUTCOME ANALYSES 
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) of linear 
transformed scores will be reported for all the subscales (including peripheral 
neuropathy, joint/muscle pain, and skin problems) of the EORTC QLQ-C30 
questionnaire and the modified BR23 for each assessment time-point according to the 
EORTC scoring manual guidelines for each assessment timepoint.  The mean change of 
the linear transformed scores from baseline (and 95% CIs using the normal 
approximation) will also be assessed.  Line charts depicting the mean changes (and 
standard errors) of items and subscales over time will be provided for each treatment 
arm from the baseline assessment.   
Completion and compliance rates will be summarized at each timepoint for each 
measure by treatment arm with reasons for missing data.  Only patients with a baseline 
assessment and at least one post-treatment assessment will be included in the analyses.   
The number and proportion of patients reporting clinically meaningful differences in 
treatment-related symptoms based on the threshold reported by Cocks et al. (2011) at 
each time-point will be the primary analysis. In addition, the proportion of patients 
reporting “a little” or “quite a bit” for each of the neuropathy, joint/muscle pain and 
skin single items will be reported by treatment armwho improved, worsened, or 
remained stable for all of the symptom and functional domains, global QoL, and single 
items of the EORTC QLQ C30 and modified BR23 will be summarized at each timepoint. 
The proportion of patients with clinically meaningful deterioration in global health 
status/HRQoL and function (physical, role, and cognitive) scales will also be assessed. 
The deterioration will be based on the respective thresholds reported by 
Osaba  et  al  (1998) and Cocks et al. (2011).  
Analysis will be performed to compare the two treatment arms at the “Cycle 1 Day 1 
(C1D1) of anthracycline treatment period” timepoint and the “C1D1 of HER2-targeted 
treatment period” timepoint to descriptively assess treatment group comparability 
between the two treatment arms. The “‘C1D1 of HER2-targeted treatment” timepoint will 
be utilized as the reference for time-to-event Kaplan-Meier analysis, provided that the 
treatment groups are comparable at this timepoint.   


 
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The time to clinically meaningful deterioration in the global health status/HRQoL 
subscale (question 29 and 30 Time to event Kaplan Meier analysis of global health 
status/QoL (subscale of the QLQ-C30) will be used to assessdemonstrate the time from 
first HER2-targeted treatment to worsening in HRQoL.  An event for a given patient is a 
decrease in mean score by 10 points or more, at two consecutive time points, with a 
10-point or greater change in mean score defined as a “moderate” to “very much” 
perceived important change from the patient’s perspective (Osoba et al. 1998).  Time-to-
event analyses to investigate the time to clinically meaningful deterioration in function 
(physical, role, and cognitive function scales) will also be assessed using the published 
thresholds by Cocks et al. (2011).  A stratified log-rank test will be used to test the 
differences between treatment arms. 
Additionally, in order to elucidate if the taxane-sparing arm reduces patient treatment 
burden, an analyseis of covariance (repeated mixed effects model) will be used to 
compare change from baseline in the global health status/HRQoL and functional scales 
of the EORTC QLQ-C30.  each symptom score of special interest resulting in three 
individual models.  The symptom subscale scores to be assessed are joint/muscle pain, 
peripheral neuropathy, and skin problems.  In each mixed model, change from baseline 
of the symptom of special interest will be the response variable; treatment, visit, and 
treatment by visit interaction terms will be the fixed factorseffects; baseline of the 
symptom subscale score (joint/muscle pain, peripheral neuropathy, and skin problem) 
will be the covariate; and the patient will be denoted as a repeated factor. If substantial 
interaction effect is present, pair-wise comparison will be conductedthe random effect. 
SECTION 6.8.1:  Interim Efficacy Analyses 
A futility analysis may be incorporated to evaluate lack of superiority for the treatment 
arm of trastuzumab emtansine + pertuzumab following anthracyclines.  The timing and 
details of this futility analysis will be described in the SAP and aligned with the 
availability of information from other relevant studies (e.g., KRISTINE and/or 
APHINITY). 
Interim IDFS Analyses 
The An interim efficacy analysis of IDFS will be performed after approximately 75% of 
the targeted IDFS events are observed in the overall protocol-defined population 
(i.e. 128 of the 171 target events) and node-positive population (i.e. 120 of 160 target 
events) and is projected to occur approximately 40 43 months from FPI (see Table 20).  
A hierarchical testing procedure will be used for the primary endpoint IDFS for the 
node-positive subpopulation and the overall protocol-defined population as defined in 
Section 6.4.3.  The type I error will be controlled at the 5% level at the interim and final 
analyses within the node-positive subpopulation and the overall protocol-defined 
population using a Lan-DeMets α-spending function with an O’Brien-Fleming boundary.  


 
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Interim OS Analyses 
For the OS interim analyses and final OS analysis, the Lan-DeMets α-spending function 
with an O’Brien-Fleming boundary will be used such that the overall type I error will be 
controlled at the 5% level for the OS endpoint.  With the study sample size and 
approximately 10 years of follow-up from FPI, this study has 38% 47% power in the 
overall protocol-defined population and 35%44% power in the node-positive 
subpopulation to detect an HR of 0.8.  This in the overall protocol-defined population 
corresponds to a 0.8% improvement in 3-year OS, from 96.1% in the control arm to 
96.9% in the experimental arm and in the node-positive subpopulation to a 0.9% 
improvement in 3-year OS, from 95.7% in the control arm to 96.6% in the experimental 
arm, at a two-sided significance level of 5%.  
All OS interim and final analyses will be performed by the Sponsor subsequent to the 
primary IDFS analysis and after the Sponsor is unblinded.  If the interim IDFS analyses 
in both the node-positive subpopulation and the overall protocol-defined population cross 
the statistical efficacy boundaries, the first OS interim analysis will be performed in both 
populations hierarchically at that time (approximately at 4340 months from FPI).  If the 
final IDFS analysis crosses the statistical boundaries, then the second interim OS 
analysis will be performed hierarchically at the time of the final IDFS analysis 
(approximately 5747 months from FPI), followed by the third and the final OS analyses 
performed hierarchically in both populations (planned to occur at 84 months [7 years] 
and 120 months [10 years], respectively, from FPI).  If, at any OS interim analysis, the 
O’Brien-Fleming efficacy boundary is crossed, that analysis of OS will be considered as 
confirmatory and all subsequent analyses of OS will be considered as descriptive. 
SECTION 9.5:  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 Regardless of the outcome of a trial, the Sponsor is dedicated to openly 
providing information on the trial to healthcare professionals and to the public, both at 
scientific congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 


 
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additional endpoints and exploratory data that are clinically meaningful and 
statistically sound..,  
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. 
TABLE 1:  Overview of Selected Adverse Events of Special Interest with 
Trastuzumab Emtansine Alone (n = 884) 
Table 1 was updated to reflect the available safety data. 
TABLE 4:  Overview of Selected Adverse Events of Special Interest with 
Trastuzumab Emtansine in Combination with Pertuzumab (n = 87) 
Table 1 was updated to reflect the available safety data. 
TABLE 5:  Overview of Adverse Events (Safety Population) 
Table 5 was added.  Subsequent tables have been renumbered accordingly. 
TABLE 19:  Summary of Sample Size Assumptions for IDFS 
Table 19 was updated to reflect the new sample size calculations. 
TABLE 20:  Summary of Planned Analyses of IDFS in Overall 
Protocol-Defined Population and Node-Positive Subpopulation 
Table 20 was updated to reflect the new estimated timing. 
TABLE 22:  Summary of Planned Analyses of IDFS in Overall 
Protocol-Defined Population and Node-Positive Subpopulation 
Table 22 was updated to reflect the new timing and number of events for analyses. 
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 10:  Acceptable Contraception Methods 
Appendix 10 has been revised to note the effective nonhormonal contraception and 
altenatives thereto. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 31 
PROTOCOL SYNOPSIS .................................................................................... 32 
1. 
BACKGROUND .......................................................................................... 47 
1.1 
Background on HER2-Positive Early Breast 
Cancer and Adjuvant Treatment............................................ 47 
1.1.1 
Herceptin® Adjuvant Trials.................................................... 48 
1.2 
Background on Trastuzumab Emtansine and 
Pertuzumab ........................................................................... 49 
1.2.1 
Trastuzumab Emtansine........................................................ 49 
1.2.1.1 
Trastuzumab Emtansine Clinical Experience in 
Metastatic Breast Cancer ...................................................... 50 
1.2.1.2 
Trastuzumab Emtansine Clinical Experience in 
Early Breast Cancer .............................................................. 55 
1.2.1.3 
Pooled Safety Analysis of Single-Agent 
Trastuzumab Emtansine........................................................ 57 
1.2.2 
Pertuzumab ........................................................................... 58 
1.2.2.1 
Pertuzumab Clinical Experience in MBC ............................... 59 
1.2.2.2 
Pertuzumab Clinical Experience in Early Breast 
Cancer................................................................................... 60 
1.2.3 
Pooled Safety Analysis of Trastuzumab 
Emtansine in Combination with Pertuzumab ......................... 62 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 64 
1.3.1 
Study Rationale ..................................................................... 64 
1.3.2 
Benefit-Risk Assessment....................................................... 67 
2. 
OBJECTIVES.............................................................................................. 69 
2.1 
Efficacy Objectives ................................................................ 69 
2.2 
Safety Objective .................................................................... 70 
2.3 
Patient-Reported Outcome Objectives .................................. 70 
2.4 
Exploratory Objectives........................................................... 70 
3. 
STUDY DESIGN......................................................................................... 71 
3.1 
Description of Study .............................................................. 71 
3.1.1 
Data Monitoring Committee................................................... 74 


 
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3.1.2 
Clinical Events Committee..................................................... 74 
3.2 
End of Study.......................................................................... 75 
3.3 
Rationale for Study Design.................................................... 75 
3.3.1 
Rationale for Test Product Dosage........................................ 75 
3.3.2 
Rationale for Patient Population ............................................ 75 
3.3.2.1 
Rationale for Capping Subgroup Enrollment ......................... 76 
3.3.2.2 
Rationale for Powering for Node-Positive 
Subgroup............................................................................... 77 
3.3.2.3 
Rationale for Sample Size Reduction.................................... 77 
3.3.3 
Rationale for Control Group................................................... 77 
3.3.4 
Rationale for Adjuvant Regimens and Duration of 
Therapy ................................................................................. 78 
3.3.4.1 
Rationale for Selection of Anthracycline 
Regimens .............................................................................. 79 
3.3.4.2 
Rationale for Selection of Taxane Dose and 
Schedule................................................................................ 79 
3.3.5 
Rationale for Patient-Reported Outcome 
Assessments ......................................................................... 80 
3.3.6 
Rationale for Biomarker Assessments................................... 80 
3.4 
Outcome Measures ............................................................... 83 
3.4.1 
Efficacy Outcome Measures.................................................. 83 
3.4.1.1 
Primary Efficacy Outcome Measures .................................... 83 
3.4.1.2 
Secondary Efficacy Outcome Measures................................ 83 
3.4.2 
Safety Outcome Measures .................................................... 83 
3.4.3 
Patient-Reported Outcome Measures ................................... 84 
3.4.4 
Exploratory Biomarker Outcome Measures........................... 85 
3.4.5 
Exploratory Anti-Therapeutic Antibody Outcome 
Measures............................................................................... 85 
3.4.6 
Exploratory Health Economic Outcome Measures ................ 85 
4. 
MATERIALS AND METHODS .................................................................... 85 
4.1 
Patients.................................................................................. 85 
4.1.1 
Inclusion Criteria.................................................................... 86 
4.1.2 
Exclusion Criteria................................................................... 88 
4.2 
Method of Treatment Assignment.......................................... 90 


 
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4.3 
Study Treatment.................................................................... 90 
4.3.1 
Formulation, Packaging, and Handling.................................. 91 
4.3.1.1 
Trastuzumab Emtansine........................................................ 91 
4.3.1.2 
Pertuzumab ........................................................................... 91 
4.3.1.3 
Trastuzumab for Intravenous Administration ......................... 91 
4.3.1.4 
Doxorubicin, Epirubicin, Cyclophosphamide, 5-
Fluorouracil, Paclitaxel, and Docetaxel.................................. 91 
4.3.2 
Dosage, Administration, and Compliance.............................. 91 
4.3.2.1 
Anthracycline Treatment Phase............................................. 91 
4.3.2.2 
Concurrent Taxane Phase and/or HER2 
Targeted Only Phase............................................................. 92 
4.3.3 
Investigational Medicinal Product Accountability ................... 95 
4.3.4 
Post-Trial Access to Trastuzumab Emtansine 
and Pertuzumab .................................................................... 95 
4.4 
Prior Therapy......................................................................... 95 
4.4.1 
Minimum Requirements for Patients Undergoing 
Sentinel Lymph Node Biopsy................................................. 96 
4.5 
Concomitant Therapy ............................................................ 96 
4.5.1 
Permitted Therapy................................................................. 96 
4.5.1.1 
Adjuvant Radiotherapy .......................................................... 97 
4.5.1.2 
Concomitant Hormonal Therapy............................................ 97 
4.5.2 
Prohibited Therapy ................................................................ 98 
4.6 
Treatments during Follow-Up ................................................ 99 
4.7 
Study Assessments ............................................................... 99 
4.7.1 
Description of Study Assessments ........................................ 99 
4.7.1.1 
Medical History and Demographic Data ................................ 99 
4.7.1.2 
Physical Examinations......................................................... 100 
4.7.1.3 
Vital Signs............................................................................ 100 
4.7.1.4 
Radiographic Assessments ................................................. 100 
4.7.1.5 
Disease Recurrence Status................................................. 100 
4.7.1.6 
Laboratory Assessments ..................................................... 103 
4.7.1.7 
Cardiac Assessments.......................................................... 105 
4.7.1.8 
Patient-Reported Outcomes ................................................ 105 


 
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4.7.1.9 
Mandatory Samples for HER2 Testing and 
Biomarker Analysis.............................................................. 106 
4.7.1.10 
Optional Biomarker Research Samples and 
Study Biosample Research Repository ............................... 109 
4.7.1.11 
Samples for ATA ................................................................. 111 
4.7.2 
Timing of Study Assessments ............................................. 112 
4.7.2.1 
Screening and Pretreatment Assessments.......................... 112 
4.7.2.2 
Assessments during Treatment........................................... 112 
4.7.2.3 
Assessments at Study End-of-Treatment Visit .................... 112 
4.7.2.4 
Follow-Up Assessments ...................................................... 113 
4.8 
Patient, Study, and Site Discontinuation.............................. 113 
4.8.1 
Patient Discontinuation........................................................ 113 
4.8.1.1 
Discontinuation from Study Drug......................................... 114 
4.8.1.2 
Withdrawal from Study......................................................... 114 
4.8.2 
Study and Site Discontinuation............................................ 115 
5. 
ASSESSMENT OF SAFETY..................................................................... 115 
5.1 
Safety Plan .......................................................................... 115 
5.1.1 
Study Drugs Associated Risks, Warnings, and 
Precautions.......................................................................... 116 
5.1.1.1 
Trastuzumab Emtansine...................................................... 116 
5.1.1.2 
Pertuzumab ......................................................................... 119 
5.1.1.3 
Trastuzumab and Adjuvant Chemotherapy 
Agents ................................................................................. 120 
5.1.2 
Safety Considerations for Eligibility and Safety 
Assessments ....................................................................... 120 
5.1.3 
General Guidance for Dose Modifications and 
Delays.................................................................................. 121 
5.1.3.1 
Dose Delays and Dose Reductions..................................... 122 
5.1.3.2 
Dose Discontinuation........................................................... 123 
5.1.4 
Dose Modifications/Management for Specific 
Adverse Events ................................................................... 124 
5.1.4.1 
Specific Adverse Events for Multiple Agents ....................... 124 
5.1.4.2 
Specific Adverse Events for Individual Agents..................... 128 
5.1.4.3 
Radiotherapy Toxicity .......................................................... 132 
5.2 
Safety Parameters and Definitions ...................................... 132 


 
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5.2.1 
Adverse Events ................................................................... 132 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor).................................................................... 132 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................. 133 
5.2.4 
Selected Adverse Events..................................................... 134 
5.2.4.1 
Cardiac General .................................................................. 134 
5.2.4.2 
Asymptomatic Left Ventricular Systolic 
Dysfunction.......................................................................... 134 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters.............................................. 134 
5.3.1 
Adverse Event Reporting Period ......................................... 134 
5.3.2 
Eliciting Adverse Event Information..................................... 135 
5.3.3 
Assessment of Severity of Adverse Events ......................... 135 
5.3.4 
Assessment of Causality of Adverse Events ....................... 136 
5.3.5 
Procedures for Recording Adverse Events.......................... 136 
5.3.5.1 
Diagnosis versus Signs and Symptoms............................... 136 
5.3.5.2 
Adverse Events Occurring Secondary to Other 
Events.................................................................................. 137 
5.3.5.3 
Persistent or Recurrent Adverse Events.............................. 137 
5.3.5.4 
Abnormal Laboratory Values ............................................... 138 
5.3.5.5 
Abnormal Vital Sign Values ................................................. 138 
5.3.5.6 
Hepatotoxicity...................................................................... 139 
5.3.5.7 
Deaths ................................................................................. 139 
5.3.5.8 
Preexisting Medical Conditions............................................ 140 
5.3.5.9 
Recurrence/Progression of Breast Cancer .......................... 140 
5.3.5.10 
Hospitalization or Prolonged Hospitalization........................ 140 
5.3.5.11 
Overdoses ........................................................................... 141 
5.3.5.12 
Patient-Reported Outcome Data ......................................... 141 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor........................................................ 141 
5.4.1 
Emergency Medical Contacts.............................................. 142 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest................... 142 
5.4.3 
Reporting Requirements for Pregnancies............................ 143 


 
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5.4.3.1 
Pregnancies in Female Patients.......................................... 143 
5.4.3.2 
Pregnancies in Female Partners of Male Patients............... 143 
5.4.3.3 
Abortions ............................................................................. 144 
5.4.3.4 
Congenital Anomalies/Birth Defects .................................... 144 
5.5 
Follow-Up of Patients after Adverse Events ........................ 144 
5.5.1 
Investigator Follow-Up......................................................... 144 
5.5.2 
Sponsor Follow-Up .............................................................. 144 
5.6 
Post-Study Adverse Events................................................. 145 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees............................................................... 145 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN..................... 146 
6.1 
Determination of Sample Size ............................................. 146 
6.2 
Summaries of Conduct of Study.......................................... 147 
6.3 
Summaries of Treatment Group Comparability ................... 147 
6.4 
Efficacy Analyses ................................................................ 148 
6.4.1 
Primary Efficacy Endpoint.................................................... 148 
6.4.2 
Secondary Efficacy Endpoints............................................. 148 
6.4.3 
Hierarchical Testing Procedure ........................................... 149 
6.5 
Safety Analyses................................................................... 149 
6.6 
Patient-Reported Outcome Analyses .................................. 150 
6.7 
Exploratory Analyses........................................................... 151 
6.7.1 
Subgroup Analyses for Efficacy........................................... 151 
6.8 
Interim Analyses .................................................................. 152 
6.8.1 
Interim Efficacy Analyses..................................................... 152 
6.8.2 
Interim Safety Analyses....................................................... 155 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 157 
7.1 
Data Quality Assurance....................................................... 157 
7.2 
Electronic Case Report Forms............................................. 158 
7.3 
Source Data Documentation................................................ 158 
7.4 
Use of Computerized Systems ............................................ 158 
7.5 
Retention of Records........................................................... 159 
8. 
ETHICAL CONSIDERATIONS.................................................................. 159 


 
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8.1 
Compliance with Laws and Regulations .............................. 159 
8.2 
Informed Consent................................................................ 159 
8.3 
Institutional Review Board or Ethics Committee.................. 160 
8.4 
Confidentiality...................................................................... 161 
8.5 
Financial Disclosure ............................................................ 161 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 162 
9.1 
Study Documentation .......................................................... 162 
9.2 
Protocol Deviations.............................................................. 162 
9.3 
Site Inspections ................................................................... 162 
9.4 
Administrative Structure....................................................... 162 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 162 
9.6 
Protocol Amendments ......................................................... 163 
10. REFERENCES ......................................................................................... 164 
 
 
LIST OF TABLES 
Table 1 
Overview of Selected Adverse Events with Trastuzumab 
Emtansine Alone (n = 884).......................................................... 58 
Table 2 
Early Breast Cancer and pCR Rates in Study WO20697 ........... 60 
Table 3 
Cardiac Safety and pCR Rates in Study BO22280..................... 61 
Table 4 
Overview of Selected Adverse Events with Trastuzumab 
Emtansine in Combination with Pertuzumab (n = 87) ................. 63 
Table 5 
Overview of Adverse Events (Safety Population)........................ 64 
Table 6 
Protocol-Approved Chemotherapy Regimens (Investigator's 
Choice)⎯Taxane is for Arm 1 Only ............................................ 73 
Table 7 
5-Fluorouracil, Epirubicin, and Cyclophosphamide (FEC) .......... 92 
Table 8 
Doxorubicin OR Epirubicin, and Cyclophosphamide (AC/EC) .... 92 
Table 9 
Treatment Regimen for Arm 1..................................................... 94 
Table 10 
Treatment Regimen for Arm 2..................................................... 95 
Table 11 
Recommendations for Hormonal Therapy .................................. 98 
Table 12 
Dose Reduction Levels for Taxane (Arm 1) and Trastuzumab 
Emtansine (Arm 2).................................................................... 123 
Table 13 
Management of Infusion-Related Reactions/Hypersensitivity 
Reactions.................................................................................. 125 
Table 14 
Dose Modification/Delays for Pneumonitis/Interstitial Lung 
Disease Adverse Events........................................................... 126 
Table 15 
Dose Modification/Delays for Neuropathy................................. 126 


 
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Table 16 
Dose Modification/Delays for Trastuzumab 
Emtansine−Specific Adverse Events ........................................ 128 
Table 17 
Dose Modifications and Delays for Docetaxel- or 
Paclitaxel-Related Neutropenia................................................. 131 
Table 18 
Adverse Event Severity Grading Scale ..................................... 135 
Table 19 
Summary of Sample Size Assumptions for IDFS...................... 147 
Table 20 
Summary of Planned Analyses of IDFS in Overall 
Protocol-Defined Population and Node-Positive 
Subpopulation........................................................................... 153 
Table 21 
Summary of Assumptions for Overall Survival Analyses .......... 153 
Table 22 
Summary of Planned Analyses of Overall Survival in Overall 
Protocol-Defined Population and Node-Positive 
Subpopulation........................................................................... 155 
Table 23 
Probability of Observing > 3% Increase of Death...................... 156 
Table 24 
Probability of Observing > 3% Increase in Confirmed Hy’s 
Law Cases ................................................................................ 157 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema............................................................................. 72 
Figure 2 
HER2-Directed Therapy Management Based on LVEF 
Assessments............................................................................. 127 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 172 
Appendix 2 
Schedule of Anti-Therapeutic Antibody Assessments............... 179 
Appendix 3 
New York Heart Association Classifications.............................. 180 
Appendix 4 
Adjuvant Radiotherapy Guidelines............................................ 181 
Appendix 5 
Guidelines for Liver Biopsy ....................................................... 184 
Appendix 6 
Ventana HER2 IHC Assay ........................................................ 185 
Appendix 7 
Ventana HER2 ISH Assay ........................................................ 186 
Appendix 8 
PRO Measures:  QLQ-C30 and Modified QLQ-BR23............... 187 
Appendix 9 
EuroQoL EQ-5D........................................................................ 191 
Appendix 10  Acceptable Contraception Methods ......................................... 194 
 


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31 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, 
PHASE III TRIAL COMPARING TRASTUZUMAB 
PLUS PERTUZUMAB PLUS A TAXANE 
FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB 
FOLLOWING ANTHRACYCLINES AS ADJUVANT 
THERAPY IN PATIENTS WITH OPERABLE 
HER2-POSITIVE PRIMARY BREAST CANCER 
PROTOCOL NUMBER: 
BO28407 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-004902-82 
IND NUMBER: 
71072 
TEST PRODUCTS: 
Trastuzumab Emtansine (RO5304020) and 
Pertuzumab (RO4368451) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche 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 to your local study monitor.  Please retain a 
copy for your study files. 
 


 
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PROTOCOL SYNOPSIS 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III TRIAL 
COMPARING TRASTUZUMAB PLUS PERTUZUMAB PLUS A 
TAXANE FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB FOLLOWING 
ANTHRACYCLINES AS ADJUVANT THERAPY IN PATIENTS 
WITH OPERABLE HER2-POSITIVE PRIMARY BREAST CANCER 
PROTOCOL NUMBER: 
BO28407 
VERSION NUMBER: 
3 
EUDRACT NUMBER: 
2012-004902-82 
IND NUMBER: 
71072 
TEST PRODUCTS: 
Trastuzumab Emtansine (RO5304020) and  
Pertuzumab (RO4368451) 
PHASE: 
III 
INDICATION: 
HER2-positive operable primary breast cancer 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Efficacy Objectives 
The co-primary efficacy objective for this study is as follows: 
• 
To compare invasive disease−free survival (IDFS) (1) in the node-positive subpopulation 
and (2) in the overall protocol-defined population of patients with human epidermal growth 
(HER) factor 2−positive breast cancer randomized to receive either a taxane and 1 year of 
trastuzumab plus pertuzumab following anthracycline-based chemotherapy or 1 year of 
trastuzumab emtansine plus pertuzumab following anthracycline-based chemotherapy 
 
The secondary efficacy objectives for this study are as follows: 
• 
To compare IDFS plus second non-breast primary cancers, disease-free survival (DFS), 
and distant recurrence−free interval (DRFI) (1) in the node-positive subpopulation and (2) in 
the overall protocol-defined population between the two treatment arms 
• 
To compare overall survival (OS) (1) in the node-positive subpopulation and (2) in the 
overall protocol-defined population between the two treatment arms 
 
Safety Objective 
The safety objective for this study is as follows: 
• 
To compare overall safety, cardiac safety, hepatic, and pulmonary safety in the overall 
protocol-defined population between the two treatment arms 
 


 
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Patient-Reported Outcome Objectives 
Patient-reported outcome (PRO) objectives in the overall protocol-defined population for this 
study are as follows: 
• 
To compare PROs of treatment-related symptoms, patient functioning, and health-related 
quality of life (HRQoL) to better understand treatment impact and tolerability, as measured 
by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life Questionnaire−Core 30 (QLQ-C30) and the modified EORTC Breast Cancer module 
(Quality of Life Questionnaire−Breast Cancer 23 [QLQ-BR23]), between 
‘Trastuzumab + Pertuzumab + Taxane following Anthracyclines’ and ‘Trastuzumab 
Emtansine + Pertuzumab following Anthracyclines’ treatment arms. 
 
Exploratory Objectives 
The exploratory biomarker objectives for this study are as follows: 
• 
To evaluate the impact of HER2 mRNA level on treatment benefit using the efficacy 
endpoints  
• 
To evaluate the impact of the PIK3CA mutation status on prognosis and treatment benefit 
using the efficacy endpoints 
• 
To assess correlations between candidate biomarkers or biomarker panels and efficacy 
and/or safety in the overall protocol-defined population 
• 
To identify whether changes in expression levels of biomarker or biomarker panels during 
treatment correlate with treatment efficacy in the overall protocol-defined population 
 
Efficacy endpoints considered for these objectives will include IDFS and OS, as appropriate. 
The exploratory anti-therapeutic antibodies (ATAs) objective in the trastuzumab 
emtansine−treated patient population for this study is as follows: 
• 
To assess the incidence of ATAs to trastuzumab emtansine and the effect of ATAs on 
safety and efficacy 
 
The health economic exploratory objective is as follows: 
• 
To assess health status as measured using the EuroQol 5-Dimension Questionnaire 
(EQ-5D) questionnaire for health economic modeling 
 
Study Design 
Description of Study 
This is a prospective, two-arm, Phase III, randomized, multicenter, multinational, open-label 
study in patients with newly diagnosed HER2-positive primary invasive breast cancer who have 
had curative-intent surgery of their primary tumor and are candidates for adjuvant systemic 
chemotherapy following surgery.  HER2-positive status of the primary tumor will be confirmed 
by the central pathology laboratory prior to enrollment of the patient in the study.  Approximately 
1850 patients are anticipated to be randomized to one of the two treatment arms listed below in 
a 1:1 ratio. 
• 
Arm 1:  Anthracycline chemotherapy of choice followed by trastuzumab at 6 mg/kg every 
3 weeks (q3w; 8-mg/kg loading dose) in combination with pertuzumab 420 mg q3w (840-mg 
loading dose) and paclitaxel (80 mg/m2) weekly (qw) or docetaxel q3w (see protocol for 
details of dose and duration).  After the taxane-concurrent phase, HER2-targeted therapy 
(i.e., trastuzumab at 6 mg/kg q3w in combination with pertuzumab 420 mg q3w) will 
continue for up to 1 year. 
• 
Arm 2:  Anthracycline chemotherapy of choice followed by trastuzumab emtansine 
3.6 mg/kg q3w in combination with pertuzumab 420 mg q3w (840-mg loading dose).  
HER2-targeted therapy (i.e., trastuzumab emtansine at 3.6 mg/kg q3w in combination with 
pertuzumab 420 mg q3w) will continue for up to 1 year. 
 
Randomization will be stratified by world region (United States/Canada, Western 
Europe/Australia/New Zealand, Asia, or rest of the world); nodal status (0, 1−3, or ≥ 4 positive 


 
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nodes); centrally assessed hormonal receptor status (estrogen receptor [ER] and/or 
progesterone receptor [PR] positive or both ER and PR negative); and type of anthracycline 
(doxorubicin or epirubicin). 
In Arm 1, HER2-targeted study therapy with trastuzumab plus pertuzumab must start 
concurrently with the taxane component of chemotherapy following anthracycline therapy.  In 
both arms, after anthracycline treatment, a minimum interval of 3 weeks from the last dose of 
anthracycline to initiation of HER2-targeted therapy is required.  Prior to commencing the 
HER2-targeted therapy, patients must have a left ventricular ejection fraction (LVEF) ≥ 50% and 
must not have experienced any clinical symptoms suggesting heart failure or asymptomatic 
LVEF declines of 15 percentage points or more from baseline and below the lower limit of 
normal. 
Patients will receive up to 1 year of HER2-targeted therapy.  Study treatment will be 
discontinued in the event of invasive disease recurrence, unacceptable toxicity, withdrawal of 
consent, or study termination by the Sponsor.  
Adjuvant radiotherapy is to be given as clinically indicated at the end of chemotherapy (end of 
taxane in Arm 1; after four cycles of trastuzumab emtansine plus pertuzumab in Arm 2, to be 
consistent with Arm 1 in terms of timing of initiation) while receiving HER2-targeted therapy.  
For patients with ER-positive and/or PR-positive tumors, hormonal agents should be 
administered at the end of chemotherapy (end of taxane in Arm 1; after four cycles of 
trastuzumab emtansine plus pertuzumab in Arm 2, to be consistent with Arm 1 in timing of 
initiation).  
Number of Patients 
Approximately 1850 patients are anticipated to be enrolled at approximately 350 sites 
worldwide. 
Target Population 
The target population for this study will be patients with newly diagnosed primary invasive 
breast cancer that is HER2 positive (as determined by the central pathology laboratory) and 
who will be treated with adjuvant systemic chemotherapy following definitive surgery. 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age ≥ 18 years 
• 
Eastern Cooperative Oncology Group Performance Status ≤ 1 
• 
Non-metastatic histologically confirmed primary invasive breast carcinoma that was 
operable 
• 
HER2-positive breast cancer prospectively determined on the primary tumor by a central 
pathology laboratory and defined as follows: 
Immunohistochemistry (IHC) score of 3+ and/or positive by in situ hybridization (ISH), 
as defined by ISH ratio of ≥ 2.0 for the number of HER2 gene copies to the number of 
chromosome 17 copies.  Both IHC and ISH assays will be performed; however, only 
one positive result is required for eligibility. 
Availability of formalin-fixed paraffin-embedded (FFPE) tissue block or partial block (for 
minimum dimensions, see laboratory manual) with a representative invasive part of the 
tumor for central pathology laboratory confirmation of HER2 eligibility, hormonal 
receptor status, and additional biomarker analysis is required. 
• 
Known hormone receptor status of the primary tumor determined by a central pathology 
laboratory 
Hormone receptor-positive status can be determined by either known positive ER or 
known positive PR status.  Hormone receptor−negative status must be determined by 
both known negative ER and known negative PR.  
• 
Adequately excised:  Patients must have undergone either breast-conserving surgery or 
mastectomy/nipple- or skin-sparing mastectomy.   
For patients who undergo breast-conserving surgery, the margins of the resected 
specimen must be histologically free of invasive tumor and ductal carcinoma in situ 


 
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(DCIS) as determined by the local pathologist.  If pathologic examination demonstrates 
tumor at the line of resection, additional operative procedures may be performed to 
obtain clear margins.  If tumor is still present at the resected margin after re-excision(s), 
the patient must undergo total mastectomy to be eligible.  Patients with margins 
positive for lobular carcinoma in situ (LCIS) are eligible without additional resection. 
For patients who undergo mastectomy/nipple- or skin-sparing mastectomy, margins 
must be free of gross residual tumor.  It is recommended that patients should have a 
negative microscopic margin in accordance with local pathology protocol.  Patients with 
a microscopic positive deep margin are eligible (see radiation therapy [RT] 
requirements in the protocol). 
• 
Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 7th edition):  Patients must 
have had sentinel lymph node biopsy and/or axillary lymph node dissection for evaluation of 
pathologic nodal status.  Pathological classification of regional lymph node 
micrometastases (tumor deposits > 0.2 mm and ≤ 2 mm) is considered to be pN1, and 
isolated tumor cells are considered to be pN0.  
Eligible patients must have one of the following: 
Node-positive disease (pN ≥ 1), any tumor size except T0, and any hormonal receptor 
status 
Enrollment of patients with 1−3 nodes was planned to be limited to no more 
than 50% of the total number of randomized patients.  However, no formal 
capping of enrollment will be implemented (see Section 3.3.2.1 for details). 
There is no prespecified limit for the enrollment of patients with ≥ 4 nodes. 
Node-negative disease (pN0) with pathologic tumor size > 2.0 cm by standard local 
assessment AND negative for ER and PR as determined by a central pathology 
laboratory 
Enrollment of patients with node-negative disease was planned to be limited to no 
more than 10% of the total number of randomized patients.  However, no formal 
capping of enrollment will be implemented (see Section 3.3.2.1 for details). 
• 
Patients with synchronous bilateral invasive disease are eligible only if both lesions are 
HER2 positive. 
• 
No more than 9 weeks (63 days) may elapse between definitive breast surgery (or the last 
surgery if additional resection required for breast cancer) and randomization.   
• 
Baseline LVEF ≥ 55% measured by echocardiogram (preferred) or multiple-gated 
acquisition scans 
• 
Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required.  
This includes hepatitis B surface antigen and/or total hepatitis B core antibody in addition to 
HCV antibody testing.  The most recent serologic testing must have occurred within 
3 months prior to randomization.  If such testing has not been done, it must be performed 
during screening.  
Patients who have positive HBV or HCV serologies without known active disease must 
meet the eligibility criteria for ALT, AST, total bilirubin (TBILI), INR, activated partial 
thromboplastine time (aPTT), and alkaline phosphatase (ALP) on at least two 
consecutive occasions, separated by at least 1 week, within the 30-day screening 
period.  The second of these evaluations must be performed within 3 days prior to the 
first administration of study drug.  Note:  positive serology markers that indicate 
immunity will not be considered as clinically meaningful positive serology to trigger 
these tests.  
• 
Female patients of childbearing potential must be willing to use one highly effective form of 
nonhormonal contraception or two effective forms of nonhormonal contraception.  For male 
patients with partners of childbearing potential, one highly effective form of contraception or 
two effective forms of contraception must be used (see protocol for descriptions of highly 
effective and effective contraception).  Contraception must continue for the duration of study 
treatment and for 7 months after the last dose of study treatment.  


 
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The above contraception is not a requirement in the case of any of the following: 
The patient or partner of the patient is surgically sterilized. 
The female patient is > 45 years of age and is postmenopausal (has not 
menstruated for at least 12 consecutive months). 
The patient truly abstains from sexual activity and when this is the preferred 
option to avoid conception and contraception and/or usual lifestyle of the patient. 
• 
Male patients whose partners are pregnant must use condoms or truly refrain from sexual 
activity for the duration of the pregnancy 
• 
Willing and able to comply with the requirements of the protocol 
• 
Signed informed consent 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma 
• 
History of non-breast malignancies within the 5 years prior to randomization, except for the 
following: 
Carcinoma in situ (CIS) of the cervix 
CIS of the colon 
Melanoma in situ 
Basal cell and squamous cell carcinomas of the skin 
• 
Any clinical T4 tumor as defined by tumor-node-metastasis classification in UICC/AJCC, 7th 
edition, including inflammatory breast cancer 
• 
For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment 
(e.g., neoadjuvant or adjuvant), including but not limited to chemotherapy, anti-HER2 
therapy (e.g., trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or 
other tyrosine kinase inhibitors), hormonal therapy, OR anti-cancer RT (intraoperative 
radiotherapy as a boost at the time of primary surgery is acceptable) 
• 
Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any 
malignancy 
• 
History of DCIS and/or LCIS that was treated with any form of systemic chemotherapy, 
hormonal therapy, or RT to the ipsilateral breast where invasive cancer subsequently 
developed.  Patients who had their DCIS/LCIS treated with only surgery and/or contralateral 
DCIS treated with radiation are allowed to enter the study. 
• 
Patients with contraindication to RT while adjuvant RT is clinically indicated 
• 
Concurrent anti-cancer treatment in another investigational trial 
• 
Cardiopulmonary dysfunction as defined by any of the following prior to randomization: 
History of National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) Version 4.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or 
New York Heart Association (NYHA) criteria Class ≥ II  
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 
> 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or 
higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 [Mobitz 
2] or third degree AV-block]) 
Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia  
Myocardial infarction within 12 months prior to randomization 
Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic blood 
pressure > 100 mmHg) 


 
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Evidence of transmural infarction on ECG 
Requirement for oxygen therapy 
• 
Other concurrent serious diseases that may interfere with planned treatment, including 
severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes, or 
known infection with HIV 
• 
Any known active liver disease, including but not limited to disease due to HBV, HCV, 
autoimmune hepatic disorders, or sclerosing cholangitis.  For patients who are known 
carriers of HBV/HCV, active hepatitis B/C infection must be ruled out on the basis of 
negative serologic testing and/or determination of HBV DNA/HCV RNA viral load per local 
guidelines. 
• 
Any of the following abnormal laboratory tests prior to randomization: 
Serum TBILI > 1.0 times the upper limit of normal (ULN).  In cases of known Gilbert’s 
syndrome, direct bilirubin should be within the normal range. 
ALT and/or AST > ULN 
ALP > 1.5 × ULN 
Serum creatinine > 1.5 × ULN 
Total WBC < 2500/µL (< 2.5 × 109/L) 
ANC < 1500/µL (< 1.5 × 109/L) 
Platelets < 100,000/µL (< 100 × 109/L) 
INR or aPTT > 1.5 × ULN 
• 
Pregnant or lactating women or women of childbearing potential without a negative serum 
pregnancy test result, within 7 days prior to randomization, regardless of the method of 
contraception used 
• 
Hypersensitivity to any of the study medications or any of the ingredients or excipients of 
these medications, including hypersensitivity to benzyl alcohol 
• 
Chronic immunosuppressive therapies, including systemic corticosteroids 
 
Length of Study 
The total length of this study will be from randomization of the first patient to completion of the 
last follow-up assessment of the last patient, which is estimated to occur approximately 
10 years after the first patient is randomized.   
End of Study 
To enable long-term follow-up for survival and safety information, the study is planned to end 
approximately 10 years after the first patient is randomized. 
The Sponsor has the right to terminate this study, including long-term follow-up, at any time 
(e.g., if emerging safety signals indicate a potential health hazard to patients). 
Outcome Measures 
Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are listed below. 
• 
IDFS, defined as the time from randomization until the date of the first occurrence of one of 
the following events:  
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion) 
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral 
breast) 
Contralateral or ipsilateral second primary invasive breast cancer 
Distant recurrence (i.e., evidence of breast cancer in any anatomic site [other than the 
three sites mentioned above]) that has either been histologically confirmed or 
clinically/radiographically diagnosed as recurrent invasive breast cancer 


 
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Death attributable to any cause, including breast cancer, non-breast cancer, or 
unknown cause   
 
The secondary efficacy outcome measures for this study are as follows: 
• 
IDFS plus second primary non-breast cancer, excluding non-melanoma skin cancers and 
CIS of any site 
• 
DFS, defined as the time between randomization and the date of the first occurrence of any 
of the IDFS events described above, second primary non-breast cancer event (excluding 
non-melanoma skin cancers and CIS of any non-breast site), and contralateral or ipsilateral 
DCIS 
• 
DRFI, defined as the time between randomization and the first occurrence of distant breast 
cancer recurrence 
• 
OS, defined as the time from randomization to death due to any cause 
 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Incidence, type, and severity of all adverse events based on NCI CTCAE v4.0 
• 
Incidence, type, and severity of serious adverse events 
• 
Incidence, type and severity of ≥ Grade 3 adverse events 
• 
Incidence and type of adverse events leading to dose discontinuation, modification, or delay 
• 
Cause of death 
• 
Abnormal laboratory values 
• 
Decrease in LVEF from baseline over time 
• 
Cardiac safety outcome measures 
Primary cardiac endpoints:  cardiac events defined as death from cardiac cause or 
severe CHF (NYHA Class III or IV) with a decrease in LVEF of ≥ 10 percentage points 
from baseline to an LVEF of < 50% 
Secondary cardiac endpoints:  other cardiac-related events (e.g., any mild 
symptomatic CHF [NYHA Class II] associated with a ≥ 10% drop in LVEF to < 50%; 
asymptomatic declines in LVEF requiring dose delay or discontinuation) 
• 
Hepatic safety outcome measures 
Death from hepatic cause 
Severe drug-induced liver injury (Hy’s law cases) 
Nodular regenerative hyperplasia 
• 
Pulmonary safety outcome measures 
Death from pulmonary cause 
Pneumonitis and interstitial lung disease 
 
Patient-Reported Outcome Measures 
The PRO outcome measures for this study are as follows: 
• 
HRQoL, including bothersome side effects of therapy (e.g., peripheral neuropathy, 
joint/muscle pain, or skin problems), and patient functioning as measured using the EORTC 
QLQ-C30 and the modified breast cancer module QLQ-BR23 


 
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• 
Time from first HER2-targeted treatment, ± a taxane, to clinically meaningful deterioration 
in the global health status/quality of life (QoL) and functional (physical, role, and 
cognitive) subscales of the QLQ-C30.  The event of worsening of global health status/QoL 
for a given patient is defined as a decrease in baseline mean score by 10 points or more at 
two consecutive timepoints.  A 10-point or greater change in mean score is defined as 
being a “moderate” to “very much” and perceived an important change from the patient’s 
perspective.  Deterioration in function will be assessed using the published corresponding 
MIDs by Cocks et al. (2011). 
 
Exploratory Outcome Measures 
The exploratory biomarker outcome measures for this study are the relationship between 
molecular markers and efficacy and/or safety outcomes.  Efficacy outcomes considered for this 
analysis will include IDFS and OS, as appropriate. 
Correlations between biomarker status and efficacy and/or safety will include but not be limited 
to the following: 
• 
Level of HER2 mRNA expression assessed by quantitative real-time polymerase chain 
reaction (qRT-PCR) with efficacy outcome 
• 
Status of PIK3CA mutations assessed by PIK3CA allele−specific polymerase chain reaction 
assay with efficacy outcome 
• 
Level of HER2 gene amplification assessed by ISH with efficacy outcome 
• 
Level of HER2 protein expression assessed by IHC with efficacy outcome 
• 
Level of HER3 mRNA expression assessed by qRT-PCR with efficacy outcome 
• 
Changes in expression levels of biomarker or biomarker panels over time with efficacy 
outcome  
 
The ATA outcome measures to be assessed in patients receiving trastuzumab emtansine are 
the following: 
• 
Incidence of ATAs to trastuzumab emtansine 
• 
Effect of ATAs on safety and efficacy 
 
The EQ-5D will be used to obtain health status information for health economic modeling. 
The EQ-5D is a generic, preference-based health utility measure with questions about mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression that are used to build a 
composite of the patient’s health status.  A single summary index from the EQ-5D health states 
will be utilized in this study for economic modeling, and the results will not be reported in the 
clinical study report. 
Investigational Medicinal Products 
Study treatment is defined as non-hormonal systemic adjuvant (post-operative) treatment.  
Trastuzumab emtansine, pertuzumab, and trastuzumab are considered investigational 
medicinal products (IMPs) in this study.  Paclitaxel and docetaxel are also considered IMPs in 
this study; however, paclitaxel and docetaxel may be considered non-IMPs on the basis of local 
legislation.  
Doxorubicin, epirubicin, cyclophosphamide, and 5-fluorouracil are considered non-IMPs in this 
study.  Depending on local legislation, doxorubicin, epirubicin, cyclophosphamide, and 
5-fluorouracil may be considered IMPs.  If considered an IMP, then appropriate information on 
formulation, packaging, handling, and administration will be provided.   
Test Product 
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by intravenous (IV) infusion q3w in 
combination with pertuzumab 420 mg IV q3w (840 mg loading dose) for up to a total duration of 
1 year. 
Comparator 
Pertuzumab will be given at a dose of 420 mg IV q3w (840 mg loading dose) in combination 
with trastuzumab at 6 mg/kg IV q3w (8 mg/kg loading dose) and paclitaxel (80 mg/m2) qw or 


 
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docetaxel q3w (details regarding docetaxel dose and duration are described in the protocol).  
After the taxane concurrent phase, administration of trastuzumab/pertuzumab will continue for 
up to a total duration of 1 year 
Non-Investigational Medicinal Products 
Standard-of-care chemotherapy backbone treatments should include three to four cycles of an 
anthracycline-based regimen.  Either 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 
doxorubicin and cyclophosphamide (AC)/epirubicin and cyclophosphamide (EC) regimens that 
are protocol approved may be selected at the discretion of the investigator.  Paclitaxel and 
docetaxel may be considered non-IMPs on the basis of local legislation.  In Arm 1, three to four 
cycles of docetaxel or 12 weeks of paclitaxel will be administered.   
For non-IMPs, refer to local prescribing information/institutional guidelines for detailed 
guidelines on administration, premedications, dose delays/reductions for toxicities, 
contraindications, requirements on contraception duration, and concomitant medications. 
Statistical Methods 
Primary Analysis 
The primary efficacy variable is IDFS, defined as the time between randomization and date of 
first occurrence of an IDFS event as described in the Efficacy Outcome Measures section.  Data 
from patients who have not had an event at the time of data analysis will be censored on the 
date on which they are last known to be alive and event free, on or before the clinical data cutoff 
date of the respective analysis. 
The log-rank test, stratified by the protocol-defined stratification factors (excluding region), will 
be used to compare IDFS between the two treatment arms.  Region will be excluded because of 
the potential that some of the strata may have very few patients, which would result in a loss of 
power.  The unstratified log-rank test results will also be provided for sensitivity analysis.  If, at 
the time of analysis, it is deemed that the smallest stratum per arm necessary to conduct robust 
stratified analyses contains < 5 events, unstratified analyses will be used as the primary analysis.  
The Cox proportional hazards model, stratified by the previously noted stratification factors, 
excluding region, will be used to estimate the hazard ratio (HR) between the two treatment arms 
and the corresponding 95% CI.  The Kaplan-Meier approach will be used to estimate 3-year 
IDFS rates and corresponding 95% CIs for each treatment arm. 
Determination of Sample Size 
The sample size of the study is primarily driven by the analysis of IDFS in both the 
node-positive subpopulation and the overall protocol-defined population. 
To detect a target HR of 0.64 in IDFS in the overall protocol-defined population and the 
node-positive subpopulation, approximately 171 and 160 IDFS events will be required to 
achieve 82.5% and 80% power, respectively, in the two populations, at a two-sided 
significance level of 5% using a log-rank test.  Approximately 1850 and 1665 patients will be 
enrolled in the overall protocol-defined population and node-positive subpopulation, respectively, 
including a dropout/ineligibility rate of 8% for both arms as estimated from previous trials in this 
setting. 
Hierarchical Testing Procedure 
The hierarchical testing procedure will be employed according to the order given below on the 
primary and secondary endpoints to control the overall study Type I error rate at 5%: 
• 
Primary endpoint of IDFS in the node−positive subpopulation 
• 
Primary endpoint of IDFS in the overall protocol−defined population 
• 
Secondary endpoint of OS in the node−positive subpopulation 
• 
Secondary endpoint of OS in the overall protocol-defined population 
 
Interim Analyses 
One interim analysis of IDFS and three interim analyses of OS in both the node-positive 
subpopulation and the overall protocol-defined population are planned. 
A futility analysis may be incorporated to evaluate lack of superiority for the treatment arm 
of trastuzumab emtansine + pertuzumab following anthracyclines.  The timing and details of 


 
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this futility analysis will be described in the SAP and aligned with the availability of 
information from other relevant studies (e.g., KRISTINE and/or APHINITY). 
Interim IDFS Analyses 
An interim efficacy analysis of IDFS will be performed after approximately 75% of the targeted 
IDFS events are observed in the overall protocol-defined population (i.e. 128 of the 171 target 
events) and node-positive population (i.e. 120 of 160 target events) and is projected to occur 
approximately 43 months from first patient initiation (FPI). 
A hierarchical testing procedure will be used for the primary endpoint IDFS for the node-positive 
subpopulation and the overall protocol-defined population as defined in the protocol.  The type I 
error will be controlled at the 5% level at the interim and final analyses within the node-positive 
subpopulation and the overall protocol-defined population using a Lan-DeMets α-spending 
function with an O’Brien-Fleming boundary.  
The interim analysis will be performed by the independent Data Coordination Center (iDCC) 
statistician, and the results will be presented to the independent Data Monitoring Committee 
(iDMC) by the iDCC statistician.   
If the interim analyses in both populations cross the interim efficacy boundaries of the 
O’Brien-Fleming design, on the basis of the totality of both efficacy and safety data, the iDMC 
may recommend releasing the primary endpoint results before the targeted number of 160 and 
171 events have occurred in the node-positive subpopulation and overall protocol-defined 
population, respectively.  In this case, the Sponsor will be unblinded to study results, and a full 
data package including the first OS interim analysis results will be prepared for discussion with 
the regulatory authorities.  The study will continue until 10 years of follow-up from FPI have 
occurred, and the IDFS analysis will be updated descriptively.  If the IDFS interim analyses fail 
to cross the statistical efficacy boundaries of the O’Brien-Fleming design, then the study will 
continue as planned.  The Sponsor will conduct the final analyses.  
The protocol summarizes the planned IDFS analyses in the overall protocol-defined population 
and the node-positive subpopulation; the efficacy stopping boundaries based on the expected 
number of events; and the estimated timing of these analyses.  The boundaries to be used at 
each interim and final IDFS analysis will depend on the number of IDFS events actually 
included in the analyses and so may vary from the numbers stated in the protocol. 
Interim OS Analyses 
Three interim OS analyses and one final OS analysis are planned in both the overall 
protocol-defined population and the node-positive subpopulation.   
For the OS interim analyses and final OS analysis, the Lan-DeMets α-spending function with an 
O’Brien-Fleming boundary will be used such that the overall type I error will be controlled at the 
5% level for the OS endpoint.  With the study sample size and approximately 10 years of 
follow-up from FPI, this study has 38% power in the overall protocol-defined population and 
35% power in the node-positive subpopulation to detect an HR of 0.8.  This in the overall 
protocol-defined population corresponds to a 0.8% improvement in 3-year OS, from 96.1% in 
the control arm to 96.9% in the experimental arm and in the node-positive subpopulation to a 
0.9% improvement in 3-year OS, from 95.7% in the control arm to 96.6% in the experimental 
arm, at a two-sided significance level of 5%.  
All OS interim and final analyses will be performed by the Sponsor subsequent to the primary 
IDFS analysis and after the Sponsor is unblinded.  If the interim IDFS analyses in both the 
node-positive subpopulation and the overall protocol-defined population cross the statistical 
efficacy boundaries, the first OS interim analysis will be performed in both populations 
hierarchically at that time (approximately at 43 months from FPI).  If the final IDFS analysis 
crosses the statistical boundaries, then the second interim OS analysis will be performed 
hierarchically at the time of the final IDFS analysis (approximately 57 months from FPI), 
followed by the third and the final OS analyses performed hierarchically in both populations 
(planned to occur at 84 months [7 years] and 120 months [10 years], respectively, from FPI).  If, 
at any OS interim analysis, the O’Brien-Fleming efficacy boundary is crossed, that analysis of 
OS will be considered as confirmatory and all subsequent analyses of OS will be considered as 
descriptive.  
The protocol summarizes the planned OS analyses in the overall protocol-defined population 
and the node-positive subpopulation, respectively; the efficacy stopping boundaries based on 


 
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the expected number of events; and the estimated timing of these analyses.  The boundaries to 
be used at each interim and final IDFS analysis will depend on the number of IDFS events 
actually included in the analyses and may vary from the numbers stated in the protocol. 
Interim Safety Analyses 
An iDMC will monitor accruing patient safety data at least once every 6 months during the study 
until the last patient has completed study treatment.  In addition, safety data related to 
concurrent radiotherapy and/or hormonal therapy, serious adverse events, and deaths will be 
monitored by the iDMC at least once every 3 months during the study until the last patient has 
completed study treatment.  At each iDMC review, relevant safety information from ongoing 
trastuzumab emtansine and/or pertuzumab studies will also be provided to the iDMC. 
After the first 600 patients have been randomized and followed for 3 months (anticipated to 
occur at approximately 13 months after FPI), the iDMC will perform an interim safety analysis 
regarding overall numbers of deaths (all causes, including cardiac deaths) and hepatic events 
defined as confirmed Hy’s law cases.  The Clinical Events Committee (CEC) will communicate 
their findings to the iDMC to aid iDMC review. 
If an absolute increase of > 3% in the percentage of death (from any cause) is observed in the 
trastuzumab emtansine + pertuzumab arm compared with the trastuzumab + pertuzumab arm, 
the iDMC will consider a recommendation of pausing enrollment for further data review, 
stopping the trial, or modifying the trial. 
If the true difference in the percentage of death is > 3% (e.g., 2% vs. 6%), then there is 
approximately a 70% chance of observing an absolute difference of > 3% at the interim with 
600 patients.  The protocol presents the probability of observing an increase of > 3% in the 
percentage of deaths in the trastuzumab emtansine + pertuzumab arm compared with the 
trastuzumab + pertuzumab arm, with different assumptions for the percentage of deaths in the 
two treatment arms. 
If an absolute increase of > 3% in the percentage of Hy’s law cases (confirmed by the 
independent CEC) is observed in the trastuzumab emtansine + pertuzumab arm compared with 
the trastuzumab + pertuzumab arm, the iDMC will consider a recommendation of pausing 
enrollment for further data review, stopping the trial, or modifying the trial. 
If the true difference in the percentage of confirmed Hy’s law cases is > 3% (e.g., 0.33% 
vs. 3.67%), then there is approximately a 54% chance of observing an absolute difference of 
> 3% at the interim with 600 patients.  The protocol presents the probability of observing a > 3% 
increase in the percentage of Hy’s law cases in the trastuzumab emtansine + pertuzumab arm 
compared with the trastuzumab + pertuzumab arm, with different assumptions for the number of 
Hy’s law cases in the two treatment arms. 
The iDMC will work according to guidelines defined in the iDMC Charter.  The iDMC Charter will 
contain details regarding frequency of meetings, guidelines for decision making, and processes 
for requesting further information.  The iDMC members will review and sign off the charter 
before the first iDMC review. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AC 
doxorubicin and cyclophosphamide 
AC-T 
doxorubicin and cyclophosphamide followed by docetaxel or paclitaxel 
AC-TH 
doxorubicin and cyclophosphamide followed by a taxane (docetaxel or 
paclitaxel) with concurrent trastuzumab 
ADC 
antibody-drug conjugate 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastine time 
AST 
aspartase transaminase 
ATA 
anti-therapeutic antibody 
AV 
atrioventricular 
CEC 
Clinical Events Committee 
CI 
confidence interval 
CIS 
carcinoma in situ 
CHF 
congestive heart failure 
CSR 
Clinical Study Report 
CT 
computed tomography 
DCIS 
ductal carcinoma in situ 
DFS 
disease-free survival 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DRFI 
distant recurrence−free interval 
EBC 
early breast cancer 
EC 
epirubicin and cyclophosphamide 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EQ-5D 
EuroQol 5-Dimension Questionnaire™ 
ER 
estrogen receptor 


 
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Abbreviation 
Definition 
FAC 
5-fluorouracil, doxorubicin, and cyclophosphamide 
FACT-B 
Functional Assessment of Cancer Therapy−Breast 
FDA 
U.S. Food and Drug Administration 
FEC 
5 fluorouracil, epirubicin, and cyclophosphamide 
FEC-TH 
FEC followed by a taxane plus trastuzumab 
FFPE 
formalin-fixed paraffin-embedded 
FPI 
first patient initiation 
G-CSF 
granulocyte colony-stimulating factor 
HBcAb 
hepatitis B core antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER 
human epidermal growth 
HIPAA 
U.S. Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRQoL 
health-related quality of life 
ICH 
International Conference on Harmonisation 
iDCC 
independent Data Coordination Center 
IDFS 
invasive disease−free survival 
iDMC 
independent Data Monitoring Committee 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
international normalized ratio 
IRB/EC 
Institutional Review Board/Ethics Committee 
IRF 
independent review facility 
IRR 
infusion-related reaction 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous 
IVRS/IWRS 
interactive voice response system/interactive web response system 
LABC 
locally advanced breast cancer 
LCIS 
lobular carcinoma in situ 
LVEF 
left ventricular ejection fraction 
LVSD 
left ventricular systolic dysfunction 


 
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Abbreviation 
Definition 
MBC 
metastatic breast cancer 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse 
Events 
NCCN 
National Comprehensive Cancer Network 
NRH 
nodular regenerative hyperplasia 
NYHA 
New York Heart Association 
OBRP 
optional biomarker research program 
ORR 
objective response rate 
OS 
overall survival 
pCR 
pathological complete response 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PK 
pharmacokinetic 
PO 
by mouth; orally 
PR 
progesterone receptor 
PRO 
patient-reported outcome 
PTEN 
phosphatase and tensin homolog 
QLQ-BR23 
Quality of Life Questionnaire−Breast Cancer 23 
QLQ-C30 
Quality of Life Questionnaire−Core 30 
QoL 
quality of life 
q2w 
every 2 weeks 
q3w 
every 3 weeks 
qw 
weekly 
qRT-PCR 
quantitative real-time polymerase chain reaction 
RNA 
ribonucleic acid 
RR 
relative risk 
RT 
radiation therapy 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SLNB 
sentinel lymph node biopsy 
SoC 
standard of care 
SOC 
system organ class 


 
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Abbreviation 
Definition 
TAC 
docetaxel, doxorubicin, and cyclophosphamide 
TBILI 
total bilirubin 
TMA  
tissue microarray 
TOI-B 
Trial Outcome Index−Breast 
TPC 
Treatment of Physician’s Choice 
ULN 
upper limit of normal 
UICC/AJCC 
Union for International Cancer Control/American Joint Committee on 
Cancer 
WBC 
white blood cell 


 
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1. 
BACKGROUND 
1.1 
BACKGROUND ON HER2-POSITIVE EARLY BREAST CANCER 
AND ADJUVANT TREATMENT 
Breast cancer remains a highly significant cause of morbidity and mortality worldwide.  
There are over 1.3 million cases of breast cancer diagnosed globally each year 
(Jemal et al. 2011).  In 2011, in the United States alone, it is estimated that over 
230,000 new cases of breast cancer were diagnosed and close to 40,000 women died 
from this disease (Siegel et al. 2012).  Approximately 15%−20% of human breast 
cancers overexpress the human epidermal growth (HER) factor−2, a transmembrane 
receptor tyrosine kinase, because of an amplification event in the gene encoding HER2 
on chromosome 17.  Without treatment, HER2 overexpression is associated with 
aggressive tumor growth and poor clinical outcomes (Slamon et al. 1987, 1989; 
Wolff et al. 2007; Chia et al. 2008; Ross et al. 2009). 
Trastuzumab (Herceptin®), an anti-HER2 humanized monoclonal antibody, is approved 
in multiple countries for the adjuvant treatment of patients with HER2-overexpressing 
early breast cancer (EBC).  Several randomized studies (Section 1.2.1) have 
demonstrated that adjuvant trastuzumab improves outcomes for patients with 
early-stage HER2-positive breast cancer when administered in combination with 
chemotherapy concurrently (Romond et al. 2005, 2012; Slamon et al. 2011).  
Trastuzumab has also proven to be effective when given sequentially after completion of 
chemotherapy (Piccart-Gebhart et al. 2005, Smith et al. 2007, Gianni et al. 2011, 
Goldhirsch et al. 2013).   
A variety of trastuzumab-based chemotherapy regimens are considered effective for the 
treatment of non-metastatic HER2-positive breast cancer (Benson et al. 2009, 
Wong and Toppmeyer 2010, Slamon et al. 2011), including the following: 
• 
Anthracycline-based regimens, including doxorubicin and cyclophosphamide 
followed by a taxane (docetaxel or paclitaxel) with concurrent trastuzumab (AC-TH) 
or 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by a taxane plus 
trastuzumab (FEC-TH) 
• 
Non−anthracycline-based regimens, such as docetaxel, carboplatin, and 
trastuzumab (TCH) concurrently 
 
A total of 1 year of HER2-directed adjuvant therapy with trastuzumab remains the 
standard of care (SoC) on the basis of recent results from studies comparing different 
adjuvant trastuzumab treatment durations (1 year vs. shorter [6 months] or longer 
[2 years]) (Pivot et al. 2013, Goldhirsch et al. 2013). 
The 3-year disease-free survival (DFS) rate is approximately 85%−90% for the overall 
population of patients with HER2-positive EBC treated with adjuvant chemotherapy and 
trastuzumab in Herceptin® adjuvant trials.  Recurrence rate at 10 years is reported to be 
approximately 26% (Romond et al. 2012).  The majority of these patients eventually 


 
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have disease recurrence at distant sites, which is generally considered to be incurable.  
Thus, there is an unmet need and potential to further improve outcomes, particularly in 
higher-risk patient subpopulations, by incorporating newer HER2-directed agents, with 
manageable toxicity, into the treatment paradigm.  
1.1.1 
Herceptin® Adjuvant Trials 
Two large trials (Study NSABP B-31 and Study NCCTG N9831) conducted in North 
America have investigated concurrent trastuzumab and paclitaxel following doxorubicin 
and cyclophosphamide (AC-TH) versus AC-T.  The combined results of the two trials 
(Romond et al. 2005) demonstrated that the addition of trastuzumab to AC-T significantly 
improved DFS and overall survival (OS) in women with HER2-positive breast cancer.  At 
the time of the first scheduled interim efficacy analysis, the hazard ratio (HR) for a first 
event in the AC-TH arm relative to the AC-T arm was 0.48 (95% CI: 0.39, 0.59; 
p < 0.0001), corresponding to a 52% reduction in relative risk (RR) for recurrence.  The 
3-year DFS rate for the AC-TH arm was 87.1%.  There was also an increase in OS for 
patients who received trastuzumab + chemotherapy.  For OS, the HR for 
trastuzumab + chemotherapy relative to chemotherapy alone was 0.67 (95% CI: 0.48, 
0.92; p = 0.014).  After a median follow-up of 5.5 years in the NCCTG N9831 study, DFS 
rates with AC→T, AC→T→H, and AC→TH→H were 72%, 80%, and 84%, respectively.  
A comparison between the two trastuzumab-containing arms demonstrated a 4% 
improvement in DFS in the AC→TH→H arm compared with the sequential arm 
AC→T→H, which represented a 25% risk reduction, although this was not statistically 
significant.  The final planned analysis of these two studies demonstrated that at a 
median follow-up of 8.4 years, the AC-TH regimen was associated with a significant and 
substantial improvement in OS, with a RR reduction of 37% (HR = 0.63).  For patients 
with high-risk HER2-positive breast cancer, treatment with this regimen reduced the risk 
of a DFS event at 10 years by 40% (HR = 0.60).  The benefit of RR reduction for both 
DFS and OS was present and of similar magnitude in important subsets of the patients 
included in the analysis (e.g., regardless of hormonal receptor status, nodal status, or 
tumor size) (Romond et al. 2012).  
A Phase III randomized trial, Study BCIRG 006 (Slamon et al. 2006, 2009, 2011), 
compared doxorubicin and cyclophosphamide followed by docetaxel (AC-T) versus 
doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC-TH) 
versus TCH for the adjuvant treatment of women with HER2-positive EBC.  The results 
of the second interim efficacy analysis, at a median follow-up time of 36 months, 
demonstrated that the HR for a first event for the AC-TH arm relative to the AC-T arm 
was 0.61 (95% CI: 0.49, 0.77; p < 0.0001), corresponding to a 39% reduction in RR for 
recurrence.  The 3-year DFS rate was 86.7% for the AC-TH arm.  The 3-year OS rates 
were 95.5% for the AC-TH arm and 93% for the control arm.  At a median follow-up of 
65 months, the HR for the comparison of AC-TH with AC-T was 0.64 (p < 0.001).  The 
estimated 3- and 5-year DFS rates for the AC-TH arm were 88% and 84%, respectively.  
The estimated 5-year OS rate was 92% for the AC-TH arm (HR compared with 


 
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AC-T = 0.63; p < 0.001).  For patients receiving TCH, the estimated 3- and 5-year DFS 
rates were 87% and 81%, respectively (HR = 0.75; p = 0.04); the estimated 5-year OS 
rate was 91% (HR = 0.77; p = 0.04). 
Trastuzumab can also be given sequentially after chemotherapy.  In the HERA trial, 
patients had surgery and completed standard chemotherapy and radiotherapy prior to 
study enrollment.  Patients were randomly allocated either to an observation-only arm or 
to a trastuzumab treatment arm every 3 weeks (q3w) for either 1 or 2 years.  The 
efficacy analysis of the 1-year treatment arm versus the observation-only arm 
demonstrated that treatment with trastuzumab was associated with improved outcomes 
(Piccart-Gebhart et al. 2005).  Patients treated with trastuzumab for 1 year experienced 
a 46% lower risk of a first event than patients in the observation-only arm (HR = 0.54; 
p < 0.0001), corresponding to an absolute DFS benefit of 8.4% at 2 years favoring 
trastuzumab.  At a median follow-up of 8 years, HERA results showed sustained and 
statistically significant DFS and OS benefits for the 1-year trastuzumab treatment arm 
versus the observation-only arm despite selective crossover.  Benefit for 1 year of 
trastuzumab treatment versus observation only was shown across both hormone 
receptor−positive and hormone receptor-negative cohorts.  There is no evidence of a 
long-term benefit from 2 years compared with 1 year of trastuzumab treatment when 
administered as a sequential treatment following chemotherapy.  Most cardiac events 
occurred during trastuzumab administration and were reversible (Goldhirsch et al. 2013). 
1.2 
BACKGROUND ON TRASTUZUMAB EMTANSINE AND 
PERTUZUMAB 
1.2.1 
Trastuzumab Emtansine 
Trastuzumab emtansine (also known as T-DM1) is a novel antibody-drug conjugate 
(ADC).  ADCs represent a new approach to conferring selectivity to highly potent 
cytotoxic agents.  Linkage of a cytotoxic agent to highly specific monoclonal antibodies 
targeting unique and/or overexpressed cell surface tumor antigens focuses the delivery 
of such agents to tumor cells, creating a more favorable therapeutic window than could 
be achieved by the administration of such agents as free drugs.  Trastuzumab 
emtansine is specifically designed for the treatment of HER2-positive breast cancer.  It is 
composed of the cytotoxic agent DM1 (a thiol-containing maytansinoid anti-microtubule 
agent) conjugated to trastuzumab via lysine side chains, with an average 
drug to antibody ratio of approximately 3.5:1.  The DM1 component of trastuzumab 
emtansine is an inhibitor of tubulin polymerization, binding to the β subunit of tubulin, at 
the same binding site as the vinca alkaloids; however, DM1 derivatives are up to 
100-fold more cytotoxic than vinca alkaloids and taxanes (e.g., 25- to 500-fold more 
potent than paclitaxel) (Kovtun et al. 2010, Junttila et al. 2011).  
Trastuzumab emtansine binds to HER2 with an affinity similar to that of trastuzumab; 
such binding is required for its anti-tumor activity.  It is hypothesized that after binding to 


 
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HER2, trastuzumab emtansine undergoes receptor-mediated internalization, followed by 
intracellular release of DM1 and subsequent cytotoxicity.  
Completed and ongoing Phase I, II, and III studies of trastuzumab emtansine have 
demonstrated clinical activity when trastuzumab emtansine is given as a single agent to 
patients with HER2-positive metastatic breast cancer (MBC) with tolerable/favorable 
safety.  In addition, trastuzumab emtansine has been studied in patients with EBC in 
Phase Ib and II settings.  Clinical trials of trastuzumab emtansine relevant to the design 
of the current trial are described in the following subsections.  Please refer to the most 
recent version of the Trastuzumab Emtansine Investigator’s Brochure for further 
information on all completed and ongoing nonclinical and clinical studies.  
A summary of trastuzumab emtansine safety profile is provided in Section 5.1.1.1. 
1.2.1.1 
Trastuzumab Emtansine Clinical Experience in Metastatic 
Breast Cancer 
Trastuzumab emtansine has been studied as a single agent as well as in combination 
with other therapies in MBC.   
1.2.1.1.1 
Single-Agent Studies 
Study TDM4370g/BO21977 (EMILIA) is a randomized Phase III study of trastuzumab 
emtansine versus lapatinib plus capecitabine for patients with HER2-positive 
unresectable locally advanced breast cancer (LABC) or MBC previously treated with 
trastuzumab and a taxane (n = 991) (Verma et al. 2012).  Patients received trastuzumab 
emtansine (3.6 mg/kg intravenous [IV] q3w) or capecitabine (1000 mg/m2 orally [PO] 
twice daily, Days 1 to 14 q3w) + lapatinib (1250 mg PO daily) until progressive disease or 
unmanageable toxicity.  Primary endpoints were progression-free survival (PFS) by an 
independent review, OS, and safety.  There was a significant improvement in PFS 
favoring trastuzumab emtansine (HR = 0.650, p < 0.0001; median 9.6 vs. 6.4 months).  
OS was significantly improved in patients receiving trastuzumab emtansine, with a 
31.8% reduction in the risk of death associated with trastuzumab emtansine compared 
with lapatinib and capecitabine (HR = 0.682 [95% CI: 0.548, 0.849]; p = 0.0006) 
(Verma et al. 2012).  The median duration of survival was 25.1 months in patients 
treated with lapatinib plus capecitabine, compared with 30.9 months in patients treated 
with trastuzumab emtansine. 
Trastuzumab emtansine was well tolerated.  The incidence of Grade ≥ 3 adverse events 
in the trastuzumab emtansine arm was 40.8% versus 57% in the lapatinib plus 
capecitabine arm.  The most frequently occurring Grade ≥ 3 adverse events in the 
trastuzumab emtansine arm were predominately related to laboratory test abnormalities.  
Thrombocytopenia was the most common Grade ≥ 3 adverse event; other Grade 
≥ 3 adverse events occurring in at least 2% of patients were increased AST, increased 
ALT, anemia, fatigue, hypokalemia, and neutropenia.  Fewer patients receiving 


 
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trastuzumab emtansine (15.5%) developed a serious adverse event (SAE) compared 
with patients receiving lapatinib plus capecitabine (18%). 
Median time to symptom progression, as defined by a 5-point decrease in the score 
derived from the Trial Outcome Index−Breast (TOI-B) subscale of the Functional 
Assessment of Cancer Therapy−Breast (FACT-B) quality of life (QoL) questionnaire, 
was delayed in female patients receiving trastuzumab emtansine compared with those 
receiving lapatinib plus capecitabine (7.1 months for trastuzumab emtansine, compared 
with 4.6 months: HR = 0.796 [95% CI: 0.667, 0.951]; p = 0.0121). 
Study TDM4450g/BO21976 was a randomized, multicenter, Phase II open-label trial of 
the efficacy and safety of trastuzumab emtansine (3.6 mg/kg IV q3w) versus 
trastuzumab plus docetaxel in patients with metastatic HER2-positive breast cancer who 
had not received prior chemotherapy for metastatic disease.  The primary endpoints 
were investigator-assessed PFS and safety.  Key secondary endpoints included OS, 
objective response rate (ORR), duration of objective response, clinical benefit rate, and 
QoL.  A total of 137 patients were enrolled in the study. 
Trastuzumab emtansine demonstrated significant improvement in PFS over trastuzumab 
plus docetaxel as first-line MBC therapy.  The median PFS was 14.2 months in the 
trastuzumab emtansine arm compared with 9.2 months in the trastuzumab plus 
docetaxel arm (HR = 0.59 [95% CI: 0.364, 0.968]; log-rank p-value = 0.035), with a 
median follow-up of approximately 14 months in both arms.  The ORR was 58.0% with 
trastuzumab plus docetaxel and 64.2% with trastuzumab emtansine.  Tumor response 
was more durable with trastuzumab emtansine (median duration of response was not 
reached compared with the median duration of 9.5 months in the trastuzumab plus 
docetaxel arm).  Preliminary OS results in this study were similar between treatment 
arms, with a median follow-up of approximately 23 months in both arms.  Of note, OS 
data were not mature (< 20% of the patients in the study had died at the time of the data 
cutoff and the median duration of OS was not reached for either arm).  Results were also 
potentially confounded by the crossover allowed in the.  At the time of OS follow-up, 
there were 35 patients (50%) from the trastuzumab plus docetaxel arm who had crossed 
over to trastuzumab emtansine following documented disease progression. 
Grade ≥ 3 adverse events were reported less frequently in the trastuzumab emtansine 
group compared with the trastuzumab plus docetaxel group (46.4% vs. 90.9%), as were 
adverse events leading to treatment discontinuations (7.2% vs. 34.8%) and SAEs 
(20.3% vs. 25.8%).  
The worsening of QoL, reflected by the FACT-B and TOI-B scores, was delayed in the 
trastuzumab emtansine arm compared with the trastuzumab plus docetaxel arm (7.5 vs. 
3.5 months; HR = 0.58; p = 0.022). 


 
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Study TDM4997g/BO25734 (TH3RESA) is a Phase III study to evaluate efficacy of 
trastuzumab emtansine versus Treatment of Physician’s Choice (TPC) in patients who 
received at least two prior regimens of HER2-directed therapies, including trastuzumab 
and lapatinib, in the metastatic or unresectable locally advanced/recurrent setting.  
Co-primary efficacy endpoints were PFS per investigator assessment and OS.  There 
were 404 patients who received trastuzumab emtansine as their planned treatment, and 
198 patients who received TPC.  Patients receiving trastuzumab emtansine had a 
47.2% reduction in the risk of disease progression or death.  Median PFS was 3.3 
months in the TPC arm and 6.2 months in the trastuzumab emtansine arm (HR = 0.528; 
95% CI: 0.422, 0.661; p < 0.0001).  There was a strong positive trend in OS in favor of 
trastuzumab emtansine at the first interim analysis.  Patients receiving trastuzumab 
emtansine had a 44.8% reduction in the risk of death (HR = 0.552; 95% CI: 0.369, 
0.826; p = 0.0034) compared with patients receiving TPC; however, this result did not 
cross the pre-specified O’Brien-Fleming stopping boundary of HR < 0.363 
(p < 0.0000013).  Patients receiving trastuzumab emtansine also showed a consistent 
treatment benefit compared with the subgroup of TPC patients receiving a 
trastuzumab-containing regimen (74.7% of the intent-to-treat [ITT] population).  
Numerically fewer patients receiving trastuzumab emtansine than those receiving TPC 
had Grade ≥ 3 AEs (39.0% vs. 46.2%) or AEs leading to dose reduction (12.4% vs. 
20.7%).  The incidence of SAEs (24.1% vs. 22.3%) and of AEs leading to treatment 
discontinuation of any component of therapy (11.7% vs. 10.9%) are similar between 
treatment arms.  Across the majority of the most commonly affected body systems, 
patients receiving trastuzumab emtansine reported more AEs compared with those 
receiving TPC.  However, the higher frequency of events seen for trastuzumab 
emtansine was driven by Grade 1−2 AEs. 
The patient-reported outcome (PRO) measures including “time to pain symptom 
progression” were utilized to evaluate QoL.  The time to pain symptom progression was 
similar different between the two treatment arms (HR = 1.115; 95% CI: 0.819, 1.517). 
1.2.1.1.2 
Combination Studies 
Study TDM4373g/BO22495 was a Phase Ib/II study of trastuzumab emtansine 
plus pertuzumab in patients with HER2-positive LABC (unresectable local or regional) or 
MBC.  Sixty-seven patients were enrolled.  Nine patients with relapsed MBC (i.e., treated 
in the second-line setting or beyond) were enrolled in the dose-escalation phase of the 
study (Phase Ib).  On the basis of data from the Phase Ib portion, the recommended 
dose for the expansion phase of the study (Phase II) was trastuzumab emtansine 
3.6 mg/kg q3w in combination with full-dose pertuzumab (840-mg loading dose, followed 
by 420 mg q3w).  One patient experienced a dose-limiting toxicity (DLT) (Grade 4 
thrombocytopenia) at the recommended dose level for trastuzumab emtansine and 
pertuzumab. 


 
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The Phase II portion enrolled 37 relapsed patients (i.e., relapsed or progressed on prior 
HER2-directed therapy) and 21 first-line patients (i.e., received no prior treatment for 
MBC) at the recommended dose level. 
For the patients treated at the recommended Phase II dose (n = 64), the most common 
adverse events (occurring in ≥ 25% of patients) were as follows:  fatigue (60.9%), 
nausea (50%), diarrhea (39.1%), cough (37.5%), decreased appetite (34.4%), 
constipation (32.8%), thrombocytopenia (32.8%), pyrexia (31.3%), chills (31.3%), 
vomiting (29.7%), increased AST (29.7%), increased ALT (28.1%), dyspnea (26.6%), 
dysgeusia (25%), peripheral sensory neuropathy (25%), mucosal inflammation (25%), 
epistaxis (25%), and headache (25%). 
The rates of Grade 3 to 4 thrombocytopenia observed in this study were comparable to 
those in studies of single-agent trastuzumab emtansine (12.5% vs. 7.5%−12.9%) 
(Diéras et al. 2010, LoRusso et al. 2011, Verma et al. 2012).  Similarly, the rates of 
Grade 3 to 4 AST or ALT elevation were within the range of previously reported studies 
(approximately 9.4% vs. 2.9%−13.4%).  The overall incidence of diarrhea appeared to 
be greater than for single-agent trastuzumab emtansine (39.1% vs. 10.4%−25.9%), 
which is likely due to combination treatment with pertuzumab. 
For the 64 patients treated with trastuzumab emtansine at the recommended Phase II 
dose (21 first-line and 43 relapsed), the ORR (complete response + partial response) 
was 40.6%, with a higher response rate among first-line patients (57.1%) than among 
relapsed patients (32.6%).  The majority of responses observed in the 64 patients were 
partial responses (23 of 26 patients). 
For the patients who had an objective response, the median duration of response was 
slightly longer for first-line patients (13.9 months) than for relapsed patients 
(11.8 months). 
Study TDM4688g was a Phase Ib/II, single-arm study to evaluate the effect of 
trastuzumab emtansine (3.6 mg/kg q3w) on the QT interval in patients with 
HER2-positive LABC or MBC.  A subgroup of patients (n = 20) who developed early 
disease progression while receiving single-agent trastuzumab emtansine (i.e., within 
6 cycles or 18 weeks from study start) were eligible to receive combination treatment 
with trastuzumab emtansine plus pertuzumab in subsequent cycles.  Two patients who 
received the combination therapy achieved partial response.  Safety data are 
summarized in the pooled analysis for trastuzumab emtansine plus pertuzumab 
(Section 1.2.3). 
Study TDM4788g/BO22589 (MARIANNE) is a randomized three-arm, Phase III study of 
trastuzumab emtansine combined with pertuzumab versus trastuzumab emtansine 
combined with pertuzumab-placebo (blinded for pertuzumab) versus trastuzumab plus 
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LABC or MBC.  The primary objectives of the study are to compare the efficacy (PFS) 
and safety across the three arms.  A total of 1095 patients were enrolled in this study.  
Efficacy and safety data were recently described (Ellis et al. 2015).  For the primary 
endpoint of PFS based on independent review facility (IRF) assessment, both 
trastuzumab emtansine + placebo and trastuzumab emtansine + pertuzumab were 
non-inferior to trastuzumab + taxane:  the upper bounds of the 97.5% CIs for the 
stratified HRs were below the pre-specified non-inferiority margin of HR 1.1765:  1.13 
for trastuzumab emtansine + placebo (HR = 0.91; 97.5% CI: 0.73, 1.13) and 1.08 for 
trastuzumab emtansine + pertuzumab (HR = 0.87; 97.5% CI: 0.69, 1.08), each versus 
trastuzumab + taxane.  The addition of pertuzumab to trastuzumab emtansine did not 
result in a statistically significant increase in PFS in the ITT population.  Median PFS 
was 13.7 months for trastuzumab + taxane, 14.1 months for trastuzumab 
emtansine + placebo and 15.2 months for trastuzumab emtansine + pertuzumab. 
The safety profile of trastuzumab emtansine as a single agent or in combination with 
pertuzumab was consistent with prior experience, with no new safety signals identified 
compared with those already known for these study drugs.  Trastuzumab emtansine as a 
single agent or in combination with pertuzumab was more tolerable than 
trastuzumab + taxane, with respect to a numerical lower incidence and/or severity of 
certain clinically important and/or symptomatic toxicities, fewer Grade ≥ 3 AEs and 
fewer AEs leading to treatment discontinuation (Ellis et al. 2015). 
Study TDM4652g/GO01355 was a Phase Ib/Iia open-label study to evaluate the safety, 
tolerability, and pharmacokinetics of trastuzumab emtansine weekly (qw) or q3w with 
paclitaxel, with or without pertuzumab, in patients with HER2-positive LABC or MBC who 
have previously received HER2-directed therapy.  A total of 104 patients were enrolled 
in the study.  The Phase Ib dose-escalation portion of the study was to determine the 
maximum tolerated dose (MTD) of the combination regimen(s).  The MTD of 
trastuzumab emtansine q3w was 3.6 mg/kg with paclitaxel 80 mg/m2 qw.  The addition of 
the pertuzumab 840-mg loading dose followed by 420 mg q3w to the regimen was 
feasible (Modi et al. 2012). 
The Phase Iia portion of this study was to further evaluate trastuzumab emtansine with 
paclitaxel with or without pertuzumab at the MTD in order to determine the safety and 
feasibility of delivering at least 12 doses of qw paclitaxel in combination with 
trastuzumab emtansine with or without pertuzumab within the first 15 weeks after 
Cycle 1 Day 1.  Enrollment in the Phase Iia portion was completed in January 2013, with 
22 patients in Group A (paclitaxel + trastuzumab emtansine) and 22 patients in Group B 
(paclitaxel + trastuzumab emtansine + pertuzumab).  All patients enrolled had received 
prior trastuzumab, and 36 of 44 (81.8%) had received previous taxane therapy.  As of 
23 May 2013, in Groups A and B, 23 of 42 evaluable patients (54.8%) were able to 
receive at least 12 doses of paclitaxel within 15 weeks after Cycle 1 Day 1.  Exposure 
data demonstrated that the median dose intensities achieved for trastuzumab emtansine, 


 
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paclitaxel, and pertuzumab were 93.95%, 50.12%, and 100.00%, respectively.  The 
most commonly observed Grade 3 or 4 adverse events (peripheral neuropathy, 
neutropenia, fatigue, and thrombocytopenia) were consistent with the known safety 
profiles of the three study agents.  However, the incidence rate of Grade ≥ 3 peripheral 
neuropathy increased compared with the use of single-agent trastuzumab emtansine in 
patients with MBC.  Peripheral neuropathy was the major reason for paclitaxel dose 
reduction and/or discontinuation. 
1.2.1.2 
Trastuzumab Emtansine Clinical Experience in Early Breast 
Cancer 
Study TDM4874g/BO22857 was a single-arm Phase II study to assess the safety and 
feasibility of administering trastuzumab emtansine at a dose of 3.6 mg/kg IV q3w for up 
to 17 cycles following anthracycline-based chemotherapy for patients with early-stage 
HER2-positive breast cancer, in neoadjuvant and/or adjuvant settings.  Radiation 
therapy (RT) was administered after the first four cycles of trastuzumab emtansine to 
patients in whom it was indicated.  Four cycles of trastuzumab/docetaxel (given after the 
first four cycles of trastuzumab emtansine) were optional.  The primary objectives of the 
study are to evaluate the safety profile of trastuzumab emtansine and to evaluate the 
rate of prespecified cardiac events (death from cardiac cause or severe congestive heart 
failure [CHF]; New York Heart Association [NYHA] Class III or IV) following initiation of 
trastuzumab emtansine treatment. 
The final analysis (clinical cutoff 12 June 2013) indicated that there were no 
prespecified cardiac events occurred and there were no reports of symptomatic left 
ventricular systolic dysfunction (LVSD) or heart failure.  Overall, 123 (83.1%) patients 
completed the planned course of trastuzumab emtansine treatment, 119 (80.4%) of 
whom had no dose reduction.  Twenty patients (13.5%) had adverse events leading to 
trastuzumab emtansine discontinuation:  in 11 of these patients, the adverse events 
were laboratory abnormalities requiring discontinuation (none were Grade 4), and in 9 
patients, discontinuation was because of symptomatic adverse events (2 were Grade 3 
[fatigue, joint crepitation]; none were Grade 4).  Of the 148 patients, 32.4% had Grade 3 
trastuzumab emtansine−related adverse events and 2.7% had Grade 4 trastuzumab 
emtansine−related adverse events (1 patient each:  febrile neutropenia and 
pancytopenia, atrial fibrillation, decreased platelet count, and hypokalemia); no deaths 
occurred.  The adverse events observed to date are consistent with the known safety 
profile of trastuzumab emtansine.  There were no cases of portal hypertension/nodular 
regenerative hyperplasia (NRH) reported.  For additional safety details for this study, 
please refer to the trastuzumab emtansine Investigator’s Brochure. 
Of the 116 patients receiving RT, 39 received it concurrently with trastuzumab 
emtansine and 77 received it sequentially.  The percentage of patients who completed 
the planned RT dose without delay was similar to the percentage who received 
concurrent or sequential treatment (90% and 92%, respectively).  Radiation pneumonitis 
occurred in 3 patients (1 in concurrent and 2 in sequential treatments). 


 
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Fifty patients (Stage I, 8%; Stage II, 56%; Stage III, 36%) received neoadjuvant 
trastuzumab emtansine and underwent surgery.  The pathological complete response 
(pCR) rate (ypT0/is ypN0) was 56.0% (95% CI: 41.3%, 69.6%). 
Study BP22572 is a Phase Ib/II study designed to assess the safety, feasibility, and/or 
efficacy of combining docetaxel with trastuzumab emtansine with or without pertuzumab 
in patients with HER2-positive MBC or newly diagnosed LABC. 
The feasibility of combining these agents in patients with HER2-positive MBC and LABC 
was demonstrated in the Phase Ib portion of the study.  A total of 70 patients with LABC 
have been treated with the following combinations: 
• 
Trastuzumab emtansine 3.6 mg/kg + docetaxel 75 mg/m2 q3w (n = 15) 
• 
Trastuzumab emtansine 3.6 mg/kg + docetaxel 100 mg/m2 q3w (with primary 
granulocyte colony-stimulating factor [G-CSF]) (n = 22) 
• 
Trastuzumab emtansine 3.6 mg/kg + docetaxel 60 mg/m2
 + pertuzumab 840-mg 
loading dose, then 420 mg q3w (n = 11) 
• 
Trastuzumab emtansine 3.6 mg/kg + docetaxel 75 mg/m2 (with primary 
G-CSF) + pertuzumab 840-mg loading dose, then 420 mg q3w (n = 22) 
 
As of 2 May 2013, 97.3% of the patients have received five or more cycles of the doublet 
combination and 87.8% of the patients have received four or more cycles of the triplet 
combination.  Grade 2 or worse skin toxicity was observed, including a Grade 4 
dermatomyositis.  Incidences of increased ALT and thrombocytopenia observed with the 
docetaxel combination were higher than expected on the basis of the known safety 
profile of the individual agents.  One patient treated in the cohort of docetaxel 100 mg/m2 
(starting docetaxel dose at 100 mg/m2 and dose reduced to 75 mg/m2 after the first dose) 
combined with trastuzumab emtansine died, with a reported SAE of pneumonitis. 
In the MBC population (n = 25), the ORR was 80.0% (95% CI: 59.3, 93.2).  In the 
overall LABC population (n = 73), the pCR rate was 60.3% (95% CI: 48.1, 71.5).  In 
LABC patients receiving trastuzumab emtansine + docetaxel (n = 40), the pCR rate was 
60.0%, and in those receiving trastuzumab emtansine + docetaxel + pertuzumab (n = 33), 
it was 60.6%. 
Study WSG-ADAPT is a Phase II study evaluating trastuzumab emtansine with or 
without endocrine therapy in comparison to trastuzumab + endocrine therapy as 
neoadjuvant treatment in HER2+/HR+ EBC patients.  After 4 cycles of either 
neoadjuvant trastuzumab + endocrine therapy or neoadjuvant trastuzumab emtansine 
with or without endocrine therapy, patients underwent definitive breast surgery with 
total pCR serving as the primary endpoint.  Notable therapeutic activity was observed 
at the planned interim analysis (January 2015) among 130 patients.  Total pCR 
(ypT0/is, ypN0) rates after 4 cycles of neoadjuvant trastuzumab + endocrine therapy, 


 
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trastuzumab emtansine + endocrine therapy, or trastuzumab emtansine alone were 
6.7%, 45.8%, and 40.5%, respectively (Harbeck et al. 2015). 
Study BO27938 (KATHERINE) is a randomized, multinational, multicenter, open-label 
Phase III study, evaluating adjuvant treatment with trastuzumab emtansine compared 
with trastuzumab in patients with EBC who have not achieved a pCR following 
neoadjuvant treatment with chemotherapy and trastuzumab.  The primary objective of 
this trial, which started in April 2013, is to compare invasive disease−free survival (IDFS) 
between treatment arms.  As of 11 May 2015, unblinded safety and efficacy data were 
not available to the Sponsor, but the independent Data Monitoring Committee (iDMC), 
which reviews data from the trial, had thus far recommended that the study continue as 
planned. 
Study BO28408/TRIO021 (KRISTINE) is a randomized, multicenter, open-label Phase 
III study, evaluating neoadjuvant treatment with trastuzumab emtansine + pertuzumab 
compared with chemotherapy + trastuzumab and pertuzumab in patients with EBC.  
The primary objective of this trial, which started in June 2014, is to compare the pCR 
rate (ypT0/is, ypN0) using local evaluation between treatment arms.   
1.2.1.3 
Pooled Safety Analysis of Single-Agent Trastuzumab 
Emtansine 
Pooled safety data are available for 884 patients with MBC treated with single-agent 
trastuzumab emtansine at a dose of 3.6 mg/kg q3w.  The most common adverse events 
associated with single-agent trastuzumab emtansine (in ≥ 25% of patients) were fatigue 
(46.4%), nausea (43.0%), thrombocytopenia (29.6%), headache (29.4%), and 
constipation (26.5%).  Most of these events were Grade 1 or 2 in intensity.  The most 
common Grade ≥ 3 adverse events (occurring in > 2% of patients) were 
thrombocytopenia (10.7%), increased AST (4.3%), fatigue (3.2%), increased ALT (3.1%), 
hypokalemia (2.9%), and anemia (2.9%).  Sixty-two patients (7.0%) experienced 
adverse events that resulted in their trastuzumab emtansine treatment being 
discontinued:  The most common adverse events leading to discontinuation were blood 
and lymphatic system disorders (primarily thrombocytopenia [1.5%]) and investigations 
system organ classes (SOCs) (increased AST [0.8%] and increased ALT [0.5%]). 
Selected adverse events for all patients include hepatotoxicity, peripheral neuropathy, 
thrombocytopenia, infusion-related reactions (IRR)/hypersensitivity, cardiac dysfunction, 
and pneumonitis.  Table 1 provides an overview of these adverse events. 


 
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Table 1 
Overview of Selected Adverse Events with Trastuzumab 
Emtansine Alone (n = 884) 
No (%) of Patients with AE of Special Interest 
Type of Event 
Any 
Grade > 3 
SAE 
AE Leading to 
Withdrawal 
Thrombocytopenia 
285 (32.2%) 
105 (11.9%) 
8 (0.9%) 
15 (1.7%) 
Hemorrhage 
323 (36.5%) 
18 (2.0%) 
14 (1.6%) 
0 
Hepatotoxicitya 
292 (33.2%) 
81 (9.2%) 
10 (1.1%) 
18 (2.0%) 
Peripheral neuropathy 
257 (29.1%) 
22 (2.5%) 
2 (0.2%) 
4 (0.5%) 
Infusion-related 
reactions/hypersensitivity 
61 (6.9%) 
1 (0.1%) 
2 (0.2%) 
1 (0.1%) 
Cardiac dysfunctionb 
14 (1.6%) 
2 (0.2%) 
⎯ 
2 (0.2%) 
Pneumonitis/ILD 
10 (1.1%) 
3 (0.3%) 
3 (0.3%) 
4 (0.5%) 
Single-agent pooled analyses: cut-off date of 31 July 2012 
AE = adverse event; CHF = congestive heart failure; ILD = interstitial lung disease; LVEF = left 
ventricular ejection fraction; NRH = nodular regenerative hyperplasia; SAE = serious adverse 
event. 
a Hepatotoxicity includes increases in serum AST or ALT and NRH of the liver. 
b Cardiac dysfunction refers to left ventricular dysfunction including CHF and decreases in 
LVEF. 
 
 
Please refer to the Investigator’s Brochure for a full description of the trastuzumab 
emtansine safety profile, warnings, and precautions. 
1.2.2 
Pertuzumab 
Pertuzumab is a fully humanized IgG1κ monoclonal antibody that targets HER2 by 
inhibiting HER2 heterodimerization with other HER family members such as 
HER1/epidermal growth factor receptor (EGFR), HER3, and HER4.  HER2 functions as 
a co-receptor and is frequently activated by forming heterodimers with another HER 
family receptor when activated in a HER ligand−dependent manner. 
Like trastuzumab, pertuzumab is directed against the extracellular domain of HER2.  
However, pertuzumab binds to an epitope within subdomain 2 of HER2, whereas the 
epitope for trastuzumab is localized to subdomain 4 (Cho et al. 2003, 
Franklin et al. 2004).  As a result of heterodimerization inhibition, pertuzumab inhibits 
ligand-initiated intracellular signaling through two major signaling pathways:  
MAP-kinase and PI3-kinase.  Inhibition of these signaling pathways can result in growth 
arrest and apoptosis, respectively (Hanahan and Weinberg 2000).  In vitro studies have 
shown that heregulin-activated HER3-HER2 heterodimers elicit the strongest 
proliferative and transformation responses of any possible receptor combination.  
Consequently, ligand-activated downstream signaling is blocked more effectively by 
pertuzumab than by trastuzumab.  Therefore, as a result of their complementary modes 


 
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of action, there is a potential role for the combination of pertuzumab and trastuzumab in 
HER2-overexpressing diseases, which has been demonstrated in clinical trials 
(Section 1.2.2.1 and Section 1.2.2.2). 
Pertuzumab as a single agent has been studied in several Phase I or II clinical trials in 
solid tumors, including breast, prostate, ovarian, and lung cancer.  Low clinical activity 
has been observed in Phase I/II studies conducted in patients with HER2 low-expressing 
tumors receiving single-agent pertuzumab; complete responses have not been observed 
in any of these trials. 
Pertuzumab has also been evaluated in Phase II and III studies in combination with 
trastuzumab and has demonstrated clinical efficacy with acceptable safety profile in 
patients with HER2-positive MBC.  Pertuzumab is approved in several countries for use 
in combination with trastuzumab and docetaxel for the treatment of patients with 
HER2-positive MBC who have not received prior anti-HER2 therapy or chemotherapy for 
metastatic disease. 
A summary of the pertuzumab safety profile is provided in Section 5.1.1.2.  Clinical trials 
of pertuzumab relevant to the design of the current trial are listed in the following 
subsections.  Please refer to the most recent version of the Pertuzumab Investigator’s 
Brochure for further information. 
1.2.2.1 
Pertuzumab Clinical Experience in MBC 
Phase III Study WO20698/TOC4129g (CLEOPATRA) was a randomized, multicenter, 
double-blind, placebo-controlled trial of 808 patients with HER2-positive MBC, in which 
patients were randomized 1:1 to receive either placebo plus trastuzumab and docetaxel 
or pertuzumab plus trastuzumab and docetaxel.   
The primary endpoint of this randomized trial was PFS as assessed by an IRF.  The 
randomized trial demonstrated a statistically significant improvement in IRF-assessed 
PFS in the pertuzumab-treated group compared with the placebo-treated group 
(HR = 0.62 [95% CI: 0.51, 0.75]; p < 0.0001) and an increase in median PFS of 
6.1 months (median PFS of 18.5 months in the pertuzumab-treated group vs. 
12.4 months in the placebo-treated group) (Baselga et al. 2012c).  The final analysis of 
OS took place when 389 deaths had occurred, after a median follow-up of 50 months.  
Despite crossover, OS benefit in favor of the pertuzumab-treated group was maintained 
(HR = 0.68; 95% CI: 0.56, 0.84; p = 0.0002).  The median OS was longer by 15.7 
months in the pertuzumab-treated group (median 56.5 months) compared to the 
placebo-treated group (median 40.7 months) (Swain et al. 2015). 
In this study, the addition of pertuzumab to trastuzumab did not increase the rates of 
symptomatic or asymptomatic cardiac dysfunction.  Adverse events (any grade) of 
diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin were reported 
more frequently in the pertuzumab group than in the control group.  The events were 


 
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mostly Grade 1 or 2 and occurred during the period of concomitant docetaxel 
administration.  Grade 3 or worse febrile neutropenia (13.8% vs. 7.6%) and diarrhea 
(7.9% vs. 5%) were increased in the pertuzumab group.  
1.2.2.2 
Pertuzumab Clinical Experience in Early Breast Cancer 
Pertuzumab in combination with trastuzumab and docetaxel has been generally well 
tolerated and has improved pCR rates in neoadjuvant therapy of EBC (Gianni et al. 2012, 
Schneeweiss et al. 2013). 
Neoadjuvant Study WO20697 (NEOSPHERE) evaluated patients with newly diagnosed 
HER2-positive breast cancer (n = 417) who were randomized to receive in the 
neoadjuvant setting the treatments specified in Table 2.  As seen in Table 2, the pCR 
rate (ypT0/is ypN0) improved with the addition of pertuzumab. 
Table 2 
Early Breast Cancer and pCR Rates in Study WO20697 
Treatment Arm A 
(trastuzumab and 
docetaxel) a 
Treatment Arm B 
(trastuzumab, 
docetaxel and 
pertuzumab) b 
Treatment Arm C 
(trastuzumab and 
pertuzumab, without 
chemotherapy) 
Treatment 
Arm D 
(pertuzumab 
and docetaxel)
pCR rates 
(ypT0/is ypN0) 
21.5% 
39.3% 
11.2% 
17.7% 
pCR = pathological complete response. 
a Reference treatment. 
b Primary comparison arm. 
 
The safety analysis for the neoadjuvant treatment period showed that the tolerability of 
pertuzumab in combination with trastuzumab and docetaxel was acceptable.  The most 
frequently occurring adverse events in the neoadjuvant period (in ≥ 25% of patients in 
any arm) were alopecia, neutropenia, diarrhea, nausea, fatigue, rash, and mucosal 
inflammation.  The majority of Grade ≥ 3 adverse events were blood and lymphatic 
system disorders SOC (neutropenia, leukopenia, and febrile neutropenia).  The rates of 
severe neutropenia for trastuzumab with docetaxel and for trastuzumab with docetaxel 
and pertuzumab were 57% and 44.9%, respectively, with corresponding rates of febrile 
neutropenia of 7.5% and 8.5%, respectively.  In the principal arms of the study (Arms A 
and B), there was no substantial difference in the occurrence of cardiac events during 
the neoadjuvant treatment period. 
Results from the post-treatment follow-up period (up to the third clinical cutoff of 
12 July 2013) showed that there were no clinically relevant, long-term toxicities. 
Five-year pre-planned analyses of pertuzumab in combination with trastuzumab and 
docetaxel compared with trastuzumab and docetaxel showed 81% and 82% PFS (similar 
to event-free survival) and 88% and 84% DFS rate, respectively.  These analyses 
showed that these results are consistent with breast pCR results and shows long-term 


 
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benefits of adding pertuzumab to trastuzumab and docetaxel as neoadjuvant therapy 
(Gianni et al. 2015). 
Neoadjuvant Study BO22280 (TRYPHAENA) evaluated cardiac safety and pCR rates 
when pertuzumab was administered concurrently or sequentially with 
anthracycline-based therapy (epirubicin, FEC regimen) or with a 
non−anthracycline-based regimen (TCH regimen) in a neoadjuvant setting 
(Schneeweiss et al. 2013).  A total of 225 patients were randomized to receive the 
treatments specified in Table 3.  The pCR rate (ypT0/is ypN0) is reported in Table 3. 
Table 3 
Cardiac Safety and pCR Rates in Study BO22280 
Treatment Arm Aa 
Treatment Arm Bb 
Treatment Arm Cc 
Cycles 1−3 
Cycles 4−6 
Cycles 1−3 
Cycles 4−6 
Cycles 1−6 
FECHP 
THP 
FEC 
THP 
TCHP 
pCR rates 
(ypT0/is ypN0) 
56.2% 
54.7% 
63.6% 
FEC = 5-fluorouracil, epirubicin, and cyclophosphamide; FECHP = 5-fluorouracil, epirubicin, 
cyclophosphamide, trastuzumab, and pertuzumab; H = trastuzumab; pCR = pathological complete 
response; P = pertuzumab; T = docetaxel; TCH = docetaxel, carboplatin, and trastuzumab. 
a Trastuzumab and pertuzumab given from Cycles 1 to 3 concurrently with FEC and given from 
Cycles 4 to 6 concurrently with docetaxel (FECHP × 3→THP × 3). 
b Trastuzumab and pertuzumab given from Cycles 4 to 6 concurrently with docetaxel following 
three cycles of FEC (FEC × 3→THP × 3). 
c TCH + pertuzumab (TCHP × 6). 
 
The safety analysis showed that the combination of pertuzumab with trastuzumab with 
standard anthracycline-based chemotherapy or non−anthracycline-based chemotherapy 
was generally well tolerated. 
The cardiac safety outcomes were similar across all three arms of the study in both the 
anthracycline-based regimens and the non−anthracycline-based regimen.  There was a 
low incidence of left ventricular dysfunction (Grades 1 to 4) in all arms of the study 
(Arm A, 5.6%; Arm B, 4%; Arm C, 2.6%) in the neoadjuvant treatment period. 
The most common adverse event in the neoadjuvant period was diarrhea (in 61% to 
72% of patients).  Other common adverse events (> 20% incidence in any arm) included 
alopecia, nausea, neutropenia, vomiting, fatigue, anemia, mucosal inflammation, 
constipation, dyspepsia, leukopenia, decreased appetite, and headache.  Grade ≥ 3 
events were predominately blood and lymphatic system disorders SOC. 
The following rates were seen across Arms A, B, and C in the neoadjuvant treatment 
period:  Grade ≥ 3 neutropenia, 47.2%, 42.7%, and 46.1%, respectively; and febrile 
neutropenia, 18.1%, 9.3%, and 17.1%, respectively. 


 
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Study BO25126 (APHINITY) is a Phase III, randomized trial designed to demonstrate 
the superiority of adjuvant pertuzumab + trastuzumab + standard chemotherapy treatment 
(anthracycline and non−anthracycline based regimens) compared with placebo and 
trastuzumab −containing regimens in early-stage HER2-positive breast cancer.  The 
primary endpoint is IDFS.  Secondary endpoints include DFS, OS, and safety. 
The main selection criteria include patients with newly diagnosed, HER2-positive primary 
invasive breast cancer who have undergone definitive surgery and are intended to 
receive adjuvant systemic chemotherapy (either node-positive or node-negative and 
tumor size > 1 cm or node-negative and tumor size 0.5−1.0 cm with at least one high-risk 
feature [histologic/nuclear Grade 3, both estrogen receptor (ER)− and progesterone 
receptor (PR)−negative, or age < 35 years]).  The investigator chooses either an 
anthracycline-based chemotherapy or a non−anthracycline-based chemotherapy 
according to local practice guidelines.  Eligible patients are randomized to receive 
chemotherapy plus trastuzumab and placebo or chemotherapy plus trastuzumab and 
pertuzumab.  As of 14 January 2015, unblinded safety and efficacy data were not 
available to the Sponsor, but the iDMC, which reviews data from the trial, had thus far 
recommended that the study continue as planned. 
1.2.3 
Pooled Safety Analysis of Trastuzumab Emtansine in 
Combination with Pertuzumab 
Pooled safety data are available for 87 patients treated with trastuzumab emtansine and 
pertuzumab (Studies TDM4373g/BO22495 [n = 67] and TDM4688g [n = 20]; including 
follow-up data for any patients continuing to receive treatment in the extension study 
[TDM4529g/BO25430]).  The most common adverse events of any grade (in ≥ 20% of 
patients) were fatigue (52.9%), nausea (42.5%), diarrhea (35.6%), cough (33.3%), 
decreased appetite (31%), thrombocytopenia (27.6%), constipation (26.4%), vomiting 
(27.6%), pyrexia (26.4%), increased AST (26.4%), chills (25.3%), epistaxis (25.3%), 
increased ALT (23%), headache (23%), dyspnea (23%), dysgeusia (20.7%), and rash 
(21.8%), with most of these events being Grade 1 or 2.  The most common Grade ≥ 3 
adverse events (occurring in > 2 patients [2.5%]) were fatigue (11.5%), 
thrombocytopenia (10.3%), increased AST (9.2%), dyspnea (9.2%), increased ALT 
(6.9%), anemia (5.7%), cellulitis (4.6%), peripheral sensory neuropathy (4.6%), pleural 
effusion (3.4%), and pneumonia (3.4%). 
Selected adverse events of relevance to trastuzumab emtansine for all patients include 
hepatotoxicity, peripheral neuropathy, thrombocytopenia, infusion reactions, cardiac 
dysfunction, and pneumonitis.  Table 4 provides an overview of these adverse events. 


 
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Table 4 
Overview of Selected Adverse Events with Trastuzumab 
Emtansine in Combination with Pertuzumab (n = 87) 
No (%) of Patients with AE of Special Interest 
Type of Event 
Any 
Grade > 3 
SAE 
AE Leading to 
Withdrawal 
Thrombocytopenia 
25 (28.7%) 
9 (10.3%) 
1 (1.1%) 
⎯ 
Hemorrhage 
35 (40.2%) 
5 (5.7%) 
5 (5.7%) 
4 (4.6%) 
Hepatotoxicitya 
28 (32.2%) 
13 (14.9%) 
2 (2.3%) 
3 (3.4%) 
Peripheral 
neuropathy 
29 (33.3%) 
5 (5.7%) 
⎯ 
1 (1.1%) 
Infusion reactions 
3 (3.4%) 
⎯ 
⎯ 
⎯ 
Cardiac dysfunctionb 
3 (3.4%) 
1 (1.1%) 
 ⎯  
1 (1.1%) 
ILD 
1 (1.1%) 
1 (1.1%) 
1 (1.1%) 
⎯ 
Trastuzumab emtansine plus pertuzumab pooled analyses: cut-off date of 30 September 2013 
AE = adverse event; CHF = congestive heart failure; ILD = interstitial lung disease; LVEF = left 
ventricular ejection fraction; NRH = nodular regenerative hyperplasia; SAE = serious adverse 
event. 
a Hepatotoxicity includes increases in serum AST or ALT, and NRH of the liver. 
b Cardiac dysfunction refers to left ventricular dysfunction including CHF and decreases in 
LVEF. 
 
Based on new safety data from Study TDM4788g/BO22589 (MARIANNE), the safety 
profile of trastuzumab emtansine in combination with pertuzumab is consistent with this 
pooled analysis, with no new safety signals identified. Overview of adverse events for 
Study TDM4788g/BO22589 (MARIANNE) for safety population is described below in 
Table 5. 


 
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Table 5 
Overview of Adverse Events (Safety Population) 
 
Trastuzumab + taxane
(N=353) 
T-DM1 + Placebo  
(N=361) 
T-DM1 + Pertuzumab 
(N=366) 
Any AE 
348 (98.6%) 
357 (98.9%) 
361 (98.6%) 
Any Grade ≥ 3 AE 
191 (54.1%) 
164 (45.4%) 
169 (46.2%) 
AE leading to discontinuation  
 
 
 
Taxane 
97 (27.5%) 
0 
0 
Trastuzumab 
19 ( 5.4%) 
1 ( 0.3%) 
0 
T-DM1 
0 
63 (17.5%) 
67 (18.3%) 
Pertuzumab/Placebo 
0 
32 ( 8.9%) 
40 (10.9%) 
Any treatment component 
105 (29.7%) 
66 (18.3%) 
70 (19.1%) 
Deaths 
123 (34.8%) 
114 (31.6%) 
116 (31.7%) 
Deaths due to PD 
116 (32.9%) 
106 (29.4%) 
106 (29.0%) 
Deaths due to AEs 
6 ( 1.7%) 
4 ( 1.1%) 
7 ( 1.9%) 
Deaths due to other causes  
1 ( 0.3%) 
4 ( 1.1%) 
3 ( 0.8%) 
SAEs 
80 (22.7%) 
77 (21.3%) 
85 (23.2%) 
Selected AEs 
 
 
 
Hepatotoxicity 
20 ( 5.7%) 
98 (27.1%) 
71 (19.4%) 
Pulmonary Toxicity 
7 ( 2.0%) 
8 ( 2.2%) 
11 ( 3.0%) 
Left Ventricular Dysfunction 
38 (10.8%) 
10 ( 2.8%) 
18 ( 4.9%) 
Pregnancy/Fetal Harm 
3 ( 0.8%) 
5 ( 1.4%) 
5 ( 1.4%) 
Peripheral Neuropathy 
211 (59.8%) 
132 (36.6%) 
151 (41.3%) 
Thrombocytopenia 
0 
50 (13.9%) 
53 (14.5%) 
IRR/Hypersensitivity (Type 1) 
54 (15.3%) 
105 (29.1%) 
153 (41.8%) 
IRR/Hypersensitivity Symptoms 
44 (12.5%) 
97 (26.9%) 
140 (38.3%) 
Hemorrhage 
76 (21.5%) 
142 (39.3%) 
167 (45.6%) 
Rash 
155 (43.9%) 
112 (31.0%) 
142 (38.8%) 
Diarrhea 
172 (48.7%) 
91 (25.2%) 
176 (48.1%) 
Neutropenia 
103 (29.2%) 
45 (12.5%) 
33 ( 9.0%) 
Mucositis 
122 (34.6%) 
89 (24.7%) 
108 (29.5%) 
Venous Thromboembolism 
10 ( 2.8%) 
5 ( 1.4%) 
4 ( 1.1%) 
Source:  Synopsis of Clinical Study Report 1056171 (Protocol TDM4788G/BO22589) 
 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
1.3.1 
Study Rationale 
Despite improved DFS and OS with trastuzumab-containing adjuvant systemic therapy, 
a significant number of patients remain at risk for relapse and death from their disease.  
Given the curative intent of adjuvant therapy, there is the potential to further improve 
outcomes, with manageable toxicity, using newer HER2-directed agents, particularly in 
higher-risk patient populations. 
The combination of two HER2-targeted therapies with complementary mechanisms of 
action, such as pertuzumab and trastuzumab, has been shown to further improve 
efficacy for HER2-positive breast cancer with a manageable safety profile in a first-line 
metastatic setting (Study WO20698/TOC4129g [CLEOPATRA]) and neoadjuvant setting 
(Study WO20697 [NEOSPHERE] and Study BO22280 [TRYPHAENA]) 
(see Section 1.2.2 for details).  Dual HER2-blockade therapy with trastuzumab and 
lapatinib has also improved pCR rates over the use of trastuzumab combined with 


 
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chemotherapy (Baselga et al. 2012a).  Therefore, it is anticipated that there will be a 
future change in the SoC for HER2-positive EBC to include pertuzumab on the basis of 
the results of Study BO25126 (APHINITY) (see Section 1.2.2.2 for details).  Please see 
Section 3.3.3 for further details on rationale of the selection of trastuzumab combined 
with pertuzumab as control arm.   
The highly potent chemotherapeutic agent DM1 should complement the HER2 signaling 
pathway inhibition caused by the combination of trastuzumab and pertuzumab.  
Furthermore, DM1 may provide higher dose intensity and longer duration when delivered 
as a HER2-targeted chemotherapy with potentially less systemic toxicity compared with 
conventional chemotherapy.  Therefore, trastuzumab emtansine may reduce the risk of 
recurrence and increase the likelihood of DFS in HER2-positive EBC, with an acceptable 
safety profile compared with the current or anticipated future SoC. 
The Phase III EMILIA study demonstrated improved efficacy (PFS and OS), with a 
favorable safety profile and QoL, with trastuzumab emtansine as a single agent 
compared with lapatinib plus capecitabine in patients with recurrent/metastatic 
HER2-positive breast cancer who have previously received taxanes and trastuzumab.  
Furthermore, this benefit was seen both in patients treated as first-line therapy for 
MBC who had progressed early as well as those who received therapy in second line and 
later (Section 1.2.1.1.1; Blackwell et al. 2012; Verma et al. 2012). 
The Phase III TH3RESA study also showed improved efficacy in PFS and a trend for 
OS benefit at the first interim analysis, with a favorable safety profile for single-agent 
trastuzumab emtansine compared with TPC in patients who received at least two prior 
regimens of HER2-directed therapies, including trastuzumab and lapatinib, in the 
metastatic or unresectable locally advanced/recurrent setting (Section 1.2.1.1.1; 
Krop et al. 2014). 
A randomized Phase II study, TDM4450g/BO21976 (Section 1.2.1.1.1), demonstrated 
improvements in PFS, safety, and QoL with trastuzumab emtansine compared with 
trastuzumab combined with docetaxel in the first-line recurrent/metastatic setting 
(Hurvitz et al. 2013).   
The Phase III MARIANNE study demonstrated that trastuzumab emtansine as single 
agent or in combination with pertuzumab were non-inferior to taxane + trastuzumab 
with respect to PFS as assessed by independent review, with numerical improvements 
in tolerability and QoL; however, neither of the trastuzumab emtansine-containing 
arms showed superiority over taxane plus trastuzumab (Section 1.2.1.1.2; 
Ellis et al. 2015). 
These results, taken in context with the totality of data from all the MBC studies 
described above, demonstrated the therapeutic potential of trastuzumab emtansine, as 
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compared with trastuzumab or lapatinib plus a concurrent systemic 
chemotherapy/taxane in the MBC setting.  
In Study TDM4874g/BO22857, trastuzumab emtansine following anthracycline-based 
chemotherapy showed acceptable safety as neoadjuvant and/or adjuvant treatment in 
HER2-positive early-stage breast cancer.  Furthermore, clinical activity in the 
neoadjuvant setting (pCR [ypT0/is, ypN0] rate of 56%) was also demonstrated 
(Section 1.2.1.2).   
In the WSG-ADAPT Study MO23078 (Section 1.2.1.2), a planned interim analysis 
demonstrated clinically meaningful pCR (ypT0/is, ypN0) rates ( > 40%) in 
HER2+/HR+ EBC patients treated with 4 cycles of neoadjuvant trastuzumab emtansine 
alone or with endocrine therapy, versus a pCR rate of 6.7% treated with 
trastuzumab + endocrine therapy.  These interim pCR results observed in the WGS-
ADAPT trial are among the highest reported for ER+, HER2+ EBC and are an 
improvement over the previously reported 22% total pCR rate observed with 4 cycles of 
docetaxel, trastuzumab, and pertuzumab in subset of patients with ER+ breast cancer 
treated in the WO20697 (NEOSPHERE) study (Gianni et al. 2012).  With the 
acknowledged caveats regarding cross trial comparisons, these promising pCR data 
from the TDM4874g/BO22857 and WSG-ADAPT studies indicate that trastuzumab 
emtansine is an active agent in HER2-positive EBC, regardless of hormonal receptor 
status, and further supported developing trastuzumab emtansine + pertuzumab as a 
treatment option for the EBC population.  
Synergy has been demonstrated in the nonclinical setting between trastuzumab 
emtansine and pertuzumab.  Studies with three HER2-positive mouse xenograft models 
in vivo consistently showed enhanced anti-tumor activity when trastuzumab emtansine 
was administered in combination with pertuzumab compared with trastuzumab 
emtansine administered as a single agent.  Furthermore, the combination of 
trastuzumab emtansine and pertuzumab has shown clinical activity and acceptable 
tolerability in patients with recurrent LABC/MBC in the Phase Ib/II Studies 
TDM4373g/BO22495 and TDM4688g (see details in Section 1.2.1.1.2 and Section 1.2.3).  
In MARIANNE, no clinically or statistically significant synergy between trastuzumab 
emtansine and pertuzumab was observed in the ITT population.  Uncertainties exist 
regarding the translation of results of MBC trials where equivalent or inferior outcomes 
are observed into results of adjuvant studies due to differences in tumor biology (e.g., 
less intratumor heterogeneity in EBC due to temporal variaions in cancer evolution, 
bulky disease in MBC vs. microscopic disease in the adjuvant setting, and the 
hypothesized potential pre-existing suppression of anti-cancer immunoresponse in the 
metastatic tumor microenvironment), study endpoints (imaging based PFS vs. IDFS), 
as well as the mechanism of action of trastuzumab emtansine and pertuzumab (e.g., 
potential MOA as immunotherapy) (Liakou et al. 2007; Stagg et al. 2011; 
Loi et al 2013; Apolo et al. 2014; Bianchini et al. 2014; Perez et al. 2015).  As an 


 
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example, the Phase III study comparing docetaxel, doxorubicin, and cyclophosphamide 
(TAC) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as the first-line 
chemotherapy for MBC patients demonstrated similar time to tumor progression 
(HR = 1.0380; p = 0.51) (Mackey et al. 2002).  However, it was reported in the 
BCIRG001 study that adjuvant TAC showed improved DFS rates compared to FAC 
(HR = 0.72, p = 0.0020) (Mackey et al. 2013).  Therefore, the lack of clinically 
meaningful synergy between trastuzumab emtansine and pertuzumab in the MBC 
setting may not be of full predictive value on whether there would be a potential 
synergy between trastuzumab emtansine and pertuzumab in the adjuvant setting.  
In the adjuvant setting, it may be of particular clinical importance to evaluate 
trastuzumab emtansine without concurrent taxane, which may utilize the full potential of 
this ADC in efficacy and safety improvement or demonstrating numerically equivalent 
efficacy with better tolerability or different safety profile in EBC and avoid 
compromised safety and dose intensity observed in Studies TDM4652g and BP22572 
(Section 1.2.1).  The combination of trastuzumab emtansine and pertuzumab without a 
taxane will therefore be compared with trastuzumab and pertuzumab plus taxane in this 
study.  The goal is to assess whether trastuzumab emtansine−based adjuvant regimens 
will improve the benefit-risk outcome of high-risk patients with HER2-positive EBC.  This 
study question remains clinically and scientifically important since MARIANNE 
results in the MBC setting may not fully predict the outcome of the combination of 
trastuzumab emtansine and pertuzumab in the adjuvant setting.  
Further rationales for the study design and study design changes can be found in 
Section 3.3. 
1.3.2 
Benefit-Risk Assessment 
Trastuzumab emtansine has shown a favorable benefit-risk profile in patients whose 
disease has progressed after prior HER2-directed therapies for MBC (Krop et al. 2014), 
Blackwell et al. 2012, Verma et al. 2012).  Trastuzumab emtansine also appears to have 
an acceptable or favorable benefit-risk profile in patients who have not received prior 
chemotherapy for metastatic disease, including patients who have previously received 
trastuzumab in the adjuvant setting (Hurvitz et al. 2013; Ellis et al. 2015).  Trastuzumab 
emtansine monotherapy has demonstrated a favorable or tolerable toxicity profile across 
studies conducted to date in patients with breast cancer, including a Phase II cardiac 
safety study of trastuzumab emtansine in patients with EBC (Study TDM4874g/BO22857, 
see Section 1.2.1.2) and the WSG-ADAPT Study, see Section 1.2.1.2).  Furthermore, 
Studies TDM4874g and WSG-ADAPT indicate that trastuzumab emtansine is an 
active agent in HER2-positive EBC, regardless of hormonal receptor status. 
In the curative treatment setting, certain acute adverse events and/or potential chronic 
accumulative organ effects (e.g., cardiac, hepatic, and pulmonary toxicities) may 
constitute a specific concern for trastuzumab emtansine.  With all available safety data, 
there does not appear to be an increased risk for cardiac adverse events with 


 
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trastuzumab emtansine compared with other HER2-directed therapies.  Increases in 
transaminases are observed with the administration of trastuzumab emtansine, but the 
potential for severe acute drug-induced liver injury (DILI) is not clear due to confounding 
factors in patients who experienced DILI (e.g., the use of concomitant medication that is 
known to induce DILI).  Cases of NRH of the liver have been identified from liver 
biopsies in patients treated with trastuzumab emtansine presenting with signs and 
symptoms of portal hypertension.  NRH is a rare liver condition characterized by 
widespread benign transformation of hepatic parenchyma into small regenerative 
nodules.  NRH may lead to the development of non-cirrhotic portal hypertension and 
potentially fatal hepatic failure.  Severe pulmonary events, including cases of interstitial 
lung disease (ILD) such as pneumonitis, some leading to acute respiratory distress 
syndrome or a fatal outcome, have been reported in clinical trials with trastuzumab 
emtansine.  Patients with dyspnea at rest due to complications of advanced malignancy 
and comorbidities may be at an increased risk of pulmonary events.  In patients with 
EBC in Study TDM4874g/BO22857, 148 patients had received trastuzumab emtansine 
and 112 patients (76%) had received at least 13 cycles of trastuzumab emtansine 
therapy.  No protocol- prespecified cardiac events or portal hypertension/NRH have 
been reported.  Radiation pneumonitis occurred in 3 patients (with 1 patient having a 
Grade 3 event). 
Although safety data to date involving trastuzumab emtansine in previously untreated 
patients in both the adjuvant (Dang et al. 2012) and the metastatic setting 
(Hurvitz et al. 2013; Ellis et al. 2015) appear acceptable, the long-term safety of 
trastuzumab emtansine in the EBC setting is not fully known.  A safety plan for this study, 
including appropriate eligibility criteria, dose modification guidelines, interim safety 
analyses for overall deaths and hepatic events defined as confirmed Hy’s law cases, and 
regular monitoring of accumulating patient safety data by an iDMC, has been put into 
place to minimize any potential risk in the trial patient population.  Furthermore, iDMC 
recommendations and available safety and efficacy data from Study MARIANNE 
(TDM4788g/BO22589; see Section 1.2.1.1.2) have been provided to the iDMC; and 
iDMC recommendations and available safety and efficacy data from Study BO25126 
(APHINITY; see Section 1.2.2.2) will be provided as applicable to the iDMC for 
consideration during the conduct of Study BO28407.   
The combination of trastuzumab emtansine and pertuzumab following systemic 
anthracyclines has the potential to further improve the efficacy outcome in high-risk 
patients with HER2-positive EBC.  The totality of data regarding trastuzumab 
emtansine and pertuzumab (see Sections 1.2.1, 1.2.2, and 1.3.1), support that the 
experimental arm (trastuzumab emtansine and pertuzumab following anthracyclines) 
in this study is highly likely to demonstrate a risk/benefit profile at least equivalent to 
the current anthracycline-trastuzumab based adjuvant SoC for patients with 
HER2-positive EBC.  Specifically, the efficacy in MARIANNE is at least equivalent to 
taxane and trastuzumabin the MBC setting with AE profile that may be more tolerable 


 
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than taxane and trastuzumab which is the current EBC adjuvant SoC. In addition the 
interim data from WGS-ADAPT demonstrated clinically meaningful pCR rates ( > 
40%) with single agent trastuzumab emtansine, which is better than or comparable to 
pCR rates achieved with trastuzumab containing regimens with concurrent systemic 
chemotherapy in the EBC setting. (Harback et al, 2015). 
Toxicities observed in studies with combination of trastuzumab emtansine and 
pertuzumab appear to be manageable, on the basis of final Phase II study results 
(TDM4373g/BO22495 and TDM4688g) and Phase III MARIANNE Study 
TDM4788g/BO22589.  On the basis of available data, the safety of trastuzumab 
emtansine when combined with pertuzumab appears consistent with the known toxicity 
profiles of each drug as a single agent (see Section 1.2.3).  MARIANNE data suggested 
that the combination of trastuzumab emtansine and pertuzumab may be more tolerable 
than trastuzumab + taxane, which may be of particular importance to the EBC 
population(see Sections 1.2.1, 1.2.2, and 1.3.1).  
Overall, considering the known tolerable safety profiles of these study drugs, the 
totality of efficacy data in the MBC and EBC settings, a potential better efficacy 
outcome of the combination of trastuzumab emtansine and pertuzumab in the adjuvant 
setting compared to the MBC setting due to the long treatment duration of additional 
HER2 targeted DM1 and biology differeneces between EBC and MBC (see Section 1.3.1 
for more details), and the known benefit-risk for the current 
anthracycline-trastuzumab−based adjuvant SOC, it is anticipated that the combination 
regimens in this study will have a manageable safety profile and has an acceptable 
benefit-risk assessment for the conduct of the study.  It is important and justified to 
evaluate the benefit-risk of trastuzumab emtansine plus pertuzumab following 
anthracyclines, compared with the anticipated new SOC 
(taxane + trastuzumab + pertuzumab following anthracyclines), in the adjuvant clinical 
trial setting. 
2. 
OBJECTIVES 
2.1 
EFFICACY OBJECTIVES 
The co-primary efficacy objectives for this study are as follows: 
• 
To compare IDFS (1) in the node-positive subpopulation and (2) in the overall 
protocol-defined population of patients with HER2-positive breast cancer 
randomized to receive either a taxane and 1 year of trastuzumab plus pertuzumab 
following anthracycline-based chemotherapy or 1 year of trastuzumab emtansine 
plus pertuzumab following anthracycline-based chemotherapy 
 
The secondary efficacy objectives for this study are as follows: 
• 
To compare IDFS plus second non-breast primary cancers, DFS, and distant 
recurrence−free interval (DRFI) (1) in the node-positive subpopulation and (2) in the 
overall protocol-defined population between the two treatment arms 


 
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• 
To compare OS (1) in the node-positive subpopulation and (2) in the overall 
protocol-defined population between the two treatment arms 
 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is as follows: 
• 
To compare overall safety, cardiac safety, hepatic, and pulmonary safety in the 
overall protocol-defined population between the two treatment arms 
 
2.3 
PATIENT-REPORTED OUTCOME OBJECTIVES 
PRO objectives in the overall protocol-defined population for this study are as follows: 
• 
To compare PROs of treatment-related symptoms, patient functioning, and 
health-related quality of life (HRQoL) to better understand treatment impact and 
tolerability, as measured by the European Organisation for Research and Treatment 
of Cancer (EORTC) Quality of Life Questionnaire−Core 30 (QLQ-C30) and the 
modified EORTC Breast Cancer module (Quality of Life Questionnaire−Breast 
Cancer 23 [QLQ-BR23]), between ‘Trastuzumab + Pertuzumab + Taxane following 
Anthracyclines’ and ‘Trastuzumab Emtansine + Pertuzumab following 
Anthracyclines’ treatment arms. 
 
2.4 
EXPLORATORY OBJECTIVES 
The exploratory biomarker objectives for this study are as follows: 
• 
To evaluate the impact of HER2 mRNA level on treatment benefit using the efficacy 
endpoints  
• 
To evaluate the impact of the PIK3CA mutation status on prognosis and treatment 
benefit using the efficacy endpoints 
• 
To assess correlations between candidate biomarkers or biomarker panels and 
efficacy and/or safety in the overall protocol-defined population 
• 
To identify whether changes in expression levels of biomarker or biomarker panels 
during treatment correlate with treatment efficacy in the overall protocol-defined 
population 
 
Efficacy endpoints considered for these objectives will include IDFS and OS, as 
appropriate. 
The exploratory anti-therapeutic antibodies (ATAs) objective in the trastuzumab 
emtansine−treated patient population for this study is as follows: 
• 
To assess the incidence of ATAs to trastuzumab emtansine and the effect of ATAs 
on safety and efficacy 
 
The health economic exploratory objective is as follows: 
• 
To assess health status as measured using the EuroQol 5-Dimension Questionnaire 
(EQ-5D) questionnaire for health economic modeling 
 


 
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3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
This is a prospective, two-arm, Phase III, randomized, multicenter, multinational, 
open-label study in patients with newly diagnosed HER2-positive primary invasive breast 
cancer who have had curative-intent surgery of their primary tumor and are candidates 
for adjuvant systemic chemotherapy following surgery.  HER2-positive status of the 
primary tumor will be confirmed by the central pathology laboratory prior to enrollment of 
the patient in the study.  Approximately 1850 patients are anticipated to be randomized 
to one of the two treatment arms listed below in a 1:1 ratio (see Section 4.2 for 
stratification factors).  
• 
Arm 1:  Anthracycline chemotherapy of choice (see Table 6) followed by trastuzumab 
at 6 mg/kg q3w (8-mg/kg loading dose) in combination with pertuzumab 420 mg q3w 
(840-mg loading dose) and paclitaxel (80 mg/m2) qw or docetaxel q3w (see Table 5 
for dose and duration).  After the taxane-concurrent phase, HER2-targeted therapy 
(i.e., trastuzumab at 6 mg/kg q3w in combination with pertuzumab 420 mg q3w) will 
continue for up to 1 year. 
• 
Arm 2:  Anthracycline chemotherapy of choice (see Table 6) followed by 
trastuzumab emtansine 3.6 mg/kg q3w in combination with pertuzumab 420 mg q3w 
(840-mg loading dose).  HER2-targeted therapy (i.e., trastuzumab emtansine at 
3.6 mg/kg q3w in combination with pertuzumab 420 mg q3w) will continue for up to 
1 year. 
 
The study schema is illustrated in Figure 1.  The investigator should select one of the 
protocol-approved adjuvant anthracycline-based chemotherapy regimens (FEC; 
epirubicin, cyclophosphamide [EC]; doxorubicin, cyclophosphamide [AC]; or dose-dense 
AC/EC) followed by either paclitaxel or docetaxel (choice of taxane applies only to Arm 1; 
Arm 2 is taxane free) as described in Table 6 for each patient prior to randomization.  
Choice of adjuvant chemotherapy must be recorded by the investigator on the electronic 
Case Report Form (eCRF), and this choice should be maintained throughout adjuvant 
chemotherapy whenever possible. 


 
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Figure 1 Study Schema 
 
ER = estrogen receptor; HER2 = human epidermal growth factor−2; PR = progesterone receptor; 
q3w = every 3 weeks. 
 


 
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Table 6 
Protocol-Approved Chemotherapy Regimens (Investigator's 
Choice)⎯Taxane is for Arm 1 Only 
Regimen 
Dose 
Frequency 
Anthracycline Therapy:  FECÆT 
F:  500−600 mg/m2 
E:  90−100 mg/m2 
C:  500−600 mg/m2 
q3w 
3 cycles or 4 cycles FEC 
Æ3 cycles or 4 cycles docetaxela 
Followed by: 
Docetaxela:  100 mg/m2 for 3 cycles OR 
75 mg/m2 for 4 cyclesa 
OR Docetaxel:  75 mg/m2 in Cycle 1, 
escalating to 100 mg/m2 in subsequent 
cycles, for a total of 3 cycles 
q3w 
F:  500−600 mg/m2 
E:  90−100 mg/m2 
C:  500−600 mg/m2 
q3w 
3 cycles or 4 cycles 
FECÆ12 weeks of paclitaxel 
Followed by paclitaxela:  80 mg/m2 
qw 
Anthracycline Therapy:  AC (or EC) Æ T 
A:  60 mg/m2 or E: 90−100 mg/m2 
C:  500−600 mg/m2 
q3w 
4 cycles of ACb (or ECb)Æ 
3 cycles or 4 cycles of docetaxel 
Followed by: 
Docetaxela:  100 mg /m2 for 3 cycles OR 
75 mg/m2 for 4 cyclesa 
OR Docetaxel:  75 mg/m2 in Cycle 1, 
escalating to 100 mg/m2 in subsequent 
cycles, for a minimum of 3 total docetaxel 
cycles 
q3w 
A:  60 mg/m2 or E:  90−100 mg/m2 
C:  500−600 mg/m2 
q3w 
4 cycles of ACb (or 
ECb)Æ12 weeks of paclitaxela 
Followed by paclitaxela 80 mg/m2 
qw 
A = doxorubicin; C = cyclophosphamide; E = epirubicin; ESMO = European Society for Medical 
Oncology; F = 5-fluorouracil; G-CSF = granulocyte colony-stimulating factor; NCCN = National 
Comprehensive Cancer Network; qw = weekly; q3w = every 3 weeks; T = taxane. 
a Choice of taxane applies only to the control arm (Arm 1).  If docetaxel 75 mg/m2 is used and 
not escalated to 100 mg/m2, then four cycles should be given.  Prophylactic use of G-CSF 
should be in accordance with NCCN, ESMO, or local guidelines. 
b AC or EC can be given every 2 weeks (dose dense) with G-CSF support for a total of 
four cycles. 
 
In Arm 1, HER2-targeted study therapy with trastuzumab plus pertuzumab must start 
concurrently with the taxane component of chemotherapy following anthracycline 
therapy.  In both arms, after anthracycline treatment, a minimum interval of 3 weeks from 
the last dose of anthracycline to initiation of HER2-targeted therapy is required.  Prior to 
commencing the HER2-targeted therapy, patients must have a left ventricular ejection 
fraction (LVEF) ≥ 50% and must not have experienced any clinical symptoms suggesting 


 
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heart failure or asymptomatic LVEF declines of 15 percentage points or more from 
baseline and below the lower limit of normal. 
Patients will receive up to 1 year of HER2-targeted therapy.  Study treatment will be 
discontinued in the event of invasive disease recurrence, unacceptable toxicity, 
withdrawal of consent, or study termination by the Sponsor.  
Adjuvant radiotherapy is to be given as clinically indicated at the end of chemotherapy 
(end of taxane in Arm 1; after four cycles of trastuzumab emtansine plus pertuzumab in 
Arm 2, to be consistent with Arm 1 in terms of timing of initiation) while receiving 
HER2-targeted therapy (Section 4.5.1.1 and Appendix 4).  For patients with ER-positive 
and/or PR-positive tumors, hormonal agents should be administered at the end of 
chemotherapy (end of taxane in Arm 1; after four cycles of trastuzumab emtansine plus 
pertuzumab in Arm 2, to be consistent with Arm 1 in timing of initiation) (Section 4.5.1.2).  
Each patient will be followed for disease status and survival according to the Schedule of 
Assessments for approximately 10 years after the first patient initiation (FPI) (i.e., first 
patient randomized).  Evaluations of efficacy and safety and a detailed Schedule of 
Assessments are provided in the study assessment section (Section 4.7) and in 
Appendix 1. 
3.1.1 
Data Monitoring Committee 
An iDMC will monitor accruing patient safety data at least once every 6 months during 
the study until the last patient has completed study treatment.  In addition, safety data 
reports related to concurrent radiotherapy and/or hormonal therapy, SAEs, and 
deaths will be monitored by the iDMC at least once every 3 months during the study.  At 
each iDMC review, relevant safety information from ongoing trastuzumab emtansine 
and/or pertuzumab studies will also be provided to the iDMC.  The iDMC will also 
assess safety and efficacy as part of the planned interim efficacy and safety analyses as 
pre-specified in the protocol. 
An independent Data Coordination Center (iDCC) will perform unblinded analyses to 
support the periodic iDMC review of safety data and the interim analysis.  Additional 
details will be provided in an iDMC Charter.  The iDMC members will review and sign off 
the charter before the first data review. 
3.1.2 
Clinical Events Committee 
An independent Clinical Events Committee (CEC) will adjudicate prespecified safety 
events of interest (cardiac and hepatic dysfunction events) in a blinded fashion.  A 
separate charter will outline committee composition, meeting timelines, and the roles 
and responsibilities of members.  The committee members will review all potential cases 
of CHF and cardiac death as well as all potential cases of hepatic dysfunction and Hy’s 
law.  Ad hoc members may be added to the CEC to review/adjudicate other safety 


 
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events if a new safety signal emerges.  Adjudicated cases by the CEC will be forwarded 
to the iDMC on a regular basis as part of ongoing safety reviews of the study. 
3.2 
END OF STUDY 
To enable long-term follow-up for survival and safety information, the study is planned to 
end approximately 10 years after the first patient is randomized. 
The Sponsor has the right to terminate this study, including long-term follow-up, at any 
time (e.g., if emerging safety signals indicate a potential health hazard to patients). 
3.3 
RATIONALE FOR STUDY DESIGN 
It is anticipated that there will be a future change in the SoC for HER2-positive EBC to 
include pertuzumab, on the basis of the results of Study BO25126 (APHINITY).  
Trastuzumab emtansine has the potential to increase cure rates in high-risk patients with 
EBC and also improve safety during the traditional taxane-concurrent phase when 
combined with pertuzumab following anthracycline-based chemotherapy.  The design of 
this study will allow the evaluation of a taxane-sparing approach with trastuzumab 
emtansine as part of an anthracyline-based pertuzumab-containing adjuvant regimen.  
The objective is to determine whether trastuzumab emtansine is a more effective 
treatment than trastuzumab plus taxane, as part of the adjuvant regimen described 
above, while sparing the taxane-associated toxicities.   
3.3.1 
Rationale for Test Product Dosage 
In a Phase I study (TDM3569g), the MTD of trastuzumab emtansine administered by IV 
infusion q3w was 3.6 mg/kg.  Clinical efficacy has been demonstrated at a dose of 
3.6 mg/kg q3w in studies of single-agent trastuzumab emtansine, with a favorable safety 
profile in both pretreated and previously untreated HER2-positive MBC.  In the adjuvant 
or neoadjuvant setting following anthracycline therapy, trastuzumab emtansine 
3.6 mg/kg q3w has been tolerated as a single agent (see details in Section 1.2.1.1.1). 
The dose of 3.6 mg/kg of trastuzumab emtansine has been combined with pertuzumab 
(loading dose of 840 mg with a subsequent dose of 420 mg) q3w in the Phase I/II 
Studies TDM4373g/BO22495 and TDM4688g and in the Phase III 
Study TDM4788g/BO22589 (MARIANNE).  Toxicities in these studies appear to be 
manageable/tolerable, on the basis of final study results (Studies TDM4373g/BO22495, 
TDM4688g, and TDM4788g/BO22589) (see details in Section 1.2.1.1). 
Please refer to the Trastuzumab Emtansine and Pertuzumab Investigator’s Brochures 
for further information. 
3.3.2 
Rationale for Patient Population 
Despite improved DFS and OS with trastuzumab-containing adjuvant systemic therapy, 
there remains a substantial risk for recurrence and breast cancer−related death in 
HER2-positive EBC, especially in the higher-risk subpopulation.  Factors such as lymph 


 
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node status, hormone receptor status, and tumor size can be used to define a subgroup 
of patients at substantial risk of recurrence who may require more effective therapies.  
This study is designed to enroll patients with a sufficiently high risk of disease recurrence 
in order to achieve a clinically meaningful improvement in absolute treatment effect with 
a positive benefit-risk profile.  This study will enroll a population of patients with newly 
diagnosed HER2-positive EBC who are node-positive or node-negative AND 
ER/PR-negative AND have a tumor size > 2 cm. 
This study population is a higher-risk subset of the patient population selected in 
ongoing Study BO25126 (APHINITY; see Section 1.2.2.2) as well as in adjuvant 
trastuzumab trials (e.g., BCIRG 006).  Study BO25126 (APHINITY) includes a broader 
group of node-negative patients with lower overall risk (i.e., tumor size > 1 cm regardless 
of hormonal receptor status or tumor size of 0.5 cm to 1.0 cm with at least one high-risk 
feature [histologic/nuclear Grade 3, negative for ER and PR, or age < 35 years]), 
compared with the node-negative subpopulation selected for this study (ER/PR-negative 
AND tumor size > 2 cm).  The node-negative subpopulation proposed for this study 
would have an estimated 3-year IDFS rate of 91.8% with AC-TH treatment on the basis 
of the results of the BCIRG 006 study, which is similar to that for node-positive patients 
with 1−3 nodes (91.1%, unpublished data).  Therefore, the risk of recurrence at 3 years 
and the benefit-risk considerations for the node-negative subset are expected to be 
similar to those for the node-positive subset (with one to three nodes).   
Assuming that Study BO25126 (APHINITY) is positive and that the target HR of that 
study (0.75) is observed, the proposed overall population (node positive plus protocol 
defined node negative) in this study is estimated to have a 3-year IDFS rate of 89.5% in 
the control arm with the added effect from pertuzumab.  Therefore, even with presumed 
additional treatment effect of pertuzumab, the recurrence rate in the overall population 
proposed for Study BO28407 is estimated to remain approximately 10% at 3 years, with 
a continued risk of recurrence and breast cancer−related death with longer follow-up 
(e.g., estimated 5-year IDFS rate of 82.2%). 
3.3.2.1 
Rationale for Capping Subgroup Enrollment  
Capping was planned to be implemented to ensure that an appropriately high-risk 
patient population is enrolled.  The proportions of subgroups enrolled in the BCIRG 006 
study that form the basis for assumptions on IDFS rates in the proposed study will be 
utilized to guide capping.  Hence, the proportion of node-positive patients with one to 
three nodes will be capped at 50% of the study population, and the proportion of 
node-negative patients will be capped at 10% of the study population.  Given the small 
size of the node-negative subset in the BCIRG 006 study, there may be considerable 
variability in the 3- and 5-year IDFS rate estimates for this subgroup, and the 3−year 
IDFS rate may not be an ideal late recurrence risk indicator for lower-risk population(s).  
Therefore, these two subsets were planned to be capped independently. 


 
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The capping as of Protocol Version 2 will not be implemented since the study 
enrollment is stopped earlier than planned.  Therefore, the planned proportion of node-
positive patients with one to three nodes and/or node-negative patients may not be 
achieved as described above. 
3.3.2.2 
Rationale for Powering for Node-Positive Subgroup 
Given the relatively broad range of recurrence rates in the target population among 
subpopulations with four or more nodes, one to three nodes, and node-negative disease, 
descriptive analyses are planned to assess overall benefit versus risk within each of the 
subgroups.  Furthermore, the node-positive subgroup is sufficiently powered to support a 
co-primary efficacy objective to assess IDFS in both the overall protocol-defined 
population and the node-positive subpopulation. 
3.3.2.3 
Rationale for Sample Size Reduction 
The MARIANNE study results (see Section 1.2.1.1.1) have further informed the 
assumptions that drove the original study design (i.e., trastuzumab emtansine improves 
both PFS and safety and a synergy between trastuzumab emtansine and pertuzumab 
will be demonstrated clinically in the first-line MBC setting).  Therefore, the likelihood 
of this study meeting its primary efficacy endpoint for superiority has decreased.  A 
sample size reduction is warranted to mitigate the risk of this study not meeting its 
primary efficacy endpoint.  However, due to the uncertainty of translating MBC results 
to the adjuvant setting (see details in Section 1.3.1), the study question of whether the 
regimen of trastuzumab emtansine in combination with pertuzumab following 
anthracyclines may be superior to the regimen of trastuzumab in combination with a 
taxane and pertuzumab following anthracyclines in the adjuvant setting remains 
unanswered and is of clinical/scientific importance.  With a sample size reduction from 
2500 to approximately 1850 patients, the study objectives can still be adequately 
addressed with the original statistical power and validity with the prolonged analyses 
timing (see Table 19 in Section 6.1).  
3.3.3 
Rationale for Control Group 
The ongoing Phase III Study BO25126 (APHINITY; see Section 1.2.2.2) has been 
designed to demonstrate the superiority of adjuvant pertuzumab + trastuzumab 
+ standard chemotherapy (anthracycline and non−anthracycline-based regimens) 
compared with standard trastuzumab-containing regimens in HER2-positive EBC.  
Assuming Study BO25126 (APHINITY) is positive, it is expected that adjuvant 
pertuzumab + trastuzumab + standard chemotherapy will become the new SoC for the 
adjuvant treatment of HER2-positive EBC before the results from this study become 
available.  On the basis of this rationale and the observed safety and efficacy profiles in 
neoadjuvant Studies WO20697 (NEOSPHERE) and BO22280 (TRYPHAENA; 
Section 1.2.2.2), anthracycline-based chemotherapy followed by 
trastuzumab + pertuzumab + taxane has been selected as the comparator. 


 
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3.3.4 
Rationale for Adjuvant Regimens and Duration of Therapy 
Several studies demonstrated that adding complementary and dual HER2-targeted 
agents, such as pertuzumab and trastuzumab, further improves outcomes in patients 
with HER2-positive MBC or EBC with an acceptable safety profile (see Section 1.2).  
The efficacy and safety profiles of pertuzumab in combination with trastuzumab and 
chemotherapy shown in the neoadjuvant Study WO20697 (NEOSPHERE) and 
Study BO22280 (TRYPHAENA) indicate that treatment with 
pertuzumab + trastuzumab + standard chemotherapy (including anthracycline- and 
taxane-based regimens) is the likely direction of further significant efficacy improvements 
in EBC. 
Proof of concept has been established in the randomized MBC Studies 
TDM4450g/BO21976, TDM4370g/BO21977 (EMILIA), and TDM4997g/BO25734 
(TH3RESA) that trastuzumab emtansine as a single agent can improve efficacy and 
safety compared with a combination of a HER2-directed agent and traditional 
chemotherapy.  The TDM4788g/BO22589 (MARIANNE) study supports trastuzumab 
emtansine+ pertuzumab as a non-inferior regimen to trastuzumab + taxane, with a more 
tolerable safety profile in the first-line MBC setting.  In addition, the pCR rates 
observed in the single-arm Study TDM4874g/BO22857 and WGS-ADAPT Study 
MO23078 suggest robust clinical activity of trastuzumab emtansine in EBC.  
Furthermore, a meta-analysis (EBCTCG 2013) of long-term outcome among 
100,000 patients with EBC in 123 randomized trials has shown that in trials adding four 
cycles of taxane to a fixed anthracycline-based control regimen, extending treatment 
duration, mortality due to breast cancer was reduced (RR = 0.86, SE = 0.04, two-sided 
significance p = 0.0005).  However, in trials with four such extra cycles of taxane, 
counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling 
non-taxane dosage, there was no significant difference (RR = 0.94, SE = 0.06, two-sided 
significance p = 0.33).  On the basis of this analysis, the totality of data for trastuzumab 
emtansine and/or pertuzumab in the MBC and EBC setting, and the uncertainties 
regarding the translation of results of trastuzumab emtansine plus pertuzumab in the 
MARIANNE study into results of this combination in this adjuvant study, it is 
anticipated that 1 year of trastuzumab emtansine + pertuzumab, with the HER2-targeted 
chemotherapeutic agent DM1 (i.e., with higher dose intensity and longer duration than 
four cycles of concurrent taxane) will provide risk reduction that is the same as or better 
than that provided by the four cycles of concurrent taxane and 14 cycles of 
trastuzumab + pertuzumab in the control arm.  Therefore, this study will evaluate 
whether trastuzumab emtansine without concurrent taxane as a replacement for 
trastuzumab plus taxane, in combination with pertuzumab following anthracyclines, can 
provide an improved benefit-risk ratio in high-risk patients with HER2-positive EBC.  
Systemic anthracyclines will mitigate potential efficacy risk due to intratumor 
heterogeneity.  The cardiac safety of both pertuzumab and trastuzumab emtansine 
following anthracycline-based regimens appears acceptable to date on the basis of data 


 
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from Study BO22280 (TRYPHAENA; see Section 1.2.2.2) and 
Study TDM4874g/BO22857 EBC safety study; (see Section 1.2.1.1.1 ).   
On the basis of the rationale provided above, anthracycline-based chemotherapy 
(Section 3.3.4.1) followed by trastuzumab emtansine + pertuzumab has been selected as 
the trastuzumab emtansine−based adjuvant regimen in this study. 
The 1-year duration of HER2-directed therapy is based on current standard guidelines 
as well as data from both the PHARE and HERA trials, in which neither shorter nor 
longer durations of HER2-directed therapy were demonstrated to have an advantage 
(Goldhirsch et al. 2013, Pivot et al. 2013).   
3.3.4.1 
Rationale for Selection of Anthracycline Regimens 
Doxorubicin at 60 mg/m2 and epirubicin at approximately 100 mg/m2 are considered to 
be equally efficacious with overlapping but different safety profiles 
(Kaklamani and Gradishar 2003; Glück 2005; Khasraw and Bell 2012; 
Khasraw et al. 2012).  Regimens such as FEC, EC, AC, or dose-dense AC/EC with G-
CSF support are included to allow for differences in local practice.  Epirubicin at doses 
between 90 and 100 mg/m2 is also included to allow for differences in local SoC.  These 
anthracycline-based regimens are included in practice guidelines such as those of the 
National Comprehensive Cancer Network (NCCN) and the St. Gallen Early Breast 
Cancer Guidelines. 
3.3.4.2 
Rationale for Selection of Taxane Dose and Schedule 
The use of paclitaxel in combination with trastuzumab is supported by a number of 
studies in the adjuvant and neoadjuvant settings (Buzdar et al. 2005, 
Romond et al. 2005, Paluch-Shimon et al. 2008).  Both Studies NCCTG N9831 and 
NSABP B31 utilized q3w or qw paclitaxel in combination with trastuzumab.  Following 
anthracycline-based chemotherapy, paclitaxel 80 mg/m2 qw is better tolerated and more 
active than paclitaxel 175 mg/m2 q3w (Sparano et al. 2008).  Weekly paclitaxel 
(12 doses) following anthracycline therapy is a preferred regimen for the adjuvant 
treatment of EBC, according to the NCCN Guidelines (NCCN 2012).   
It is recognized that docetaxel at a dose of 100 mg/m2 in combination with trastuzumab 
has been associated with a positive benefit-risk ratio in patients with 
HER2-overexpressing MBC when compared with docetaxel alone (100 mg/m2 q3w; 
Marty et al. 2005).  The clinical utility of docetaxel 100 mg/m2 in combination with 
trastuzumab, used in sequence with an anthracycline and cyclophosphamide, has been 
previously demonstrated in the BCIRG 006 EBC study (Slamon et al. 2011).  The risks 
and benefits associated with a variety of single-agent docetaxel doses (60−100 mg/m2 
q3w) have been established in randomized studies in breast cancer (Harvey et al. 2006, 
Bono et al. 2009).  To allow for differences in local SoC, alternative docetaxel dose and 
duration are permitted in this study.  Four cycles of docetaxel at 75 mg/m2 following 
anthracycline-based chemotherapy is an acceptable adjuvant treatment option that 


 
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confers superior efficacy over a non-taxane regimen (Nitz et al. 2008) and is recognized 
by the NCCN guidelines (NCCN 2012).  Alternatively, the dose of docetaxel may be 
started at 75 mg/m2 in the first cycle and escalated to 100 mg/m2 in subsequent cycles 
according to individual tolerability; a minimum of three cycles will be given for this dosing 
regimen. 
3.3.5 
Rationale for Patient-Reported Outcome Assessments 
EBC is often asymptomatic, especially after tumor removal; therefore, it is important to 
assess treatment impact and tolerability in order to inform the benefit-risk ratio for a 
patient on adjuvant therapy. 
PRO measures will contextualize a patient’s experience on trial, elucidating symptom 
and treatment burden between ‘Trastuzumab + Pertuzumab + Taxane following 
Anthracyclines’ and ‘Trastuzumab Emtansine + Pertuzumab following Anthracyclines’ 
treatment arms.  Because treatment-related side effects (e.g., peripheral neuropathy, 
joint/muscle pain, and skin problems) have the potential to affect patient functioning and 
HRQoL, it is crucial to characterize not only the incidence of these side effects but also 
the associated trends and burden from the patient’s perspective, which would contribute 
to a more comprehensive understanding of treatment impact and tolerability.  The 
EORTC QLQ-C30 and QLQ-BR23 demonstrate strong psychometric properties, of both 
reliability and validity, and meet the requirements for this study.  The QLQ-BR23 will be 
modified to include validated items on peripheral neuropathy (1 item), joint/muscle pain 
(1 item), and skin problems (2 items) in order to characterize these symptoms of special 
interest (Appendix 8). 
3.3.6 
Rationale for Biomarker Assessments  
This study includes mandatory collection of tumor tissue and plasma samples.  Apart 
from HER2 expression, there are no known additional predictors of response to 
trastuzumab, pertuzumab, or trastuzumab emtansine, nor are there accurate predictors 
of resistance to these therapies.  Tumor tissue will be collected to centrally assess HER2 
status and hormonal receptor status and to assess potential predictive and prognostic 
candidate markers.  Additional biomarker assessments potentially related to the 
mechanism of action of trastuzumab emtansine, pertuzumab, or trastuzumab; HER 
signaling; or breast cancer biology may be performed.  For example, expression of other 
receptors of the HER family (e.g., HER1/EGFR or HER3), which may affect HER2, could 
be explored.  HER2 signaling is known to be modulated by expression levels of other 
HER family members and their ligands, the expression of which may correlate with 
response or resistance to HER2-targeted therapies (Wiseman et al. 2005, 
Robinson et al. 2006).  Additionally, alterations in the HER2 intracellular signaling 
pathway (e.g., activating mutations in PI3K) and its regulation (e.g., loss of negative 
regulation by phosphatase and tensin homolog [PTEN]) may also affect responsiveness 
of tumors to HER2-directed therapies (Berns et al. 2007, Mellinghoff et al. 2007). 


 
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Level of HER2 mRNA expression in tumor tissue has been explored in prior clinical trials 
with trastuzumab emtansine, pertuzumab, and trastuzumab.  The WO20698 
(CLEOPATRA) MBC trial showed that increased levels of HER2 mRNA (above median 
cutoff) were associated with longer PFS outcome in both treatment arms 
(Baselga et al. 2012b).  The TDM4370g (EMILIA) MBC trial, similar to previous Phase II 
and single-agent trastuzumab emtansine MBC studies, showed that the degree of HER2 
mRNA expression correlated with ORR and/or PFS outcome (LoRusso 2011, 
Perez 2012, Baselga et al. 2013).  In the TDM4370g (EMILIA) trial, this correlation was 
present in both treatment arms for PFS but apparent only in the trastuzumab 
emtansine−treated patients when correlated to OS.  HER2 mRNA expression level may 
be predictive for trastuzumab emtansine benefit in the adjuvant setting and will be 
explored in this study.  
Additionally, activating PIK3CA mutations have been evaluated as a resistance marker 
for HER2-targeted therapies in prior trials.  In metastatic HER2-positive breast cancer 
(the CLEOPATRA study), worse outcome was observed in patients with PIK3CA 
mutations than in those without (Baselga et al. 2012b).  Lower pCR rates were observed 
in the neoadjuvant setting in HER2-positive breast cancer with PIK3CA mutations 
(Schneeweis et al. 2012, Baselga et al. 2012a).  The role of PIK3CA mutations in the 
adjuvant setting in HER2-positive breast cancer is, however, unknown.  Data from the 
BCIRG 006 trial suggest that PIK3CA mutations are associated with worse DFS when 
treatment arms were pooled (Gardner et al. 2009).  This study will explore the prognostic 
value of PIK3CA mutations and the potential predictive value for predicting efficacy with 
trastuzumab emtansine. 
Identification of possible markers of benefit or resistance to therapy could have 
significant future clinical impact upon patient treatment decisions.  Additional candidate 
markers of response to treatments that emerge from other clinical or nonclinical studies 
may also be assessed in this study. 
The study also requires mandatory plasma/serum samples for biomarker research, 
which may include, among other analyses, the assessment of circulating tumor DNA.  
There is increasing evidence that circulating DNA can be obtained from the blood 
specimens of patients with cancer, which represents the DNA and mutational status of 
tumor cells (Diehl et al. 2008, Maheswaran et al. 2008, Punnoose et al. 2012, 
Rosell et al. 2012, Dawson et al. 2013, Murtaza et al. 2013).  Another example of 
markers that could be assessed in serum or plasma are circulating ligands of HER family 
members.  The serial sampling gives the opportunity to evaluate changes in circulating 
biomarker levels over time that may allow further understanding of potential resistance 
mechanisms or of (early) indicators of recurrence.  
Additional candidate markers of response to treatments that emerge from other clinical 
or nonclinical studies may also be assessed in this study and can be assessed with 
different types of technologies. 


 
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In addition, a mandatory whole-blood sample for clinical genotyping will be collected.  
Both safety and efficacy questions will be explored with the clinical genotyping analyses.  
The following are examples describing potential questions that could be explored by 
clinical genotyping. 
For example, reversible thrombocytopenia has been observed in completed and ongoing 
studies with trastuzumab emtansine in a subset of patients.  It is hypothesized that this 
effect may be related to an interaction between trastuzumab emtansine and proteins 
expressed in megakaryocytes and/or platelets:  Fcγ receptor (FcγRIIa).  FcγRIIa is the 
only FcγR expressed in platelets, and it has been shown to bind to and internalize IgG 
(Cassel et al. 1993, Anderson et al. 1995, Worth et al. 2006).  The H131R polymorphism 
in FcγRIIa has been associated with differential affinity for binding of IgG Fc and, in 
some cases, with heparin-induced thrombocytopenia (Bachelot-Loza et al. 1998, 
Chen et al. 2003). 
One possible hypothesis to explain the observation of trastuzumab emtansine−induced 
thrombocytopenia in some but not all patients is a differential ability of megakaryocytes 
and/or platelets to bind to and internalize the drug conjugate.  In relationship to efficacy, 
it has been hypothesized that the mechanism of action of antibody therapeutics, such as 
rituximab and trastuzumab, could include Fc-mediated attraction of immune effector cells 
known as antibody-dependent cell-mediated cytotoxicity (ADCC).  The affinity of IgG to 
the Fcγ receptors is influenced by the FcγRIIa and FcγRIIIa polymorphisms and may 
cause a difference in the efficacy of trastuzumab, trastuzumab emtansine, or 
pertuzumab or the efficacy of the combination of trastuzumab emtansine and 
pertuzumab, as a result of different FcγR-mediated ADCC (Shields et al. 2001). 
P-glycoprotein (P-gp), which is encoded in the ABCB1 (also known as MDR1) gene, is 
known to act as an energy-dependent drug efflux pump for various chemotherapeutic 
drugs, such as anthracyclines, vinca alkaloids, and taxanes (Gottesman et al. 2002).  
Previous studies showed that ABCB1 3435CC genotype carriers had significantly higher 
P-gp expression in the duodenum and in breast cancer tissue (Taheri et al. 2010), which 
may result in a decreased drug concentration in cells.  Additional data support the theory 
that ABCB1 polymorphisms may predict PFS after first-line trastuzumab and taxane 
therapy in patients with HER2-positive MBC (Kim et al. 2012).  Polymorphisms in this 
gene and their correlation to efficacy in this trial may also be explored. 
Examples of other safety markers may also include polymorphisms in the human 
leukocytic antigen or genes involved in trastuzumab emtansine metabolism to evaluate 
their correlation to hepatotoxicity (Andrade et al. 2009, Xu et al. 2010).  


 
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3.4 
OUTCOME MEASURES  
3.4.1 
Efficacy Outcome Measures 
3.4.1.1 
Primary Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are listed below. 
• 
IDFS, defined as the time from randomization until the date of the first occurrence of 
one of the following events:  
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer 
involving the same breast parenchyma as the original primary lesion) 
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive 
breast cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the 
ipsilateral breast) 
Contralateral or ipsilateral second primary invasive breast cancer 
Distant recurrence (i.e., evidence of breast cancer in any anatomic site [other 
than the three sites mentioned above]) that has either been histologically 
confirmed or clinically/radiographically diagnosed as recurrent invasive breast 
cancer 
Death attributable to any cause, including breast cancer, non-breast cancer, or 
unknown cause   
 
3.4.1.2 
Secondary Efficacy Outcome Measures 
The secondary efficacy outcome measures for this study are as follows: 
• 
IDFS plus second primary non-breast cancer, excluding non-melanoma skin 
cancers and carcinoma in situ (CIS) of any site 
• 
DFS, defined as the time between randomization and the date of the first 
occurrence of any of the IDFS events described above, second primary non-breast 
cancer event (excluding non-melanoma skin cancers and CIS of any non-breast 
site), and contralateral or ipsilateral ductal carcinoma in situ (DCIS) 
• 
DRFI, defined as the time between randomization and the first occurrence of distant 
breast cancer recurrence 
• 
OS, defined as the time from randomization to death due to any cause 
 
3.4.2 
Safety Outcome Measures 
Clinical and laboratory adverse events will be reported according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.  LVEF 
will be assessed using either echocardiogram (ECHO) or multiple-gated acquisition 
(MUGA) scans. 
The safety outcome measures for this study are as follows: 
• 
Incidence, type, and severity of all adverse events based on NCI CTCAE v4.0 
• 
Incidence, type, and severity of SAEs 
• 
Incidence, type and severity of ≥ Grade 3 adverse events 


 
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• 
Incidence and type of adverse events leading to dose discontinuation, modification, 
or delay 
• 
Cause of death 
• 
Abnormal laboratory values 
• 
Decrease in LVEF from baseline over time 
• 
Cardiac safety outcome measures 
Primary cardiac endpoints:  cardiac events defined as death from cardiac cause 
or severe CHF (NYHA Class III or IV) with a decrease in LVEF of 
≥ 10 percentage points from baseline to an LVEF of < 50% 
Secondary cardiac endpoints:  other cardiac-related events (e.g., any mild 
symptomatic CHF [NYHA Class II] associated with a ≥ 10% drop in LVEF 
to < 50%; asymptomatic declines in LVEF requiring dose delay or 
discontinuation) 
• 
Hepatic safety outcome measures 
Death from hepatic cause 
Severe DILI (Hy’s law cases) 
NRH 
• 
Pulmonary safety outcome measures 
Death from pulmonary cause 
Pneumonitis and ILD 
 
3.4.3 
Patient-Reported Outcome Measures 
The PRO measures for this study are as follows: 
• 
HRQoL, including bothersome side effects of therapy (e.g., peripheral neuropathy, 
joint/muscle pain, or skin problems), and patient functioning as measured using the 
EORTC QLQ-C30 and the modified breast cancer module QLQ-BR23 (Appendix 8) 
• 
Time from first HER2-targeted treatment, ± a taxane, to clinically meaningful 
deterioration in the global health status/QoL and functional (physical, role, and 
cognitive) subscales of the QLQ-C30.  The event of worsening of global health 
status/QoL for a given patient is defined as a decrease in baseline mean score by 
10 points or more at two consecutive timepoints.  A 10-point or greater change 
in mean score is defined as being a “moderate” to “very much” and perceived an 
important change from the patient’s perspective (Osoba et al. 1998).  Deterioration 
in function will be assessed using the published corresponding MIDs by Cocks et al. 
(2011). 
 


 
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3.4.4 
Exploratory Biomarker Outcome Measures 
The exploratory biomarker outcome measures for this study are the relationship between 
molecular markers and efficacy and/or safety outcomes.  Efficacy outcomes considered 
for this analysis will include IDFS and OS, as appropriate. 
Correlations between biomarker status and efficacy and/or safety will include but not be 
limited to the following: 
• 
Level of HER2 mRNA expression assessed by quantitative real-time polymerase 
chain reaction (qRT-PCR) with efficacy outcome 
• 
Status of PIK3CA mutations assessed by PIK3CA allele−specific polymerase chain 
reaction assay with efficacy outcome 
• 
Level of HER2 gene amplification assessed by in situ hybridization (ISH) with 
efficacy outcome 
• 
Level of HER2 protein expression assessed by immunohistochemistry (IHC) with 
efficacy outcome 
• 
Level of HER3 mRNA expression assessed by qRT-PCR with efficacy outcome 
• 
Changes in expression levels of biomarker or biomarker panels over time with 
efficacy outcome  
 
3.4.5 
Exploratory Anti-Therapeutic Antibody Outcome Measures 
The ATA outcome measures to be assessed in patients receiving trastuzumab 
emtansine are the following: 
• 
Incidence of ATAs to trastuzumab emtansine 
• 
Effect of ATAs on safety and efficacy 
 
3.4.6 
Exploratory Health Economic Outcome Measures 
The EQ-5D will be used to obtain health status information for health economic modeling 
(Appendix 9). 
The EQ-5D is a generic, preference-based health utility measure with questions about 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that are used 
to build a composite of the patient’s health status.  A single summary index from the 
EQ-5D health states will be utilized in this study for economic modeling, and the results 
will not be reported in the Clinical Study Report (CSR). 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
The target population for this study will be patients with newly diagnosed primary 
invasive breast cancer that is HER2 positive (as determined by the central pathology 
laboratory) and who will be treated with adjuvant systemic chemotherapy following 
definitive surgery.  Approximately 1850 patients are anticipated to be enrolled at 
approximately 350 sites worldwide. 


 
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4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Age ≥ 18 years 
• 
Eastern Cooperative Oncology Group Performance Status ≤ 1 
• 
Non-metastatic histologically confirmed primary invasive breast carcinoma that was 
operable 
• 
HER2-positive breast cancer prospectively determined on the primary tumor by a 
central pathology laboratory and defined as follows: 
IHC score (see Appendix 6) of 3+ and/or positive by ISH (see Appendix 7), as 
defined by ISH ratio of ≥ 2.0 for the number of HER2 gene copies to the number 
of chromosome 17 copies.  Both IHC and ISH assays will be performed; 
however, only one positive result is required for eligibility. 
Availability of formalin-fixed paraffin-embedded (FFPE) tissue block or partial 
block (for minimum dimensions, see laboratory manual) with a representative 
invasive part of the tumor for central pathology laboratory confirmation of 
HER2 eligibility, hormonal receptor status, and additional biomarker analysis is 
required. 
• 
Known hormone receptor status of the primary tumor determined by a central 
pathology laboratory 
Hormone receptor-positive status can be determined by either known positive 
ER or known positive PR status.  Hormone receptor−negative status must be 
determined by both known negative ER and known negative PR.  
• 
Adequately excised:  Patients must have undergone either breast-conserving 
surgery or mastectomy/nipple- or skin-sparing mastectomy.   
For patients who undergo breast-conserving surgery, the margins of the 
resected specimen must be histologically free of invasive tumor and DCIS as 
determined by the local pathologist.  If pathologic examination demonstrates 
tumor at the line of resection, additional operative procedures may be 
performed to obtain clear margins.  If tumor is still present at the resected 
margin after re-excision(s), the patient must undergo total mastectomy to be 
eligible.  Patients with margins positive for lobular carcinoma in situ (LCIS) are 
eligible without additional resection. 
For patients who undergo mastectomy/nipple- or skin-sparing mastectomy, 
margins must be free of gross residual tumor.  It is recommended that patients 
should have a negative microscopic margin in accordance with local pathology 
protocol.  Patients with a microscopic positive deep margin are eligible (see RT 
requirements in Appendix 4). 
• 
Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 7th edition):  Patients 
must have had sentinel lymph node biopsy (SLNB) and/or axillary lymph node 
dissection for evaluation of pathologic nodal status (minimum requirements for 
patients undergoing SLNB are provided in Section 4.4.1).  Pathological classification 


 
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of regional lymph node micrometastases (tumor deposits > 0.2 mm and ≤ 2 mm) is 
considered to be pN1, and isolated tumor cells are considered to be pN0.  
Eligible patients must have one of the following: 
Node-positive disease (pN ≥ 1), any tumor size except T0, and any hormonal 
receptor status 
Enrollment of patients with 1−3 nodes was planned to be limited to no more 
than 50% of the total number of randomized patients.  However, no formal 
capping of enrollment will be implemented (see Section 3.3.2.1 for details). 
There is no prespecified limit for the enrollment of patients with ≥ 4 nodes. 
Node-negative disease (pN0) with pathologic tumor size > 2.0 cm by standard 
local assessment AND negative for ER and PR as determined by a central 
pathology laboratory 
Enrollment of patients with node-negative disease was planned to be 
limited to no more than 10% of the total number of randomized patients.  
However, no formal capping of enrollment will be implemented (see 
Section 3.3.2.1 for details). 
• 
Patients with synchronous bilateral invasive disease are eligible only if both lesions 
are HER2 positive. 
• 
No more than 9 weeks (63 days) may elapse between definitive breast surgery (or 
the last surgery if additional resection required for breast cancer) and randomization.   
• 
Baseline LVEF ≥ 55% measured by ECHO (preferred) or MUGA scans 
• 
Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is 
required.  This includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B 
core antibody (HBcAb) in addition to HCV antibody testing.  The most recent 
serologic testing must have occurred within 3 months prior to randomization.  If such 
testing has not been done, it must be performed during screening.  
Patients who have positive HBV or HCV serologies without known active 
disease must meet the eligibility criteria for ALT, AST, total bilirubin (TBILI), INR, 
activated partial thromboplastine time (aPTT), and alkaline phosphatase (ALP) 
on at least two consecutive occasions, separated by at least 1 week, within the 
30-day screening period.  The second of these evaluations must be performed 
within 3 days prior to the first administration of study drug.  Note:  positive 
serology markers that indicate immunity will not be considered as clinically 
meaningful positive serology to trigger these tests.  
• 
Female patients of childbearing potential must be willing to use one highly effective 
form of nonhormonal contraception or two effective forms of nonhormonal 
contraception.  For male patients with partners of childbearing potential, one highly 
effective form of contraception or two effective forms of contraception must be used 
(see Appendix 10 for descriptions of highly effective and effective contraception).  
Contraception must continue for the duration of study treatment and for 7 months 
after the last dose of study treatment.  


 
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The above contraception is not a requirement in the case of any of the following: 
The patient or partner of the patient is surgically sterilized. 
The female patient is > 45 years of age and is postmenopausal (has not 
menstruated for at least 12 consecutive months; for additional details, see 
Section 4.5.1.2 on definition of postmenopausal status). 
The patient truly abstains from sexual activity and when this is the 
preferred option to avoid conception and contraception and/or usual 
lifestyle of the patient. 
• 
Male patients whose partners are pregnant must use condoms or truly refrain from 
sexual activity for the duration of the pregnancy 
• 
Willing and able to comply with the requirements of the protocol 
• 
Signed informed consent 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma 
• 
History of non-breast malignancies within the 5 years prior to randomization, 
except for the following: 
CIS of the cervix 
CIS of the colon 
Melanoma in situ 
Basal cell and squamous cell carcinomas of the skin 
• 
Any clinical T4 tumor as defined by tumor-node-metastasis classification in 
UICC/AJCC, 7th edition, including inflammatory breast cancer 
• 
For the currently diagnosed breast cancer, any previous systemic anti-cancer 
treatment (e.g., neoadjuvant or adjuvant), including but not limited to chemotherapy, 
anti-HER2 therapy (e.g., trastuzumab, trastuzumab emtansine, pertuzumab, 
lapatinib, neratinib, or other tyrosine kinase inhibitors), hormonal therapy, OR 
anti-cancer RT (intraoperative radiotherapy as a boost at the time of primary surgery 
is acceptable) 
• 
Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any 
malignancy 
• 
History of DCIS and/or LCIS that was treated with any form of systemic 
chemotherapy, hormonal therapy, or RT to the ipsilateral breast where invasive 
cancer subsequently developed.  Patients who had their DCIS/LCIS treated with 
only surgery and/or contralateral DCIS treated with radiation are allowed to enter the 
study. 
• 
Patients with contraindication to RT while adjuvant RT is clinically indicated 
• 
Concurrent anti-cancer treatment in another investigational trial 


 
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• 
Cardiopulmonary dysfunction as defined by any of the following prior to 
randomization: 
History of NCI CTCAE Version 4.0 Grade ≥ 3 symptomatic CHF or NYHA 
criteria Class ≥ II  
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia 
not controlled by adequate medication, severe conduction abnormality, or 
clinically significant valvular disease 
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate 
> 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], 
or higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 
[Mobitz 2] or third degree AV-block]) 
Significant symptoms (Grade ≥ 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia  
Myocardial infarction within 12 months prior to randomization 
Uncontrolled hypertension (systolic blood pressure > 180 mmHg and/or diastolic 
blood pressure > 100 mmHg) 
Evidence of transmural infarction on ECG 
Requirement for oxygen therapy 
• 
Other concurrent serious diseases that may interfere with planned treatment, 
including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled 
diabetes, or known infection with HIV 
• 
Any known active liver disease, including but not limited to disease due to HBV, 
HCV, autoimmune hepatic disorders, or sclerosing cholangitis.  For patients who are 
known carriers of HBV/HCV, active hepatitis B/C infection must be ruled out on the 
basis of negative serologic testing and/or determination of HBV DNA/HCV RNA 
viral load per local guidelines. 
• 
Any of the following abnormal laboratory tests prior to randomization: 
Serum TBILI > 1.0 times the upper limit of normal (ULN).  In cases of known 
Gilbert’s syndrome, direct bilirubin should be within the normal range. 
ALT and/or AST > ULN 
ALP > 1.5 × ULN 
Serum creatinine > 1.5 × ULN 
Total WBC < 2500/µL (< 2.5 × 109/L) 
ANC < 1500/µL (< 1.5 × 109/L) 
Platelets < 100,000/µL (< 100 × 109/L) 
INR or aPTT > 1.5 × ULN 
• 
Pregnant or lactating women or women of childbearing potential without a negative 
serum pregnancy test result, within 7 days prior to randomization, regardless of the 
method of contraception used 


 
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• 
Hypersensitivity to any of the study medications or any of the ingredients or 
excipients of these medications, including hypersensitivity to benzyl alcohol 
• 
Chronic immunosuppressive therapies, including systemic corticosteroids 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT  
After written informed consent has been obtained and eligibility has been established 
and approved, the study site will obtain the patient randomization number and treatment 
assignment from the interactive voice response system/interactive web response system 
(IVRS/IWRS).  Patients should receive their first dose of study treatment the day of 
randomization, if possible, but no later than 7 days after randomization.  Patients will be 
randomized in a 1:1 ratio by a permuted block randomization scheme to one of the 
two treatment arms through use of the IVRS/IWRS. 
Randomization will be stratified by the following stratification factors: 
• 
World region (United States/Canada, Western Europe/Australia/New Zealand, 
Asia, or rest of the world) 
• 
Nodal status (0, 1−3, or ≥ 4 positive nodes) 
• 
Centrally assessed hormonal receptor status (ER- and/or PR-positive or both 
ER- and PR-negative) 
• 
Type of anthracycline (doxorubicin or epirubicin)  
 
4.3 
STUDY TREATMENT  
Study treatment is defined as non-hormonal systemic adjuvant (post-operative) 
treatment.  Trastuzumab emtansine, pertuzumab, and trastuzumab are considered 
investigational medicinal products (IMPs) in this study.  Paclitaxel and docetaxel are also 
considered IMPs in this study; however, paclitaxel and docetaxel may be considered 
non-IMPs on the basis of local legislation.  
Doxorubicin, epirubicin, cyclophosphamide, and 5-fluorouracil are considered non-IMPs 
in this study.  Depending on local legislation, doxorubicin, epirubicin, cyclophosphamide, 
and 5-fluorouracil may be considered IMPs.  If considered an IMP, then appropriate 
information on formulation, packaging, handling, and administration will be provided.   
Concomitant therapy and premedication (Section 4.5) are defined as non-IMPs. 
The choice of which adjuvant chemotherapy regimen (see Table 6 in Section 3.1) is 
given will be determined by the investigator prior to randomization.  Randomization will 
determine whether a patient receives adjuvant therapy with trastuzumab plus 
pertuzumab plus taxane OR trastuzumab emtansine plus pertuzumab.  


 
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4.3.1 
Formulation, Packaging, and Handling 
4.3.1.1 
Trastuzumab Emtansine 
The formulation, packaging, and handling should be performed according to the current 
Trastuzumab Emtansine Investigator’s Brochure.  For further details, see the Study 
Pharmacy Binder and/or local prescribing information for Kadcyla®. 
4.3.1.2 
Pertuzumab 
The formulation, packaging, and handling should be performed according to the current 
Pertuzumab Investigator’s Brochure.  For further details, see the Study Pharmacy Binder 
and/or local prescribing information for Perjeta®. 
4.3.1.3 
Trastuzumab for Intravenous Administration 
For information on the formulation, packaging, and handling of trastuzumab, see the 
most recent version of the Trastuzumab Investigator's Brochure as well as local 
prescribing information. 
4.3.1.4 
Doxorubicin, Epirubicin, Cyclophosphamide, 5-Fluorouracil, 
Paclitaxel, and Docetaxel 
Please refer to local prescribing information for details on drug formulation, packaging, 
and handling. 
4.3.2 
Dosage, Administration, and Compliance 
SoC chemotherapy backbone treatments should include three to four cycles of an 
anthracycline-based regimen.  In Arm 1, three to four cycles or 12 weeks of taxane will 
also be administered.  Administration of HER2-targeted therapy will be up to 1 year (up 
to 18 cycles).  Adjuvant study treatment will be discontinued in the event of invasive 
disease recurrence, unacceptable toxicity, withdrawal of consent, or study termination by 
the Sponsor.  Patients diagnosed with in situ breast cancer or a second primary cancer 
not requiring systemic therapy and with no evidence of invasive breast cancer 
recurrence should continue with adjuvant study treatment, if considered by the 
investigator to be in the patient’s best interest, whenever possible. 
4.3.2.1 
Anthracycline Treatment Phase 
Either FEC (see Table 7) or AC/EC (see Table 8) regimens as described in following 
subsections may be selected at the discretion of the investigator in this study.  Please 
refer to local prescribing information/institutional guidelines for detailed guidelines on 
administration, premedications, dose delays/reductions for toxicities, contraindications, 
requirements for duration of contraception, and concomitant medications. 


 
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Table 7 
5-Fluorouracil, Epirubicin, and Cyclophosphamide (FEC) 
Drug 
Dose  
Dosing Interval 
Planned 
Duration 
5-Fluorouracil (F) 
500−600 mg/m2 IV bolus or 
infusion, according to local policy; 
dose should be capped at 1200 mg 
for BSA > 2 m2 
Day 1 of q3w cycle 
3−4 cycles
Epirubicin (E) 
90−100 mg/m2 IV infusion over 
15−30 minutes or infuse according 
to local policy 
Day 1 of q3w cycle 
3−4 cycles
Cyclophosphamide (C) 500−600 mg/m2 IV infusion over 
30 minutes or infuse according to 
local policy 
Day 1 of q3w cycle 
3−4 cycles
BSA = body surface area; IV = intravenous; q3w = every 3 weeks. 
 
Table 8 
Doxorubicin OR Epirubicin, and Cyclophosphamide (AC/EC) 
Drug 
Dose 
Dosing Interval 
Planned 
Duration 
Doxorubicin (A) 
60 mg/m2 IV over 15−30 minutes or 
infuse according to local policy 
Day 1 of q3w cycle or 
q2w cycle (dose 
dense) 
4 cycles 
Epirubicin (E) 
90−100 mg/m2 IV infusion over 
15−30 minutes or infuse according 
to local policy 
Day 1 of q3w cycle or 
q2w cycle (dose 
dense) 
4 cycles 
Cyclophosphamide (C) 500−600 mg/m2 IV infusion over 
30 minutes or infuse according to 
local policy 
Day 1 of q3w cycle or 
q2w cycle (dose 
dense) 
4 cycles 
IV = intravenous; q2w = every 2 weeks; q3w = every 3 weeks. 
 
The dose-dense (every 2 weeks [q2w]) AC/EC regimen may be administered with 
G-CSF support (e.g., pegfilgrastim 6 mg subcutaneously on Day 2 of q2w cycle).   
Anti-emetic regimens may be used as premedication at the physician’s discretion. 
4.3.2.2 
Concurrent Taxane Phase and/or HER2 Targeted Only Phase 
Concurrent taxane phase applies only to treatment Arm 1 (control arm).  Trastuzumab 
plus pertuzumab must start concurrently with the taxane component of chemotherapy 
following anthracycline therapy in the control arm.  After anthracycline treatment, a 
minimum interval of 3 weeks from the last dose of anthracycline to initiation of 
HER2-targeted therapy is required.  Prior to commencing the HER2-targeted component 
of therapy, patients must have an LVEF ≥ 50% and must not have experienced any 
clinical symptoms suggesting heart failure or asymptomatic LVEF declines by an 
absolute point of > 15% from baseline and below the lower limit of normal.  


 
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HER2-targeted treatment will continue for up to a total duration of 1 year and will be 
discontinued in the event of invasive disease recurrence, unacceptable toxicity, 
withdrawal of consent, or study termination by the Sponsor. 
A ± 3-day window is allowed for q3w dosing, and a + 3-day window is allowed for qw 
dosing.  This time window does not apply when dose delay is indicated due to toxicities. 
4.3.2.2.1 
Trastuzumab plus Pertuzumab plus Taxane Treatment (Arm 1) 
During the taxane-concurrent phase, either docetaxel q3w (at 100 mg/m2 for three cycles; 
at 75 mg/m2 for four cycles; or start at 75 mg/m2 in the first cycle and escalate to 
100 mg/m2 if no DLT occurs, for a total of three cycles at minimum) or 12 weeks of 
paclitaxel 80 mg/m2 qw will be administered concurrently with trastuzumab in 
combination with pertuzumab.  Please refer to local prescribing information/institutional 
guidelines for detailed guidelines on docetaxel or paclitaxel administration, 
premedications, dose delays/reductions for toxicities, contraindications, requirements 
for duration of contraception, and concomitant medications. 
After the concurrent phase, only administration of only trastuzumab plus pertuzumab will 
continue, for up to a total duration of 1 year (up to 18 cycles).  
Trastuzumab will be given at a loading dose of 8 mg/kg and pertuzumab at 840 mg.  For 
subsequent cycles, trastuzumab will be given as a maintenance dose of 6 mg/kg and 
pertuzumab at 420 mg q3w.  The dose of trastuzumab does not need to be recalculated 
unless the body weight has changed by ±10% or greater from baseline.  Dose must be 
readjusted for ± 10% or greater weight change based on the previous weight used for 
dose recalculation.  The Investigator may choose to re-calculate dose at every cycle 
using actual weight at that time according to their local practice.  If the patient misses 
a dose of trastuzumab for any cycle (i.e., the two sequential administration times are 6 
weeks or more apart), a re-loading dose of 8 mg/kg of trastuzumab should be given.  If 
the patient misses a dose of pertuzumab for any cycle and the time between doses is 6 
weeks or more, a re-loading dose of pertuzumab (840 mg) should be given.  Re-loading 
of doses for trastuzumab per local prescribing information may be followed.  Patients 
who experience trastuzumab or pertuzumab infusion−related symptoms may be pre-
medicated with paracetamol and anti-histamines for subsequent infusions.   
The sequence of administration for this treatment arm should follow that outlined in 
Table 9 (sequence from top to bottom). 


 
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Table 9 
Treatment Regimen for Arm 1 
Drug 
Infusion Perioda 
Observation 
Period 
Planned 
Duration 
First dose 
60 minutes  
60 minutes 
Pertuzumab 
Subsequent doses
30−60 minutes 
according to tolerability
30 minutes if 
well tolerated 
Up to 18 cycles 
First dose 
90 minutes (first dose)
Trastuzumabb 
Subsequent doses
30−90 minutes 
according to tolerability
See national 
prescribing 
information 
Up to 18 cycles 
Docetaxel 
60 minutes 
4 cycles 
Taxane 
OR Paclitaxel 
30−60 minutes 
See national 
prescribing 
information 
12 weeks 
a At the investigator’s discretion, infusion period may be longer than described here, for patient 
safety. 
b Trastuzumab infusion to start only after observation period for pertuzumab is completed. 
 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.3 and Section 5.1.4. 
4.3.2.2.2 
Trastuzumab Emtansine plus Pertuzumab Treatment (Arm 2) 
Taxane will not be administered in patients in treatment Arm 2.  Trastuzumab emtansine 
plus pertuzumab will continue for up to a total duration of 1 year (up to 18 cycles).  
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by IV infusion in 
combination with pertuzumab at an initial loading dose of 840 mg IV followed by a 
maintenance dose of 420 mg IV q3w.  The dose of trastuzumab emtansine does not 
need to be recalculated unless the body weight has changed by ± 10% or greater from 
baseline.  Dose must be readjusted for ± 10% or greater weight change based on 
the previous weight used for dose recalculation.  The Investigator may choose to re-
calculate dose at every cycle using actual weight at that time according to local practice.  
If the patient misses a dose of pertuzumab for any cycle and the time between doses is 
6 weeks or more, a re-loading dose of pertuzumab (840 mg) should be given.  Patients 
who experience pertuzumab infusion−related symptoms may be pre-medicated with 
paracetamol and anti-histamines for subsequent infusions.   
The sequence of administration for this treatment arm should follow that outlined in 
Table 10 (sequence from top to bottom). 


 
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Table 10 Treatment Regimen for Arm 2 
Drug 
Infusion Period 
Observation 
Period 
Planned 
Duration 
First dose 
60 minutes  
60 minutes 
Pertuzumab 
Subsequent doses 
30−60 minutes 
according to tolerability
30 minutes if well 
tolerated 
Up to 18 cycles
First dose 
90 minutes 
90 minutes 
Trastuzumab 
emtansinea 
Subsequent doses 
30−90 minutes 
according to tolerability
30 minutes if well 
tolerated 
Up to 18 cycles
a Trastuzumab emtansine infusion to start only after observation period for pertuzumab is 
completed. 
 
Guidelines for dosage modification and treatment interruption or discontinuation are 
provided in Section 5.1.3 and Section 5.1.4. 
4.3.3 
Investigational Medicinal Product Accountability 
All IMPs required for completion of this study (trastuzumab emtansine, pertuzumab, 
trastuzumab, docetaxel, and paclitaxel) will be provided by the Sponsor, with the 
exception of trastuzumab, docetaxel, and paclitaxel, which may be sourced locally in 
some countries.  The investigational site will acknowledge receipt of IMPs, using the 
IVRS/IWRS to confirm the shipment condition and content.  Any damaged shipments will 
be replaced.  
IMPs will be either disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed upon by the 
Sponsor.  The site must obtain written authorization from the Sponsor before any IMP is 
destroyed, and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log or a similar document at the 
site. 
4.3.4 
Post-Trial Access to Trastuzumab Emtansine and Pertuzumab 
The Sponsor does not intend to provide trastuzumab emtansine, pertuzumab, or other 
study interventions to patients after conclusion of the study or any earlier patient 
withdrawal.   
4.4 
PRIOR THERAPY 
Prior anti-cancer therapy for this study population includes primary surgery.  Date and 
extent of primary surgery should be collected in the eCRF.  


 
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4.4.1 
Minimum Requirements for Patients Undergoing Sentinel 
Lymph Node Biopsy 
Patients with positive SLNB must undergo axillary dissection unless all of the following 
characteristics apply (Giuliano et al. 2011):   
• 
No palpable nodes 
• 
No more than two positive lymph nodes  
• 
Breast-conserving surgery  
• 
Tangential whole breast irradiation 
• 
Clinical tumor size ≤ T2 (5 cm) 
 
In the event that all of the above are applicable, it is not mandatory to have the axillary 
dissection, but it is left to the discretion of the investigator as per site standard practice. 
4.5 
CONCOMITANT THERAPY 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal/homeopathic remedies, or nutritional supplements) used by a patient from 
7 days prior to randomization to the end-of-treatment visit.   
All concomitant medications should be reported to the investigator and recorded on the 
Concomitant Medications eCRF.  All concomitant medications are to be reported until 
the end-of-treatment visit.  In addition, adjuvant hormonal therapy will be reported in the 
eCRF until hormonal therapy completion or study completion. 
4.5.1 
Permitted Therapy  
Permitted therapy includes adjuvant radiotherapy and adjuvant hormonal therapy or any 
medication that the investigator deems necessary for the supportive management of the 
patient. 
The following treatments are permitted throughout the duration of the study treatment 
phase and during follow-up:  
• 
Standard therapies for preexisting medical conditions unless listed as prohibited 
therapy in Section 4.5.2.  Any medication intended solely for supportive care 
(e.g., analgesics, anti-diarrheals, and anti-depressants) may be used at the 
investigator’s discretion.  Patients on anti-coagulant treatment should have their 
platelet count monitored closely during treatment with trastuzumab emtansine.   
• 
Hematopoietic growth factors (e.g., G-CSF) may be used at the investigator’s 
discretion for the primary prophylaxis and/or management of treatment-emergent 
neutropenia and/or for secondary prophylaxis as per NCCN/European Society for 
Medical Oncology guidelines (Crawford et al. 2010, 2013) or local standard practice. 
• 
Bisphosphonate or denosumab therapy (to be used in accordance with the 
approved labeled indication and/or nationally recognized treatment guidelines) 
 


 
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4.5.1.1 
Adjuvant Radiotherapy 
Before actively enrolling patients, each center must define a radiotherapy policy for 
treating patients in the trial.  Guidelines are given in Appendix 4. 
Radiotherapy is to be given at the end of systemic chemotherapy (end of taxane in 
Arm 1; after four cycles of trastuzumab emtansine plus pertuzumab in Arm 2, to be 
consistent with Arm 1 in timing of initiation) while HER2-targeted therapy is being 
administered. 
Any locoregional RT (extent or volume and total dose) must be reported in the eCRF. 
4.5.1.2 
Concomitant Hormonal Therapy 
Concomitant hormonal therapy should be administered after systemic chemotherapy 
(end of taxane in Arm 1; after four cycles of  trastuzumab emtansine plus pertuzumab in 
Arm 2, to be consistent with Arm 1 in timing of initiation) according to the following 
recommendations. 
Female patients must be classified according to one of the following menopausal status 
definitions on the basis of their prechemotherapy status: 
• 
Premenopausal 
< 12 months since last menstrual period AND no prior bilateral ovariectomy AND not 
receiving estrogen replacement OR biochemical evidence of premenopausal status, 
according to local guidelines 
• 
Postmenopausal 
> 12 months since last menstrual period with no prior hysterectomy OR prior 
bilateral ovariectomy OR biochemical evidence of postmenopausal status, 
according to local guidelines 
 
Female hormonal receptor−positive patients should be treated according to local 
guidelines.  A minimum of 5 years of hormonal therapy should be planned.   
Endocrine therapy in male patients is to be given according to local guidelines (see 
Table 11). 


 
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Table 11 Recommendations for Hormonal Therapy 
Clinical Scenario 
Hormonal Therapy 
Hormone receptor negativea 
Not recommendeda 
Hormone receptor positivea 
(premenopausalb) 
Tamoxifen for 5−10 years with or without ovarian suppression as 
per local policy 
Hormone receptor positivea 
(postmenopausalb) 
Any one of the following: 
Aromatase inhibitor for 5 years 
Aromatase inhibitor for 2−3 years, followed by tamoxifen to 
complete a total of 5−10 years 
Tamoxifen for 2−3 years, followed by aromatase inhibitor to 
complete a total of 5 years 
Tamoxifen for 5−10 years 
Tamoxifen for 5 years, followed by aromatase inhibitor for 5 years
ER = estrogen receptor; PR = progesterone receptor. 
a Hormone receptor negative is defined as negative for both ER and PR, and hormone 
receptor positive is defined as positive for either ER or PR, on the basis of the preoperative 
or postoperative tumor pathology per central laboratory analysis.  The investigator may 
decide on the treatment policy according to local laboratory receptor status if receptor 
status is centrally “negative” and locally “positive.” 
b Patients who are initially premenopausal may become postmenopausal over the course of 
the study, in which case hormonal therapy can be adjusted according to local policy. 
 
4.5.2 
Prohibited Therapy 
Explicitly prohibited therapies prior to disease recurrence include anti-cancer therapies 
other than protocol-approved therapies administered in this study. 
• 
Anti-cancer therapies other than those administered in this study, including cytotoxic 
chemotherapy, radiotherapy (except for adjuvant radiotherapy for breast cancer 
after completion of chemotherapy), immunotherapy, and biological or targeted 
(e.g., lapatinib or neratinib) anti-cancer therapy 
• 
Any systemically active oral, injected, or implanted hormonal method of 
contraception except for previously implanted progesterone-coated intrauterine 
devices 
• 
Estrogen-replacement therapy 
• 
Chronic immunosuppressive therapies, including systemic corticosteroids 
• 
Any investigational agent, except those used in this study  
 
Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole and itraconazole) with 
trastuzumab emtansine should be avoided.  An alternate medication with no or minimal 
potential to inhibit CYP3A4/5 should be considered.  If a strong CYP3A4/5 inhibitor is 
co-administered with trastuzumab emtansine, patients should be closely monitored for 
adverse reactions. 


 
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Excessive alcohol intake should be avoided.  Occasional to moderate alcohol use is 
permitted. 
4.6 
TREATMENTS DURING FOLLOW-UP 
After the end-of-treatment visit, only medications and therapies applicable for long-term 
reporting must be reported, including the following: 
• 
Breast cancer treatments (e.g., hormone therapy) 
• 
Anti-cancer treatments for recurrence(s) 
• 
Bisphosphonate or denosumab therapy  
• 
Medications related to the treatment of SAEs that are applicable for long-term 
reporting 
 
All systemic therapies (including but not limited to drug name and duration of treatment 
for breast cancer for the first recurrence and all subsequent recurrences/disease 
progression), including chemotherapy, biologic therapy (antibody and small molecule 
therapies), hormonal therapy (including ovarian ablation and drug-induced ovarian 
suppression), or surgery/radiation will be collected during study follow-up.  
4.7 
STUDY ASSESSMENTS  
Patients will be assessed for safety, efficacy, biomarker, and QoL during the study.  All 
patients will be closely monitored for safety and tolerability during study treatment.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable.  In this study, 
one cycle is defined as 3 weeks (21 ± 3 days) unless otherwise stated (e.g., for AC/EC 
dose-dense regimens).  Study treatment will be administered in 21-day/3-week cycles if 
no additional time is required for reversal of toxicity. 
If the timing of a protocol-mandated procedure coincides with a holiday and/or weekend 
that precludes performance of the procedure within the allotted window, the procedure 
should be performed on the nearest following date.  Study assessments are outlined in 
this section and in Appendix 1 and Appendix 2. 
4.7.1 
Description of Study Assessments 
4.7.1.1 
Medical History and Demographic Data 
Medical history includes past or current clinically significant conditions, surgeries, breast 
cancer surgery and diagnosis, non-breast cancer history, reproductive status, and all 
medications (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, and nutritional supplements) used by the patient within 7 days prior to 
randomization. 
Demographic data will include age, sex, and self-reported race/ethnicity and may include 
local HER2 and hormonal receptor test information. 


 
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4.7.1.2 
Physical Examinations 
A complete physical examination, including height and weight, should include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, GI, genitourinary, and neurologic systems.  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations focusing on organ systems related to adverse events or disease should be 
performed.  Weight is to be measured on Day 1 of the specified cycles and compared 
with baseline.  If ± 10% or greater variation occurs, then study treatment doses will be 
recalculated.  Dose must be readjusted for ± 10% or greater weight change based on 
the previous weight used for dose recalculation.  The investigator may choose to 
re-calculate dose at every cycle using actual weight at that time according to local 
practice.  For anthracyclines and taxanes, local standards for dose calculations will be 
followed. 
Changes from baseline abnormalities should be recorded in patient notes.  New or 
worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF. 
Physical examination, including breast examination and evaluation of local-regional 
lymphatics, if applicable, should be conducted as part of disease status assessments 
per Section 4.7.1.5.1. 
4.7.1.3 
Vital Signs 
Vital signs will include measurements of pulse rate, and systolic and diastolic blood 
pressures while the patient is in a seated position, as well as temperature. 
4.7.1.4 
Radiographic Assessments 
Bone scan, chest X-rays/diagnostic computed tomography (CT), magnetic resonance 
imaging (MRI), liver imaging, 18-fluoro-deoxyglucose positron emission tomography 
(PET) scans, and/or other radiographic modalities may be performed as clinically 
indicated according to NCCN or national guidelines.  A baseline chest X-ray will be 
obtained. 
These radiographic assessments may be considered when clinically indicated to exclude 
metastatic disease at baseline or assess distant disease recurrence status during study 
treatment and follow-up. 
4.7.1.5 
Disease Recurrence Status 
All patients should be followed to assess disease recurrence, second primary cancer, 
and survival.  Disease recurrence or status based on all available clinical assessments 
should be evaluated and documented every 3 months during study treatment and for up 


 
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to 2 years following completion of treatment, at intervals of every 6 months from 3 to 
5 years following completion of treatment, and annually thereafter until approximately 
10 years from FPI. 
4.7.1.5.1 
Recurrence of Disease⎯Recommended Procedures for 
Confirmation 
The diagnosis of a breast cancer recurrence or second primary tumor should be 
confirmed histologically whenever possible.  Some patients may have a suspicious 
recurrence that leads to death quite quickly without the possibility of confirming relapse 
of disease.  Efforts should be made to obtain an autopsy report in such cases.  The 
earliest date of diagnosis of recurrent disease should be used and recorded.  This date 
should be based on objective clinical, radiological, histological, or cytological evidence. 
Recurrent disease includes local, regional, or distant recurrence and contralateral or 
ipsilateral second primary invasive breast cancer.  Patients who have a diagnosis of 
in situ breast disease or second, non-breast malignancies should be maintained on a 
regular follow-up schedule wherever possible in order to fully capture any subsequent 
recurrent invasive disease events.  
A tumor biopsy at recurrence for exploratory biomarker research should be taken if the 
tumor is accessible for biopsy without significant risk to the patient (in the investigator’s 
opinion).  These analyses are done in order to gain better understanding of resistance 
mechanisms and tumor biology at recurrence.  A blood sample for biomarker analysis 
should also be collected at this time. 
The definitions of and procedures for confirming invasive disease recurrence, death, and 
other noteworthy events on follow-up are as follows: 
• 
1) Local invasive recurrence 
Ipsilateral breast after previous lumpectomy 
Defined as evidence of invasive tumor (except DCIS and LCIS) in the 
ipsilateral breast after lumpectomy.  Patients who develop clinical evidence 
of tumor recurrence in the remainder of the ipsilateral breast should have a 
biopsy of the suspicious lesion to confirm the diagnosis. 
Confirmed by positive histology or cytology 
Ipsilateral after previous mastectomy 
Defined as evidence of invasive tumor in any soft tissue or skin of the 
ipsilateral chest wall.  This includes the area bounded by the midline of the 
sternum, extending superiorly to the clavicle and inferiorly to the costal 
margin.  Soft tissue recurrences in this area extending into the bony chest 
wall or across the midline will be considered as evidence of local 
recurrence. 
Confirmed by positive histology or cytology 


 
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• 
2) Regional recurrence 
Defined as the development of tumor in the ipsilateral internal mammary lymph 
nodes, ipsilateral axillary lymph nodes, or supraclavicular lymph nodes and in 
the extranodal soft tissue of the ipsilateral axilla.  Regional recurrence does not 
include tumor in the opposite breast. 
Confirmed by positive histology or cytology, or radiologic evidence (especially in 
case of PET activity or visible internal mammary lymph nodes on CT or MRI if 
no biopsy was performed) 
• 
3) Contralateral or ipsilateral second primary invasive breast cancer 
Confirmed by positive cytology or histology 
• 
4) Distant recurrence 
Defined as evidence of tumor in all areas, with the exception of those described 
in 1), 2), and 3) above 
Confirmed by the following criteria: 
Skin, subcutaneous tissue, and lymph nodes (other than local or regional) 
Positive cytology, aspirate, or biopsy OR radiologic (CT scan, MRI, 
PET, or ultrasound) evidence of metastatic disease 
Bone 
X-ray, CT scan, or MRI evidence of lytic or blastic lesions consistent 
with bone metastasis, OR bone scan (requires additional radiologic 
investigation; alone not acceptable in case of diagnostic doubt) OR 
biopsy proof of bone metastases or cytology 
Bone marrow 
Positive cytology or histology or MRI scan 
Lung 
Radiologic evidence of multiple pulmonary nodules consistent with 
pulmonary metastases 
Positive cytology or histology (in practice, rarely performed except in 
the case of solitary nodules) 
Note:  For solitary lung lesions, cytologic or histologic confirmation 
should be obtained in case of diagnostic doubt.  Proof of neoplastic 
pleural effusions should be established by cytology or pleural biopsy. 
Liver 
Radiologic evidence consistent with liver metastases OR liver biopsy 
or fine needle aspiration 
Note:  If radiologic findings are not definitive (especially in the case of 
solitary liver nodules), a liver biopsy is recommended; however, if a 
biopsy is not performed, serial scans should be obtained, if possible, to 
document stability or progression. 


 
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Central nervous system 
Positive MRI or CT scan, usually in a patient with neurologic 
symptoms, OR biopsy or cytology (e.g., for a diagnosis of meningeal 
involvement).  However, meningeal involvement may also be 
diagnosed by CT scan or MRI and, depending on the general status of 
the patient, additional investigations (including cytology of the 
cerebrospinal fluid). 
• 
5) Second primary malignancy (non-breast) 
Any positive diagnosis of a second (non-breast) primary cancer other than 
basal or squamous cell carcinoma of the skin or CIS of the cervix will be 
considered an event in the analysis of the IDFS, including second primary 
non-breast cancer endpoint; however, such diagnoses will not be included in 
the IDFS primary endpoint. 
Myelodysplastic syndrome is not considered a progression event.  The 
diagnosis of a second primary cancer must be confirmed histologically. 
All second primary malignancies are to be reported whenever they occur during 
the study. 
Note:  Patients diagnosed with a second primary malignancy not requiring 
systemic therapy (i.e., chemotherapy, hormonal therapy, targeted therapy, etc.) 
and with no evidence of breast cancer recurrence should continue, whenever 
possible, with study drug treatment and Schedule of Assessments, if 
considered by the investigator to be in the patient’s best interest. 
• 
6) Death without recurrence 
Any death occurring without prior breast cancer recurrence or second 
(non-breast) malignancy is considered an event for the following endpoints:  
IDFS, IDFS including second primary non-breast cancer, DFS, and OS. 
• 
7) Other noteworthy events 
The following events should be recorded on the eCRF: 
Ipsilateral and contralateral LCIS 
Ipsilateral and contralateral DCIS 
Note:  These events are not considered recurrent invasive disease but 
must be recorded.  
 
4.7.1.6 
Laboratory Assessments 
Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis according to the Schedule of Assessments: 
• 
Hematology (complete blood counts with differential) including hemoglobin, 
hematocrit, platelet count, WBC count, and differential including absolute neutrophil 
count 


 
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• 
Serum chemistry 
At baseline:  sodium, potassium, chloride, glucose, BUN or urea, creatinine, 
total protein (if available), albumin, TBILI (and direct bilirubin when TBILI > ULN), 
ALT, AST, and ALP   
At subsequent timepoints:  potassium, TBILI (and direct bilirubin when 
TBILI > ULN), ALT, AST, ALP, and other assessments when clinically indicated 
• 
Viral serology at screening and as clinically indicated 
HBsAg 
HBcAb and/or HBV DNA for known HBV carrier per local guidelines 
HCV antibody and/or HCV RNA for known HCV carrier per local 
guidelines  
• 
Pregnancy test 
All women of childbearing potential (including those who have had a tubal 
ligation) will have a serum pregnancy test at screening.  Urine pregnancy tests 
will be performed at specified subsequent visits.  If a urine pregnancy test is 
positive, it must be confirmed by a serum pregnancy test. 
• 
Coagulation (INR and aPTT) at screening; otherwise, as clinically indicated 
Samples for the following laboratory tests will be sent to one or several central 
laboratories or to the Sponsor for analysis.  Instruction manuals and supply kits will be 
provided for all central laboratory assessments. 
• 
Prospective central testing for HER2-positive status by IHC and ISH 
Central laboratory confirmation of a positive HER2 status is required prior to 
randomization to the study.  The outcome of this assessment will be 
communicated to the investigator. 
After completion of HER2 testing for eligibility criteria, with use of prespecified 
HER2 tests, patient samples may also be tested with other HER2 assays to 
establish performance characteristics of these assays for diagnostic 
development.  Testing may be performed on all screened patients 
(screen-failed and enrolled patients).  These testing data will have no impact on 
eligibility, and testing will be performed only after eligibility is established for 
each patient.  
• 
Prospective central testing for hormonal receptor (ER/PR) status by IHC  
• 
Assessment of potential candidate biomarkers (see Section 4.7.1.9)  
• 
Analysis of serum, plasma, and whole blood samples collected as part of the 
optional biomarker program  
• 
Analysis of serum samples for trastuzumab emtansine pharmacokinetic (PK) and 
ATA assessments 
 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual. 


 
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These samples will be stored until the end of the study, with the following exceptions: 
• 
Mandatory biomarker samples will be destroyed no later than 5 years after the date 
of final closure of the clinical database. 
 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4. 
4.7.1.7 
Cardiac Assessments 
4.7.1.7.1 
Electrocardiograms 
Single 12-lead ECGs will be performed locally and assessed at screening and otherwise 
as clinically indicated. 
For safety monitoring purposes, any abnormalities on any of the ECGs will be 
documented on the eCRF.  The investigator or designee must review, sign, and date all 
ECG tracings.  Paper copies will be kept as part of the patient’s permanent study file at 
the site.  For ECG tracings that will fade over time (e.g., ECGs on thermal paper), lasting, 
legible copies should be filed together with the original.  
4.7.1.7.2 
Left Ventricular Ejection Fraction 
LVEF cardiac monitoring will be assessed by ECHO or MUGA in all patients.  LVEF 
assessment by ECHO is preferred, but LVEF can also be assessed by MUGA.  The 
same modality should be used throughout the study for each patient and, preferably, 
performed and assessed by the same assessor.  Results of ECHO/MUGA will be 
collected in the eCRF.  
4.7.1.8 
Patient-Reported Outcomes  
PRO data will be elicited from the patients to more fully characterize the clinical profile of 
trastuzumab emtansine.  The PRO instruments, translated as required into the local 
language, will be distributed by the investigator or staff and must be completed in their 
entirety by the patient.  To ensure instrument validity and that data standards meet 
health authority requirements, PRO questionnaires should be self-administered at the 
investigational site prior to the completion of other study assessments and the 
administration of study treatment.  
The EORTC QLQ-C30 and the modified Breast Cancer module QLQ-BR23 
questionnaires (Appendix 8) will be used to assess HRQoL, including side effects of 
therapy (e.g., peripheral neuropathy, joint/muscle pain, skin issues) and patient 
functioning (refer to Schedule of Assessments for detailed description of timepoints).  
The EORTC QLQ-C30 is a validated and reliable self-report measure 
(Aaronson et al. 1993; Osoba et al. 1997) that consists of 30 questions that assess five 
aspects of patient functioning (physical, emotional, role, cognitive, and social); three 
symptom scales (fatigue; nausea, vomiting, and pain); the global health/QoL scale; and 
six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial 


 
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difficulties), within a recall period of ”the last week.”  Scale scores can be obtained for 
each of the multi-item scales, the global health status/QoL scale, and the six single items 
by using a liner transformation for standardization of the calculated raw score.   
The EORTC QLQ-BR23 breast cancer module was first validated for use in 1995, uses a 
recall period of ”the past week,“ and is intended for use across multiple treatment 
modalities (i.e., surgery, chemotherapy, radiotherapy, and hormonal treatment; 
Sprangers et al. 1998).  As peripheral neuropathy (1 item), joint/muscle pain (1 item), 
and skin problems (2 items) are key symptoms of therapy not assessed by currently 
available tools, validated items from the EORTC Item Bank will be added to assess the 
presence and bothersomeness of these treatment-related side effects.  Data analysis 
will be performed on the final modified BR23 data set outside of the protocol in parallel 
with the final data analysis to confirm the psychometric properties of the modified 
instrument.  Scale scores can be obtained for each of the multi-item and single-item 
scales by using a linear transformation for standardization of the calculated raw score.   
4.7.1.9 
Mandatory Samples for HER2 Testing and Biomarker Analysis 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual.  The mandatory tissue and blood samples will be stored 
for up to 5 years after final database lock, unless the patient consents to long-term 
storage as part of the optional biomarker research program (OBRP) for 15 years. 
Tumor Tissue Samples 
As a requirement for study enrollment, tumor tissue samples in the form of a FFPE 
tumor tissue block or a partial block (for minimal dimensions, see Sample Handling and 
Logistics Manual) from the primary tumor (definitive surgery sample) must be submitted 
to a Sponsor-designated central pathology laboratory for assessment of HER2 status by 
IHC (see Appendix 6) and ISH (see Appendix 7) and hormone receptor status by IHC.  
Tissue that has been submitted for HER2, hormonal receptor testing, and mandatory 
biomarker analysis may also be used for the assessment of additional in situ methods, 
or newly available alternative diagnostic technologies may also be applied on these 
samples from all screened patients.  
Tumor Biopsy at Recurrence 
There is a need to further understand the relapse of the tumor during or after adjuvant 
therapy.  Molecular characterization of the tumor at time of relapse will help to further our 
understanding of the underlying resistance mechanisms and tumor biology at recurrence.  
A tumor biopsy at recurrence for exploratory biomarker research should be taken if the 
tumor is accessible for biopsy without significant risk (in the investigator’s opinion) to the 
patient.   
Biomarker Analysis 
Tumor samples will be used to assess the potential prognostic or predictive value of 
candidate markers or biomarker panels, improve diagnostic tests, improve 


 
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understanding of breast cancer biology, or discover new biomarker profiles related to 
treatment benefit and/or safety or disease characteristics.  Tumor tissue from the tumor 
block or partial block will be used to assess the potential relationship between the 
degree of HER2 gene amplification and the level of HER2/3 mRNA and response to 
study treatment.  Other markers that may be selected for exploratory analyses are, for 
example, other HER family members⎯markers that are involved in downstream 
signaling of HER2, belong to a group of related receptor tyrosine kinases that could 
serve as salvage routes for an inhibited HER2 pathway (e.g., PIK3CA mutations, PTEN), 
or are ligands of HER family proteins that induce activation of the HER pathway. 
Analysis of the tissue block will include the following markers for all patients in screening: 
• 
HER2 eligibility testing, including hematoxylin and eosin stain, IHC, and ISH 
(6−8 slides) 
• 
ER/PR status (2−3 slides) 
 
Analysis of the tissue block of all randomized patients will include, but not be limited to, 
the following markers: 
• 
RNA extraction to allow, for example, for the analysis of HER2/3 mRNA levels using 
qRT-PCR (2−3 slides) 
• 
DNA extraction to allow, for example, for the analysis of PIK3CA mutations 
(1−2 slides) 
• 
PTEN (2 slides for IHC) 
• 
Additional markers or alternative technologies (based on scientific developments 
and/or novel technologies) to explore potential prognostic or predictive candidate 
markers/panels or markers related to treatment benefit and/or safety, to improve 
diagnostic tests, or to understand breast biology 
 
After initial HER2, ER/PR, and mandatory biomarker testing, the tissue blocks will be 
used for tissue microarray (TMA) construction (after study enrollment) before they are 
returned to sites to allow for additional biomarker analysis.  Analysis of additional 
markers may be required, because science is rapidly and constantly evolving, and 
therefore the definitive list of biomarkers that will be analyzed remains to be determined 
and may include additional markers as well as novel or alternative technologies to be 
evaluated.  These TMAs will be destroyed no later than 2 years after the date of final 
closure of the clinical database, unless the patient gives specific consent for the 
remainder of the samples to be stored for optional exploratory research in the study 
biosample repository (see Section 4.7.1.10). 
There is a need to further understand the relapse of the tumor during or after adjuvant 
therapy.  Molecular characterization of the tumor at time of relapse will be conducted if 
tumor sample is available at disease recurrence.  


 
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The implementation and use of the study biomarker specimens is governed by the study 
Steering Committee (SC) (Section 9.4), with guidance from a dedicated translational 
research committee to ensure the appropriate use of the study specimens.  All 
biomarker specimens will be retained for new research related to this study and/or 
disease in accordance with the recommendations and approval of the study SC. 
Blood Samples 
Blood samples for collection of serum (6 mL) and plasma (2 × 6 mL) will be collected as 
shown in the Schedule of Assessments for all patients.  These specimens will be used 
for research purposes to identify biomarkers that are predictive of response to study 
treatment (in terms of dose, safety, and tolerability) and will help to better understand the 
pathogenesis, course, and outcome of EBC and related diseases.  The serial sampling 
gives the opportunity to evaluate changes in circulating biomarker levels, which may give 
further understanding of potential resistance mechanisms.  Measurement of these 
samples may include, but not be limited to, circulating ligands of HER family members, 
such as transforming growth factor−alpha, epidermal growth factor, betacellulin, 
amphiregullin, or neuregulin-1/heregulin or circulating tumor DNA.  Somatic mutations in 
known oncogenes and tumor suppressor genes (i.e., PIK3CA) and other genes related 
to the mechanism of action or resistance mechanism of the investigational genes will be 
determined. 
Candidate markers of response to treatments that emerge from other clinical or 
nonclinical studies may also be assessed in this study and can be assessed with use of 
different types of technologies. 
Clinical Genotyping 
At baseline (Cycle 1 Day 1 of anthracyclines), an approximate 3-mL whole blood sample 
will be taken for genetic biomarker analysis (polymorphisms).  If, however, the genetic 
blood sample is not collected during the scheduled visit, it may be collected at any time 
(after randomization) during the treatment phase of the clinical study.   
Clinical genotyping analysis will be used to investigate genetic markers in correlation to 
efficacy and safety of trastuzumab emtansine.  Several hypotheses may be evaluated in 
this trial, and some example hypotheses are further described in Section 3.3.6. 
Data arising from clinical genotyping will be subject to the confidentiality standards 
described in Section 8.4. 
Samples will be destroyed no later than 2 years after the date of final closure of the 
clinical database. 
For sampling procedures, storage conditions, and shipment instructions, see the Sample 
Handling and Logistics Manual.  


 
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4.7.1.10 
Optional Biomarker Research Samples and Study Biosample 
Research Repository 
There will be an OBRP for which samples will be stored in a study biosample repository 
for the long term.  The collection and analysis of biomarker specimens as part of the 
OBRP will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
patients in the future. 
Specimens for the OBRP will be collected from patients who give specific consent to 
participate in this optional research.  The OBRP specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or disease 
progression 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
Approval by the Institutional Review Board or Ethics Committee 
Sampling for the OBRP is contingent upon the review and approval of the exploratory 
research and long term storage in the study biosample repository portion of the Informed 
Consent Form by each site's Institutional Review Board or Ethics Committee (IRB/EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for ORBP sampling, this section of the protocol will not be applicable at that site. 
Sample Collection 
Patients who are enrolled in the study will be asked to consent to allow the remainders 
of mandatory tissue and blood/plasma/serum samples as described above to also be 
used for exploratory biomarker research. 
In addition, the following sample will be collected for patients who consent to Optional 
Biomarker Research for identification of genetic (inherited) biomarkers: 
• 
Whole blood samples for DNA extraction to assess for biomarkers 
 
For all samples, dates of consent and specimen collection should be recorded on the 
associated page of the eCRF.  For sampling procedures, storage conditions, and 
shipment instructions, see the Sample Handling and Logistics Manual.   
Specimens stored in the study biosample repository will be destroyed no later than 
15 years after the date of final closure of the associated clinical database.  The storage 
period of this OBRP will be in accordance with the IRB/EC-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements). 


 
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The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4.  The genetic biomarker specimens will undergo additional 
processes to ensure confidentiality, as described below.   
Confidentiality 
Given the sensitive nature of genetic data, Roche has implemented additional processes 
to ensure patient confidentiality for the genetic sample taken as part of the OBRP and 
associated data.  Upon receipt by the study biosample repository, each specimen is 
"double-coded" by replacing the patient identification number with a new independent 
number.  Data generated from the use of these specimens and all clinical data 
transferred from the clinical database and considered relevant are also labeled with this 
same independent number.  A "linking key" between the patient identification number 
and this new independent number is stored in a secure database system.  Access to the 
linking key is restricted to authorized individuals and is monitored by audit trail.  
Legitimate operational reasons for accessing the linking key are documented in a 
standard operating procedure.  Access to the linking key for any other reason requires 
written approval from the Pharma Repository Governance Committee and Roche’s Legal 
Department, as applicable. 
Data generated from OBRP specimens in the study biosample repository must be 
available for inspection upon request by representatives of national and local health 
authorities and Roche monitors, representatives, and collaborators, as appropriate. 
Patient medical information associated with OBRP specimens 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. 
Data derived from OBRP specimen analysis on individual patients will not generally be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using specimens in the study biosample 
repository will be available via study data publication. 
Any inventions and resulting patents, improvements, and/or knowhow originating from 
the use of specimens in the study biosample repository data will become and remain the 
exclusive and unburdened property of Roche, except where agreed otherwise. 
Consent to Participate in the Optional Biomarker Research Program 
The Informed Consent Form will contain a separate section that addresses participation 
in the OBRP.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the OBRP.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 


 
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required to document a patient’s agreement to provide the optional biomarker specimen.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the OBRP Informed Consent eCRF. 
In the event of an OBRP participant's death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the OBRP research. 
A separate, specific signature is not required for the following mandatory biomarker 
samples, which will be stored until 2 years after final closure of the database: 
• 
Tumor tissue collection for HER2 testing and biomarker analyses 
• 
Clinical genotyping blood sample 
• 
Blood samples for plasma/serum  
 
Withdrawal from the Optional Biomarker Research Program 
Patients who give consent to provide specimens for the OBRP have the right to withdraw 
their specimens from this program at any time and for any reason.  If a patient wishes to 
withdraw consent for the testing of his or her specimens, the investigator must inform the 
Medical Monitor in writing of the patient’s wishes using the OBRP Subject Withdrawal 
Form and, if the trial is ongoing, must enter the date of withdrawal on the OBRP 
Withdrawal of Informed Consent eCRF.  The patient will be provided with instructions on 
how to withdraw consent after the trial is closed.  A patient’s withdrawal from 
Study BO28407 does not, by itself, constitute withdrawal of specimens from the OBRP.  
Likewise, a patient’s withdrawal from the OBRP does not constitute withdrawal from 
Study BO28407. 
Monitoring and Oversight 
OBRP specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality and adherence to 
authorized use of specimens as specified in this protocol and in the Informed Consent 
Form.  Roche monitors and auditors will have direct access to appropriate parts of 
records relating to patient participation in the OBRP for the purposes of verifying the 
data provided to Roche.  The site will permit monitoring, audits, IRB/EC review, and 
health authority inspections by providing direct access to source data and documents 
related to the OBRP samples. 
4.7.1.11 
Samples for ATA 
Serum samples for ATA and pharmacokinetics will be taken from all patients receiving 
trastuzumab emtansine as indicated in Schedule of ATA Assessments (Appendix 2).  
The ATAs to trastuzumab emtansine will be measured and characterized using validated 
assays.  The PK samples will be analyzed using validated assays.   


 
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For details of sampling procedures, storage conditions, and shipment instructions, see 
the Sample Handling and Logistics Manual. 
4.7.2 
Timing of Study Assessments 
4.7.2.1 
Screening and Pretreatment Assessments 
Written informed consent for participation in the study must be obtained before any 
study-specific screening tests or evaluations are performed.  Informed Consent Forms 
for enrolled patients and for patients who are not subsequently enrolled will be 
maintained at the study site.  Screening tests and evaluations will be performed within 
30 days prior to enrollment unless otherwise specified.  Results of SoC tests or 
examinations performed prior to obtaining informed consent and within 30 days prior to 
enrollment may be used; such tests do not need to be repeated for 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. 
Central HER2 testing to confirm patient HER2 status and hormonal receptor status will 
be performed at a Sponsor-designated central laboratory.  In addition, local HER2 test 
information, baseline demographic, and disease-related characteristic data for all 
screened patients may be collected in order to support potential registration of a 
companion diagnostic assay for trastuzumab emtansine. 
Pretreatment tests and evaluations will be performed within 7 days prior to enrollment 
after confirmation of other eligibility criteria, unless otherwise specified. 
Please see Appendix 1 for the schedule of screening and pretreatment assessments. 
4.7.2.2 
Assessments during Treatment 
During adjuvant therapy, patients will be assessed for safety and efficacy.  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 and Appendix 2).  
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. 
Please see Appendix 1 and Appendix 2 for the Schedule of Assessments performed 
during the treatment period. 
4.7.2.3 
Assessments at Study End-of-Treatment Visit 
Patients who complete the study treatment (defined as completion of 1 year of 
HER2 targeted therapy) or discontinue from the study treatment early will be asked to 
return to the clinic 28−42 days after the last dose of study drug for a follow-up visit.   


 
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Please see Appendix 1 for the Schedule of Assessments performed at the study 
completion/early termination visit. 
4.7.2.4 
Follow-Up Assessments 
The follow-up period begins from the date of the end-of-treatment visit.  Visit windows 
are ± 28 days for quarterly and semiannual assessments and ± 42 days for annual 
assessments (see Appendix 1). 
After the end-of-treatment visit, adverse events should be followed as outlined in 
Section 5.5 and Section 5.6. 
All patients must be followed up for approximately 10 years from the date of 
randomization of the first patient (or until sites are notified that the study is closed by the 
Sponsor) according to the Schedule of Assessments, even if the assigned treatment is 
discontinued permanently. 
The schedule of follow-up visits and tests for this study is the minimum required; 
investigators may see their patients more frequently according to their routine practice. 
In cases of disease recurrence that is defined as an IDFS event in Section 3.4.1, 
diagnosed at any time during the study, patients will be out of the study schedule and 
will be followed up once a year (starting 1 year after first recurrence) for approximately 
10 years from the date of randomization of the first patient for survival (or until sites are 
notified that the study is closed by the Sponsor), and new recurrence/disease 
progression events. 
Please see Appendix 1 for the schedule of follow-up assessments. 
4.8 
PATIENT, STUDY, AND SITE DISCONTINUATION 
4.8.1 
Patient Discontinuation 
The investigator has the right to discontinue a patient from study drug or withdraw a 
patient from the study at any time.  In addition, patients have the right to voluntarily 
discontinue study drug or withdraw from the study at any time for any reason.  Reasons 
for discontinuation of study drug or withdrawal from the study may include, but are not 
limited to, the following: 
• 
Patient withdrawal of consent at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient 
• 
Completion of all assessments, including 10 years of follow-up  
• 
The study is closed by the Sponsor 
 


 
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4.8.1.1 
Discontinuation from Study Drug 
Patients must discontinue study drug if they experience any of the following: 
• 
Invasive disease recurrence 
• 
Unacceptable toxicity (Section 5.1.3 and Section 5.1.4) 
• 
Pregnancy 
• 
Intercurrent, non−cancer-related illness that prevents continuation of protocol 
therapy or follow-up 
• 
Major protocol violation that may jeopardize the patient’s safety according to the 
Sponsor 
• 
Repeated patient noncompliance with protocol requirements 
• 
Changes in the patient’s condition or study drug−related toxicity such that in the 
opinion of the investigator, continued participation in the protocol would compromise 
the patient’s well-being 
• 
Withdrawal of patient consent 
 
Patients who discontinue study drug prematurely will be asked to return to the clinic for 
an end-of-treatment visit (see Schedule of Assessments) and may undergo follow-up 
assessments.  The primary reason for premature study drug discontinuation should be 
documented on the appropriate eCRF.  Patients who discontinue study drug prematurely 
will not be replaced. 
4.8.1.2 
Withdrawal from Study 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  Patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 
Withdrawal from Entire Study 
Should a patient decide to withdraw from the study, all efforts will be made to complete 
and report the observations for that patient as thoroughly as possible.  No further data 
will be collected after the date of the patient’s withdrawal from study.  The investigator 
should contact the patient or a legally authorized relative by telephone or through a 
personal visit to establish as completely as possible the reason for the withdrawal.  A 
complete final evaluation at the time of the patient’s withdrawal should be made, along 
with an explanation of why the patient is withdrawing from the study. 
Partial Withdrawal from Study 
All of the above provisions regarding withdrawal from the entire study are applicable to 
partial withdrawal from the study, except that the patient must agree to be contacted for 
further information on recurrence as per the primary study endpoint and survival status.  
Whenever possible, information on recurrence should be documented through review of 
medical records as well as patient contact.  It should be documented in both the medical 


 
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records and the eCRF that the patient agreed to be contacted for information on survival 
despite the patient’s withdrawal of informed consent. 
In the case of patients who miss scheduled visits, site staff should make at least three 
attempts within a reasonable period of time after a missed visit to contact these patients 
for follow-up information.  The collection of follow-up data is extremely important for the 
reliable estimation of study endpoints. 
If a patient is lost to follow-up, contact will initially be attempted through the trial research 
nurse and the lead investigator at each study site.  If these attempts are unsuccessful, 
the patient’s physician will be contacted and asked to contact the patient or the patient’s 
family and provide follow-up information to the recruiting study site. 
Only after sufficient unsuccessful attempts at contact have been made may a patient be 
declared lost to follow-up. 
4.8.2 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the study is placed on hold or if the Sponsor 
decides to discontinue the study or development program.   
The Sponsor has the right to replace a site at any time.  Reasons for replacing a site 
may include, but are not limited to, the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) guideline 
for Good Clinical Practice 
 
5. 
ASSESSMENT OF SAFETY  
5.1 
SAFETY PLAN 
The safety monitoring plan for patients in this study is based on the known safety profiles 
of trastuzumab emtansine, pertuzumab, trastuzumab, and protocol-approved 
chemotherapy agents.  


 
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5.1.1 
Study Drugs Associated Risks, Warnings, and Precautions  
5.1.1.1 
Trastuzumab Emtansine 
Identified and potential risks of treatment with trastuzumab emtansine are based on all 
available nonclinical and clinical data relating to trastuzumab emtansine and clinical 
toxicities related to its components (trastuzumab and DM1, a derivative of maytansine) 
and to other DM1-containing ADCs.   
Pulmonary toxicity, hepatotoxicity, cardiac toxicity (left ventricular dysfunction), 
IRR/hypersensitivity, thrombocytopenia (including thrombocytopenia associated with 
severe hemorrhage), and peripheral neuropathy are important identified risks of 
trastuzumab emtansine and are detailed in the subsections below.  Fetal harm and 
impaired fertility are important potential risks with trastuzumab emtansine.  
Guidance on dose modifications and discontinuation upon toxicities are provided in 
Section 5.1.3 and Section 5.1.4. 
Please refer to the Investigator’s Brochure for full description of the trastuzumab 
emtansine safety profile, warnings, precautions, and guidance for investigators. 
5.1.1.1.1 
Pulmonary Toxicity 
Cases of ILD, including pneumonitis, some leading to acute respiratory distress 
syndrome or fatal outcome, have been reported in clinical trials with trastuzumab 
emtansine.  Signs and symptoms include dyspnea, cough, fatigue, and pulmonary 
infiltrates.  These events may or may not occur as sequelae of infusion reactions.  
Treatment has included administration of steroids and oxygen, as well as study drug 
discontinuation.  
5.1.1.1.2 
Hepatotoxicity 
Hepatotoxicity, predominantly in the form of asymptomatic increases in the 
concentrations of serum transaminases (Grade 1−4 transaminitis), has been observed in 
patients while on treatment with trastuzumab emtansine in clinical trials.  Transaminase 
elevations were generally transient with peak elevation at Day 8 after therapy 
administration and subsequent recovery to Grade 1 or lower prior to the next cycle.  The 
incidence of increased AST was substantially higher than that for ALT.  A cumulative 
effect of trastuzumab emtansine on transaminases has been observed:  the proportion 
of patients with Grade 1 or 2 elevated transaminases increases with successive cycles; 
however, no increase in the proportion of Grade 3 abnormalities over time was observed.  
The majority of patients with elevated transaminases improved to Grade 1 or normal 
within 30 days of the last dose of trastuzumab emtansine. 
Rare cases of severe hepatotoxicity, including death due to DILI and associated hepatic 
encephalopathy, have been observed in patients treated with trastuzumab emtansine.  
Some of the observed cases may have been confounded by concomitant medications 
with known hepatotoxic potential and/or underlying conditions.  Nevertheless, a 


 
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contributory role of trastuzumab emtansine in these cases cannot be excluded.  
Therefore, acute severe liver injury (Hy’s law) is an important risk with trastuzumab 
emtansine.  A Hy’s law case has the following components: 
• 
Aminotransferase enzymes are greater than 3 × ULN with concurrent elevation of 
serum TBILI to > 2 × ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase). 
• 
No other reason can be found to explain the combination of increased 
aminotransferases and serum TBILI, such as viral hepatitis A, B, or C; 
preexisting or acute liver disease; or another drug capable of causing the 
observed injury. 
 
Cases of NRH of the liver have been identified from liver biopsies in patients treated with 
trastuzumab emtansine and presenting with signs and symptoms of portal hypertension.  
NRH confirmed by biopsy was observed leading to fatal hepatic failure.  NRH is a rare 
liver condition characterized by widespread benign transformation of hepatic 
parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal 
hypertension (Hartleb et al. 2011).  NRH should be considered in patients who develop 
clinical symptoms of portal hypertension and/or a cirrhosis-like pattern seen on CT scan 
of the liver but with normal transaminases and no other manifestations of cirrhosis or 
liver failure following long-term treatment with trastuzumab emtansine.  Diagnosis of 
NRH can be confirmed only by histopathology. 
5.1.1.1.3 
Cardiac Toxicity 
Patients treated with trastuzumab emtansine are at risk of developing left ventricular 
dysfunction.  LVEF < 40% has been observed in patients treated with trastuzumab 
emtansine.   
5.1.1.1.4 
Infusion-Related Reactions/Hypersensitivity 
IRRs (anaphylactoid/cytokine release reactions) and hypersensitivity 
(anaphylactic/allergic reactions) may occur with the administration of monoclonal 
antibodies and have been reported with trastuzumab emtansine.  Treatment with 
trastuzumab emtansine has not been studied in patients who had trastuzumab 
permanently discontinued because of an IRR/hypersensitivity; treatment with 
trastuzumab emtansine is not recommended for these patients.   
IRRs, characterized by one or more of the following symptoms⎯flushing, chills, pyrexia, 
dyspnea, hypotension, wheezing, bronchospasm, and tachycardia⎯have been reported 
in clinical trials of trastuzumab emtansine.  In general, these symptoms were not severe.  
In most patients, these reactions resolved over the course of several hours to a day after 
the infusion was terminated.  Serious hypersensitivity (anaphylactic-like reactions) has 
been observed in clinical trials of trastuzumab emtansine.   


 
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Administration of trastuzumab emtansine will be performed in a setting with access to 
emergency facilities and staff who are trained to monitor and respond to medical 
emergencies.  Patients will be observed closely for infusion-related/hypersensitivity 
reactions during and after each trastuzumab emtansine infusion.  Premedication is 
allowed according to standard practice guidelines.  In the event of a true hypersensitivity 
reaction (in which severity of reaction increases with subsequent infusions), trastuzumab 
emtansine treatment must be permanently discontinued. 
5.1.1.1.5 
Thrombocytopenia 
Thrombocytopenia, or decreased platelet count, was reported in patients in clinical trials 
of trastuzumab emtansine.  The majority of these patients had Grade 1 or 2 events 
(≥ 50,000/mm3), with the nadir occurring by Day 8 and generally improving to Grade 0 
or 1 (≥ 75,000/mm3) by the next scheduled dose.  In clinical trials, the incidence and 
severity of thrombocytopenia were higher in Asian patients.  Among Asian patients, the 
incidence of thrombocytopenia was higher (52.5%) compared with the overall population 
(30.4%) in Study TDM4370g.  However, the incidence rate of Grade ≥ 2 hemorrhage did 
not increase in Asian patients compared with the overall population. 
Cases of bleeding events with a fatal outcome have been observed.  Independent of 
race, cases of severe hemorrhagic events, including central nervous system 
hemorrhage, have been reported in clinical trials with trastuzumab emtansine.  In some 
of the observed cases, the patients were also receiving anti-coagulation therapy.  
Patients on anti-coagulant treatment have to be monitored closely during treatment with 
trastuzumab emtansine.  Platelet counts will need to be monitored prior to each 
trastuzumab emtansine dose.   
5.1.1.1.6 
Neurotoxicity 
Peripheral neuropathy, mainly Grade 1 and predominantly sensory, has been reported in 
clinical trials of trastuzumab emtansine.  Patients should be examined for signs of 
peripheral neuropathy prior to each dose of trastuzumab emtansine. 
5.1.1.1.7 
Extravasation 
In trastuzumab emtansine clinical studies, reactions secondary to extravasation have 
been observed.  These reactions were usually mild and comprised erythema, 
tenderness, skin irritation, pain, or swelling at the infusion site.  Rare reports of more 
severe events, such as cellulitis, pain (tenderness and burning sensation), and skin 
irritation, have been received as part of the continuing surveillance of trastuzumab 
emtansine safety.  These reactions have been observed more frequently within 24 hours 
of infusion.  Specific treatment for trastuzumab emtansine extravasation is unknown at 
this time.  The infusion site should be closely monitored for possible subcutaneous 
infiltration during drug administration. 


 
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5.1.1.2 
Pertuzumab 
Overall, safety data indicates 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 toxicities.  No unexpected toxicities of pertuzumab were encountered 
other than those known for agents that target the HER family of receptors (see details in 
Section 5.1.1.2.1 and Section 5.1.1.2.2).  IRRs (chills, fatigue, headache, nausea, and 
pyrexia), hypersensitivity reactions and anaphylaxis, neutropenia/febrile neutropenia, 
diarrhea, mucositis, rash, and left ventricular dysfunction are adverse events (AEs) of 
particular clinical relevance for this study.  Diarrhea has been observed in approximately 
60% of patients (treatment-related diarrhea in 50% of patients) being treated with 
pertuzumab in Phase II single-agent studies and in up to 90% of patients in combination 
therapy studies.  Diarrhea was Grade 1 or 2 in the majority of cases.  Rash has been 
observed in approximately 17% of patients receiving pertuzumab in Phase II 
single-agent studies and up to 73% of patients in combination studies.  The rash was 
generally Grade 1 or 2 in severity.  The toxicities described above are to be closely 
monitored during the course of the study as detailed in Section 5.1.4 and/or in the 
Pertuzumab Investigator’s Brochure. 
Serious or severe infusion-associated symptoms have been observed rarely in patients 
receiving pertuzumab.  A low level of cardiac AEs, predominantly asymptomatic declines 
in LVEF, has been reported.  In the pivotal Phase III Study WO20698/TOC4129g, the 
rates of symptomatic and asymptomatic LVSD were lower in patients receiving 
pertuzumab than in those receiving placebo. 
Because of pertuzumab’s role in inhibiting heterodimerization with EGFR, there is a 
potential risk of ILD with pertuzumab treatment.  However, few reports of ILD have been 
received from patients receiving pertuzumab, and, in all cases, these indicated 
alternative possible causes for the events (e.g., concomitant medication, 
preceding/concurrent neutropenia with potential infection, relevant medical history).  In 
Study WO20698/TOC4129g, 2.2% of patients receiving pertuzumab developed 
pneumonitis/ILD, compared with 1.5% of patients receiving placebo.  The incidence of 
Grade ≥ 3 AEs was similar in both treatment arms (0.7% in the pertuzumab-treated arm 
vs. 0.5% in the placebo-controlled arm).  
5.1.1.2.1 
Single-Agent Pertuzumab 
The most commonly reported AEs in patients (n = 386) receiving single-agent 
pertuzumab were diarrhea, fatigue, nausea, vomiting, and decreased appetite.  The 
majority of AEs reported were Grade 1 or 2 in severity, and the proportion of patients 
across the pertuzumab program who have discontinued study medication as a result of 
AEs is low. 
5.1.1.2.2 
Pertuzumab in Combination with Trastuzumab and Docetaxel 
Pertuzumab was well tolerated in combination with trastuzumab (Study WO20697 and 
Study BO17929), with an increase in the incidence but not severity of the common AEs 


 
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seen with single-agent pertuzumab (notably diarrhea, rash, and fatigue).  Pertuzumab 
also added little toxicity (predominantly diarrhea and febrile neutropenia) to the AE 
profile of trastuzumab and docetaxel when all three drugs were used concurrently 
(Study WO20698/TOC4129g and Study WO20697), and had minor impact on the doses 
received, interruptions, discontinuations, or treatment-related mortality.  Diarrhea, rash, 
mucosal inflammation, febrile neutropenia, pruritus, and dry skin were more common 
(> 5% difference) in patients receiving the pertuzumab + trastuzumab + docetaxel regimen 
than in patients in the placebo-controlled arm in Study WO20698/TOC4129g.   
Importantly, despite targeting the same HER2 pathway, pertuzumab adds no significant 
cardiac toxicity when given with trastuzumab (with or without chemotherapy). 
An increased incidence of febrile neutropenia was observed for Asian patients in both 
treatment arms compared with patients of other races and from other geographic regions.  
Among Asian patients, the incidence of febrile neutropenia was higher in the 
pertuzumab-treated group (26%) compared with the placebo-treated group (12%) in 
Study WO20698/TOC4129g. 
Please refer to the Investigator’s Brochure for full description of the pertuzumab safety 
profile, warnings, precautions, and guidance for investigators.   
5.1.1.3 
Trastuzumab and Adjuvant Chemotherapy Agents 
For adverse reactions, warnings, precautions, contraindications, requirements for 
contraception duration, and concomitant medications for trastuzumab, doxorubicin, 
epirubicin, cyclophosphamide, 5-fluorouracil, paclitaxel, and docetaxel, refer to local 
prescribing information. 
Dose modifications for overlapping toxicities with study drugs are detailed in 
Section 5.1.4. 
5.1.2 
Safety Considerations for Eligibility and Safety Assessments 
To mitigate the potential for treatment-related toxicities in the study, patients with the 
following characteristics will be excluded from participation in the study because of the 
risks associated with the study drugs as described in Section 5.1.1: 
• 
Inadequate organ function as indicated by abnormal laboratory tests specified in 
Section 4.1.2 
• 
Known active liver disease 
• 
LVEF < 55%, cardiopulmonary dysfunction including history of past symptomatic 
CHF, myocardial infarction within 12 months 
• 
Pregnant or lactating women 
 
All patients will be closely monitored for safety and tolerability during study treatment 
and during follow-up if they meet the criteria for long-term safety follow-up.  LVEF will be 


 
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monitored up to 5 years of survival follow-up.  Abnormal platelet count, ALT, AST, and 
total and/or direct bilirubin will be followed at a minimum of every 4 weeks (monthly) until 
normalization or until they are clinically stable as assessed by the investigator.  Any AE 
that is believed to be related to prior study drug treatment will be followed beyond study 
completion.  The investigator will be instructed to 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 to prior study drug treatment, even 
after the completion of this study (see Appendix 1 and Section 5.5 and Section 5.6 for 
details).  Patients will be assessed for toxicity before each dose.  Dosing will occur only if 
the clinical assessment and local laboratory test values are acceptable.  
Clinical and laboratory AEs will be reported according to the NCI CTCAE v4.0.  In 
addition, cardiovascular side effects will be reported according to predefined criteria 
(NCI CTCAE and NYHA).  
The study will also utilize iDMC and CEC (Section 3.1.1 and Section 3.1.2) to routinely 
monitor accruing patient safety data.  The CEC will adjudicate prespecified safety events 
of interest (cardiac and hepatic dysfunction events) and communicate their findings 
regarding cardiac and hepatic events to the iDMC to aid iDMC review.   
An interim safety analysis (Section 6.8.2) is planned to evaluate protocol-specified 
hepatic events and overall death rate to ensure patient safety. 
5.1.3 
General Guidance for Dose Modifications and Delays 
Chemotherapy and trastuzumab emtansine doses may be delayed and/or reduced and 
trastuzumab and pertuzumab may be delayed as a result of toxicities.  No dose 
reductions are allowed for trastuzumab or pertuzumab.  
Patients will be instructed to notify their physician immediately for any and all toxicities.  
NCI CTCAE v4.0 must be used to grade the severity of AEs.  Assessment of causality 
(chronology, confounding factors, concomitant medications, diagnostic tests, and 
previous experience with the study treatment) should be conducted by the investigator 
prior to dose modification and/or delay whenever possible.  
As a general approach, it is suggested that all AEs be managed with supportive care, 
when possible, at the earliest signs of toxicity.  Should this be ineffective, a dose delay 
or dose reduction may be considered to avoid worsening toxicity.  
All dose modifications should be based on the AE requiring the greatest modification and 
should be properly documented in source documents.  Investigators may take a more 
conservative approach than the guidelines outlined in the protocol on the basis of clinical 
judgment that this is in the best interest of their patients.  


 
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For protocol-approved anthracyline regimens (i.e., FEC, AC/EC, or dose-dense AC/EC), 
please refer to local prescribing information for AE management and dose 
delay/modifications.  
For taxane, trastuzumab, pertuzumab, and trastuzumab emtansine, general guidelines 
on dose delay and modifications are detailed in the following subsections.  Please refer 
to Section 5.1.4 for guidance on management of specific AEs related to study treatment 
safety profiles.  Local prescribing information for taxane may be followed in case of 
discrepancy between the local prescribing information and the general guidelines 
provided in the protocol.  Please refer to local prescribing information for taxane for dose 
delay and modifications details that are not specified in the protocol.  
5.1.3.1 
Dose Delays and Dose Reductions 
General guidelines on dose delays for study treatment−related toxicity, other than those 
specified in Section 5.1.4, are as follows:  
• 
If the patient has not recovered from significant treatment-related toxicities to 
Grade 1 or baseline, the next scheduled dose may be delayed for up to 42 days 
from last dose for the q3w regimen or 28 days from the last dose for qw paclitaxel 
(Arm 1 only).  The definitions of “significant” and “related” will be based on the 
judgment of the investigator (in consultation with the Sponsor’s Medical Monitor or 
designee, when appropriate).  For example, alopecia, even if considered related, 
would most likely not be considered to be significant.  Fatigue may or may not be 
considered related or significant. 
• 
After a treatment delay, study therapy should be resumed as soon as possible.  In 
general, when the significant and related toxicity (or any other toxicity for which the 
investigator has chosen to delay dosing) resolves to Grade 1 or baseline, the patient 
may resume study treatment if the delay has not exceeded the timeframe defined 
above for corresponding dosing schedule.  Patients should be re-evaluated at least 
qw during the delay, whenever possible.  If dosing resumes, a patient may receive 
study treatment at the previous dose or at a reduced dose per investigator’s clinical 
judgment if applicable (unless a reduced dose is required as described in 
Section 5.1.4).  If a patient requires a dose reduction, dosing will be reduced by one 
dose level at a time (see Table 12). 
• 
In the event that any of the individual study drugs in a regimen is delayed as a result 
of toxicity, the administration of other agents may be continued based on the 
following guidelines: 
If trastuzumab or trastuzumab emtansine is delayed, pertuzumab should also 
be withheld. 
If pertuzumab is withheld, trastuzumab or trastuzumab emtansine may continue.  
Do not make up missed pertuzumab dose.   
During the taxane-concurrent phase (Arm 1 only), taxane treatment may 
continue if trastuzumab and/or pertuzumab is withheld.  If taxane is withheld, 


 
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trastuzumab and pertuzumab may continue.  Whether to make up for missed 
taxane dose is at the investigator's clinical discretion. 
• 
During each 3-week cycle, 3 weeks of qw paclitaxel should be given.  If a paclitaxel 
dose is missed during a cycle, the subsequent cycle should not be delayed for 
trastuzumab and pertuzumab.   
 
Table 12 Dose Reduction Levels for Taxane (Arm 1) and Trastuzumab 
Emtansine (Arm 2) 
Drug 
Dose Level 0 
(Starting Dose)
Dose Level −1
Dose Level −2 Dose Level −3
Docetaxel (mg/m2) 
100 
75 
60 
Discontinue 
Docetaxel (mg/m2) 
75 
60 
50 
Discontinue 
Paclitaxel (mg/m2) 
80 
65 
Discontinue 
NA 
Trastuzumab emtansine 
(mg/kg) 
3.6 
3.0 
2.4 
Discontinue 
A = doxorubicin; C = cyclophosphamide; E = epirubicin; F = 5-fluorouracil; NA = Not applicable. 
Note:  Please refer to local prescribing information for dose reduction levels for 
protocol-approved anthracyline regimens (i.e., FEC, AC/EC, or dose-dense AC/EC). 
 
5.1.3.2 
Dose Discontinuation  
In case of unacceptable toxicity, the following general rules should apply to determine 
study treatment discontinuation/continuation: 
• 
If toxicity does not resolve within the timeframe defined in the protocol or does not 
resolve after level(s) of dose reduction per the protocol (see Table 12), the patient 
will discontinue the study drug(s) that caused dose delay/reduction. 
• 
Patients who discontinue chemotherapy (one or more agents) because of toxicity 
should not be systematically withdrawn from all study treatments.  The remaining 
study treatment should be continued based on the following guidelines: 
Patients who discontinue anthracyclines because of toxicity before completion 
of anthracycline dosing period may start taxanes and/or HER2-targeted 
treatment at the investigator’s discretion, as long as criteria defined in 
Section 4.3.2.2 are met to start taxane and/or HER2-targeted agents following 
anthracyclines.   
During the taxane-concurrent phase (Arm 1), patients who discontinue taxanes 
because of toxicity should complete 1 year of HER2-targeted treatment if 
possible.  
• 
For patients who discontinue one or more HER2-targeted agents because of toxicity, 
the rules listed below will apply. 
During the taxane-concurrent phase (Arm 1 only), taxane treatment should be 
continued to complete 3-4 cycles/12 weeks if possible. 


 
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Trastuzumab (Arm 1) or trastuzumab emtansine (Arm 2) may be continued if 
pertuzumab has been discontinued because of pertuzumab-specific toxicity 
(e.g., diarrhea or rash). 
In Arm 1, if trastuzumab is discontinued because of toxicity, then pertuzumab 
must also be discontinued.  Patients will continue to have safety, efficacy, and 
survival follow-up per the protocol. 
In Arm 2, in the case of trastuzumab emtansine−specific toxicity 
(e.g., thrombocytopenia or hepatotoxicity), trastuzumab should be considered 
to replace trastuzumab emtansine for up to 1 year of HER2-targeted therapy, if 
considered appropriate by the investigator.  Pertuzumab may be continued with 
trastuzumab treatment. 
In Arm 2, if trastuzumab emtansine is discontinued because of toxicity that 
precludes the substitution to trastuzumab (such as cardiac toxicity or infusion 
reaction), then pertuzumab must also be discontinued.  Patients will continue to 
have safety, efficacy, and survival follow-up per the protocol. 
 
5.1.4 
Dose Modifications/Management for Specific Adverse Events 
Please refer to local prescribing information/institution guidelines for AE management 
and dose modifications for protocol-approved anthracyline regimens (i.e., FEC, AC/EC, 
or dose-dense AC/EC).  
Please refer to local prescribing information for docetaxel, paclitaxel, trastuzumab, 
and/or pertuzumab for managing toxicities that are not described in detail in the protocol, 
including reversible chemotherapy-induced myelosuppression. 
Guidance on management of specific AEs related to study treatment safety profiles is 
provided in the following subsections for HER2-targeted agents and taxanes. 
5.1.4.1 
Specific Adverse Events for Multiple Agents 
During study treatment, some toxicity may be attributable to multiple agents.  It is 
important to evaluate the possible cause of toxicity and weigh risk versus benefit for 
each agent to determine the schema of dose modifications (e.g., which agent to prioritize 
for maintaining dose level and the sequence of dose modifications).  
General guidelines are provided in the following subsections based on the known safety 
profile of study drugs. 
5.1.4.1.1 
Infusion-Related Reactions 
IRRs are known to occur with the administration of monoclonal antibodies and have 
been reported with trastuzumab, trastuzumab emtansine, and pertuzumab.  Refer to 
Table 13 for guidance on management of IRR/allergic/hypersensitivity reactions. 


 
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Table 13 Management of Infusion-Related Reactions/Hypersensitivity 
Reactions 
Event 
Action to be Taken with HER2-Directed Therapy 
Grade 4 
IRR/allergic/hypersensitivity 
reaction 
Stop infusion.  Study treatment should be permanently 
discontinued.  
Supportive care with oxygen, β-agonists, antihistamines, 
antipyretics, or corticosteroids may be used, as appropriate, at 
the investigator's discretion. 
Patients should be monitored until complete resolution of 
symptoms. 
Grade 3 
IRR/allergic/hypersensitivity 
reaction 
Stop infusion.  
Supportive care with oxygen, β-agonists, antihistamines, 
antipyretics, or corticosteroids may be used, as appropriate, at 
the investigator's discretion.  Patients should be monitored 
until complete resolution of symptoms. 
May re-treat at investigator’s discretion.  In the event of a 
true hypersensitivity reaction (in which severity of 
reaction increases with subsequent infusions), study 
treatment should be permanently discontinued. 
Premedication with corticosteroids, antihistamines, and 
antipyretics may be used before subsequent infusions, at the 
investigator’s discretion. 
Grade 2 
IRR/allergic/hypersensitivity 
reaction 
Decrease infusion rate by 50% or interrupt infusion. 
Supportive care with oxygen, β-agonists, antihistamines, 
antipyretics, or corticosteroids may be used as appropriate at 
the investigator's discretion.  Patients should be monitored 
until complete resolution of symptoms. 
When symptoms have completely resolved, infusion may be 
restarted at ≤ 50% of prior rate and increased in 50% 
increments every 30 minutes as tolerated.  Infusions may be 
restarted at the full rate at the next cycle, with appropriate 
monitoring.  In the event of a true hypersensitivity reaction 
(in which severity of reaction increases with subsequent 
infusions), study treatment must be permanently 
discontinued. 
Premedication with corticosteroids, antihistamines, and 
antipyretics may be used before subsequent infusions, at the 
investigator’s discretion. 
HER2 = human epidermal growth factor-2; IRR = infusion-related reaction. 
 
5.1.4.1.2 
Pneumonitis/Interstitial Lung Disease 
Pneumonitis/ILD has been reported with trastuzumab emtansine, trastuzumab, 
pertuzumab, docetaxel, paclitaxel, or radiation.  Guidance on dose modifications/delays 
for pneumonitis/ILD is provided in Table 14. 


 
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Table 14 Dose Modification/Delays for Pneumonitis/Interstitial Lung 
Disease Adverse Events 
Adverse Event 
(NCI CTCAE v4.0) 
Docetaxel/Paclitaxel, Trastuzumab Emtansine, 
Trastuzumab/Pertuzumab, or Radiation 
Interstitial lung 
disease/pneumonitis 
Grade 1 or 2 
Discontinue study treatment permanently if not radiotherapy-related and 
suspected to be caused by study treatment.  For symptomatic (Grade 2) 
radiotherapy- related pneumonitis, discontinue if not resolving with 
standard treatment (e.g., steroids).  Relationship to radiotherapy should 
be determined on the basis of timing and location of radiographic 
abnormalities relative to the radiation treatment. 
Patients discontinued from trastuzumab emtansine for pneumonitis may 
not continue study treatment with trastuzumab. 
Interstitial lung 
disease/pneumonitis 
Grade 3 or 4 
Discontinue all study treatment permanently regardless of attribution. 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
 
5.1.4.1.3 
Neuropathy 
Neuropathy has been reported with trastuzumab emtansine, paclitaxel, and docetaxel.  
Guidance on dose modifications/delays for neuropathy is provided in Table 15. 
Table 15 Dose Modification/Delays for Neuropathy 
Paresthesias/Dysesthesias 
Persistent for > 7 Days or Causing the 
Next Cycle to be Delayed 
Docetaxel/Paclitaxel 
Trastuzumab Emtansine 
Grade 1 paresthesias/dysesthesias 
that do not interfere with function 
Maintain dose 
Maintain dose 
Grade 2 paresthesias/dysesthesias 
that interfere with function but not 
activities of daily living 
Continue to treat with dose 
reduced one level 
Maintain dose 
Grade 3 paresthesias/dysesthesias 
with pain or with function impairment 
that interfere with activities of daily 
living 
Withhold therapy dose until 
neuropathy < Grade 3.  
Reduce one dose level. 
Withhold therapy dose until 
neuropathy < Grade 3.  
May consider reducing one 
dose level.  
Grade 4 persistent 
paresthesias/dysesthesias that are 
disabling or life-threatening 
Discontinue therapy. 
Discontinue therapy if 
event does not resolve to 
Grade < 3 within 42 days. 
 
5.1.4.1.4 
Cardiovascular Safety Assessments and Dose Modifications 
Due to Cardiovascular Events 
All patients will undergo scheduled LVEF assessments:  ECHO or MUGA scans 
(Schedule of Assessments).  The results of the LVEF assessments will be used to 
determine whether trastuzumab, pertuzumab, and trastuzumab emtansine 
administration can be continued (Schedule of Assessments). 


 
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Asymptomatic Decrease in LVEF 
Refer to Figure 2  for the algorithm for continuation and discontinuation of study 
treatment on the basis of asymptomatic LVEF assessment. 
Grade 3−4 LVSD; Grade 3−4 Heart Failure; or Grade 2 Heart Failure 
Accompanied by LVEF < 45% 
Patients should be permanently discontinued from HER2-targeted treatment.  An SAE 
should be reported. 
Figure 2 HER2-Directed Therapy Management Based on LVEF 
Assessments 
 
EF = ejection fraction; LVEF = left ventricular ejection fraction. 
Note:  Baseline refers to the screening LVEF.  
a Three intermittent holds of study treatment will lead to discontinuation. 
 


 
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5.1.4.2 
Specific Adverse Events for Individual Agents 
For toxicities that have not been described in Section 5.1.3.1 and are likely to be 
attributable to trastuzumab, docetaxel, or paclitaxel on the basis of known safety profiles 
of these drugs, please refer to local prescribing information/institution guidelines for AE 
management and dose modifications.  
For toxicities that are likely to be attributable to trastuzumab emtansine or pertuzumab, 
please refer to the following subsections.  For some of the toxicities listed below, the 
investigator may consider modifying the dose of other agent(s) as well, on the basis of 
the investigator’s clinical judgment (e.g., rash and diarrhea may be attributed to both 
pertuzumab and chemotherapy).  
For neutropenia that is likely to be attributable to taxanes, please refer to local 
prescribing information in case of discrepancy between local prescribing information and 
the general guidelines (see Table 17) provided in the protocol.  
5.1.4.2.1 
Trastuzumab Emtansine 
Guidelines for managing trastuzumab emtansine specific AEs are provided in Table 16.  
Please refer to the Investigator’s Brochure for a full description of trastuzumab 
emtansine-related AE management and dose modification guidelines. 
Table 16 Dose Modification/Delays for Trastuzumab Emtansine−Specific 
Adverse Events 
Event 
Action to Be Taken 
Hepatotoxicity 
ALT 
For a Grade 2−3 increase in ALT that occurs on the laboratory evaluation for 
cycle Day 1 or the planned day of dosing, hold trastuzumab emtansine until 
ALT recovers to ≤ Grade 1.  Resume with dose reduction by one level for 
Grade 2 or 3 elevations.  Grade 2 or 3 ALT elevations that are noted between 
cycles do not require dose delay or reduction unless ALT remains elevated 
(≥ Grade 2) at the time of planned dosing. 
 
For a Grade 4 increase in ALT, discontinue trastuzumab emtansine.  A repeat 
laboratory evaluation (within 24 hours) may be done to exclude laboratory 
error prior to discontinuing study treatment. 


 
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Event 
Action to Be Taken 
AST 
For a Grade 2 increase in AST on the laboratory evaluation for cycle Day 1 or 
the planned day of dosing, hold trastuzumab emtansine until AST recovers to 
≤ Grade 1.  Resume without dose reduction when AST has recovered. 
 
For Grade 3 increase in AST on the laboratory evaluation for cycle Day 1 or 
the planned day of dosing, hold trastuzumab emtansine until AST recovers to 
≤ Grade 1.  Resume with dose reduction by one level when AST has 
recovered. 
 
For Grade 4 increase in AST, discontinue trastuzumab emtansine.  A repeat 
laboratory evaluation (within 24 hours) may be done to exclude laboratory 
error prior to discontinuing study treatment. 
TBILI 
For TBILI > 1.0 × ULN to ≤ 2.0 × ULN that occurs on the laboratory evaluation 
for cycle Day 1 or the day of planned dosing, hold trastuzumab emtansine 
until TBILI recovers to ≤ 1.0 × ULN (or direct bilirubin recovers to ≤ 1.0 × ULN 
for patients with Gilbert’s syndrome).  For TBILI elevations > 1.0 × ULN 
to ≤ 2.0 × ULN, resume when recovered, with a one-level dose reduction.  
 
For TBILI > 2 × ULN at any time (or direct bilirubin > 2 × ULN for patients with 
Gilbert’s syndrome), discontinue trastuzumab emtansine and report the event 
as an SAE (if applicable) or non-serious expedited AE (if applicable). 
NRH 
For any clinical signs of liver dysfunction, discontinue trastuzumab emtansine 
and have the patient evaluated by a hepatologist.  If there are signs of portal 
hypertension (e.g., ascites and/or varices) and a cirrhosis-like pattern is seen 
on CT scan of the liver, the possibility of NRH should be considered.  For liver 
biopsy guidelines, please see Appendix 5.  Trastuzumab emtansine should 
be permanently discontinued in the event of a diagnosis of NRH. 
 
Note:  Assess AST, ALT, and TBILI qw or as medically indicated until 
recovery.  Allow a maximum dose delay of 42 days from the last administered 
dose to recovery as described above or otherwise discontinue study 
treatment.   
For ALT or AST > 3.0 × ULN concurrent with TBILI > 2.0 × ULN, discontinue 
trastuzumab emtansine permanently. 
Thrombocytopenia 
Grade 2 or 3 on 
day of scheduled 
treatment 
Assess platelet counts qw or as medically indicated until recovery.  Hold 
study treatment until Grade ≤ 1.  Resume treatment without dose reduction.  If 
a patient requires two delays due to thrombocytopenia, consider reducing 
dose by one level. 
Grade 4 at any 
time 
Assess platelet counts qw or as medically indicated until recovery.  Hold 
trastuzumab emtansine until Grade ≤ 1, then resume with one-level dose 
reduction (i.e., from 3.6 to 3 mg/kg or from 3 to 2.4 mg/kg) in subsequent 
cycles.  If event occurs with 2.4 mg/kg dose, discontinue study treatment. 
Other Hematologic Toxicity 


 
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Event 
Action to Be Taken 
Grade ≥ 3 
Withhold study treatment until recovery to ≤ Grade 2.  Weekly CBC 
assessments should be done until recovery, or as medically indicated. 
A maximum dose delay of 42 days from the last administered dose to 
Grade ≤ 2 or baseline will be allowed; otherwise, patient must be discontinued 
from study treatment. 
AE = adverse event; CT = computed tomography; NRH = nodular regenerative hyperplasia; 
qw = weekly; SAE = serious adverse event; TBILI = total bilirubin; ULN = upper limit of normal. 
 


 
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5.1.4.2.2 
Pertuzumab 
Pertuzumab dose may be delayed because of toxicities.  Pertuzumab dose modifications 
are not permitted.   
Diarrhea and rash are considered EGFR-related risks on the basis of the mechanism of 
action of pertuzumab.  To prevent dehydration, early treatment of diarrhea with 
anti-diarrheal medication should be considered, and patients should be treated with 
fluids and electrolyte replacement, as clinically indicated.  Treatment recommendations 
for EGFR-associated rash include topical or oral antibiotics, topical pimecrolimus, and 
topical or (for severe reactions) systemic steroids.  These agents may be used in 
patients experiencing pertuzumab-related rash, as clinically indicated; although they 
have not been studied in this context. 
Please refer to the Investigator’s Brochure for full description of pertuzumab-related AE 
management and dose delay guidelines. 
5.1.4.2.3 
Taxane 
General guidelines on managing taxane-related neutropenia are provided in Table 17.  
Please refer to local prescribing information in case of discrepancy between local 
prescribing information and the general guidelines provided in the protocol. 
Table 17 Dose Modifications and Delays for Docetaxel- or 
Paclitaxel-Related Neutropenia 
For AEs that occur during a cycle but 
resolve prior to the next treatment 
cycle 
For Grades 2−4 
Maintain dose 
For AEs that require a delay in 
administration of the treatment cycle 
For Grades 2−4  
For docetaxel:  
Hold until ≥ 1500/mm
3.  
If recovery takes 1−3 weeks, maintain dose and add 
G-CSF. 
If receiving G-CSF and recovery takes  
1 week:  maintain dose 
2−3 weeks:  reduce one dose level 
 
For paclitaxel:  
Hold until ≥ 1000/mm
3.  
If recovery takes 1−3 weeks, maintain dose and add 
G-CSF. 
If receiving G-CSF and recovery takes 
1 week:  maintain dose 
2−3 weeks:  reduce one dose level 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
 


 
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5.1.4.3 
Radiotherapy Toxicity 
For radiotherapy-related skin toxicity Grade 3−4 (e.g., moist desquamation), study 
treatment should be held until recovery to Grade ≤ 1. 
For radiotherapy pneumonitis, refer to Table 14. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording AEs, including SAEs and 
non-SAEs of special interest; measurement of protocol-specified safety laboratory 
assessments; measurement of protocol-specified vital signs; and other 
protocol-specified tests that are deemed critical to the safety evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an AE is any untoward 
medical occurrence in a clinical investigation subject administered a pharmaceutical 
product, regardless of causal attribution.  An AE can therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.9. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) 
that is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., screening invasive procedures such as 
biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A SAE is any AE that meets any of the following criteria: 
• 
Fatal (i.e., the AE actually causes or leads to death) 
• 
Life threatening (i.e., the AE, in the view of the investigator, places the patient at 
immediate risk of death) 
This does not include any AE that, had it occurred in a more severe form or was 
allowed to continue, might have caused death. 


 
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• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.10). 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient’s ability to conduct normal life functions) 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
• 
Significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an AE (rated as mild, moderate, or severe, or according to NCI CTCAE criteria; see 
Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on 
the eCRF. 
SAEs are required to be reported by the investigator to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2 for reporting 
instructions). 
5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
AEs of special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).  AEs of special interest for this study include the following: 
• 
Potential cases of DILI as assessed by laboratory criteria for Hy’s law regardless of 
seriousness criteria and causality.  The following laboratory abnormalities define 
potential Hy’s Law cases: 
Treatment-emergent serum ALT and/or AST > 3 × ULN concurrent with serum 
TBILI > 2 × ULN 
Treatment-emergent serum ALT and/or AST > 3 × ULN concurrent with clinical 
jaundice 
 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings indicating an infection 
in a patient exposed to a medicinal product.  This term applies ONLY when a 
contamination of the study drug is suspected, NOT for infections supported by 
the mode of action (e.g., immunosuppression.) 
 


 
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5.2.4 
Selected Adverse Events  
Additional data will be collected for the selected AEs described below. 
5.2.4.1 
Cardiac General 
Symptomatic LVSD should be reported as an SAE.  If the diagnosis is heart failure, it 
should be reported as such and not in terms of the individual signs and symptoms 
thereof.   
Heart failure should be graded according to NCI CTCAE v4.0 for “heart failure” (Grade 2, 
3, 4, or 5) and in addition according to the NYHA classification. 
Heart failure occurring during the study and post-study (Section 5.6) must be reported, 
irrespective of causal relationship, and followed until one of the following occurs:  
resolution or improvement to baseline status, no further improvement can be expected, 
or death. 
5.2.4.2 
Asymptomatic Left Ventricular Systolic Dysfunction 
Asymptomatic declines in LVEF should generally not be reported as AEs because LVEF 
data are collected separately in the eCRF.  Exceptions to this rule are as follows: 
• 
An asymptomatic decline in LVEF ≥ 10 percentage-points from baseline to an LVEF 
< 50% must be reported as an AE with the term “ejection fraction decreased” as per 
NCI CTCAE v4.0, and, in addition, a comment in the AE comments field should 
confirm that this was asymptomatic. 
• 
An asymptomatic decline in LVEF requiring treatment delay or leading to 
discontinuation of trastuzumab emtansine, pertuzumab, or trastuzumab must also 
be reported. 
 
5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all AEs (see Section 5.2.1 for definition) 
are recorded on the Adverse Event eCRF and reported to the Sponsor in accordance 
with instructions provided in this section and in Section 5.4−Section 5.6. 
For each AE recorded on the Adverse Event eCRF, the investigator will make an 
assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity 
(see Section 5.3.3), and causality (see Section 5.3.4).   
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on AEs at each patient contact.  All AEs, whether 
reported by the patient or noted by study personnel, will be recorded in the patient’s 
medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention should be reported (e.g., SAEs 
related to invasive procedures such as biopsies). 


 
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After initiation of study drug, all AEs, regardless of relationship to study drug, will be 
reported until 28 days after the last dose of study drug.  After this period, investigators 
should report any deaths, SAEs, or other AEs of concern that are believed to be related 
to prior treatment with study drug (see Section 5.6).  
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all patient evaluation timepoints.  Examples of non-directive questions 
include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?”  
 
5.3.3 
Assessment of Severity of Adverse Events 
The AE severity grading scale for the NCI CTCAE (v4.0) will be used for assessing AE 
severity.  Table 18 will be used for assessing severity for AEs that are not specifically 
listed in the NCI CTCAE. 
Table 18 Adverse Event Severity Grading Scale 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; or 
intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily livinga 
3 
Severe or medically significant, but not immediately life threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; or limiting self-care activities 
of daily livingb,c 
4 
Life-threatening consequences or urgent intervention indicatedd 
5 
Death related to AEd 
AE = adverse event; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
Note:  Based on the NCI CTCAE (v4.0), which can be found at 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding one's self, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a SAE 
(see Section 5.4.2 for reporting instructions), per the definition of SAE in Section 5.2.2. 
d Grade 4 and Grade 5 events must be reported as SAEs (see Section 5.4.2 for reporting 
instructions), per the definition of SAE in Section 5.2.2. 
 


 
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5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an AE is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording AEs on 
the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event eCRF. 
5.3.5.1 
Diagnosis versus Signs and Symptoms 
Infusion-Related Reactions  
AEs that occur during or within 24 hours after study drug administration and are judged 
to be related to study drug infusion should be captured as a diagnosis 
(e.g., infusion-related reaction” or “allergic reaction”, “hypersensitivity,” “anaphylactic 
reaction”) on the Adverse Event eCRF.  If possible, avoid ambiguous terms such as 
"systemic reaction."  Associated signs and symptoms should be recorded on the 
dedicated Infusion-Related Reaction eCRF.  If a patient experiences both a local and a 
systemic reaction to the same dose of study drug, each reaction should be recorded 
separately on the Adverse Event eCRF, with signs and symptoms also recorded 
separately on the dedicated Infusion-Related Reaction eCRF.  
Other Adverse Events  
For AEs other than IRRs, a diagnosis (if known) should be recorded on the Adverse 
Event eCRF rather than individual signs and symptoms (e.g., record only liver failure or 
hepatitis rather than jaundice, asterixis, and elevated transaminases).  However, if a 
constellation of signs and/or symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, each individual event should be recorded 
on the Adverse Event eCRF.  If a diagnosis is subsequently established, all previously 


 
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reported AEs based on signs and symptoms should be nullified and replaced by one AE 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.2 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or 
serious secondary events.  However, medically significant AEs occurring secondary to 
an initiating event that are separated in time should be recorded as independent events 
on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe GI hemorrhage leads to renal failure, both events should be reported 
separately on the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
All AEs should be recorded separately on the Adverse Event eCRF if it is unclear as to 
whether the events are associated. 
5.3.5.3 
Persistent or Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation timepoints.  Such events should only be recorded once on the Adverse Event 
eCRF.  The initial severity (intensity or grade) of the event should be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, then 
the most extreme severity should also be recorded on the Adverse Event eCRF.  Details 
regarding any increases in severity should be captured on the Adverse Event Intensity 
or Grade Changes eCRF.  If the event becomes serious, then it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from “non-serious” to “serious,” providing the date 
that the event became serious, and completing all data fields related to SAEs. 
A recurrent AE is one that resolves between patient evaluation timepoints and 
subsequently recurs.  Each recurrence of an AE should be recorded separately on the 
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5.3.5.4 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an AE.  A laboratory test result must be 
reported as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an AE. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5 × ULN associated with cholecystitis), only the diagnosis 
(i.e., cholecystitis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., "elevated 
potassium," as opposed to "abnormal potassium").  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the AE.  For example, an elevated serum potassium level of 7.0 mEq/L 
should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.5 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an AE.  A vital sign result must be reported 
as an AE if it meets any of the following criteria: 
• 
Accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Clinically significant in the investigator’s judgment  
 


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an AE. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes.  The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens. 
5.3.5.6 
Hepatotoxicity 
The finding of an elevated ALT or AST (> 3 × ULN value) in combination with either an 
elevated TBILI (> 2 × ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury.  
Therefore, investigators must report as an AE the occurrence of either of the following: 
• 
Treatment-emergent ALT or AST > 3 × ULN value in combination with 
TBILI > 2 × ULN  
• 
Treatment-emergent ALT or AST > 3 × ULN value in combination with clinical 
jaundice 
 
NRH, whether or not accompanied by liver laboratory abnormalities, should be reported 
to the Sponsor as a SAE. 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a SAE or a non-SAE of special interest (see Section 5.4.2). 
5.3.5.7 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified AE reporting period (see Section 5.3.1) that are attributed by the 
investigator solely to progression of breast cancer should be recorded only on the Study 
Completion/Early Discontinuation eCRF.  All other on-study deaths, regardless of 
relationship to study drug, must be recorded on the Adverse Event eCRF and 
immediately reported to the Sponsor (see Section 5.4.2).  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should be used only for the occurrence of an 
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without preexisting heart disease, within 1 hour of the onset of acute symptoms or, in the 
case of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
5.3.5.8 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an AE only if the frequency, 
severity, or character of the condition worsens during the study.  When recording such 
events on the Adverse Event eCRF, it is important to convey the concept that the 
preexisting condition has changed by including applicable descriptors (e.g., “more 
frequent headaches”). 
5.3.5.9 
Recurrence/Progression of Breast Cancer 
Events that are clearly consistent with the expected pattern of recurrence/progression of 
the underlying disease should not be recorded as AEs.  These data will be captured as 
efficacy assessment data only.  In most cases, the expected pattern of 
recurrence/progression will be based on both clinical and laboratory findings (physical 
examination, biopsy, breast imaging, radiologic evidence, etc).  In rare cases, the 
determination of clinical recurrence/progression will be based on symptomatic 
deterioration.  However, every effort should be made to document 
recurrence/progression using objective criteria.  If there is any uncertainty as to whether 
an event is due to disease recurrence/progression, it should be reported as an AE. 
5.3.5.10 
Hospitalization or Prolonged Hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be documented 
and reported as a SAE (per the definition of SAE in Section 5.2.2), except as outlined 
below.   
The following hospitalization scenarios are not considered to be SAEs: 
• 
Hospitalization for respite care 
• 
Planned hospitalization required by the protocol (e.g., for study drug administration 
or insertion of access device for study drug administration) 
• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease 


 
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The patient has not suffered an AE 
• 
Hospitalization due solely to recurrence or progression of the underlying cancer 
 
The following hospitalization scenarios are not considered to be SAEs and should be 
reported as AEs instead:  
• 
Hospitalization for a minor condition for which the patient suffers an AE, but does 
not meet the definition of an overnight admission (e.g., tooth extraction) 
 
5.3.5.11 
Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied.  An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects.   
Any study drug overdose or incorrect administration of study drug should be noted on 
the Study Drug Administration eCRF.  
All AEs associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated AE fulfills serious criteria, the 
event should be reported to the Sponsor immediately (i.e., no more than 24 hours after 
learning of the event; see Section 5.4.2). 
5.3.5.12 
Patient-Reported Outcome Data 
AE reports will not be derived from PRO data.  However, if any patient responses 
suggestive of a possible AE are identified during site review of the PRO questionnaires, 
site staff will alert the investigator, who will determine if the criteria for an AE have been 
met and will document the outcome of this assessment in the patient's medical record 
per site practice.  If the event meets the criteria for an AE, it will be reported on the 
Adverse Event eCRF. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
SAEs 
• 
AEs of special interest 
• 
Pregnancies 
 


 
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The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 
• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
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 Contact Information for All Sites 
Medical Monitor: 
, M.D. (primary) 
Telephone No.: 
 
Mobile Telephone No.: 
 
 
Alternate Medical Monitor Contact Information for All Sites: 
Medical Monitor: 
, M.D., M.S. 
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").  
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
For reports of SAEs and non-SAEs of special interest, investigators should record all 
case details that can be gathered immediately (i.e., within 24 hours) on the 
Adverse Event 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. 
In the event that the EDC system is unavailable, a paper Serious Adverse 
Event/Non-Serious Adverse Event of Special Interest CRF and fax cover sheet should 
be completed and faxed to Roche Safety Risk Management or its designee immediately 


 
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(i.e., no more than 24 hours after learning of the event), with use of 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 systemsystem.  A pregnancy report will automatically be generated and 
sent to Roche Safety Risk Management.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should 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 Adverse Event 
eCRF. 
In the event that the EDC system is unavailable, a Pregnancy Report worksheet and 
Pregnancy fax cover sheet 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").  Once the EDC system 
is available, all information will need to be entered and submitted via this system. 
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.  Male patients whose partners are pregnant 
must use condoms for the duration of the pregnancy.  
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 
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In the event that the EDC system is unavailable, follow reporting instructions provided in 
Section 5.4.3.1. 
Additional information on any trastuzumab, pertuzumab, or and trastuzumab 
emtansine−exposed pregnancy and infant will be requested by Roche Drug Safety at 
specific timepoints (i.e., after having received the initial report, at the end of the second 
trimester, 2 weeks after the expected date of delievery, and at 3, 6, and 12 months of the 
infant’s life.) 
5.4.3.3 
Abortions 
Any spontaneous abortion should be classified as a SAE (as the Sponsor considers 
spontaneous abortions to be medically significant events), recorded on the Adverse 
Event 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 a SAE, recorded on the 
Adverse Event 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 
Adverse Event 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 Adverse Event 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.  Pathologic material, if already obtained to 


 
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evaluate the event, may be requested for review by the Sponsor or designee such as 
CEC. 
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 to prior study drug treatment or study procedures.  The Sponsor 
should also be notified if the investigator becomes aware of the development of cancer 
or a congenital anomaly/birth defect in a subsequently conceived offspring of a patient 
who participated in this study. 
The investigator should report these events to Roche Safety Risk Management on the 
Adverse Event eCRF.  If the Adverse Event eCRF is no longer available, the investigator 
should report the event directly to Roche Safety Risk Management via telephone (see 
"Protocol Administrative and Contact Information & List of Investigators"). 
During post-study survival follow-up, deaths attributed to progression of breast cancer 
should be recorded only on the Survival eCRF or Study Completion/Early 
Discontinuation eCRF.  
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all SAEs and non-serious AEs of special interest 
against cumulative product experience to identify and expeditiously communicate 
possible new safety findings to investigators, IRBs/ECs, and applicable health authorities 
based on applicable legislation. 
To determine reporting requirements for single AE cases, the Sponsor will assess the 
expectedness of these events using the following reference documents: 
• 
Trastuzumab Emtansine Investigator's Brochure 
• 
Pertuzumab Investigator's Brochure 
• 
Trastuzumab Investigator's Brochure 
• 
Summary of Product Characteristics and U.S. and other approved national 
prescribing information for doxorubicin, epirubicin, cyclophosphamide, 5-fluorouracil, 
docetaxel, and paclitaxel 
 


 
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The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
The iDMC will monitor the incidence of these expected events during the study.  An 
aggregate report of any clinically relevant imbalances that do not favor the test product 
will be submitted to health authorities. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The statistical considerations and analysis plan are summarized below.  Further details 
of the analyses will be described in the Statistical Analysis Plan (SAP) as part of the 
Data Analysis Plan (DAP).  The SAP overrides the analyses as described in the study 
protocol, as applicable. 
6.1 
DETERMINATION OF SAMPLE SIZE 
The sample size of the study is primarily driven by the analysis of IDFS in both the 
node-positive subpopulation and the overall protocol-defined population.  The statistical 
assumptions for the sample size calculations are summarized in Table 19. 
The IDFS analysis is powered at 80% for the node-positive subpopulation.  Additionally, 
the IDFS analysis with the assumptions stated below is powered at 82.5% for the overall 
protocol-defined population.  It is assumed that the overall protocol-defined population 
has approximately 10% more patients and 6% more IDFS events than the node-positive 
subpopulation.  These percentages were observed in the BCIRG 006 
(Slamon et al. 2006, 2009, 2011) trial after subsetting for the respective populations in 
this study.  
To detect a target HR of 0.64 in IDFS in the overall protocol-defined population and the 
node-positive subpopulation, approximately 171 and 160 IDFS events will be required to 
achieve 82.5% and 80% power, respectively, in the two populations, at a two-sided 
significance level of 5% using a log-rank test.  Approximately 1850 and 1665 patients will 
be enrolled in the overall protocol-defined population and node-positive subpopulation, 
respectively, including a dropout/ineligibility rate of 8% for both arms as estimated from 
previous trials in this setting.   The assumed 3-year IDFS rate for the control arms for 
both the populations were based on the IDFS rate from the BCIRG 006 data for the 
proposed populations and the assumed target HR from Study BO25126.  The six 
piecewise Kaplan-Meier estimates of the IDFS function in the control group for the 
overall protocol-defined population and the node-positive subpopulation were 99.6% and 
99.5% during the first 6 months, 98.2% and 98.0% during the second 6 months, 93.7% 
and 93.1% during Year 2, 89.5% and 89.1% during Year 3, 87.7% and 87.1% during 


 
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Year 4, and 86.2% and 85.5% during Year 5.  With the assumed target HR of 0.64, the 
estimated 3-year IDFS rate for the experimental arms in each of the two populations is 
shown in Table 19. 
Table 19 Summary of Sample Size Assumptions for IDFS 
 
BCIRG 006
3-Year 
IDFS for 
the 
proposed 
population  
Control Group 
(Study BO25126 
[APHINITY]) 
3-Year IDFS 
HR = 0.75 
Experimental 
Group 
(Study BO28407 
[KAITLIN]) 3-Year 
IDFS HR = 0.64 
Power 
AC-T
HP vs. 
AC-K
P 
No. IDFS 
Events  
Sample 
Size 
 
AC-TH 
AC-THP 
AC-KP 
 
Population 
 
 
 
 
 
 
Overall 
protocol−defined 
population 
86.3% 
89.5% 
93.2% 
82.5% 
171 
1850 
Node-positive 
subpopulation 
85.8% 
89.1% 
92.9% 
80.0%  
160 
1665 
AC-T = doxorubicin + cyclophosphamide followed by docetaxel; H = trastuzumab; HR = hazard 
ratio; IDFS = invasive disease−free survival; K = trastuzumab emtansine; P = pertuzumab. 
 
A total of approximately 1850 patients are anticipated to be enrolled.  The study is 
expected to be fully enrolled approximately 17 months after FPI.  The final IDFS analysis 
will be performed after at least 160 events have occurred in the node-positive 
subpopulation and approximately 171 events have occurred in the overall protocol-
defined population, which is projected to be approximately 57 months after FPI.   
The sample size calculations are performed using EAST v6 software (Cytel Inc.). 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patient enrollment will be tabulated by study site for each treatment arm.  Patient 
disposition and reasons for discontinuations will be summarized by treatment arm for all 
randomized patients.  Compliance with protocol-specified schedule of disease status 
clinical assessments will also be summarized by treatment arm.  In addition, protocol 
violations and eligibility violations will be summarized by treatment arm. 
6.3 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
The evaluation of treatment group comparability between the two treatment arms will 
include summaries of demographics and baseline characteristics, including age, sex, 
race, breast cancer characteristics, and medical history.  Descriptive statistics (mean, 
median, standard deviation, 25th percentile, 75th percentile, and range) will be 
presented for continuous variables, and proportions will be presented for categorical 
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6.4 
EFFICACY ANALYSES 
The randomized patient population will form the basis for all efficacy analyses unless 
otherwise specified.  In all efficacy analyses, following the intent-to-treat principle, 
patients will be included in the treatment group to which they are randomized by the 
IVRS/IWRS. 
6.4.1 
Primary Efficacy Endpoint 
The primary efficacy variable is IDFS, defined as the time between randomization and 
date of first occurrence of an IDFS event as described in the Efficacy Outcome 
Measures section.  Data from patients who have not had an event at the time of data 
analysis will be censored on the date on which they are last known to be alive and event 
free, on or before the clinical data cutoff date of the respective analysis. 
The log-rank test, stratified by the protocol-defined stratification factors (excluding 
region), will be used to compare IDFS between the two treatment arms.  Region will be 
excluded because of the potential that some of the strata may have very few patients, 
which would result in a loss of power.  The unstratified log-rank test results will also 
be provided for sensitivity analysis.  If, at the time of analysis, it is deemed that the 
smallest stratum per arm necessary to conduct robust stratified analyses contains 
< 5 events, unstratified analyses will be used as the primary analysis.  The Cox 
proportional hazards model, stratified by the previously noted stratification factors, 
excluding region, will be used to estimate the HR between the two treatment arms and 
the corresponding 95% CI.  The Kaplan-Meier approach will be used to estimate 3-year 
IDFS rates and corresponding 95% CIs for each treatment arm. 
6.4.2 
Secondary Efficacy Endpoints 
Secondary endpoints are IDFS plus second primary non-breast cancer, DFS, DRFI 
(defined in the Efficacy Outcomes Measures section), and OS. 
Secondary endpoints will be analyzed in a similar manner as the primary endpoint to 
estimate 3-year event rates (and 5-year survival rate for OS) for each treatment arm and 
the HR between the two treatment arms with 95% CI.  Data from patients who have not 
had an event at the time of data analysis will be censored at the date on which they are 
last known to be alive and event free or prior to the clinical data cutoff date for the 
respective analysis. 
The Kaplan-Meier approach will be used to estimate 5-year IDFS rates and 
corresponding 95% CIs for each treatment arm using both the overall protocol-defined 
population and the node-positive subpopulation. 


 
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6.4.3 
Hierarchical Testing Procedure 
A hierarchical testing procedure will be used in the order given below, on the primary 
and secondary endpoints to control the overall study type I error rate at 5%. 
1. 
Primary endpoint of IDFS in the node-positive subpopulation 
2. 
Primary endpoint of IDFS in the overall protocol-defined population 
3. 
Secondary endpoint of OS in the node-positive subpopulation 
4. 
Secondary endpoint of OS in the overall protocol-defined population 
 
Details of IDFS and OS interim analyses are specified in the Interim Analyses section. 
6.5 
SAFETY ANALYSES 
Patients who receive any dose of study treatment will be included in the safety analyses.  
Safety results will be summarized according to actual treatment received.  In particular, a 
patient assigned to trastuzumab who inadvertently receives a dose of trastuzumab 
emtansine will be analyzed in the trastuzumab emtansine safety group. 
The safety of trastuzumab emtansine in combination with pertuzumab and 
chemotherapy will be assessed through treatment exposure, summaries of AEs 
(including hepatic and cardiac events), SAEs, LVEF measurements, and laboratory test 
results, including platelet count, transaminases, and total/direct bilirubin. 
Study treatment exposure, such as treatment duration, number of cycles, dose intensity, 
and dose modification (including dose delay, dose reduction, etc.) will be summarized for 
each treatment arm with descriptive statistics.  Reasons for treatment discontinuation will 
also be summarized. 
Verbatim descriptions of AEs will be mapped to the MedDRA thesaurus terms and 
graded according to the NCI CTCAE v4.0.  All AEs, SAEs, AEs leading to death, and 
AEs leading to study treatment discontinuation that occur upon or after the first dose of 
study treatment (i.e., treatment-emergent AEs) will be summarized by NCI CTCAE grade.  
For repeated events of varying severity in an individual patient, the highest grade will be 
used in the summaries.  Deaths and causes of death will be summarized. 
Laboratory abnormalities for each treatment arm will be summarized by NCI CTCAE 
grade using shift tables. 
Incidence of cardiac events, defined as death from cardiac cause or severe CHF (NYHA 
Class III or IV) with a decrease in LVEF of ≥ 10% or more from baseline to an LVEF 
of < 50%, will be summarized for each treatment arm.  Other cardiac-related events 
(e.g., any mild symptomatic CHF [NYHA Class II] associated with a ≥ 10% drop in LVEF 
to < 50%; asymptomatic declines in LVEF requiring dose delay or discontinuation) will 
also be summarized.  Change in LVEF from baseline over time will be summarized for 
each treatment arm. 


 
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Incidence of hepatic AEs, pulmonary AEs, pneumonitis, ILD, NRH, and Hy’s law cases 
will be summarized for each treatment arm.  Additional analyses of transaminases and 
liver function laboratory tests will also be performed.  
Subgroup safety analyses (e.g., incidence of AEs during radiotherapy for the subgroup 
of patients who receive radiotherapy) may be performed and will be detailed in the SAP. 
6.6 
PATIENT-REPORTED OUTCOME ANALYSES 
HRQoL data will be captured using the following questionnaires:  the EORTC QLQ-C30 
and the modified breast cancer module, QLQ-BR23 (Appendix 8). 
Summary statistics (mean, SD, median, 25th and 75th percentiles, and range) of linear 
transformed scores will be reported for all the subscales (including peripheral 
neuropathy, joint/muscle pain, and skin problems) of the EORTC QLQ-C30 
questionnaire and the modified BR23 for each assessment time-point according to the 
EORTC scoring manual guidelines for each assessment timepoint.  The mean change of 
the linear transformed scores from baseline (and 95% CIs using the normal 
approximation) will also be assessed.  Line charts depicting the mean changes (and 
standard errors) of subscales over time will be provided for each treatment arm from the 
baseline assessment.   
Completion and compliance rates will be summarized at each timepoint for each 
measure by treatment arm with reasons for missing data.  Only patients with a baseline 
assessment and at least one post-treatment assessment will be included in the analyses.   
The number and proportion of patients reporting clinically meaningful differences in 
treatment-related symptoms based on the threshold reported by Cocks et al. (2011) at 
each time-point will be the primary analysis. In addition, the proportion of patients 
reporting “a little” or “quite a bit” for each of the neuropathy, joint/muscle pain and 
skin single items will be reported by treatment arm. 
The proportion of patients with clinically meaningful deterioration in global health 
status/HRQoL and function (physical, role, and cognitive) scales will also be assessed. 
The deterioration will be based on the respective thresholds reported by 
Osaba  et  al  (1998) and Cocks et al. (2011).  
Analysis will be performed to compare the two treatment arms at the “Cycle 1 Day 1 
(C1D1) of anthracycline treatment period” timepoint and the “C1D1 of HER2-targeted 
treatment period” timepoint to descriptively assess treatment group comparability 
between the two treatment arms. The “‘C1D1 of HER2-targeted treatment” timepoint will 
be utilized as the reference for time-to-event Kaplan-Meier analysis, provided that the 
treatment groups are comparable at this timepoint.   


 
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The time to clinically meaningful deterioration in the global health status/HRQoL 
subscale (question 29 and 30 of the QLQ-C30) will be used to assess the time from first 
HER2-targeted treatment to worsening in HRQoL.  An event for a given patient is a 
decrease in mean score by 10 points or more, at two consecutive time points, with a 
10-point or greater change in mean score defined as a “moderate” to “very much” 
perceived important change from the patient’s perspective (Osoba et al. 1998).  Time-to-
event analyses to investigate the time to clinically meaningful deterioration in function 
(physical, role, and cognitive function scales) will also be assessed using the published 
thresholds by Cocks et al. (2011).  A stratified log-rank test will be used to test the 
differences between treatment arms. 
Additionally, in order to elucidate if the taxane-sparing arm reduces patient treatment 
burden, analyses of covariance (repeated mixed effects model) will be used to compare 
change from baseline in the global health status/HRQoL and functional scales of the 
EORTC QLQ-C30.  In each mixed model, change from baseline will be the response 
variable; treatment, visit, and treatment by visit interaction terms will be the fixed factors; 
and the patient will be denoted as a repeated factor. If substantial interaction effect is 
present, pair-wise comparison will be conducted. 
6.7 
EXPLORATORY ANALYSES 
The relationship between molecular markers (e.g., HER family receptors; see 
Section 3.4.4) and efficacy outcomes will be evaluated as exploratory analyses.  Efficacy 
outcomes considered for this analysis will include IDFS and OS, as appropriate. 
Analyses will also be performed to explore the correlation between biomarkers, ATAs to 
trastuzumab emtansine, and clinical outcomes as appropriate.  
The EQ-5D is a generic, preference-based health utility measure with questions about 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression that are used 
to build a composite of the patient’s health status.  A single summary index is calculated 
from the EQ-5D health states after application of a weighted formula and will be utilized 
in this study for economic modeling.  The results will not be reported in the CSR. 
6.7.1 
Subgroup Analyses for Efficacy 
Exploratory analyses (e.g., for subgroups per nodal status, hormonal receptor status, 
HER2 mRNA expression level status [high vs. low], PIK3CA mutation status, or other 
important prognostic factors) will be performed for IDFS and OS, as appropriate, in the 
overall protocol-defined population and node-positive subpopulation to assess the 
robustness and consistency of treatment effect of trastuzumab emtansine plus 
pertuzumab.   


 
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6.8 
INTERIM ANALYSES 
6.8.1 
Interim Efficacy Analyses 
One interim analysis of IDFS and three interim analyses of OS in both the node-positive 
subpopulation and the overall protocol-defined population are planned. 
A futility analysis may be incorporated to evaluate lack of superiority for the treatment 
arm of trastuzumab emtansine + pertuzumab following anthracyclines.  The timing and 
details of this futility analysis will be described in the SAP and aligned with the 
availability of information from other relevant studies (e.g., KRISTINE and/or 
APHINITY). 
Interim IDFS Analyses 
An interim efficacy analysis of IDFS will be performed after approximately 75% of the 
targeted IDFS events are observed in the overall protocol-defined population (i.e. 128 of 
the 171 target events) and node-positive population (i.e. 120 of 160 target events) and is 
projected to occur approximately 43 months from FPI (see Table 20).  A hierarchical 
testing procedure will be used for the primary endpoint IDFS for the node-positive 
subpopulation and the overall protocol-defined population as defined in Section 6.4.3.  
The type I error will be controlled at the 5% level at the interim and final analyses within 
the node-positive subpopulation and the overall protocol-defined population using a Lan-
DeMets α-spending function with an O’Brien-Fleming boundary.  
The interim analysis will be performed by the iDCC statistician, and the results will be 
presented to the iDMC by the iDCC statistician.  If the interim analyses in both 
populations cross the interim efficacy boundaries of the O’Brien-Fleming design, on the 
basis of the totality of both efficacy and safety data, the iDMC may recommend releasing 
the primary endpoint results before the targeted number of 160 and 171 events have 
occurred in the node-positive subpopulation and overall protocol-defined population, 
respectively.  In this case, the Sponsor will be unblinded to study results, and a full data 
package including the first OS interim analysis results will be prepared for discussion 
with the regulatory authorities.  The study will continue until 10 years of follow-up from 
FPI have occurred, and the IDFS analysis will be updated descriptively.  If the IDFS 
interim analyses fail to cross the statistical efficacy boundaries of the O’Brien-Fleming 
design, then the study will continue as planned.  The Sponsor will conduct the final 
analyses.  
Table 20 summarizes the planned IDFS analyses in the overall protocol-defined 
population and the node-positive subpopulation; the efficacy stopping boundaries based 
on the expected number of events; and the estimated timing of these analyses.  The 
boundaries to be used at each interim and final IDFS analysis will depend on the number 
of IDFS events actually included in the analyses and so may vary from the numbers 
shown below. 


 
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Table 20 Summary of Planned Analyses of IDFS in Overall 
Protocol-Defined Population and Node-Positive Subpopulation 
Overall Population 
Node-Positive Population 
Analysis of 
IDFS 
No. of 
Events 
Efficacy Stopping 
Boundarya,b 
No. of 
Events 
Efficacy Stopping 
Boundarya,b 
Estimated 
Timingc 
Interim 
128 
p < 0.0193 or 
observed HR < 0.6618 
120 
p < 0.0193 or 
observed HR < 0.6528 
43 months 
Final 
171 
p < 0.0442 or 
observed HR < 0.7353 
160 
p < 0.0442 or 
observed HR < 0.7279  
57 months 
HR = hazard ratio; IDFS = invasive disease−free survival. 
a p-value will be based on two-sided stratified log-rank test. 
b Efficacy stopping boundaries follow O’Brien-Fleming design. 
c Time from the enrollment of first patient to data cutoff. 
 
 
Interim OS Analyses 
Three interim OS analyses and one final OS analysis are planned in both the overall 
protocol-defined population and the node-positive subpopulation.  The assumed 3-year 
OS rate for the control arms for both populations were based on the OS rate from the 
BCIRG 006 data for the proposed population and the assumed target HR from 
Study B025126.  The five piecewise Kaplan-Meier estimates of the OS function in the 
control group for the overall protocol-defined population and the node-positive 
subpopulation were 99.7% and 99.7% during Year 1, 98.6% and 98.5% during Year 2, 
96.1% and 95.7% during Year 3, 94.1% and 93.9% during Year 4, and 92.1% and 
91.9% during Year 5.  The estimated 3-year OS rate for the experimental arms in each 
of the two populations is shown in Table 21, with an assumed target HR of 0.80 between 
the control arm (AC-THP) and the experimental arm (AC-KP). 
Table 21 Summary of Assumptions for Overall Survival Analyses 
Population 
BCIRG 006 3-Year 
OS for the 
proposed 
populations AC-TH
Control Group 
(Study BO25126 
[APHINITY]) 3-Year OS 
AC-THP HR = 0.80 
Experimental Group 
(Study BO28407 
[KAITLIN]) 3-Year OS 
AC-KP HR = 0.80 
Overall 
protocol−defined 
population 
95.2% 
96.1% 
96.9% 
Node-positive 
subpopulation 
94.7% 
95.7% 
96.6% 
AC-T = doxorubicin + cyclophosphamide followed by docetaxel; H = trastuzumab; HR = hazard 
ratio; IDFS = invasive disease−free survival; K = trastuzumab emtansine; OS = overall survival 
P = pertuzumab. 
 


 
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For the OS interim analyses and final OS analysis, the Lan-DeMets α-spending function 
with an O’Brien-Fleming boundary will be used such that the overall type I error will be 
controlled at the 5% level for the OS endpoint.  With the study sample size and 
approximately 10 years of follow-up from FPI, this study has 38% power in the overall 
protocol-defined population and 35% power in the node-positive subpopulation to detect 
an HR of 0.8.  This in the overall protocol-defined population corresponds to a 
0.8% improvement in 3-year OS, from 96.1% in the control arm to 96.9% in the 
experimental arm and in the node-positive subpopulation to a 0.9% improvement in 
3-year OS, from 95.7% in the control arm to 96.6% in the experimental arm, at a 
two-sided significance level of 5%.  
All OS interim and final analyses will be performed by the Sponsor subsequent to the 
primary IDFS analysis and after the Sponsor is unblinded.  If the interim IDFS analyses 
in both the node-positive subpopulation and the overall protocol-defined population cross 
the statistical efficacy boundaries, the first OS interim analysis will be performed in both 
populations hierarchically at that time (approximately at 43 months from FPI).  If the final 
IDFS analysis crosses the statistical boundaries, then the second interim OS analysis 
will be performed hierarchically at the time of the final IDFS analysis (approximately 
57 months from FPI), followed by the third and the final OS analyses performed 
hierarchically in both populations (planned to occur at 84 months [7 years] and 
120 months [10 years], respectively, from FPI).  If, at any OS interim analysis, the 
O’Brien-Fleming efficacy boundary is crossed, that analysis of OS will be considered as 
confirmatory and all subsequent analyses of OS will be considered as descriptive.  
Table 22 summarizes the planned OS analyses in the overall protocol-defined 
population and the node-positive subpopulation, respectively; the efficacy stopping 
boundaries based on the expected number of events; and the estimated timing of these 
analyses.  The boundaries to be used at each interim and final IDFS analysis will 
depend on the number of IDFS events actually included in the analyses and may vary 
from the numbers shown below. 


 
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Table 22 Summary of Planned Analyses of Overall Survival in Overall 
Protocol-Defined Population and Node-Positive Subpopulation 
Overall Population 
Node-Positive Population 
Analysis of OS 
No. of 
Events 
Efficacy Stopping 
Boundary a,b 
No. of 
Events 
Efficacy Stopping 
Boundarya,b 
Estimated 
Timingc 
Interim 1 
(Interim IDFS) 
50 
p < 0.0000033 or 
observed 
HR < 0.2647 
50 
p < 0.000013 or 
observed 
HR < 0.2908 
43 months 
Interim 2 
(Final IDFS) 
87 
p < 0.000643 or 
observed 
HR < 0.4811 
83 
p < 0.000908 or 
observed 
HR < 0.4827 
57 months 
Interim 3 
153 
p < 0.01316 or 
observed 
HR < 0.6697 
138 
p < 0.01281 or 
observed 
HR < 0.6545 
84 months 
Final 
224 
p < 0.04585 or 
observed 
HR < 0.7658  
203 
p < 0.04591 or 
observed 
HR < 0.7556 
120 months 
HR = hazard ratio; IDFS = invasive disease−free survival; OS = overall survival. 
a 
p-value will be based on two-sided stratified log-rank test. 
b 
Efficacy stopping boundaries follow O’Brien-Fleming design. 
c 
Time from the enrollment of first patient to data cutoff. 
 
6.8.2 
Interim Safety Analyses  
An iDMC will monitor accruing patient safety data at least once every 6 months during 
the study until the last patient has completed study treatment.  In addition, safety data 
related to concurrent radiotherapy and/or hormonal therapy, SAEs, and deaths will be 
monitored by the iDMC at least once every 3 months during the study until the last 
patient has completed study treatment.  At each iDMC review, relevant safety 
information from ongoing trastuzumab emtansine and/or pertuzumab studies will also be 
provided to the iDMC. 
After the first 600 patients have been randomized and followed for 3 months (anticipated 
to occur at approximately 13 months after FPI), the iDMC will perform an interim safety 
analysis regarding overall numbers of deaths (all causes, including cardiac deaths) and 
hepatic events defined as confirmed Hy’s law cases.  The CEC will communicate their 
findings to the iDMC to aid iDMC review. 
If an absolute increase of > 3% in the percentage of death (from any cause) is observed 
in the trastuzumab emtansine + pertuzumab arm compared with the trastuzumab 
+ pertuzumab arm, the iDMC will consider a recommendation of pausing enrollment for 
further data review, stopping the trial, or modifying the trial. 


 
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If the true difference in the percentage of death is > 3% (e.g., 2% vs. 6%), then there is 
approximately a 70% chance of observing an absolute difference of > 3% at the interim 
with 600 patients.  Table 23 presents the probability of observing an increase of > 3% in 
the percentage of deaths in the trastuzumab emtansine + pertuzumab arm compared 
with the trastuzumab + pertuzumab arm, with different assumptions for the percentage 
of deaths in the two treatment arms. 
Table 23 Probability of Observing > 3% Increase of Death 
Percentage of Deaths 
Trastuzumab + 
Pertuzumab (n = 300) 
Trastuzumab Emtansine 
+ Pertuzumab (n = 300) 
Probability of Observing True Treatment 
Difference > 3% Increase  
2% 
2% 
0.00 
2% 
3% 
0.05 
2% 
4% 
0.20 
2% 
5% 
0.45 
2% 
6% 
0.70 
 
If an absolute increase of > 3% in the percentage of Hy’s law cases (confirmed by the 
independent CEC) is observed in the trastuzumab emtansine + pertuzumab arm 
compared with the trastuzumab + pertuzumab arm, the iDMC will consider a 
recommendation of pausing enrollment for further data review, stopping the trial, or 
modifying the trial. 
If the true difference in the percentage of confirmed Hy’s law cases is > 3% (e.g., 0.33% 
vs. 3.67%), then there is approximately a 54% chance of observing an absolute 
difference of > 3% at the interim with 600 patients.  Table 24 presents the probability of 
observing a > 3% increase in the percentage of Hy’s law cases in the trastuzumab 
emtansine + pertuzumab arm compared with the trastuzumab + pertuzumab arm, with 
different assumptions for the number of Hy’s law cases in the two treatment arms. 


 
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Table 24 Probability of Observing > 3% Increase in Confirmed Hy’s Law 
Cases 
Number of Confirmed Hy’s Law Cases (%) 
Trastuzumab 
+Pertuzumab 
(n = 300) 
Trastuzumab Emtansine + 
Pertuzumab (n = 300) 
Probability of Observing True Treatment 
Difference > 3% Increase 
1 (0.33%) 
4 (1.33%) 
< 0.01 
1 (0.33%) 
6 (2%) 
0.05 
1 (0.33%) 
8 (2.67%) 
0.19 
1 (0.33%) 
10 (3.33%) 
0.43 
1 (0.33%) 
11 (3.67%) 
0.54 
1 (0.33%) 
12 (4%) 
0.66 
 
The iDMC will work according to guidelines defined in the iDMC Charter.  The iDMC 
Charter will contain details regarding frequency of meetings, guidelines for decision 
making, and processes for requesting further information.  The iDMC members will 
review and sign off the charter before the first iDMC review. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for 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 Sponsor will request data clarification from the sites, which the sites will resolve 
electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’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 and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 
Data from paper PRO questionnaires will be entered into the EDC system by site staff. 


 
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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, PROs, 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. 
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 7.5. 
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 


 
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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 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO data (if applicable), Informed Consent Forms, 
laboratory test results, and medication inventory records, must be retained by the 
Principal Investigator for at least 15 years after completion or discontinuation of the 
study, or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.   
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 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).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union/EEA will comply with the E.U. Clinical Trial Directive 
(2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Assent or 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 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. 


 
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The Informed Consent Form will contain a separate section that addresses the use of 
remaining mandatory samples for optional exploratory research.  The investigator or 
authorized designee will explain to each patient the objectives of the exploratory 
research.  Patients will be told that they are free to refuse to participate and may 
withdraw their specimens at any time and for any reason during the storage period.  A 
separate, specific signature will be required to document a patient's agreement to allow 
any remaining specimens to be used for exploratory research.  Patients who decline to 
participate will not provide a separate signature. 
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.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
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. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
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.  


 
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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 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting SAEs to the local health 
authority and IRB/EC.  Investigators may receive written IND safety reports or other 
safety-related communications from the Sponsor.  Investigators are responsible for 
ensuring that such reports 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 (i.e., last patient, last 
visit). 


 
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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. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
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. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will have an SC that will provide guidance on the protocol and study design 
and the SAP and will provide guidance on the review of any relevant study-related 
documents or procedures to ensure that the data will be collected in a timely fashion and 
will be accurate and complete.  A separate SC charter will outline the committee’s 
composition, meeting timelines, and members’ roles and responsibilities.  Additionally, 
the SC will be kept apprised of all relevant efficacy and safety data from this and related 
clinical trials. 
In addition, the study will have an iDMC and CEC (see Section 3.1.1 and Section 3.1.2). 
9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 


 
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The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization 
application has been filed or approved in any country, the Sponsor aims to submit a 
journal manuscript reporting primary clinical trial results within 6 months after the 
availability of the respective clinical study report.  In addition, for all clinical trials in 
patients involving an IMP for which a marketing authorization application has been 
filed or approved in any country, the Sponsor aims to publish results from analyses of 
additional endpoints and exploratory data that are clinically meaningful and 
statistically sound..,  
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. 
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. 
9.6 
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. 
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). 


 
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(AC→TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive 
early breast cancer patients: BCIRG 006 study. Cancer Res 2009;69(24 Suppl 
3):62. 


 
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Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast 
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Smith I, Procter M, Gelber RD, et al., and the HERA Study Team. 2-year follow-up of 
trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a 
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Appendix 1  
Schedule of Assessments 
 
Screeninga 
(30 days) 
Anthracycline 
Treatment 
Period 
HER2-Targeted Treatment Period within 
3 Days of Day 1 of Cycle Number X 
End-of-Treatment 
Visitb 
Follow-Upc 
(± 28 days) 
Follow-Upc 
(± 42 days) 
 
 
Cycles 1a−3 
or Cycle 4 
Cycles 1−4 (concurrent taxane in 
Arm 1 only) 
Cycles 
5−18 
 
Year 
1−2 
Year 
3−5 
Year 6−10 
 
 
Day 1 
Day 1 
Day 8 
Day 15 
Day 1 
 
 
 
 
Informed consentd 
x 
 
 
 
 
 
 
 
 
 
Mandatory tumor tissue 
sample for 
determination of HER2, 
ER/PR; and exploratory 
biomarkerse 
x 
xe (at disease recurrence) 
Bilateral mammogramf,g 
x (within 
6 months) 
x (q12mo) 
Chest X-rayh 
x (within 
2 months) 
As clinically indicated 
Demography, medical 
history 
x 
 
 
 
 
 
 
 
 
 
Disease status 
assessmentg 
x 
x (q3mo) 
x 
(q3mo) 
x 
(q6mo) 
x (q12mo) 
Physical examinationg,i 
x 
x (Cycle 1) 
x 
 
 
x 
x 
x 
(q3mo) 
x 
(q6mo) 
x (q12mo) 
Vital signsj 
x 
x 
x 
x (for 
paclitaxel 
only) 
x (for 
paclitaxel 
only) 
x 
 
 
 
 
ECOG Performance 
x 
 
 
 
 
 
x 
 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
 
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Screeninga 
(30 days) 
Anthracycline 
Treatment 
Period 
HER2-Targeted Treatment Period within 
3 Days of Day 1 of Cycle Number X 
End-of-Treatment 
Visitb 
Follow-Upc 
(± 28 days) 
Follow-Upc 
(± 42 days) 
 
 
Cycles 1a−3 
or Cycle 4 
Cycles 1−4 (concurrent taxane in 
Arm 1 only) 
Cycles 
5−18 
 
Year 
1−2 
Year 
3−5 
Year 6−10 
 
 
Day 1 
Day 1 
Day 8 
Day 15 
Day 1 
 
 
 
 
Status 
ECG 
x 
As clinically indicated 
x 
 
 
 
ECHO/MUGAk 
x 
xk (end of last 
cycle) 
xk (in last week of Cycle 2, and every 
4 cycles thereafter) 
xk 
xk 
xk 
 
PRO HRQoL 
assessmentl 
 
xl 
xl 
 
 
xl 
x 
xl 
(q6mo) 
 
 
Hematologym 
xn 
xo 
xo 
xo (for 
paclitaxel 
only)p 
xo (for 
paclitaxel 
only)p 
xo 
x 
xm 
 
 
Serum chemistryq 
xn 
xo 
xo 
 
 
xo 
x 
xq 
 
 
HBV and HCV serologyr 
x 
As clinically indicated 
INR and aPTT 
xn 
As clinically indicated 
Pregnancy tests 
xn 
 
xo,s (C1D1 then every 3 cycles thereafter) 
 
xs 
 
 
Clinical genotyping 
whole blood samplet 
 
xt 
x (C1D1 
predose) 
x (C1D1 
predose
) 
 
 
 
x 
xs 
 
Mandatory serum and 
plasma sample for 
exploratory biomarker 
analysisu,v 
 
xu (at disease recurrence) 


Appendix 1  
Schedule of Assessments (cont.) 
 
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Screeninga 
(30 days) 
Anthracycline 
Treatment 
Period 
HER2-Targeted Treatment Period within 
3 Days of Day 1 of Cycle Number X 
End-of-Treatment 
Visitb 
Follow-Upc 
(± 28 days) 
Follow-Upc 
(± 42 days) 
 
 
Cycles 1a−3 
or Cycle 4 
Cycles 1−4 (concurrent taxane in 
Arm 1 only) 
Cycles 
5−18 
 
Year 
1−2 
Year 
3−5 
Year 6−10 
 
 
Day 1 
Day 1 
Day 8 
Day 15 
Day 1 
 
 
 
 
OBRP whole blood 
sample for genetic 
analysis (optional)v 
 
xv(to be done at baseline if possible) 
Adverse eventsw 
x 
x 
x 
x (for 
paclitaxel 
only) 
x (for 
paclitaxel 
only) 
x 
x 
xw 
Concomitant 
medicationsx 
x 
x 
x 
x (for 
paclitaxel 
only) 
x (for 
paclitaxel 
only) 
x 
x 
 
 
 
Record post-recurrence 
anti-cancer−related 
therapiesy 
 
As required 
Survival 
post-recurrencey 
 
q12mo 
AE = adverse event; ALP = alkaline phosphatase; aPTT = activated partial thromboplastine time; ATA = anti-therapeutic antibody; C1D1 = Cycle 1 Day 1; 
CT = computed tomography; eCRF = electronic Case Report Form; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; ER = estrogen receptor; 
EORTC = European Organisation for Research and Treatment of Cancer; EQ-5D = EuroQol 5-Dimension Questionnaire; FFPE = formalin-fixed paraffin-embedded; 
FPI = first patient initiation; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCG = human chorionic gonadotropin; 
HCV = hepatitis C virus; HER2 = human epidermal growth factor-2; HRQoL = health-related quality of life; IDFS = invasive disease−free survival; 
IVRS/IWRS = interactive voice response system/interactive web response system; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
MUGA = multiple-gated acquisition; OBRP = optional biomarker research program; pac = paclitaxel; PK = pharmacokinetic; PR = progesterone receptor; 
PRO = patient-reported outcome; QLQ-BR23 = Quality of Life Questionnaire−Breast Cancer 23; QLQ-C30 = Quality of Life Questionnaire−Core 30; qw = weekly; 
SAE = serious adverse event; SoC = standard of care; TBILI = total bilirubin; ULN = upper limit of normal. 


Appendix 1  
Schedule of Assessments (cont.) 
 
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a Screening to be performed within 30 days prior to randomization.  The randomization visit may be combined with anthracycline Cycle 1 Day 1 visit.  Patients 
should receive their first dose of study treatment on the day of randomization, if possible, but no later than 7 days after randomization.  No more than 9 weeks 
(63 days) may elapse between definitive breast surgery (or the last surgery if additional resection required for breast cancer) and randomization. 
b End-of-treatment visit or early termination visits will optimally be scheduled within 28 to 42 days following the last dose of study treatment. 
c The follow-up period begins from the date of the end-of-treatment visit, with a duration of up to 10 years from the date of randomization of the first patient. 
d Informed consent may be obtained at any time (including prior to the 30-day screening period) but must be obtained prior to the performance of any screening 
assessments.  Results of screening tests or examinations performed as SoC prior to obtaining informed consent and within 30 days prior to randomization may 
be used rather than repeating required tests unless the tests are required to be within 7 days prior to randomization. 
e FFPE tumor tissue must be obtained for central laboratory assessment of HER2 status for eligibility.  ER/PR determination will also be evaluated by a central 
laboratory.  A tissue block (FFPE material) collected at definitive breast cancer surgery is acceptable.  Sections and/or slides are not acceptable.  Biomarker 
analysis will only be performed on tissue from randomized patients.  At recurrence, tumor biopsy sample should be taken if the tumor is accessible for biopsy 
sample collection without (in the investigator’s opinion) significant risk to the patient.  In case tissue becomes available at time of recurrence, this tissue will be 
used for exploratory biomarker analysis.  If a biopsy is collected as part of routine medical practice at relapse/recurrence, a tissue block or up to five unstained 
slides should be sent for biomarker analysis in order to gain better understanding of resistance mechanisms. 
f 
Bilateral mammogram (or breast MRI if indicated) is to be performed within 6 months prior to randomization.  If mammogram is not available, then it could be 
performed after surgery.  During treatment and follow-up, mammograms of any remaining breast tissue should be performed at least annually ( ± 28 days) since 
the previous mammogram.  If there is no remaining breast tissue, then mammograms are not mandated. 
g Disease status based on all available clinical assessments should be documented from the date of randomization at the following timepoints:  every 3 months 
( ± 3 days) during study treatment and for the first 2 years after study treatment completion/early termination, every 6 months ( ± 7 days) from Years 3 to 5 after 
study treatment completion, and annually ( ± 28 days) from Year 6 up to Year 10 after study treatment completion, unless a recurrence that is defined as an 
IDFS event in Section 3.4.1 has occurred.  Patients who have a diagnosis of in situ breast cancer or second non-breast cancer should be maintained on a 
regular follow-up schedule as described above wherever possible in order to fully capture any subsequent recurrent invasive disease events.  Such patients 
should continue with adjuvant study treatment, if not yet completed and considered by the investigator to be in the patient’s best interest, whenever possible.  In 
addition to physical examinations and mammograms, liver function tests, bone scans, chest X-rays/diagnostic CT, liver imaging, or other radiographic modality 
may be considered when clinically indicated to exclude metastatic disease and within a timeline as per current local standard of practice.  Whenever possible, 
disease recurrence should be confirmed histopathologically.  In cases of first disease recurrence (an IDFS event as defined in Section 3.4.1) diagnosed at any 
time during the study, patients will be out of the study schedule and will be followed annually starting 1 year after first recurrence until Year 10 from FPI for 
survival, anti-cancer medications, and new relapse (recurrence or disease progression) events. 
h If a CT scan is already available within 2 months prior to randomization, it may be used in lieu of chest X-ray. 
i 
A complete physical examination, including height and weight, should be measured at baseline.  Throughout the study, limited symptom-directed physical 
examination focusing on organ systems related to AE or disease may be performed.  Weight is to be measured on Day 1 of the specified cycles and compared 
to baseline.  If ± 10% or greater variation occurs, then study treatment doses will be recalculated.  Dose must be readjusted for ± 10% or greater weight change 
based on the previous weight used for dose recalculation.  For anthracyclines and taxanes, local standards for dose calculations will be followed. 
j 
Vital signs include blood pressure, pulse rate, and body temperature.  Vital signs should be obtained and reviewed, but it is not required that they should always 


Appendix 1  
Schedule of Assessments (cont.) 
 
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be entered into the eCRF.  Abnormal vital signs at any time during the course of study treatment should be recorded as AEs or SAEs if clinically significant. 
k Cardiac monitoring (ECHO/MUGA) will be performed to assess LVEF.  LVEF assessment by ECHO is preferred.  The same method should be used throughout 
the study for each patient and, preferably, performed and assessed by the same assessor.  At baseline, LVEF must be done within 14 days prior to 
randomization.  At the end of anthracycline therapy, LVEF should be assessed to determine if patient can start HER2-targeted therapy.  During HER2-targeted 
study treatment, ECHO/MUGA should be obtained at Cycle 2, and every 4 cycles thereafter (Cycles 6, 10, 14, and 18).  All assessments will be performed within 
the last week of the treatment cycle to allow evaluation of the results before the next treatment cycle.  ECHO/MUGA should be obtained at the end-of-treatment 
visit if not performed within the previous 6 weeks and at 3, 6, 12, 18, 24, 36, 48, and 60 months of follow-up regardless of the occurrence of invasive disease 
recurrence.  Note:  Cardiac signs/symptoms and an additional LVEF assessment must be completed after the last cycle of anthracycline is administered, but prior 
to the first cycle of targeted therapy.  Patients treated with anthracyclines must have an LVEF ≥ 50% and must have not experienced any clinical symptoms 
suggesting heart failure or asymptomatic LVEF declines by an absolute point of > 15% from baseline and below the lower limit of normal prior to commencing 
the HER2-targeted component of therapy. 
l 
The PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) and EQ-5D will be completed by the patients at the investigational site.  Assessments are to 
be completed on Cycle 1 Day 1 of the anthracycline treatment period; Day 1 of Cycles 1 through 5, Cycle 9, and Cycle 14 of the HER2-targeted treatment period; 
at treatment completion/treatment discontinuation visit; and at the 6- and 12-month follow-up visits after the end-of-treatment visit regardless of the occurrence of 
invasive disease recurrence.  All PRO questionnaires are required to be completed by patients prior to administration of study drug and prior to any other study 
assessment(s) or health care provider interactions to ensure that the validity of the instrument is not compromised and to ensure that data quality meets 
regulatory requirements.  Study personnel should review all questionnaires for completeness before the patient leaves the investigational site, and the hard copy 
originals of the questionnaires must be maintained as part of the patient’s medical record at the site for source data verification. 
m Hematology tests (complete blood count with differential) including hemoglobin, hematocrit, counts of WBCs, platelets, and differential including absolute 
neutrophils.  Abnormal CBC, including platelet counts, will be followed until resolution, until they are stable as assessed by the investigator, until the patient is 
lost to follow-up, or until the patient withdraws consent.  Only if abnormal platelets have not returned to ≥ 100,000/mm3 at the time of end-of-treatment visit, it 
should be checked at a minimum of every four weeks (monthly) during the follow-up period until ≥ 100,000/mm3, until they are clinically stable as assessed by 
the investigator, until the patient is lost to follow-up, or until the patient withdraws consent, regardless of the occurrence of invasive disease recurrence.  
Clinicians should consider more frequent evaluation (qw, etc.) for increasing grade of toxicity.  
n Screening laboratory tests to be performed within 7 days prior to randomization.  Screening laboratory assessments may be done on the day of randomization, 
and their results may be used for randomization visit purposes.  Results must be reviewed and documented prior to administration of first dose of study treatment.  
(Local laboratory [hematology, biochemistry, INR, and aPTT assessments] to be used for these assessments.) 
o Prior to the first dose of study treatment (i.e., antracycline treatment), screening tests within 7 days prior to randomization will be utilized.  Protocol-specified 
subsequent tests will be performed within 72 hours preceding administration of study treatment; results must be reviewed and documented prior to administration 
of study treatment.  (Local laboratory [hematology, biochemistry, INR, and aPTT assessments] to be used for these assessments.) 
p For patients receiving paclitaxel, sample for hematology should be collected qw during treatment.  Paclitaxel will be administered every 7 + 3 days.  


Appendix 1  
Schedule of Assessments (cont.) 
 
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q Serum chemistry tests at baseline include sodium, potassium, chloride, glucose, BUN or urea, creatinine, TBILI (and direct bilirubin when TBILI > ULN), total 
protein, albumin, ALT, AST, and ALP.  Patients who have positive HBV or HCV serology without known active disease must meet the eligibility criteria for ALT, 
AST, TBILI, INR, aPTT, and ALP on at least two consecutive occasions, separated by at least 1 week, within the 30 day screening period.  Assessments at each 
treatment and at the end-of-treatment visit include potassium, TBILI, ALT, AST, and ALP; other assessments may be obtained as clinically indicated.  For 
patients who have positive HBV or HCV serology without known active disease, ALT, AST, TBILI, INR, aPTT, and ALP need to be assessed within 72 hours 
prior to the first dose on C1D1.  Abnormal ALT, AST, and total and/or direct bilirubin will be re-tested at a minimum of every 4 weeks (monthly) until normalization 
(i.e., until they are clinically stable for at least 3 months, as assessed by the investigator), until the patient is lost to follow-up or until the patient withdraws 
consent, regardless of the occurrence of invasive disease recurrence.  Clinicians should consider more frequent evaluation (qw, etc.) for increasing grade of 
toxicity.  Note: positive serology markers that indicate immunity will not be considered as clinically meaningful positive serology to trigger these tests.  
r Documentation of HBV and HCV serologies is required:  This includes HBsAg and/or total HBcAb in addition to HCV antibody testing.  The most recent serologic 
testing must have occurred no more than 3 months prior to randomization.  If such testing has not been done, it must be performed during screening.  For 
patients who are known carriers of HBV and/or HCV, active hepatitis B infection and active hepatitis C infection must be ruled out on the basis of negative 
serologic testing and/or determination of HBV DNA viral load/HCV RNA load per local guidelines. 
s For all women of childbearing potential and for those who do not meet the definition of postmenopausal status (see definition in Section 4.5.1.2) or who have not 
undergone surgical sterilization, a serum β-HCG must be performed within 7 days prior to randomization.  During the treatment period, in all treatment arms, a 
urine pregnancy test must be performed in women of childbearing potential within 72 hours prior to C1D1 of HER2-targeted therapy, then every 3 cycles 
thereafter during study treatment, at 3 and 6 months after the end-of-treatment visit, and as clinically indicated regardless of the occurrence of invasive disease 
recurrence.  All positive urine pregnancy tests must be confirmed by a serum β-HCG test.   
t 
A whole blood sample for DNA isolation will be collected at baseline or at any time (after randomization) during the conduct of the clinical study.  
u Collection of serum and plasma samples for biomarker analysis is mandatory.  After the end-of-treatment visit, these samples will be collected once a year for 
5 years, whenever possible, unless a recurrence that is defined as an IDFS event in Section 3.4.1 has occurred.  Biomarker samples (or processed samples) will 
be stored for up to 5 years after final database lock unless the patient consents to long-term storage for 15 years.   
v If the patient gives OBRP consent, the serum and plasma samples for biomarker analysis will undergo long-term storage in the study biosample repository for 
use in future exploratory biomarker analyses.  For patients that consented to the OBRP, a whole blood sample for DNA analysis will be collected as well at 
baseline if possible or any time after randomization. 
w AE and SAEs will be recorded from the start of study screening procedures if related to protocol-mandated intervention.  All non-serious AEs occurring prior to 
Day 1 (administration of study treatment) will be reported in the medical history, unless AE reporting is deemed more appropriate.  AEs are to be monitored 
continuously during study treatment.  All AEs occurring during the study and until the end-of-treatment/treatment discontinuation visit 28 days after the last dose 
of study treatment are to be recorded; thereafter, only drug-related SAEs and AEs/SAEs that qualify for long-term reporting should continue to be collected.  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 treatment or study 
participation if the event is believed to be related to prior study drug treatment or study procedures. 
x Concomitant medication will be recorded in the interval beginning 7 days prior to the patient being randomized into the study until the end of the treatment period, 
except for medications that are also collected during follow-up (Section 4.6). 


Appendix 1  
Schedule of Assessments (cont.) 
 
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y In cases of invasive disease recurrence (an IDFS event as defined in Section 3.4.1) diagnosed at any time during the study, patients will be out of the study 
schedule for disease status assessments and will be followed annually (± 28 days) starting 1 year after first recurrence until 10 years after FPI for survival, 
anti-cancer medications, and new relapse (recurrence or disease progression) events.  If a patient has a recurrence, any anti-cancer medication given after the 
date of diagnosis must be recorded on the post-treatment anti-cancer medication page. 


 
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Appendix 2  
Schedule of Anti-Therapeutic Antibody Assessments 
Study Visit 
Time 
Sample Acquisitiona 
Cycle 1, Day 1 and 
Cycle 4, Day 1 
Before infusion of 
trastuzumab emtansine 
Serum sample for trastuzumab emtansine 
concentration 
Serum sample for ATA to trastuzumab 
emtansine 
Cycle 1, Day 1 
15−30 minutes after 
infusion of trastuzumab 
emtansine 
Serum sample for trastuzumab emtansine 
concentration 
Study treatment 
termination 
Any point during study 
visit 
Serum sample for trastuzumab emtansine 
concentration 
Serum sample for ATA to trastuzumab 
emtansine 
3 months after last 
dose of trastuzumab 
emtansine 
Any point during study 
visit 
Serum sample for ATA to trastuzumab 
emtansine 
ATA=anti-therapeutic antibody; PK=pharmacokinetic. 
Note:  These samples will be collected in all patients receiving trastuzumab emtansine. 
a Blood sample for PK/ATA should not be obtained using the same line through which 
trastuzumab emtansine is infused.  Please see the Sample Handling and Logistics Manual for 
details. 


 
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Appendix 3  
New York Heart Association Classifications 
Table 1 
Clinical Evaluation of Functional Capacity of Patients with Heart 
Disease in Relation to Ordinary Physical Activity 
NYHA 
Class 
Functional 
Class 
Description 
Objective Assessment 
I 
Mild 
No limitation of physical activity.  Ordinary 
physical activity does not cause undue 
fatigue, palpitation, or dyspnea 
No objective evidence 
of cardiovascular 
disease 
II 
Mild 
Slight limitation of physical activity.  
Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation, or 
dyspnea 
Objective evidence of 
minimal cardiovascular 
disease 
III 
Moderate 
Marked limitation of physical activity.  
Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or 
dyspnea 
Objective evidence of 
moderately severe 
cardiovascular disease 
IV 
Severe 
Unable to carry out any physical activity 
without discomfort.  Symptoms of cardiac 
insufficiency at rest.  If any physical activity 
is undertaken, discomfort is increased 
Objective evidence of 
severe cardiovascular 
disease 
NYHA = New York Heart Association. 


 
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Appendix 4  
Adjuvant Radiotherapy Guidelines 
I. BREAST-CONSERVING THERAPY 
MANDATORY:  Breast radiotherapy (RT) after complete local excision 
Breast RT may be contraindicated in patients with significant comorbidity (e.g., 
scleroderma and systemic lupus erythematosus).  Patients with contraindication to RT 
while adjuvant RT is clinically indicated are not eligible for this study.   
Target volume 
• 
Whole breast including the primary tumor bed 
• 
Primary tumor bed boost in conjunction with whole breast RT may be used as per 
local policy.  
• 
Partial breast RT may be used as per local policy declared by the center prior to 
local activation. 
• 
Regional nodal RT:  Refer to Item III below. 
 
Dose fractionation  
• 
Whole breast recommended schedules:  
50 Gy in 25 fractions, 5 fractions per week; or 
42.5 Gy in 16 fractions, 5 fractions per week; or 
40 Gy in 15 fractions, 5 fractions per week  
• 
Other schedules may be used as per local policy declared by the center prior to 
local activation.  
Primary tumor bed boost in conjunction with whole breast RT:  as per local 
policy declared by the center prior to local activation 
Partial breast RT:  as per local policy declared by the center prior to local 
activation 
 
Treatment planning 
• 
Computer tomography (CT)−based treatment planning is strongly recommended for 
whole breast RT and tumor bed boost. 
• 
CT-based treatment planning is mandatory for partial breast irradiation delivered 
using external beam RT. 
 
II. POSTMASTECTOMY RADIOTHERAPY 
MANDATORY:  
• 
4 or more positive axillary nodes or pathologic T4 disease 
• 
“Non-resectable” microscopic positive deep margin (invasive carcinoma or ductal 
carcinoma in situ) 
 


Appendix 4  
Adjuvant Radiotherapy Guidelines (cont.)  
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OPTIONAL:  
• 
1−3 positive axillary nodes or higher risk node-negative disease (for example, T3 
primary in the presence of high histologic grade and/or lymphovascular invasion) 
 
Target Volume 
• 
Whole chest wall 
• 
Primary tumor bed boost in conjunction with chest wall RT may be used as per local 
policy declared by the center prior to local activation.  
• 
Regional nodal RT:  Refer to Item III below. 
 
Dose Fractionation  
• 
Whole breast:  Recommended schedule is 50 Gy in 25 fractions, 5 fractions per 
week.  Other schedules may be used as per local policy declared by the center prior 
to local activation. 
• 
Primary tumor bed boost in conjunction with chest wall RT:  as per local policy 
declared by the center prior to local activation 
 
Treatment planning 
• 
CT−based treatment planning is strongly recommended for chest wall RT. 
 
III. REGIONAL NODAL RT 
For patients who have completed SNB alone or ALND as per protocol: 
• 
RECOMMENDED:  Any breast surgery, 4 or more positive axillary nodes 
• 
OPTIONAL:  Any breast surgery, 0−3 positive axillary nodes, pathological T4 (pT4) 
disease 
 
Target volume 
• 
Required:   
Supraclavicular fossa if there are 4 or more positive axillary nodes  
• 
Optional:   
Supraclavicular fossa if there are 0-3 positive axillary nodes;  
Axilla as per local policy declared by the centre prior to local activation (for 
example, known or high risk of residual axillary disease postsurgery);  
Internal mammary nodes if there is a high risk of tumor involvement as per local 
policy. 
 
Dose fractionation  
• 
Recommended schedule: 50 Gy in 25 fractions, 5 fractions per week.  Other 
schedules may be used as per local policy. 
 


Appendix 4  
Adjuvant Radiotherapy Guidelines (cont.)  
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183 
Treatment planning 
• 
CT−based treatment planning is strongly recommended for supraclavicular fossa 
and/or axillary RT. 
• 
CT-based treatment planning is mandatory for internal mammary nodal RT. 
 


 
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Appendix 5  
Guidelines for Liver Biopsy 
Because nodular regenerative hyperplasia (NRH) can be a very subtle diagnosis to 
make on liver biopsy, every attempt should be made to maximize the amount of tissue 
obtained.   
The needle used should be at least 18 gauge, and percutaneous biopsies of length at 
least 1.5 cm are recommended, if clinically appropriate.  In order to diagnose NRH, 
reticulin and trichrome stains are necessary. 
Smaller biopsies obtained via a transjugular approach and smaller biopsy gun needle 
biopsies are discouraged.  Small wedge biopsies should also be discouraged. 


 
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
185 
Appendix 6  
Ventana HER2 IHC Assay 
The PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY 
HER2 [4B5]) is a rabbit monoclonal antibody intended for laboratory use for the 
semi-quantitative detection of HER2 antigen in sections of formalin-fixed, 
paraffin-embedded breast cancer tissue to determine tumor HER2 
immunohistochemistry (IHC) status and to select HER2-positive patients for enrollment 
in study BO28407.  The 4B5 IHC assay is currently being developed by Ventana 
Medical Systems as a companion diagnostic to trastuzumab emtansine and will be used 
for investigational purposes only. 
Device Description 
The PATHWAY HER2 (4B5) IHC assay is an automated immunohistochemical staining 
assay system comprising a pre-dilute, ready-to-use, rabbit monoclonal primary antibody 
(clone 4B5) directed against the internal domain of HER2, the BenchMark ULTRA 
automated slide staining platform, and ultraView universal DAB detection kit.  The 
reagents and the IHC procedure are optimized for use on the BenchMark ULTRA 
automated slide stainer, utilizing VSS software (Ventana System Software).  Details of 
the staining protocol and scoring criteria can be found in instruction for use and 
interpretation guide published by Ventana.


 
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186 
Appendix 7  
Ventana HER2 ISH Assay 
Probe Cocktail is intended to determine the ratio of the HER2 gene to chromosome 17 
using two-color chromogenic in situ hybridization (ISH) in formalin-fixed, 
paraffin-embedded human breast cancer tissue to determine tumor HER2 gene status 
and select HER2-positive patients for enrollment in study BO28407.  The INFORM 
HER2 Dual ISH DNA Probe Cocktail is currently being developed by Ventana Medical 
Systems as a companion diagnostic to trastuzumab emtansine and will be used for 
investigational purposes only for Study BO28407. 
The Ventana INFORM HER2 Dual ISH assay consists of a dinitrophenyl (DNP)-labeled 
double stranded probe that targets the HER2 gene region of chromosome 17 and a 
digoxigenin (DIG)-labeled double stranded probe that hybridizes to repetitive sequences 
in the centromeric region of chromosome 17 (INFORM Chromosome 17 probe).  The 
probes are packaged as a mixture and require the use of Ventana’s ultraView™ SISH 
DNP Detection Kit, ultraView Red DIG Detection Kit, and other accessory reagents to 
stain routinely processed, formalin-fixed paraffin-embedded tissue sections on Ventana 
automated slide stainer instruments.  


 
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187 
Appendix 8  
PRO Measures:  QLQ-C30 and Modified QLQ-BR23 
 


Appendix 8  
PRO Measures:  QLQ-C30 and Modified QLQ-BR23 (cont.)  
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
188 
 


Appendix 8  
PRO Measures:  QLQ-C30 and Modified QLQ-BR23 (cont.)  
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
189 
 


Appendix 8  
PRO Measures:  QLQ-C30 and Modified QLQ-BR23 (cont.)  
Trastuzumab Emtansine—F. Hoffmann-La Roche Ltd 
Protocol BO28407, Version 3 
190 








 
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Protocol BO28407, Version 3 
194 
Appendix 10  
 
Acceptable Contraception Methods 
For female patients of childbearing potential (who have not undergone surgical 
sterilization), agreement must be obtained to use one highly effective nonhormonal form 
of contraception or two effective forms of nonhormonal contraception.  Specific country 
and/or local requirements for contraception will be followed.  
Highly Effective Contraception 
Methods of birth control that result in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly are considered highly effective forms of contraception.   
The following nonhormonal methods of contraception are acceptable: 
• 
True abstinence when this is in line with the preferred and usual lifestyle of the 
patient.  (Periodic abstinence [e.g., calendar, ovulation, symptothermal 
postovulation methods] and withdrawal are not acceptable methods of 
contraception).  
• 
Male sterilization (with appropriate postvasectomy documentation of the absence of 
sperm in the ejaculate).  For female patients, the vasectomized male partner should 
be the sole partner. 
• 
Female surgical sterilization 
• 
Placement of a nonhormonal intrauterine device.  Consideration should be given to 
the type of device being used, as there are higher failure rates quoted for certain 
types, (e.g., steel or copper wire).  Patients who have had a progesterone-coated 
device in place prior to screening are not required to have it removed.  However, 
newly inserted devices after screening should not contain estrogen or progesterone. 
 
OR 
Effective Nonhormonal Contraception 
Alternatively two of the following effective forms of contraception may be used instead: 
• 
Condom with spermicidal foam/gel/film/cream/suppository. 
• 
Occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository.  
 
The use of barrier contraceptives should always be supplemented with the use of a 
spermicide.  The following should be noted: 
• 
Failure rates indicate that, when used alone, the diaphragm and condom are not 
highly effective forms of contraception.  Therefore, the use of additional spermicides 
does confer additional theoretical contraceptive protection. 
• 
However, spermicides alone are ineffective at preventing pregnancy when the whole 
ejaculate is spilled.  Therefore, spermicides are not a barrier method of 
contraception and should not be used alone.  


Appendix 10  
 
Acceptable Contraception Methods (cont.) 
 
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Protocol BO28407, Version 3 
195 
 
It should be noted that two forms of effective contraception are required.  A double 
barrier method defined as condom and occlusive cap (diaphragm or cervical/vault caps) 
with spermicidal foam/gel/film/cream /suppository is acceptable. 
For partners of male patients of childbearing potential (who have not undergone surgical 
sterilization), agreement must be obtained to use hormonal contraception, or one highly 
effective nonhormonal, or two effective forms of nonhormonal contraception.  Specific 
country and/or local requirements for contraception will be followed. 
 
 
 
 

SAP_001.pdf: 
Official Title: A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
TRIAL COMPARING TRASTUZUMAB PLUS PERTUZUMAB 
PLUS A TAXANE FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB 
FOLLOWING ANTHRACYCLINES AS ADJUVANT THERAPY 
IN PATIENTS WITH OPERABLE HER2-POSITIVE PRIMARY 
BREAST CANCER 
NCT Number: 
NCT01966471 
Document Date: 
SAP Version 3: 17-January-2020 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
CONFIDENTIAL 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
Trastuzumab Emtansine —F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan BO28407 
STATISTICAL ANALYSIS PLAN 
TITLE: 
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III 
TRIAL COMPARING TRASTUZUMAB PLUS PERTUZUMAB 
PLUS A TAXANE FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB FOLLOWING 
ANTHRACYCLINES AS ADJUVANT THERAPY IN PATIENTS 
WITH OPERABLE HER2-POSITIVE PRIMARY BREAST CANCER 
PROTOCOL NUMBER: 
BO28407 
STUDY DRUG: 
Trastuzumab Emtansine 
VERSION NUMBER: 
3 
IND NUMBER: 
71072 
EUDRACT NUMBER: 
2012-004902-82 
SPONSOR: 
F. Hoffmann-La Roche Ltd.
PLAN PREPARED BY: 
DATE FINAL: 
Version 1: 14 November 2017 
Version 2: 18 May 2018 
Version 3:  See electronic date stamp below 
Date and Time(UTC)        Reason for Signing
Name
17-Jan-2020 09:16:30
Company Signatory


Trastuzumab Emtansine —F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan BO28407
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE
This Statistical Analysis Plan (SAP) Version 3, for Protocol BO28407, has been 
amended to specify further sensitivity analyses for the primary endpoint. Further details 
regarding multivariate Cox regression analysis for the primary endpoint and regarding
the efficacy subgroups analyses were provided. Exploratory analysis of the occurrence 
of CNS metastases has been added. Patient-reported outcomes analyses were 
extended to the full set of treatment-related symptoms scales and function scales. 
References for the corresponding thresholds used to define clinically meaningful 
differences were updated.
Additional minor changes have been made to improve clarity and consistency.


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3/Statistical Analysis Plan BO28407
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 6
2.2
Outcome Measures ................................................................. 6
2.3
Determination of Sample Size ................................................. 6
2.4
Analysis Timing ....................................................................... 8
3.
STUDY CONDUCT....................................................................................... 9
3.1
Randomization Issues ............................................................. 9
3.2
Data Monitoring ..................................................................... 10
3.2.1
Independent Data Monitoring Committee .............................. 10
3.2.2
Clinical Events Committee Data Monitoring 
Committee ............................................................................. 10
4.
STATISTICAL METHODS .......................................................................... 10
4.1
Analysis Populations ............................................................. 10
4.1.1
Intention-to-Treat Population ................................................. 10
4.1.2
Node-Positive Subpopulation ................................................ 10
4.1.3
Pharmacokinetic-Evaluable Population ................................. 11
4.1.4
Anti-Drug Antibody Evaluable Population.............................. 11
4.1.5
Safety Population .................................................................. 11
4.2
Analysis of Study Conduct..................................................... 11
4.3
Analysis of Treatment Group Comparability .......................... 11
4.4
Efficacy Analysis.................................................................... 12
4.4.1
Primary Efficacy Endpoint...................................................... 12
4.4.2
Secondary Efficacy Endpoints............................................... 13
4.4.3
Hierarchical Testing Procedure ............................................. 14
4.4.4
Exploratory Efficacy Endpoints.............................................. 14
4.4.5
Sensitivity Analyses............................................................... 15
4.4.6
Subgroup Analyses ............................................................... 16
4.5
Patient Reported Outcome Analyses..................................... 18


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4.6
Pharmacokinetic Analyses..................................................... 19
4.7
Anti-Drug Antibody Analyses................................................. 20
4.8
Safety Analyses..................................................................... 20
4.8.1
Exposure to Study Medication............................................... 20
4.8.2
Adverse Events ..................................................................... 20
4.8.3
Deaths ................................................................................... 21
4.8.4
Laboratory Data..................................................................... 21
4.8.5
Cardiac Safety....................................................................... 21
4.8.6
Pulmonary Safety Toxicity ..................................................... 21
4.8.7
Hepatotoxicity........................................................................ 21
4.8.8
Safety Subgroup Analyses .................................................... 22
4.9
Missing Data.......................................................................... 22
4.10
Interim Analyses .................................................................... 23
4.10.1
Interim IDFS Analyses........................................................... 23
4.10.2
Interim OS Analyses.............................................................. 24
4.10.3
Interim Safety Analysis .......................................................... 25
5.
REFERENCES ........................................................................................... 27
LIST OF TABLES
Table 1
Summary of Sample Size Assumptions for IDFS.......................... 7
Table 2
Summary of Assumptions for Overall Survival Analyses .............. 8
Table 3
Summary of Planned Analyses in Overall Protocol-Defined 
Population and Node-Positive Subpopulation............................... 9
Table 4
Summary of Planned Analyses of IDFS in ITT and ITTLN+........ 23
Table 5
Summary of Planned Analyses of Overall Survival in ITT and 
ITTLN+........................................................................................ 25
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 29
Appendix 2
Schedule of Assessments........................................................... 41


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5/Statistical Analysis Plan BO28407
1.
BACKGROUND
Breast cancer remains a highly significant cause of morbidity and mortality worldwide.  
The use of adjuvant trastuzumab based therapy in HER2-positive early-stage breast 
cancer (EBC) improves patient outcomes as demonstrated in several large, randomized 
trials.
A total of 1 year of HER2-directed adjuvant therapy with trastuzumab remains the 
standard of care on the basis of recent results from studies comparing different adjuvant 
trastuzumab treatment durations (1 year vs. shorter [6 months] or longer [2 years]) 
(Pivot et al. 2013, Goldhirsch et al. 2013).
At time of current protocol version 3 (30 July 2015) the 3-year disease-free survival (DFS) 
rate is approximately 85%90% for the overall population of patients with HER2-positive 
EBC treated with adjuvant chemotherapy and trastuzumab in Herceptinadjuvant trials.  
Recurrence rate at 10 years is reported to be approximately 26% (Romond et al. 2012).
In the recent reported APHINITY study, the estimated 3-year invasive disease-free
survival (IDFS) rate was 93% for patients treated with trastuzumab based regimen and 
94% for patients treated with adjuvant pertuzumab added to chemotherapy plus 1 year 
of treatment with trastuzumab.  The study population of APHINITY included 
node-positive patients or a broader node-negative HER2-positive, operable breast
cancer patient population (von Minckwitz et al. 2017).  The majority of these patients 
eventually have disease recurrence at distant sites, which is generally considered to be 
incurable.  Thus, there is an unmet need and potential to further improve outcomes, 
particularly in higher-risk patient subpopulations, by incorporating newer HER2-directed 
agents, with manageable toxicity, into the treatment paradigm.
Study BO28407 is a randomized, multicenter, open-label, Phase III trial comparing 
trastuzumab plus pertuzumab plus a taxane following anthracyclines versus trastuzumab 
emtansine plus pertuzumab following anthracyclines as adjuvant therapy in patients with 
operable HER2-positive primary breast cancer.
The purpose of this Statistical Analysis Plan (SAP) is to provide the Sponsor’s 
(F. Hoffmann-La Roche, Ltd.’s [Roche]) proposed analysis plan for this study.  The SAP 
overrides the analyses described in the statistical section of the Protocol BO28407
version 3.  The analyses as described in the SAP will be used by the Sponsor for the
purpose of regulatory submission.  Any major deviation from the SAP will be noted in the 
Clinical Study Report (CSR).
2.
STUDY DESIGN
Study BO28407 is a prospective, two-arm, Phase III, randomized, multicenter, 
multinational, open-label study in patients with newly diagnosed and centrally confirmed
HER2-positive primary invasive breast cancer who have had curative-intent surgery of 


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6/Statistical Analysis Plan BO28407
their primary tumor and are candidates for adjuvant systemic chemotherapy following 
surgery.  According to current protocol version 3, the study was planned to enroll 
approximately 1850 patients.  Actually, 1846 patients were finally enrolled from 
342 study sites worldwide.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1.  For additional details, see the Schedule of 
Assessments in Appendix 2.
2.2
OUTCOME MEASURES
The Protocol Synopsis in Appendix 1 outlines the primary, secondary, exploratory, 
pharmacokinetic (PK), and safety outcome measures.
2.3
DETERMINATION OF SAMPLE SIZE
The sample size of the study is primarily driven by the analysis of IDFS in both the 
node-positive subpopulation and the overall protocol-defined population.  The statistical 
assumptions for the revised sample size calculations are summarized in Table 1.
The IDFS analysis is powered at 80% for the node-positive subpopulation.  Additionally, 
the IDFS analysis with the assumptions stated below is powered at 82.5% for the overall 
protocol defined population.  It is assumed that the overall protocol-defined population 
has approximately 10% more patients and 6% more IDFS events than the node-positive 
subpopulation.  These percentages were observed in the BCIRG 006 
(Slamon et al. 2006, 2009, 2011) trial after subsetting for the respective populations in 
Study BO28407.
To detect a target hazard ratio (HR) of 0.64 in IDFS in the overall protocol-defined 
population and the node-positive subpopulation, approximately 171 and 160 IDFS 
events will be required to achieve 82.5% and 80% power, respectively, in the two 
populations, at a two-sided significance level of 5% using a log rank test.  One interim 
and one final IDFS analysis are planned in both the overall protocol-defined population 
and the node-positive subpopulation (see also Section 4.10.1).  The Lan-DeMets 
-spending function with an O’Brien-Fleming boundary will be used such that the overall 
type I error will be controlled at the 5% level for the IDFS endpoint (DeMets et al. 1994). 
Approximately 1850 and 1665 patients were planned to be enrolled in the overall 
protocol-defined population and node-positive subpopulation, respectively, including a 
dropout/ineligibility hazard of 0.003, which corresponds to a cumulative drop out of 
177 patients (9.5%) over the expected study duration of 48 months.  The assumed 
3-year IDFS rate for the control arms for both the populations were based on the IDFS 
rate from the BCIRG 006 data for the proposed populations and the assumed target HR 
from Study BO25126 (APHINITY).  The six piecewise KaplanMeier estimates of the 
IDFS function in the control group for the overall protocol defined population and the 
node-positive subpopulation were 99.6% and 99.5% during the first 6 months, 98.2% 


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7/Statistical Analysis Plan BO28407
and 98.0% during the second 6 months, 93.7% and 93.1% during Year 2, 89.5% and 
89.1% during Year 3, 87.7% and 87.1% during Year 4, and 86.2% and 85.5% during 
Year 5.  With the assumed target HR of 0.64, the estimated 3-year IDFS rate for the 
experimental arms in each of the two populations is shown in Table 1.
Table 1
Summary of Sample Size Assumptions for IDFS
BCIRG 006
3-Year 
IDFS for 
the 
proposed 
population 
Control Group
(Study BO25126 
[APHINITY])
3-Year IDFS 
HR0.75
Experimental 
Group
(Study BO28407 
[KAITLIN]) 3-Year 
IDFS HR0.64
Power
AC-TH
P vs. 
AC-KP
No. 
IDFS 
Events 
Sample 
Size
AC-TH
AC-THP
AC-KP
Population
Overall 
protocoldefined 
population
86.3%
89.5%*
93.2%
82.5%
171
1850
Node-positive 
subpopulation
85.8%
89.1%*
92.9%
80.0% 
160
1665
AC-Tdoxorubicincyclophosphamide followed by docetaxel; Htrastuzumab; HRhazard ratio; 
IDFSinvasive diseasefree survival; Ktrastuzumab emtansine; Ppertuzumab.
* Assumption at time of sample size planning.  Study BO28407 completed enrolment before 
Study BO25126 results were available.
Three interim OS analyses and one final OS analysis are planned in both the overall 
protocol-defined population and the node-positive subpopulation (see also
Section 4.10.2).  The assumed 3-year OS rate for the control arms for both populations 
were based on the OS rate from the BCIRG 006 data for the proposed population and 
the assumed target HR from Study BO25126.  The five piecewise Kaplan-Meier 
estimates of the OS function in the control group for the overall protocol-defined 
population and the node-positive subpopulation were 99.7% and 99.7% during Year 1, 
98.6% and 98.5% during Year 2, 96.1% and 95.7% during Year 3, 94.1% and 93.9% 
during Year 4, and 92.1% and 91.9% during Year 5.  The estimated 3-year OS rate for 
the experimental arms in each of the two populations is shown in Table 2 with an 
assumed target HR of 0.80 between the control arm (AC-THP) and the experimental arm 
(AC-KP).


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Table 2
Summary of Assumptions for Overall Survival Analyses
Population
BCIRG 006 3-Year 
OS for the 
proposed 
populations AC-TH
Control Group
(Study BO25126 
[APHINITY]) 3-Year OS 
AC-THP HR0.80
Experimental Group
(Study BO28407 
[KAITLIN]) 3-Year OS 
AC-KP HR0.80
Overall 
protocoldefined 
population
95.2%
96.1%
96.9%
Node-positive 
subpopulation
94.7%
95.7%
96.6%
AC-T doxorubicincyclophosphamide followed by docetaxel; Htrastuzumab; HRhazard 
ratio; IDFSinvasive diseasefree survival; Ktrastuzumab emtansine; OSoverall survival 
Ppertuzumab.
For the OS interim analyses and final OS analysis, the Lan-DeMets -spending function 
with an O’Brien-Fleming boundary will be used such that the overall type I error will be 
controlled at the 5% level for the OS endpoint (DeMets et al 1994).  With the study 
sample size and approximately 10 years of follow-up from first patient initiation (FPI), the 
Study BO28407 has 38% power in the overall protocol-defined population and 35% 
power in the node-positive subpopulation to detect an HR of 0.8.  In the overall 
protocol-defined population this corresponds to a 0.8% improvement in 3-year OS, from 
96.1% in the control arm to 96.9% in the experimental arm and in the node-positive 
subpopulation to a 0.9% improvement in 3-year OS, from 95.7% in the control arm to 
96.6% in the experimental arm, at a two-sided significance level of 5%.
The sample size calculations were performed using EAST v6 software (Cytel Inc.).
2.4
ANALYSIS TIMING
One interim analysis of IDFS is planned after approximately 128 IDFS events are 
observed in the overall protocol-defined population and approximately 120 IDFS events 
are observed in the node-positive sub-population.  This is projected to occur 
approximately 43 months from FPI (see Table 3).
The final analysis of IDFS will be performed after approximately 171 events are 
observed in the overall protocol-defined population and approximately 160 events are 
observed in node-positive sub-population.  This is projected to occur approximately 
57 months from FPI.
The actual timing of the interim and final IDFS analysis will be based on regular event 
tracking on the clinical database and on event projections.
All OS interim and final analyses will be performed by the Sponsor subsequent to the 
primary IDFS analysis and after the Sponsor is unblinded.  If the final IDFS analysis 
crosses the statistical boundaries, then the second interim OS analysis will be performed 
at the time of the final IDFS analysis, followed by the third OS analysis that will be 


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9/Statistical Analysis Plan BO28407
performed at 84 months and the final OS analyses that will performed at approximately  
120 months [10 years], from FPI (see Table 3).
For details regarding hierarchical testing and alpha levels, stopping boundaries please 
refer to Sections 4.4.3 and 4.10.
Table 3
Summary of Planned Analyses in Overall Protocol-Defined 
Population and Node-Positive Subpopulation
Endpoint
Analysis
No. of Events in 
the Overall 
Population
No. of Events in 
the Node-Positive 
Subpopulation
Estimated 
Timinga
IDFS
Interim
128
120
43 months
Final
171
160
57 months
OS
Interim 1 (Interim IDFS)
50
50
43 months
Interim 2 (Final IDFS)
87
83
57 months
Interim 3
153
138
84 months
Final
224
203
120 months
IDFSinvasive disease-free survival; OSoverall survival
a
Time from the enrollment of first patient to data cutoff.
After the first 600 patients were randomized and followed for 3 months (this had been 
anticipated to occur at approximately 13 months after FPI), the independent data 
monitoring committee (iDMC) performed an interim safety analysis (see Section 3.2).
3.
STUDY CONDUCT
3.1
RANDOMIZATION ISSUES
Upon verification of inclusion and exclusion criteria, eligible patients are randomized in a 
1:1 ratio to one of the two treatment arms using a permuted block randomization scheme 
via an interactive voice/web response system (IxRS).
Randomization is stratified by the following stratification factors:

World region (United States/Canada, Western Europe/Australia/New Zealand, 
Asia, or rest of the world)

Nodal status (0, 1-3, or 4 positive nodes)

Centrally assessed hormonal receptor status (ER- and/or PR-positive or both 
ER- and PR-negative)

Type of planned anthracycline (doxorubicin or epirubicin)


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3.2
DATA MONITORING
3.2.1
Independent Data Monitoring Committee
The iDMC monitors accruing patient safety data at least once every 6 months during the 
study until the last patient has completed study treatment.  In addition, safety data 
related to concurrent radiotherapy and/or hormonal therapy, SAEs, and deaths is 
monitored by the iDMC at least once every 3 months during the study until the last 
patient has completed study treatment.  At each iDMC review, relevant safety 
information from ongoing trastuzumab emtansine and/or pertuzumab studies is provided 
to the iDMC.  The iDMC will also assess safety and efficacy as part of the planned 
interim efficacy and safety analyses.
The iDMC works according to guidelines defined in the iDMC Charter.  The iDMC 
Charter contains details regarding frequency of meetings, guidelines for decision making, 
and processes for requesting further information.  The iDMC members reviewed and 
signed off the charter before the first iDMC review.
An independent Data Coordination Center (iDCC) performs unblinded analyses to 
support the periodic iDMC review of safety data and the interim analysis.  Additional 
details are specified in the iDMC Charter.
3.2.2
Clinical Events Committee Data Monitoring Committee
An independent CEC adjudicates pre-specified safety events of interest (cardiac and 
hepatic dysfunction events) in a blinded fashion.  A separate charter outlines committee 
composition, meeting timelines, and the roles and responsibilities of members.  The 
committee members review all potential cases of congestive heart failure (CHF) and 
cardiac death as well as all potential cases of hepatic dysfunction and Hy’s law.  Ad hoc 
members may be added to the CEC to review/adjudicate other safety events if a new 
safety signal emerges.  Adjudicated cases by the CEC are forwarded to the iDMC on a 
regular basis as part of ongoing safety reviews of the Study BO28407.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
Intention-to-Treat Population
The intention-to-treat (ITT) population will be the overall protocol-defined population as 
mentioned in the protocol and will include all patients who were randomized to the study, 
whether or not they received any study medication.  Patients will be analyzed according 
to the ITT principle, where all randomized patients will be included in the treatment arm 
they were originally allocated to by the IxRS at randomization. 
4.1.2
Node-Positive Subpopulation
The node-positive subpopulation (ITTLN+) will be a part of the ITT and will include 
patients with1 positive lymph node at baseline as reported in the IxRS.


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4.1.3
Pharmacokinetic-Evaluable Population
Pharmacokinetic (PK) evaluable patients are defined as patients who have received at 
least one treatment dose of trastuzumab emtansine and have at least one 
post-treatment serum sample.
4.1.4
Anti-Drug Antibody Evaluable Population
Anti-drug antibody (ADA) evaluable patients are defined as patients who have received 
at least one treatment dose of trastuzumab emtansine and have at least one ADA 
sample.
4.1.5
Safety Population
The safety evaluable population includes all randomized patients who received at least 
one full or partial dose of any study medication (chemotherapy or HER2 treatment).  
Patients will be analyzed based on the treatment they actually received (which may be 
different from the treatment the patient was randomized to).  Patients receiving any dose 
of trastuzumab emtansine will be included in the trastuzumab emtansine arm; all other 
treated patients will be included in the control arm.
4.2
ANALYSIS OF STUDY CONDUCT
Patient enrollment, duration of follow-up, discontinuation from study treatment and study, 
and reasons for discontinuation will be summarized by treatment arm to which patients 
were randomized.  In addition, protocol violations will be summarized by treatment arm.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
The evaluation of treatment arm comparability between the two treatment arms will 
include summaries of demographics, baseline disease characteristics, and patient 
medical history.  Data will be summarized by treatment arm to which patients were 
randomized.  Descriptive statistics (mean, median, standard deviation, and 
minimum-maximum) will be presented by treatment arm for continuous variables such as 
age and time since diagnosis.  Frequency counts and proportions will be presented by 
treatment arm for categorical variables such as gender, race, and age category.
The baseline value of any variable will be defined as the last available data point prior to 
the first administration of study medication.
Numbers and percentage of patients who received adjuvant radiation therapy and 
adjuvant hormonal therapy will be summarized by treatment arm.  Anti-cancer therapies 
(including radiotherapy, systemic cancer therapy, surgery) administered during survival 
follow-up will be summarized by treatment arm.


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4.4
EFFICACY ANALYSIS
4.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is IDFS.  The co-primary efficacy objectives for this study 
are to compare IDFS (1) in the ITTLN+ and (2) in the ITT populations.
IDFS is defined as the time between randomization and date of first occurrence of any 
one of the following events:

Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion)

Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall and/or skin of the ipsilateral 
breast)

Contralateral or ipsilateral second primary invasive breast cancer

Distant recurrence (i.e., evidence of breast cancer in any anatomic site [other than 
the three sites mentioned above]) that has either been histologically confirmed or 
clinically/radiographically diagnosed as recurrent invasive breast cancer

Death attributable to any cause, including but not limited to breast cancer, 
non-breast cancer, or unknown cause
All second primary non-breast cancers and in situ carcinomas (including DCIS and LCIS)
and non-melanoma skin cancer are excluded as an event in this endpoint.
If a patient experiences an event on the same day as randomization their time from 
randomization to event will be set to be 1 day.  Data from patients who have not had an 
event at the time of clinical cut-off will be censored at the date they were last known to 
be alive and event free on or prior to the clinical data cutoff date. 
The analysis of primary efficacy endpoint will be (1) using the ITTLN+, and (2) using the 
ITT populations.  A testing hierarchy will be applied to control the overall type I error rate 
at 5% (see Section 4.4.3).
The log-rank test, stratified by the protocol-defined stratification factors nodal status (0, 
1-3, 4nodes), centrally assessed hormonal receptor status (ER and/or PR positive, 
ER and PR negative) and type of planned anthracycline (doxorubicin, epirubicin) 
(excluding region), will be used to compare IDFS between the two treatment arms.
Region will be excluded because of the potential that some of the strata may have very 
few patients, which would result in a loss of power. Stratified analysis will use the 
stratification information provided in the IxRS system (nodal status and planned 
anthracycline treatment) or central testing laboratory (hormone receptor status).  The 
unstratified log-rank test results will also be provided for sensitivity analysis.  If, at the 
time of analysis, it is deemed that the smallest stratum per arm necessary to conduct 
robust stratified analyses contains5 events, unstratified analyses will be used as the 
primary analysis.  The Cox proportional hazards model, stratified by the previously noted


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stratification factors, excluding region, will be used to estimate the HR between the 
two treatment arms and the corresponding 95% CI.  The Kaplan-Meier approach will be 
used to estimate 3-year IDFS rates and corresponding 95% CIs for each treatment arm.
Further landmark analyses at other timepoints may be conducted as appropriate.
To assess the impact of prognostic factors, multivariate Cox regression analyses 
controlling for important baseline characteristics including treatment group, region 
(United States/Canada, Western Europe/Australia/New Zealand, Asia, rest of the world), 
nodal status (0, 1-3, 4nodes), hormonal receptor status (ER and/or PR positive, ER 
and PR negative), planned anthracycline (doxorubicin, epirubicin), menopausal status at 
baseline (pre-menopausal, post-menopausal), primary surgery type (breast conserving,
non-conserving), adjuvant cancer radiotherapy (yes, no), age (40, 4049, 5064, 65, 
65), histological grade (grade 1, grade 2, grade 3), tumor size at time of diagnosis
(02 cm, 25 cm, 5 cm) and race (White, Black, Asian, all other) will be done for the 
primary efficacy endpoint IDFS to calculate HRs between treatment groups and 
corresponding 95% confidence intervals. Baseline characteristics with observed 
imbalances between treatment arms may also be included into the multivariate 
Cox regression model. Further multivariate Cox regression models including biomarkers
of interest (e.g. PIK3CA mutation status, HER2 mRNA expression) may also be fitted, 
as deemed appropriate.
4.4.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints are defined as follows:

IDFS including second primary non-breast cancer:  defined the same way as IDFS 
for the primary endpoint but including second primary non-breast invasive cancer as 
an event (with exception of non-melanoma skin cancers and carcinoma in situ [CIS] 
of any site).  This definition is to acknowledge 1) the difficulty of distinguishing 
second primaries from breast cancer metastasis and 2) that second cancers may be 
treatment related.

DFS:  defined as the time between randomization and the date of the first 
occurrence of an IDFS event including second primary non-breast cancer event or 
contralateral or ipsilateral ductal carcinoma in situ (DCIS).  This definition is 
historically the primary endpoint for breast cancer adjuvant therapy trials.  

OS:  defined as the time from randomization to death due to any cause.  OS is part 
of the testing hierarchy that will be applied to control the overall type I error rate at 5% 
(see Section 4.4.3).

DRFI:  defined as the time between randomization and the date of first occurrence 
of distant breast cancer recurrence.  Based on previous published trials, distant 
recurrence is anticipated to account for the majority of first disease recurrence 
events; hence DRFI is included.
Data from patients who have not had an event will be censored at the date that they are 
last known to be alive and event free on or prior to the clinical data cut-off date for the 


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respective analysis.  In case of multiple recurrent events in a patient, only the first event 
will be analyzed. 
Secondary endpoints will be analyzed in a similar manner as the primary endpoint to 
estimate 3-year event rates (and 5-year survival rate for OS) for each treatment arm and 
the HR between the two treatment arms with 95% CI. Further landmark analyses at 
other timepoints may be conducted as appropriate.
The log-rank test, stratified by the protocol-defined stratification factors nodal status (0, 
13 nodes, 4nodes), centrally assessed hormonal receptor status (ER and/or PR 
positive, ER and PR negative), anthracycline type (epirubicin containing regimens, 
doxorubicin containing regimen) (excluding region) will be used to compare OS between 
the two treatment arms.  The unstratified log-rank test results will also be provided for
sensitivity analysis.
The analysis of secondary efficacy endpoints will be (1) using the ITTLN+ and (2) using 
the ITT populations. 
Details of IDFS and OS interim analyses are specified in the interim analyses section.
(Section 4.10)
4.4.3
Hierarchical Testing Procedure
To control the overall study Type I error rate at 5%, the hierarchical testing procedure 
will be used on the primary and secondary endpoints IDFS and OS in the order given 
below:
1.
Primary endpoint of IDFS in the ITTLN+
2.
Primary endpoint of IDFS in the ITT population
3.
Secondary endpoint of OS in the ITTLN+
4.
Secondary endpoint of OS in the ITT population
Details of IDFS and OS interim analyses are specified in the interim analyses section
(Section 4.10).
4.4.4
Exploratory Efficacy Endpoints
The relationship between molecular markers (e.g., level of HER family receptors and 
status of PIK3CA mutations see Section 3.4.4 in the Protocol BO28407) and efficacy 
outcomes will be evaluated as exploratory analyses.  Efficacy outcomes considered for 
this analysis will include IDFS and OS, as appropriate.
Analyses will also be performed to explore the correlation between anti-drug antibodies 
(ADAs) to trastuzumab emtansine, and clinical outcomes as appropriate.


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An assessment of Breast Cancer-Free Interval (BCFI) will also be made.  BCFI is 
defined as the time between randomization and the date of local, regional, or distant 
breast cancer recurrence, invasive contralateral breast cancer or DCIS (contralateral or 
ipsilateral).  Patients who have not had a recurrence event at the time of data analysis 
will be censored at the date when they were last known to be alive or at their date of 
death.
Analyses will be performed to compare the occurrence of CNS metastases as first IDFS 
event and as only IDFS event between the treatment arms.
4.4.5
Sensitivity Analyses
Alternative definitions of IDFS, including second primary non-breast cancer; and DFS 
(including second primary non-breast cancer event or contralateral or ipsilateral ductal 
CIS) are analyzed.  Both of these two alternative definitions are secondary endpoints of 
the study (Section 4.4.2).
To assess the impact of stratification IDFS rates will be compared using an unstratified 
log-rank test (see also Section 4.4.1).
A Kaplan–Meier plot of the time to censoring for IDFS in the different treatment arms will 
be performed to investigate differences in follow-up time.  In this analysis, patients who
had an IDFS event will be censored at the date of their event and patients without an 
event will be regarded as having had an event at the censoring date.
If the primary endpoint analysis is positive further sensitivity analyses will be performed 
to assess the potential for bias in the primary endpoint IDFS due to potential imbalance 
in assessments and follow-up time, potential bias introduced by non-protocol anti-cancer
therapy and to assess the robustness of the primary endpoint by understanding the 
impact that imbalance on assessments may have on the IDFS result:
1.
To assess the impact of non-protocol adjuvant anti-cancer therapy prior to an IDFS 
event, data for patients will be censored for IDFS at the time of the last disease 
status assessment before the initiation of non-protocol anti-cancer therapy if they 
begin a non-protocol anti-cancer adjuvant therapy before reporting invasive disease 
recurrence.  Trastuzumabpertuzumab after discontinuation of 
trastuzumab emtansine before 18 cycles without experiencing an IDFS event is 
considered non-protocol anti-cancer therapy in this analysis. 
2.
The above sensitivity analysis will be repeated whereby the switch to 
trastuzumabpertuzumab after discontinuation of trastuzumab emtansine before 
18 cycles without experiencing an IDFS event is not considered non-protocol anti-
cancer therapy in this analysis. This is to account for the fact that switching from to 
trastuzumab after discontinuation of trastuzumab emtansine is allowed per protocol. 


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3.
To further assess the impact of non-protocol adjuvant anti-cancer therapy prior to an 
IDFS event, patients will be considered to have an IDFS event at the time of the 
initiation of non-protocol anti-cancer therapy if they begin a non-protocol anti-cancer 
therapy before reporting invasive disease recurrence.  As for the previous sensitivity 
analysis the switch to trastuzumabpertuzumab after discontinuation of 
trastuzumab emtansine before 18 cycles without experiencing an IDFS event is not 
considered non-protocol anti-cancer therapy in this analysis. 
4.
The number of assessments that could detect recurrence will be summarized by 
treatment arm and will include unscheduled assessments to check for any 
suggestion of a qualitative difference.
To assess the impact of completeness of protocol-specified disease assessments 
on IDFS, data for patients who withdrew from the protocol-specified assessments 
(i.e., discontinued study follow-up) will be censored for IDFS at their latest 
protocol-specified assessment where they were invasive disease recurrence-free 
(so that any deaths reported after this point through the yearly survival contact are 
not included as events).
5.
To assess the impact of differential follow-up withdrawal due to all causes the 
primary analysis will be repeated, but considering patients with incomplete follow-up 
according to the protocol-defined schedule (who have not had an IDFS event) as 
having an IDFS event one day after they were last known to be IDFS event free.  
Therefore, if a patient does not have follow-up for disease recurrence within 
3 months prior to clinical cut-off if they are in their first two years of follow-up, 
6 months in years 35 and 12 months in years 610, will be deemed to have 
incomplete follow-up.
6.
To assess the impact of differences between the stratification factors reported in the 
IxRS system against the randomization stratification factors reported in the eCRF, 
the primary analysis will be repeated, stratified according to the stratification factors 
reported in eCRF. 
Sensitivity analyses will be carried out on the ITT and ITTLN+ populations for the 
primary IDFS endpoint.
4.4.6
Subgroup Analyses
Subgroup analyses will be performed for IDFS and OS as appropriate, in the ITT and the 
ITTLN+ to assess the robustness and consistency of treatment effect of trastuzumab 
emtansine plus pertuzumab.
The following subgroups analyses will be conducted via forest plots including 3 (5) year 
IDFS (OS) rates and estimates for HR and 95% CI from unstratified Cox proportional 
hazard models:

World region (IXRS/eCRF: United States/Canada vs.  Western 
Europe/Australia/New Zealand vs. Asia vs. Rest of the world)

Nodal status at baseline (IXRS/eCRF: lymph node positive, 4positive nodes, 13
positive nodes, 0 positive nodes)


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
Centrally assessed hormonal receptor status at baseline (IXRS: ER and/or PR 
positive vs. ER- and PR-negative, Central testing laboratory: ER and/or PR positive 
vs. ER- and PR-negative, ER/PR unknown) 

Type of anthracycline planned at randomization (IXRS/eCRF: doxorubicin 
containing regimen vs. epirubicin containing regimen)

Central  ER/PgR status (Central testing laboratory: ER positive PgR positive, ER 
positive PgR negative, ER negative PgR positive, ER negative PgR negative, ER 
unknown/PgR positive, ER unknown/PgR negative, ER negative/PgR unknown, ER
positive /PgR unknown, ER unknown/PgR unknown)

Menopausal status at randomization (pre-menopausal vs. post-menopausal)

Gender (female vs. male).  The subgroup of male patients will only be analyzed if 5% 
of the ITT

Race (White vs. Black vs. Asian vs. All other)

Age at randomization (40, 4049, 5064,65,65 years)

Histological grade (grade 1 vs. grade 2 vs. grade 3)

Type of surgery for primary tumor (breast conserving surgery vs. non-conserving
breast surgery)

Tumor size at time of diagnosis (02 cm vs. 25 cm vs. 5 cm)

Adjuvant cancer radiotherapy (Yes vs. No)

ECOG performance status at baseline (0 vs. 1)
Treatment effect (as determined by HRs and corresponding 95% confidence intervals) 
and 3 (5) year IDFS (OS) rates will be estimated separately for the defined subgroups to 
assess the robustness and consistency of treatment effect. Further landmark analyses in 
defined subgroup may be conducted as appropriate.
Subgroups analyses related to stratification factors will be conducted based on
stratification factors as reported in the IXRS system and repeated based on stratification 
factors as reported in the eCRF/Central testing laboratory.
Exploratory tests of interaction between treatment effect and subgroup (at a 10% 
significance level) will be reported using Cox proportional hazards models.
Additionally, the following biomarker subgroups will be explored:

HER2 mRNA expression level by qRT-PCR (median vs.median)

HER3 mRNA expression level by qRT-PCR (median vs.median)

PIK3CA mutation status (mutated vs. non-mutated)

HER2 IHC/ISH subgroups

Heterogeneity categories based on HER2 expression level (focal vs. heterogeneous 
vs homogeneous)

HER2 gene copy number (<4 vs. 4-6 vs. >6)


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
HER2 gene ratio (<2 vs. 2-4 vs. >4)

PTEN Cytoplasm H-Score (median vs.median)

PTEN Cytoplasm Staining status (None vs. decreased vs. slightly decreased, 
equivalent vs. increased) and (None/decreased/slightly decreased vs. 
equivalent/increased)
Further biomarker subgroups, notably based on immune markers, may be explored 
depending on the outcome of the primary analysis, as deemed appropriate.
4.5
PATIENT REPORTED OUTCOME ANALYSES
The patient-reported outcomes of health-related quality of life (HRQoL), function, and 
disease/treatment-related symptoms will be assessed using the EORTC QLQ-C30 
questionnaire and a modified version of its breast cancer module (QLQ-BR23). Only
patients with a baseline assessment and at least one post-treatment assessment will be 
included in the analyses.
Summary of completion rates for the EORTC QLQ-C30 and modified  BR23 will be 
provided by treatment arm by each assessment time point per protocol specified 
assessment schedule (see schedule of assessments, Appendix 1).  Reasons for non-
completion will be summarized by treatment arm and assessment time point.
For the subscales of the QLQ-C30 and the BR23 questionnaires, if more than 50% of 
the constituent items are completed, a pro-rated scale score will be computed as is 
consistent with the EORTC scoring manual (Fayers et al. 1999).  For subscales with less 
than 50% of the items completed, the subscale will be considered missing.  
Summary statistics (mean, SD, median, 25th and 75th percentiles, range and 95% CI) of 
linear transformed scores will be reported for all scales of the EORTC QLQ-C30 
questionnaire and of the BR23.  The mean change of the linear transformed scores from 
baseline (and 95% CIs) will be calculated for each time point.  Line charts depicting the 
mean changes from the baseline assessment (and 95% CI) will be provided for each of 
the scale at each timepoint.
The number and proportion of patients reporting clinically meaningful differences in 
treatment-related symptoms scales, global health status/HRQoL, and function scales 
based on the threshold reported by Cocks et al. (2012) and Osoba (1998) will be 
provided at each time-point.  In addition, the proportion of patients reporting “a little” or 
“quite a bit” for additional neuropathy, joint/muscle pain and skin single items will be 
reported by treatment arm.
Scale scores of the EORTC QLQ C30 and BR23 scores will be compared between the 
two treatment arms at the ‘C1D1 of HER2 targeted treatment period’ timepoint to 
descriptively assess treatment group comparability between the two treatment arms.  


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The ‘C1D1 of HER2 targeted treatment’ timepoint will be utilized as the reference for 
time-to-event Kaplan-Meier analysis. 
Kaplan-Meier analysis will be used to assess the time from first HER2 targeted treatment 
to clinically meaningful deterioration in the global health status/HRQoL subscale 
(question 29 and 30 of the QLQ-C30) in the treatment arms.  An event for a given patient 
is a decrease from baseline in subscale score of QLQ-C30 by 10 points 
(Osoba et al. 1998).  Time-to-event analyses to investigate the time to clinically 
meaningful deterioration in function scales of QLQ-C30 will also be assessed using the 
published thresholds by Cocks et al. (2012).  Stratified log-rank tests will be used to test 
the differences between treatment arms.  Data of patients with no event will be censored 
at the time of the last completed questionnaire.
Additionally, in order to elucidate if the taxane-sparing arm reduces patient treatment 
burden over time, a repeated measures mixed-effects model (MMRM) may be used to 
compare change from baseline in the global health status/HRQoL and functional scales 
of the EORTC QLQ-C30.  In each mixed model, change from baseline will be the 
response variable; treatment, visit, and treatment by visit interaction terms will be the 
fixed factors; and the patient will be denoted as a repeated factor. The ‘C1D1 of HER2 
targeted treatment’ timepoint will be utilized as baseline for these analyses. If substantial 
interaction effect is present, pair-wise comparison will be conducted.  Only patients with 
a baseline assessment and at least one post-treatment assessment will be included in 
the analyses.  Missing values will be handled according to the scoring manual.
Health economic data, as assessed by the EQ-5D-5L, will be evaluated for patients with 
a baseline assessment and at least one post-baseline EQ-5D-5L assessment.  The 
results from the health economic data analysis will be reported separately from the 
clinical study report.
4.6
PHARMACOKINETIC ANALYSES
Serum samples for measurement of trastuzumab emtansine and total trastuzumab will 
be obtained at pre- and post-trastuzumab emtansine infusion in Cycle 1, 
pre-trastuzumab emtansine infusion in Cycle 4 as well as at study treatment termination
from patients randomized to the trastuzumab emtansine containing arm (Arm 2).  
Individual and mean serum trastuzumab emtansine and total trastuzumab will be 
tabulated and summarized (e.g., mean, standard deviation, coefficient of variation, 
median, minimum, and maximum). 
Analyses will be performed in the PK evaluable population (see Section 4.1.3).


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4.7
ANTI-DRUG ANTIBODY ANALYSES
Serum samples for the measurement of anti-drug antibodies ADA (also previously 
referred to as anti-therapeutic antibodies or ATA) to trastuzumab emtansine will be 
obtained at Cycle 1 and Cycle 4 before infusion of trastuzumab emtansine, at study 
treatment termination and 3 months after last dose of trastuzumab emtansine.  Incidence 
of ADAs (ATAs) will be assessed at baseline and post-baseline and characterized to 
determine if the positive response is primarily towards trastuzumab or trastuzumab 
emtansine.  The impact of ADA on PK, safety, and efficacy will be explored in the 
subgroup of patients with positive ADA results (as data allow).
4.8
SAFETY ANALYSES
Safety analyses will be performed on the safety population (see Section 4.1.5).
4.8.1
Exposure to Study Medication
The number of patients who experience any dose modification, including dose delay, 
dose interruption and dose discontinuation will be summarized for each treatment arm 
and regimen component.  Reasons for treatment discontinuation will also be 
summarized.
Descriptive statistics will be presented for treatment duration, total cumulative dose, 
number of cycles received, dose intensity, and weeks of exposure by treatment arm and 
regimen component.
4.8.2
Adverse Events
Verbatim descriptions of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
Version 4.0. All AEs, SAEs, NCI CTCAE Grade 3 or above AEs, AEs leading to death, 
and AEs leading to study treatment discontinuation, modification or delay, occurring on 
or after the first dose of study treatment (i.e., treatment-emergent AE), AEs related to 
study treatment and AEs related to radiotherapy, for patients who received radiotherapy, 
will be summarized by NCI CTCAE grade. For repeated events of varying severity in an 
individual patient, the highest grade will be used in the summaries. 
Selected AEs for trastuzumab emtansine and pertuzumab will be summarized by 
NCI CTCAE grade for each treatment arm based on project wide pre-specified category 
definitions.  In addition, any AEs occurring within 24 hours of the first dose of each 
treatment cycle will be summarized to help characterize and distinguish between 
potential infusion-related reactions, hypersensitivity, and anaphylaxis.  
AEs, NCI CTCAE Grade 3 or above AEs, and AEs leading to study treatment 
discontinuation will be summarized by study treatment phases.


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4.8.3
Deaths
The number and percentage of patients who died and reasons for death will be 
summarized by treatment arm.
4.8.4
Laboratory Data
Clinical laboratory tests will be performed at local laboratories.  Laboratory abnormalities 
will be defined based on local laboratory normal ranges and NCI CTCAE Version 4.0.
Summary tables for worst NCI CTCAE toxicity grade and shifts from baseline to the 
worst in NCI CTCAE toxicity grade during treatment will be presented.  The baseline 
measurement is defined as the latest assessment prior to receiving any study 
medication.
4.8.5
Cardiac Safety
Primary Cardiac Endpoint:
The number and percentage of patients who died from cardiac cause or who 
experienced severe CHF (New York Heart Association [NYHA] Class III or IV) with a 
decrease in left ventricular ejection fraction (LVEF) of 10 percentage points or more from 
baseline to an LVEF of 50%, will be summarized by treatment arm.
Secondary Cardiac Endpoint:
The number and percentage of patients suffering from other cardiac-related events (e.g.,
any symptomatic congestive heart failure CHF [NYHA II] associated with a 10% drop in 
LVEF to50%; asymptomatic declines in LVEF requiring dose delay or discontinuation) 
will also be summarized by treatment arm. 
Comparison of incidence of each of the primary and secondary cardiac endpoints by 
treatment arm will be made by summarizing the proportions in each arm and calculating 
the difference in proportions with 95% CI using Hauck-Anderson correction.
Change in LVEF over time will be summarized by treatment arm.  Baseline LVEF will be 
the latest assessment prior to receiving any study medication.
4.8.6
Pulmonary Safety Toxicity
The number of patients who died from pulmonary causes, and number of patients 
suffering from pneumonitis or interstitial lung disease (ILD) will be summarized by 
treatment arm.
4.8.7
Hepatotoxicity
Hepatotoxicity (i.e., deaths from hepatic causes, patients with severe drug-induced liver 
injury [Hy’s law cases] and patients with nodular regenerative hyperplasia [NRH]) will be 
summarized by treatment arm.


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Analyses of liver function laboratory test (LFT) results by treatment arm will include the 
following:

Shift in NCI CTCAE grade from baseline to worst post-baseline level in ALT, AST, 
total bilirubin (TBILI), and alkaline phosphatase (ALK)

Summary of number/percentage of patients with AST, ALT, TBILI, and ALK 
elevation by NCI CTCAE grade and by treatment cycle

Scatterplots of worst LFT value (AST vs. ALT, ALT vs. TBILI, AST vs. TBILI) relative 
to upper limit normal (ULN)

Kaplan-Meier plots of time to first ALT 3ULN, first ALT5ULN, and first 
ALT8ULN events;

Patient LFT profiles (including ALT, AST, TBILI, and ALK) over time points for 
patients satisfying one of the following two conditions:
–
TBILI elevation2ULN within 21 days after AST/ALT elevation3ULN
–
ALT elevation8ULN
4.8.8
Safety Subgroup Analyses
A summary of safety (number of patients with SAEs, NCI CTCAE Grade 3 or above AEs, 
selected AEs, number of deaths) and a summary of AEs by MedDRA system organ 
class preferred term and NCI CTCAE grade will be provided by age at randomisation
(65 vs. 6574 vs.75 years and 65 years), by race (White, Asian, Black, Other), 
for patients with ADA positive results and patients who received adjuvant radiotherapy, 
adjuvant hormonal therapy, and adjuvant radiotherapy or hormonal therapy.
A summary of safety will be provided for the subgroup of patients who received at least 
one full or partial dose of trastuzumab, trastuzumab emtansine or pertuzumab study 
medication during the HER2-targeted treatment period.  Only HER2-targeted treatment 
emergent AEs will be considered.
4.9
MISSING DATA
For the analyses of IDFS, IDFS including second primary non-breast cancer, disease 
free survival (DFS), DRFI, and BCFI, data for patients who do not experience an event 
will be censored as described in Sections 4.4.1 and 4.4.2.
For patients who died with only a partial death date available, the missing date parts will 
be imputed with the earliest possible date part such that the date is after the date of 
randomization. 
For the QLQ-C30 and QLQ-BR23 questionnaires, if less than 50% of the constituent 
items of a subscale are completed, data for the subscale will be considered to be
missing.  No imputation will be performed.


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For PK parameters, analyses will be restricted to patients with available data.  No 
imputation will be performed.
4.10
INTERIM ANALYSES
One interim analysis of IDFS and three interim analyses of OS in both the ITTLN+ and 
the ITT are planned.
4.10.1
Interim IDFS Analyses 
One interim analysis of IDFS will be performed after approximately 75% of the targeted 
IDFS events are observed in the ITT (i.e., 128 of the 171 target events) and ITTLN+ 
(i.e., 120 of 160 target events) and is projected to occur approximately 43 months from 
FPI.  The final analysis of the primary endpoint IDFS will be performed after 
approximately 171 events are observed in the ITT and approximately 160 events are 
observed in ITTLN+ and is projected to occur approximately 57 months from FPI (see 
Table 4). The actual timing of the interim IDFS analysis will be based on regular event 
tracking on the clinical database and on event projections.
A hierarchical testing procedure will be used for the primary endpoint IDFS for the 
ITTLN+ and the ITT populations as defined in Section 4.4.3.  The type I error will be 
controlled at the 5% level at the interim and final analyses within the ITTLN+ and the ITT 
populations using a Lan-DeMets -spending function with an O’Brien-Fleming boundary.
Table 4
Summary of Planned Analyses of IDFS in ITT and ITTLN+
Analysis 
of IDFS
ITT
ITTLN+
Estimated 
Timingc
No. of 
Events
Efficacy Stopping 
Boundarya,b
No. of 
Events
Efficacy Stopping 
Boundarya,b
Interim
128
p 0.0193 or 
observed HR 0.6618
120
p 0.0193 or 
observed 
HR 0.6528
43 months
Final
171
p 0.0442 or 
observed HR 0.7353
160
p 0.0442 or 
observed 
HR 0.7279 
57 months
HRhazard ratio; IDFSinvasive diseasefree survival; 
ITTintention-to-treat; ITTLN+=node-positive subpopulation.
a
p-value will be based on two-sided stratified log-rank test.
b
Efficacy stopping boundaries follow O’Brien-Fleming design.
c
Time from the enrollment of first patient to data cutoff.
The IDFS interim analysis will be performed by the independent Data Coordination 
Center (iDCC) statistician, and the results will be presented to the iDMC by the iDCC 
statistician. The Sponsor will not be unblinded to the study results.
If the interim analyses in both populations cross the interim efficacy boundaries of the 
O’Brien-Fleming design, on the basis of the totality of both efficacy and safety data, the 


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24/Statistical Analysis Plan BO28407
iDMC may recommend releasing the primary endpoint results before the targeted 
number of 160 and 171 events have occurred in the ITTLN+ and ITT populations, 
respectively.  In this case, the Sponsor will be unblinded to study results, and a full data 
package including the first OS interim analysis results will be prepared for discussion 
with the regulatory authorities.  The Study BO28407 is planned to continue until 10 years 
of follow-up from FPI have occurred (unless the sponsor terminates the study earlier), 
and the IDFS analysis will be updated descriptively.  If the IDFS interim analyses in the 
ITTLN+ and in the ITT fail to cross the statistical efficacy boundaries of the 
O’Brien-Fleming design, then the study will continue as planned.  The Sponsor will 
conduct the final analyses.
4.10.2
Interim OS Analyses
Three interim OS analyses and one final OS analysis are planned in both the ITT and 
the ITTLN.
All OS interim and final analyses will be performed by the Sponsor subsequent to the 
primary IDFS analysis and after the Sponsor is unblinded.  If the interim IDFS analyses 
in both the ITTLN+ and the ITT populations cross the statistical efficacy boundaries, the 
first OS interim analysis will be performed in both populations hierarchically at that time 
(approximately at 43 months from FPI).  If the final IDFS analyses cross the statistical 
boundaries, then the second interim OS analysis will be performed hierarchically at the 
time of the final IDFS analysis (approximately 57 months from FPI), followed by the third 
and the final OS analyses performed hierarchically in both populations (planned to occur 
at 84 months [7 years] and 120 months [10 years], respectively, from FPI) (see Table 5).  
If, at any OS interim analysis, the O’Brien-Fleming efficacy boundary is crossed, that 
analysis of OS will be considered as confirmatory and all subsequent analyses of OS will 
be considered as descriptive.  If the final IDFS analyses are not statistically significant, 
no formal second and third interim and no formal final OS analyses will be done.  
Secondary efficacy endpoints other than OS will be analyzed at the time of the final 
analysis of the primary endpoint IDFS.


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25/Statistical Analysis Plan BO28407
Table 5
Summary of Planned Analyses of Overall Survival in ITT and 
ITTLN+
Analysis of 
OS
ITT
ITTLN+
Estimated 
Timingc
No. of 
Events
Efficacy Stopping 
Boundary a,b
No. of 
Events
Efficacy 
Stopping 
Boundarya,b
Interim 1 
(Interim IDFS)
50
p 0.0000033 or 
observed 
HR 0.2647
50
p 0.000013 or 
observed 
HR 0.2908
43 months
Interim 2 
(Final IDFS)
87
p 0.000643 or 
observed 
HR 0.4811
83
p 0.000908 or 
observed 
HR 0.4827
57 months
Interim 3
153
p 0.01316 or 
observed 
HR 0.6697
138
p 0.01281 or 
observed 
HR 0.6545
84 months
Final
224
p 0.04585 or 
observed 
HR 0.7658
203
p 0.04591 or 
observed 
HR 0.7556
120 months
HRhazard ratio; ITTintention-to-treat; ITTLN+node-positive subpopulation; IDFSinvasive 
diseasefree survival; OSoverall survival.
a p-value will be based on two-sided stratified log-rank test.
b Efficacy stopping boundaries follow O’Brien-Fleming design.
c Time from the enrollment of first patient to data cutoff.
4.10.3
Interim Safety Analysis
An iDMC monitors accruing patient safety data at least once every 6 months during the 
study until the last patient has completed study treatment.  In addition, safety data 
related to concurrent radiotherapy and/or hormonal therapy, serious adverse events, and 
deaths are monitored by the iDMC at least once every 3 months during the study until 
the last patient has completed study treatment.  At each iDMC review, relevant safety 
information from ongoing trastuzumab emtansine and/or pertuzumab studies is provided 
to the iDMC.
After the first 600 patients were randomized and followed for 3 months, the iDMC 
performed an interim safety analysis regarding overall numbers of deaths (all causes, 
including cardiac deaths) and hepatic events defined as confirmed Hy’s law cases.  The 
CEC communicated their findings to the iDMC to aid iDMC review.  If an absolute 
increase of3% in the percentage of deaths (from any cause) was observed in the 
trastuzumab emtansinepertuzumab arm compared with the trastuzumabpertuzumab 
arm, the iDMC was to consider a recommendation of pausing enrollment for further data 
review, stopping the trial, or modifying the trial.
If the true difference in the percentage of deaths was 3% (e.g., 2% vs. 6%), then there 
was approximately a 70% chance of observing an absolute difference of3% at the 
interim with 600 patients.  The Protocol BO28407 presents the probability of observing 


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26/Statistical Analysis Plan BO28407
an increase of3% in the percentage of deaths in the trastuzumab 
emtansinepertuzumab arm compared with the trastuzumabpertuzumab arm, with 
different assumptions for the percentage of deaths in the two treatment arms.
If an absolute increase of3% in the percentage of Hy’s law cases (confirmed by the 
independent CEC) was observed in the trastuzumab emtansinepertuzumab arm 
compared with the trastuzumabpertuzumab arm, the iDMC was to consider a 
recommendation of pausing enrollment for further data review, stopping the trial, or 
modifying the trial.
If the true difference in the percentage of confirmed Hy’s law cases was 3% (e.g., 0.33% 
vs. 3.67%), then there was approximately a 54% chance of observing an absolute 
difference of3% at the interim with 600 patients.  Protocol BO28407 presents the 
probability of observing a3% increase in the percentage of Hy’s law cases in the 
trastuzumab emtansinepertuzumab arm compared with the trastuzumabpertuzumab
arm, with different assumptions for the number of Hy’s law cases in the two treatment 
arms.


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27/Statistical Analysis Plan BO28407
5.
REFERENCES
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research 
and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl Cancer Inst 1993;85:365–376.
Cocks K. King MT, Velikova G, et al. Evidence-based guidelines for interpreting change 
scores for the European Organisation for the Research and Treatment of Cancer 
Quality of Life Questionnaire Core 30. Eur J Cancer. 2012 ;48(11):1713-21.
DeMets D, Lan KKG. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:134152.
Fayers PM, Aaronson NK, Bjordal K, Curran D, Groenvold M on behalf of the EORTC 
Quality of Life Study Group. The EORTC QLQ-C30 Scoring Manual (2nd Edition). 
Published by: European Organization for Research and Treatment of Cancer, 
Brussels 1999.
Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, et al., and the Herceptin Adjuvant (HERA) 
Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-
positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet 
2013;382:10218.
von Minckwitz G, Procter M, de Azambuja E, et al. Adjuvant Pertuzumab and 
Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med, 2017.
Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol 1998;16:13944.
Pivot X, Romieu G, Debled M, et al., and the PHARE trial investigators. 6 months versus 
12 months of adjuvant trastuzumab for patients with HER2-positive early breast 
cancer (PHARE): a randomised phase 3 trial. Lancet Oncol 2013;14:7418.
Romond E, Suman VJ, Jeong J-H, et al. Trastuzumab plus adjuvant chemotherapy for 
HER2-positive breast cancer: final planned joint analysis of overall survival (OS) 
from NSABP B-31 and NCCTG N9831. Cancer Res 2012;72(24 Suppl 3):S55.
Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and 
survival with amplification of the HER-2/neo oncogene. Science 1987;235:177−82.
Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in 
human breast and ovarian cancer. Science 1989;244:707−12.
Slamon D, Eiermann W, Robert N, et al. San Antonio Breast Cancer Conference 2006. 
Phase III trial comparing AC-T with AC-TH and with TCH in the adjuvant treatment 
of HER2 positive early breast cancer patients: second interim efficacy analysis. 
San Antonio Breast Cancer Symposium, 2006. Available from: 
http://www.bcirg.org/NR/rdonlyres/eqkdodg2dy7t557o7s6uvj7ytpe6gcfg5gmh2ely6 
hnhh5pjlabz3nd6jddlnao7qoikej3edohsijyiisfvp367uuc/BCIRG006+2nd+Interim+An
alysis.pdf.


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Slamon DJ, Eiermann W, Robert N, et al. Phase III randomized trial comparing 
doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with 
doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→
TH) with docetaxel, carboplatin and trastuzumab (TCH) in Her2neu positive early 
breast cancer patients: BCIRG 006 study. Cancer Res 2009;69(24 Suppl 3):62.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast 
cancer. N Engl J Med 2011;365:1273−83.


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Appendix 1
Protocol Synopsis
PROTOCOL SYNOPSIS
TITLE:
A RANDOMIZED, MULTICENTER, OPEN-LABEL, PHASE III TRIAL 
COMPARING TRASTUZUMAB PLUS PERTUZUMAB PLUS A 
TAXANE FOLLOWING ANTHRACYCLINES VERSUS 
TRASTUZUMAB EMTANSINE PLUS PERTUZUMAB FOLLOWING 
ANTHRACYCLINES AS ADJUVANT THERAPY IN PATIENTS 
WITH OPERABLE HER2-POSITIVE PRIMARY BREAST CANCER
PROTOCOL NUMBER:
BO28407
VERSION NUMBER:
3
EUDRACT NUMBER:
2012-004902-82
IND NUMBER:
71072
TEST PRODUCTS:
Trastuzumab Emtansine (RO5304020) and 
Pertuzumab (RO4368451)
PHASE:
III
INDICATION:
HER2-positive operable primary breast cancer
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives
Efficacy Objectives
The co-primary efficacy objective for this study is as follows:

To compare invasive diseasefree survival (IDFS) (1) in the node-positive subpopulation 
and (2) in the overall protocol-defined population of patients with human epidermal growth
(HER) factor 2positive breast cancer randomized to receive either a taxane and 1 year of 
trastuzumab plus pertuzumab following anthracycline-based chemotherapy or 1 year of 
trastuzumab emtansine plus pertuzumab following anthracycline-based chemotherapy
The secondary efficacy objectives for this study are as follows:

To compare IDFS plus second non-breast primary cancers, disease-free survival (DFS),
and distant recurrencefree interval (DRFI) (1) in the node-positive subpopulation and (2) in 
the overall protocol-defined population between the two treatment arms

To compare overall survival (OS) (1) in the node-positive subpopulation and (2) in the 
overall protocol-defined population between the two treatment arms
Safety Objective
The safety objective for this study is as follows:

To compare overall safety, cardiac safety, hepatic, and pulmonary safety in the overall 
protocol-defined population between the two treatment arms


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Appendix 1
Protocol Synopsis (cont.)
Patient-Reported Outcome Objectives
Patient-reported outcome (PRO) objectives in the overall protocol-defined population for this 
study are as follows:

To compare PROs of treatment-related symptoms, patient functioning, and health-related 
quality of life (HRQoL) to better understand treatment impact and tolerability, as measured 
by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of 
Life QuestionnaireCore 30 (QLQ-C30) and the modified EORTC Breast Cancer module 
(Quality of Life QuestionnaireBreast Cancer 23 [QLQ-BR23]), between 
‘Trastuzumab Pertuzumab Taxane following Anthracyclines’ and ‘Trastuzumab 
Emtansine Pertuzumab following Anthracyclines’ treatment arms.
Exploratory Objectives
The exploratory biomarker objectives for this study are as follows:

To evaluate the impact of HER2 mRNA level on treatment benefit using the efficacy 
endpoints 

To evaluate the impact of the PIK3CA mutation status on prognosis and treatment benefit 
using the efficacy endpoints

To assess correlations between candidate biomarkers or biomarker panels and efficacy 
and/or safety in the overall protocol-defined population

To identify whether changes in expression levels of biomarker or biomarker panels during 
treatment correlate with treatment efficacy in the overall protocol-defined population
Efficacy endpoints considered for these objectives will include IDFS and OS, as appropriate.
The exploratory anti-therapeutic antibodies (ATAs) objective in the trastuzumab 
emtansinetreated patient population for this study is as follows:

To assess the incidence of ATAs to trastuzumab emtansine and the effect of ATAs on 
safety and efficacy
The health economic exploratory objective is as follows:

To assess health status as measured using the EuroQol 5-Dimension Questionnaire 
(EQ-5D) questionnaire for health economic modeling
Study Design
Description of Study
This is a prospective, two-arm, Phase III, randomized, multicenter, multinational, open-label 
study in patients with newly diagnosed HER2-positive primary invasive breast cancer who have 
had curative-intent surgery of their primary tumor and are candidates for adjuvant systemic 
chemotherapy following surgery.  HER2-positive status of the primary tumor will be confirmed 
by the central pathology laboratory prior to enrollment of the patient in the study.  Approximately 
1850 patients are anticipated to be randomized to one of the two treatment arms listed below in 
a 1:1 ratio.

Arm 1:  Anthracycline chemotherapy of choice followed by trastuzumab at 6 mg/kg every 
3 weeks (q3w; 8-mg/kg loading dose) in combination with pertuzumab 420 mg q3w (840-mg 
loading dose) and paclitaxel (80 mg/m2) weekly (qw) or docetaxel q3w (see protocol for 
details of dose and duration).  After the taxane-concurrent phase, HER2-targeted therapy 
(i.e., trastuzumab at 6 mg/kg q3w in combination with pertuzumab 420 mg q3w) will 
continue for up to 1 year.


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Appendix 1
Protocol Synopsis (cont.)

Arm 2:  Anthracycline chemotherapy of choice followed by trastuzumab emtansine 
3.6 mg/kg q3w in combination with pertuzumab 420 mg q3w (840-mg loading dose).  
HER2-targeted therapy (i.e., trastuzumab emtansine at 3.6 mg/kg q3w in combination with 
pertuzumab 420 mg q3w) will continue for up to 1 year.
Randomization will be stratified by world region (United States/Canada, Western 
Europe/Australia/New Zealand, Asia, or rest of the world); nodal status (0, 13, or 4 positive 
nodes); centrally assessed hormonal receptor status (estrogen receptor [ER] and/or 
progesterone receptor [PR] positive or both ER and PR negative); and type of anthracycline 
(doxorubicin or epirubicin).
In Arm 1, HER2-targeted study therapy with trastuzumab plus pertuzumab must start 
concurrently with the taxane component of chemotherapy following anthracycline therapy. In 
both arms, after anthracycline treatment, a minimum interval of 3 weeks from the last dose of 
anthracycline to initiation of HER2-targeted therapy is required. Prior to commencing the 
HER2-targeted therapy, patients must have a left ventricular ejection fraction (LVEF) 50% and
must not have experienced any clinical symptoms suggesting heart failure or asymptomatic 
LVEF declines of 15 percentage points or more from baseline and below the lower limit of 
normal.
Patients will receive up to 1 year of HER2-targeted therapy. Study treatment will be 
discontinued in the event of invasive disease recurrence, unacceptable toxicity, withdrawal of 
consent, or study termination by the Sponsor.
Adjuvant radiotherapy is to be given as clinically indicated at the end of chemotherapy (end of 
taxane in Arm 1; after four cycles of trastuzumab emtansine plus pertuzumab in Arm 2, to be 
consistent with Arm 1 in terms of timing of initiation) while receiving HER2-targeted therapy.
For patients with ER-positive and/or PR-positive tumors, hormonal agents should be 
administered at the end of chemotherapy (end of taxane in Arm 1; after four cycles of 
trastuzumab emtansine plus pertuzumab in Arm 2, to be consistent with Arm 1 in timing of 
initiation). 
Number of Patients
Approximately 1850 patients are anticipated to be enrolled at approximately 350 sites 
worldwide.
Target Population
The target population for this study will be patients with newly diagnosed primary invasive 
breast cancer that is HER2 positive (as determined by the central pathology laboratory) and
who will be treated with adjuvant systemic chemotherapy following definitive surgery.
Inclusion Criteria
Patients must meet the following criteria for study entry:

Age 18 years

Eastern Cooperative Oncology Group Performance Status 1

Non-metastatic histologically confirmed primary invasive breast carcinoma that was 
operable

HER2-positive breast cancer prospectively determined on the primary tumor by a central 
pathology laboratory and defined as follows:
Immunohistochemistry (IHC) score of 3and/or positive by in situ hybridization (ISH), 
as defined by ISH ratio of 2.0 for the number of HER2 gene copies to the number of 
chromosome 17 copies.  Both IHC and ISH assays will be performed; however, only 
one positive result is required for eligibility.
Availability of formalin-fixed paraffin-embedded (FFPE) tissue block or partial block (for 
minimum dimensions, see laboratory manual) with a representative invasive part of the 
tumor for central pathology laboratory confirmation of HER2 eligibility, hormonal 
receptor status, and additional biomarker analysis is required.


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Appendix 1
Protocol Synopsis (cont.)

Known hormone receptor status of the primary tumor determined by a central pathology 
laboratory
Hormone receptor-positive status can be determined by either known positive ER or 
known positive PR status.  Hormone receptornegative status must be determined by 
both known negative ER and known negative PR. 

Adequately excised:  Patients must have undergone either breast-conserving surgery or 
mastectomy/nipple- or skin-sparing mastectomy.
For patients who undergo breast-conserving surgery, the margins of the resected 
specimen must be histologically free of invasive tumor and ductal carcinoma in situ 
(DCIS) as determined by the local pathologist.  If pathologic examination demonstrates 
tumor at the line of resection, additional operative procedures may be performed to 
obtain clear margins.  If tumor is still present at the resected margin after re-excision(s), 
the patient must undergo total mastectomy to be eligible.  Patients with margins 
positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.
For patients who undergo mastectomy/nipple- or skin-sparing mastectomy, margins 
must be free of gross residual tumor.  It is recommended that patients should have a 
negative microscopic margin in accordance with local pathology protocol.  Patients with 
a microscopic positive deep margin are eligible (see radiation therapy [RT]
requirements in the protocol).

Pathological tumor-node-metastasis staging (Union for International Cancer 
Control/American Joint Committee on Cancer [UICC/AJCC], 7th edition):  Patients must 
have had sentinel lymph node biopsy and/or axillary lymph node dissection for evaluation of 
pathologic nodal status. Pathological classification of regional lymph node 
micrometastases (tumor deposits 0.2 mm and 2 mm) is considered to be pN1, and 
isolated tumor cells are considered to be pN0. 
Eligible patients must have one of the following:
Node-positive disease (pN 1), any tumor size except T0, and any hormonal receptor 
status
Enrollment of patients with 13 nodes was planned to be limited to no more 
than 50% of the total number of randomized patients.  However, no formal 
capping of enrollment will be implemented (see Section 3.3.2.1 for details).
There is no prespecified limit for the enrollment of patients with 4 nodes.
Node-negative disease (pN0) with pathologic tumor size 2.0 cm by standard local 
assessment AND negative for ER and PR as determined by a central pathology 
laboratory
Enrollment of patients with node-negative disease was planned to be limited to no 
more than 10% of the total number of randomized patients.  However, no formal 
capping of enrollment will be implemented (see Section 3.3.2.1 for details).

Patients with synchronous bilateral invasive disease are eligible only if both lesions are 
HER2 positive.

No more than 9 weeks (63 days) may elapse between definitive breast surgery (or the last 
surgery if additional resection required for breast cancer) and randomization. 

Baseline LVEF 55% measured by echocardiogram (preferred) or multiple-gated 
acquisition scans
Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required.  
This includes hepatitis B surface antigen and/or total hepatitis B core antibody in addition to HCV
antibody testing.  The most recent serologic testing must have occurred within 3 months prior to 
randomization.  If such testing has not been done, it must be performed during screening.


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Appendix 1
Protocol Synopsis (cont.)
Patients who have positive HBV or HCV serologies without known active disease must 
meet the eligibility criteria for ALT, AST, total bilirubin (TBILI), INR, activated partial 
thromboplastine time (aPTT), and alkaline phosphatase (ALP) on at least two 
consecutive occasions, separated by at least 1 week, within the 30-day screening 
period.  The second of these evaluations must be performed within 3 days prior to the 
first administration of study drug.  Note:  positive serology markers that indicate 
immunity will not be considered as clinically meaningful positive serology to trigger 
these tests.

Female patients of childbearing potential must be willing to use one highly effective form of 
nonhormonal contraception or two effective forms of nonhormonal contraception.  For male 
patients with partners of childbearing potential, one highly effective form of contraception or 
two effective forms of contraception must be used (see protocol for descriptions of highly 
effective and effective contraception).  Contraception must continue for the duration of study 
treatment and for 7 months after the last dose of study treatment. 
The above contraception is not a requirement in the case of any of the following:
The patient or partner of the patient is surgically sterilized.
The female patient is 45 years of age and is postmenopausal (has not 
menstruated for at least 12 consecutive months).
The patient truly abstains from sexual activity and when this is the preferred 
option to avoid conception and contraception and/or usual lifestyle of the patient.

Male patients whose partners are pregnant must use condoms or truly refrain from sexual 
activity for the duration of the pregnancy

Willing and able to comply with the requirements of the protocol

Signed informed consent
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

History of any prior (ipsilateral and/or contralateral) invasive breast carcinoma

History of non-breast malignancies within the 5 years prior to randomization, except for the 
following:
Carcinoma in situ (CIS) of the cervix
CIS of the colon
Melanoma in situ
Basal cell and squamous cell carcinomas of the skin

Any clinical T4 tumor as defined by tumor-node-metastasis classification in UICC/AJCC, 7th 
edition, including inflammatory breast cancer

For the currently diagnosed breast cancer, any previous systemic anti-cancer treatment 
(e.g., neoadjuvant or adjuvant), including but not limited to chemotherapy, anti-HER2 
therapy (e.g., trastuzumab, trastuzumab emtansine, pertuzumab, lapatinib, neratinib, or 
other tyrosine kinase inhibitors), hormonal therapy, OR anti-cancer RT (intraoperative 
radiotherapy as a boost at the time of primary surgery is acceptable)

Previous therapy with anthracyclines, taxanes, or HER2-targeted therapy for any 
malignancy

History of DCIS and/or LCIS that was treated with any form of systemic chemotherapy, 
hormonal therapy, or RT to the ipsilateral breast where invasive cancer subsequently 
developed.  Patients who had their DCIS/LCIS treated with only surgery and/or contralateral 
DCIS treated with radiation are allowed to enter the study.

Patients with contraindication to RT while adjuvant RT is clinically indicated

Concurrent anti-cancer treatment in another investigational trial


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Appendix 1
Protocol Synopsis (cont.)

Cardiopulmonary dysfunction as defined by any of the following prior to randomization:
History of National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.0 Grade 3 symptomatic congestive heart failure (CHF) or 
New York Heart Association (NYHA) criteria Class II
Angina pectoris requiring anti-anginal medication, serious cardiac arrhythmia not 
controlled by adequate medication, severe conduction abnormality, or clinically 
significant valvular disease
High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate
100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or 
higher-grade atrioventricular [AV]-block [second degree AV-block Type 2 
[Mobitz 2] or third degree AV-block])
Significant symptoms (Grade 2) relating to left ventricular dysfunction, cardiac 
arrhythmia, or cardiac ischemia 
Myocardial infarction within 12 months prior to randomization
Uncontrolled hypertension (systolic blood pressure 180 mmHg and/or diastolic blood 
pressure 100 mmHg)
Evidence of transmural infarction on ECG
Requirement for oxygen therapy

Other concurrent serious diseases that may interfere with planned treatment, including
severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes, or 
known infection with HIV

Any known active liver disease, including but not limited to disease due to HBV, HCV, 
autoimmune hepatic disorders, or sclerosing cholangitis.  For patients who are known 
carriers of HBV/HCV, active hepatitis B/C infection must be ruled out on the basis of 
negative serologic testing and/or determination of HBV DNA/HCV RNA viral load per local 
guidelines.

Any of the following abnormal laboratory tests prior to randomization:
Serum TBILI 1.0 times the upper limit of normal (ULN).  In cases of known Gilbert’s 
syndrome, direct bilirubin should be within the normal range.
ALT and/or AST ULN
ALP 1.5 ULN
Serum creatinine 1.5 ULN
Total WBC 2500/L (2.5 109/L)
ANC 1500/L (1.5 109/L)
Platelets 100,000/L (100 109/L)
INR or aPTT 1.5 ULN

Pregnant or lactating women or women of childbearing potential without a negative serum
pregnancy test result, within 7 days prior to randomization, regardless of the method of 
contraception used

Hypersensitivity to any of the study medications or any of the ingredients or excipients of 
these medications, including hypersensitivity to benzyl alcohol

Chronic immunosuppressive therapies, including systemic corticosteroids
Length of Study
The total length of this study will be from randomization of the first patient to completion of the 
last follow-up assessment of the last patient, which is estimated to occur approximately 
10 years after the first patient is randomized.  


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
35/Statistical Analysis Plan BO28407
Appendix 1
Protocol Synopsis (cont.)
End of Study
To enable long-term follow-up for survival and safety information, the study is planned to end 
approximately 10 years after the first patient is randomized.
The Sponsor has the right to terminate this study, including long-term follow-up, at any time 
(e.g., if emerging safety signals indicate a potential health hazard to patients).
Outcome Measures
Efficacy Outcome Measures
The primary efficacy outcome measures for this study are listed below.

IDFS, defined as the time from randomization until the date of the first occurrence of one of 
the following events:
Ipsilateral invasive breast tumor recurrence (i.e., an invasive breast cancer involving 
the same breast parenchyma as the original primary lesion)
Ipsilateral local-regional invasive breast cancer recurrence (i.e., an invasive breast 
cancer in the axilla, regional lymph nodes, chest wall, and/or skin of the ipsilateral 
breast)
Contralateral or ipsilateral second primary invasive breast cancer
Distant recurrence (i.e., evidence of breast cancer in any anatomic site [other than the 
three sites mentioned above]) that has either been histologically confirmed or 
clinically/radiographically diagnosed as recurrent invasive breast cancer
Death attributable to any cause, including breast cancer, non-breast cancer, or 
unknown cause  
The secondary efficacy outcome measures for this study are as follows:

IDFS plus second primary non-breast cancer, excluding non-melanoma skin cancers and 
CIS of any site

DFS, defined as the time between randomization and the date of the first occurrence of any 
of the IDFS events described above, second primary non-breast cancer event (excluding 
non-melanoma skin cancers and CIS of any non-breast site), and contralateral or ipsilateral 
DCIS

DRFI, defined as the time between randomization and the first occurrence of distant breast 
cancer recurrence

OS, defined as the time from randomization to death due to any cause
Safety Outcome Measures
The safety outcome measures for this study are as follows:

Incidence, type, and severity of all adverse events based on NCI CTCAE v4.0

Incidence, type, and severity of serious adverse events

Incidence, type and severity of Grade 3 adverse events

Incidence and type of adverse events leading to dose discontinuation, modification, or delay

Cause of death

Abnormal laboratory values

Decrease in LVEF from baseline over time

Cardiac safety outcome measures
Primary cardiac endpoints:  cardiac events defined as death from cardiac cause or 
severe CHF (NYHA Class III or IV) with a decrease in LVEF of 10 percentage points
from baseline to an LVEF of 50%


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
36/Statistical Analysis Plan BO28407
Appendix 1
Protocol Synopsis (cont.)
Secondary cardiac endpoints:  other cardiac-related events (e.g., any mild 
symptomatic CHF [NYHA Class II] associated with a 10% drop in LVEF to 50%; 
asymptomatic declines in LVEF requiring dose delay or discontinuation)

Hepatic safety outcome measures
Death from hepatic cause
Severe drug-induced liver injury (Hy’s law cases)
Nodular regenerative hyperplasia

Pulmonary safety outcome measures
Death from pulmonary cause
Pneumonitis and interstitial lung disease
Patient-Reported Outcome Measures
The PRO outcome measures for this study are as follows:

HRQoL, including bothersome side effects of therapy (e.g., peripheral neuropathy, 
joint/muscle pain, or skin problems), and patient functioning as measured using the EORTC 
QLQ-C30 and the modified breast cancer module QLQ-BR23

Time from first HER2-targeted treatment, a taxane, to clinically meaningful deterioration 
in the global health status/quality of life (QoL) and functional (physical, role, and 
cognitive) subscales of the QLQ-C30.  The event of worsening of global health status/QoL 
for a given patient is defined as a decrease in baseline mean score by 10 points or more at 
two consecutive timepoints.  A 10-point or greater change in mean score is defined as 
being a “moderate” to “very much” and perceived an important change from the patient’s 
perspective.  Deterioration in function will be assessed using the published corresponding 
MIDs by Cocks et al. 2011.
Exploratory Outcome Measures
The exploratory biomarker outcome measures for this study are the relationship between 
molecular markers and efficacy and/or safety outcomes.  Efficacy outcomes considered for this 
analysis will include IDFS and OS, as appropriate.
Correlations between biomarker status and efficacy and/or safety will include but not be limited 
to the following:

Level of HER2 mRNA expression assessed by quantitative real-time polymerase chain 
reaction (qRT-PCR) with efficacy outcome

Status of PIK3CA mutations assessed by PIK3CA allelespecific polymerase chain reaction
assay with efficacy outcome

Level of HER2 gene amplification assessed by ISH with efficacy outcome

Level of HER2 protein expression assessed by IHC with efficacy outcome

Level of HER3 mRNA expression assessed by qRT-PCR with efficacy outcome

Changes in expression levels of biomarker or biomarker panels over time with efficacy 
outcome
The ATA outcome measures to be assessed in patients receiving trastuzumab emtansine are 
the following:

Incidence of ATAs to trastuzumab emtansine

Effect of ATAs on safety and efficacy
The EQ-5D will be used to obtain health status information for health economic modeling.


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
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Appendix 1
Protocol Synopsis (cont.)
The EQ-5D is a generic, preference-based health utility measure with questions about mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression that are used to build a 
composite of the patient’s health status.  A single summary index from the EQ-5D health states 
will be utilized in this study for economic modeling, and the results will not be reported in the 
clinical study report.
Investigational Medicinal Products
Study treatment is defined as non-hormonal systemic adjuvant (post-operative) treatment.  
Trastuzumab emtansine, pertuzumab, and trastuzumab are considered investigational 
medicinal products (IMPs) in this study.  Paclitaxel and docetaxel are also considered IMPs in 
this study; however, paclitaxel and docetaxel may be considered non-IMPs on the basis of local 
legislation. 
Doxorubicin, epirubicin, cyclophosphamide, and 5-fluorouracil are considered non-IMPs in this 
study.  Depending on local legislation, doxorubicin, epirubicin, cyclophosphamide, and 
5-fluorouracil may be considered IMPs.  If considered an IMP, then appropriate information on 
formulation, packaging, handling, and administration will be provided.  
Test Product
Trastuzumab emtansine will be given at a dose of 3.6 mg/kg by intravenous (IV) infusion q3w in 
combination with pertuzumab 420 mg IV q3w (840 mg loading dose) for up to a total duration of 
1 year.
Comparator
Pertuzumab will be given at a dose of 420 mg IV q3w (840 mg loading dose) in combination 
with trastuzumab at 6 mg/kg IV q3w (8 mg/kg loading dose) and paclitaxel (80 mg/m2) qw or 
docetaxel q3w (details regarding docetaxel dose and duration are described in the protocol).  
After the taxane concurrent phase, administration of trastuzumab/pertuzumab will continue for 
up to a total duration of 1 year
Non-Investigational Medicinal Products
Standard-of-care chemotherapy backbone treatments should include three to four cycles of an 
anthracycline-based regimen.  Either 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) or 
doxorubicin and cyclophosphamide (AC)/epirubicin and cyclophosphamide (EC) regimens that 
are protocol approved may be selected at the discretion of the investigator.  Paclitaxel and 
docetaxel may be considered non-IMPs on the basis of local legislation.  In Arm 1, three to four 
cycles of docetaxel or 12 weeks of paclitaxel will be administered.  
For non-IMPs, refer to local prescribing information/institutional guidelines for detailed 
guidelines on administration, premedications, dose delays/reductions for toxicities, 
contraindications, requirements on contraception duration, and concomitant medications.
Statistical Methods
Primary Analysis
The primary efficacy variable is IDFS, defined as the time between randomization and date of 
first occurrence of an IDFS event as described in the Efficacy Outcome Measures section.  Data 
from patients who have not had an event at the time of data analysis will be censored on the 
date on which they are last known to be alive and event free, on or before the clinical data cutoff 
date of the respective analysis.
The log-rank test, stratified by the protocol-defined stratification factors (excluding region), will 
be used to compare IDFS between the two treatment arms. Region will be excluded because of
the potential that some of the strata may have very few patients, which would result in a loss of 
power. The unstratified log-rank test results will also be provided for sensitivity analysis.  If, at 
the time of analysis, it is deemed that the smallest stratum per arm necessary to conduct robust 
stratified analyses contains 5 events, unstratified analyses will be used as the primary analysis.  
The Cox proportional hazards model, stratified by the previously noted stratification factors, 
excluding region, will be used to estimate the hazard ratio (HR) between the two treatment arms


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
38/Statistical Analysis Plan BO28407
Appendix 1
Protocol Synopsis (cont.)
and the corresponding 95% CI.  The Kaplan-Meier approach will be used to estimate 3-year
IDFS rates and corresponding 95% CIs for each treatment arm.
Determination of Sample Size
The sample size of the study is primarily driven by the analysis of IDFS in both the 
node-positive subpopulation and the overall protocol-defined population.
To detect a target HR of 0.64 in IDFS in the overall protocol-defined population and the 
node-positive subpopulation, approximately 171 and 160 IDFS events will be required to 
achieve 82.5% and 80% power, respectively, in the two populations, at a two-sided 
significance level of 5% using a log-rank test.  Approximately 1850 and 1665 patients will be 
enrolled in the overall protocol-defined population and node-positive subpopulation, respectively, 
including a dropout/ineligibility rate of 8% for both arms as estimated from previous trials in this 
setting.
Hierarchical Testing Procedure
The hierarchical testing procedure will be employed according to the order given below on the 
primary and secondary endpoints to control the overall study Type I error rate at 5%:

Primary endpoint of IDFS in the nodepositive subpopulation

Primary endpoint of IDFS in the overall protocoldefined population

Secondary endpoint of OS in the nodepositive subpopulation

Secondary endpoint of OS in the overall protocol-defined population
Interim Analyses
One interim analysis of IDFS and three interim analyses of OS in both the node-positive 
subpopulation and the overall protocol-defined population are planned.
A futility analysis may be incorporated to evaluate lack of superiority for the treatment arm 
of trastuzumab emtansine pertuzumab following anthracyclines.  The timing and details of 
this futility analysis will be described in the SAP and aligned with the availability of 
information from other relevant studies (e.g., KRISTINE and/or APHINITY).
Interim IDFS Analyses
An interim efficacy analysis of IDFS will be performed after approximately 75% of the targeted 
IDFS events are observed in the overall protocol-defined population (i.e. 128 of the 171 target 
events) and node-positive population (i.e. 120 of 160 target events) and is projected to occur 
approximately 43 months from first patient initiation (FPI).
A hierarchical testing procedure will be used for the primary endpoint IDFS for the node-positive 
subpopulation and the overall protocol-defined population as defined in the protocol.  The type I 
error will be controlled at the 5% level at the interim and final analyses within the node-positive 
subpopulation and the overall protocol-defined population using a Lan-DeMets -spending 
function with an O’Brien-Fleming boundary. 
The interim analysis will be performed by the independent Data Coordination Center (iDCC) 
statistician, and the results will be presented to the independent Data Monitoring Committee 
(iDMC) by the iDCC statistician.  
If the interim analyses in both populations cross the interim efficacy boundaries of the 
O’Brien-Fleming design, on the basis of the totality of both efficacy and safety data, the iDMC 
may recommend releasing the primary endpoint results before the targeted number of 160 and 
171 events have occurred in the node-positive subpopulation and overall protocol-defined 
population, respectively.  In this case, the Sponsor will be unblinded to study results, and a full 
data package including the first OS interim analysis results will be prepared for discussion with 
the regulatory authorities.  The study will continue until 10 years of follow-up from FPI have 
occurred, and the IDFS analysis will be updated descriptively.  If the IDFS interim analyses fail 
to cross the statistical efficacy boundaries of the O’Brien-Fleming design, then the study will 
continue as planned.  The Sponsor will conduct the final analyses. 


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
39/Statistical Analysis Plan BO28407
Appendix 1
Protocol Synopsis (cont.)
The protocol summarizes the planned IDFS analyses in the overall protocol-defined population 
and the node-positive subpopulation; the efficacy stopping boundaries based on the expected 
number of events; and the estimated timing of these analyses.  The boundaries to be used at 
each interim and final IDFS analysis will depend on the number of IDFS events actually 
included in the analyses and so may vary from the numbers stated in the protocol.
Interim OS Analyses
Three interim OS analyses and one final OS analysis are planned in both the overall 
protocol-defined population and the node-positive subpopulation.  
For the OS interim analyses and final OS analysis, the Lan-DeMets -spending function with an 
O’Brien-Fleming boundary will be used such that the overall type I error will be controlled at the 
5% level for the OS endpoint.  With the study sample size and approximately 10 years of 
follow-up from FPI, this study has 38% power in the overall protocol-defined population and 35% 
power in the node-positive subpopulation to detect an HR of 0.8.  This in the overall protocol-
defined population corresponds to a 0.8% improvement in 3-year OS, from 96.1% in the control 
arm to 96.9% in the experimental arm and in the node-positive subpopulation to a 0.9% 
improvement in 3-year OS, from 95.7% in the control arm to 96.6% in the experimental arm, at 
a two-sided significance level of 5%. 
All OS interim and final analyses will be performed by the Sponsor subsequent to the primary 
IDFS analysis and after the Sponsor is unblinded.  If the interim IDFS analyses in both the 
node-positive subpopulation and the overall protocol-defined population cross the statistical
efficacy boundaries, the first OS interim analysis will be performed in both populations 
hierarchically at that time (approximately at 43 months from FPI).  If the final IDFS analysis 
crosses the statistical boundaries, then the second interim OS analysis will be performed 
hierarchically at the time of the final IDFS analysis (approximately 57 months from FPI), 
followed by the third and the final OS analyses performed hierarchically in both populations 
(planned to occur at 84 months [7 years] and 120 months [10 years], respectively, from FPI).  If, 
at any OS interim analysis, the O’Brien-Fleming efficacy boundary is crossed, that analysis of 
OS will be considered as confirmatory and all subsequent analyses of OS will be considered as 
descriptive.
The protocol summarizes the planned OS analyses in the overall protocol-defined population 
and the node-positive subpopulation, respectively; the efficacy stopping boundaries based on 
the expected number of events; and the estimated timing of these analyses.  The boundaries to 
be used at each interim and final IDFS analysis will depend on the number of IDFS events 
actually included in the analyses and may vary from the numbers stated in the protocol.
Interim Safety Analyses
An iDMC will monitor accruing patient safety data at least once every 6 months during the study 
until the last patient has completed study treatment.  In addition, safety data related to 
concurrent radiotherapy and/or hormonal therapy, serious adverse events, and deaths will be 
monitored by the iDMC at least once every 3 months during the study until the last patient has 
completed study treatment.  At each iDMC review, relevant safety information from ongoing 
trastuzumab emtansine and/or pertuzumab studies will also be provided to the iDMC.
After the first 600 patients have been randomized and followed for 3 months (anticipated to 
occur at approximately 13 months after FPI), the iDMC will perform an interim safety analysis 
regarding overall numbers of deaths (all causes, including cardiac deaths) and hepatic events 
defined as confirmed Hy’s law cases.  The Clinical Events Committee (CEC) will communicate 
their findings to the iDMC to aid iDMC review.
If an absolute increase of 3% in the percentage of death (from any cause) is observed in the 
trastuzumab emtansine pertuzumab arm compared with the trastuzumab pertuzumab arm, 
the iDMC will consider a recommendation of pausing enrollment for further data review, 
stopping the trial, or modifying the trial.
If the true difference in the percentage of death is 3% (e.g., 2% vs. 6%), then there is 
approximately a 70% chance of observing an absolute difference of 3% at the interim with 
600 patients.  The protocol presents the probability of observing an increase of 3% in the 


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
40/Statistical Analysis Plan BO28407
Appendix 1
Protocol Synopsis (cont.)
percentage of deaths in the trastuzumab emtansine pertuzumab arm compared with the 
trastuzumab pertuzumab arm, with different assumptions for the percentage of deaths in the 
two treatment arms.
If an absolute increase of 3% in the percentage of Hy’s law cases (confirmed by the 
independent CEC) is observed in the trastuzumab emtansine pertuzumab arm compared with 
the trastuzumab pertuzumab arm, the iDMC will consider a recommendation of pausing 
enrollment for further data review, stopping the trial, or modifying the trial.
If the true difference in the percentage of confirmed Hy’s law cases is 3% (e.g., 0.33% 
vs. 3.67%), then there is approximately a 54% chance of observing an absolute difference of 
3% at the interim with 600 patients.  The protocol presents the probability of observing a 3% 
increase in the percentage of Hy’s law cases in the trastuzumab emtansine pertuzumab arm 
compared with the trastuzumab pertuzumab arm, with different assumptions for the number of 
Hy’s law cases in the two treatment arms.
The iDMC will work according to guidelines defined in the iDMC Charter.  The iDMC Charter will 
contain details regarding frequency of meetings, guidelines for decision making, and processes 
for requesting further information.  The iDMC members will review and sign off the charter 
before the first iDMC review.


Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
41/Statistical Analysis Plan BO28407
Appendix 2
Schedule of Assessments
Screening
a
(30 days)
Anthracyclin
e Treatment 
Period
HER2-Targeted Treatment Period within 
3 Days of Day 1 of Cycle Number X
End-of-Tr
eatment 
Visitb
Follow-Upc
(28 days)
Follow-Up
c
(42 days)
Cycles 1a3
or Cycle 4
Cycles 14 (concurrent taxane 
in Arm 1 only)
Cycles
518
Year 
12
Year 
35
Year 610
Day 1
Day 1
Day 8
Day 15
Day 1
Informed consentd
x
Mandatory tumor tissue 
sample for 
determination of HER2,
ER/PR; and exploratory 
biomarkerse
x
xe (at disease recurrence)
Bilateral mammogramf,g
x (within 
6 months)
x (q12mo)
Chest X-rayh
x (within 
2 months)
As clinically indicated
Demography, medical 
history
x
Disease status 
assessmentg
x
x (q3mo)
x
(q3mo)
x
(q6mo
)
x (q12mo)
Physical examinationg,i
x
x (Cycle 1)
x
x
x
x
(q3mo)
x
(q6mo
)
x (q12mo)


Appendix 2
Schedule of Assessments (Cont.)
Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan BO28407
Screening
a
(30 days)
Anthracyclin
e Treatment 
Period
HER2-Targeted Treatment Period within 
3 Days of Day 1 of Cycle Number X
End-of-Tr
eatment 
Visitb
Follow-Upc
(28 days)
Follow-Up
c
(42 days)
Cycles 1a3
or Cycle 4
Cycles 14 (concurrent taxane 
in Arm 1 only)
Cycles
518
Year 
12
Year 
35
Year 610
Day 1
Day 1
Day 8
Day 15
Day 1
Vital signsj
x
x
x
x (for 
paclitaxel 
only)
x (for 
paclitaxel 
only)
x
ECOG Performance 
Status
x
x
ECG
x
As clinically indicated
x
ECHO/MUGAk
x
xk (end of last 
cycle)
xk (in last week of Cycle 2, and every 
4 cycles thereafter)
xk
xk
xk
PRO HRQoL 
assessmentl
xl
xl
xl
x
xl
(q6mo)
Hematologym
xn
xo
xo
xo (for 
paclitaxel 
only)p
xo (for 
paclitaxel 
only)p
xo
x
xm
Serum chemistryq
xn
xo
xo
xo
x
xq
HBV and HCV serologyr
x
As clinically indicated
INR and aPTT
xn
As clinically indicated
Pregnancy tests
xn
xo,s (C1D1 then every 3 cycles thereafter)
xs
Clinical genotyping 
whole blood samplet
xt


Appendix 2
Schedule of Assessments (Cont.)
Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan BO28407
Screening
a
(30 days)
Anthracyclin
e Treatment 
Period
HER2-Targeted Treatment Period within 
3 Days of Day 1 of Cycle Number X
End-of-Tr
eatment 
Visitb
Follow-Upc
(28 days)
Follow-Up
c
(42 days)
Cycles 1a3
or Cycle 4
Cycles 14 (concurrent taxane 
in Arm 1 only)
Cycles
518
Year 
12
Year 
35
Year 610
Day 1
Day 1
Day 8
Day 15
Day 1
Mandatory serum and 
plasma sample for 
exploratory biomarker 
analysisu,v
x (C1D1 
predose)
x (C1D1 
predose
)
x
xs
xu (at disease recurrence)
OBRP whole blood 
sample for genetic 
analysis (optional)v
xv(to be done at baseline if possible)
Adverse eventsw
x
x
x
x (for 
paclitaxel 
only)
x (for 
paclitaxel 
only)
x
x
xw
Concomitant 
medicationsx
x
x
x
x (for 
paclitaxel 
only)
x (for 
paclitaxel 
only)
x
x
Record post-recurrence
anti-cancerrelated 
therapiesy
As required
Survival 
post-recurrencey
q12mo
AEadverse event; ALPalkaline phosphatase; aPTT activated partial thromboplastine time; ATAanti-therapeutic antibody; C1D1Cycle 1 Day 1; 
CTcomputed tomography; eCRFelectronic Case Report Form; ECHOechocardiogram; ECOGEastern Cooperative Oncology Group; ERestrogen receptor; 
EORTCEuropean Organisation for Research and Treatment of Cancer; EQ-5DEuroQol 5-Dimension Questionnaire; FFPEformalin-fixed paraffin-embedded;
FPIfirst patient initiation; HBcAbhepatitis B core antibody; HBsAghepatitis B surface antigen; HBVhepatitis B virus; HCGhuman chorionic gonadotropin;
HCVhepatitis C virus; HER2human epidermal growth factor-2; HRQoLhealth-related quality of life; IDFSinvasive diseasefree survival; 


Appendix 2
Schedule of Assessments (Cont.)
Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
44/Statistical Analysis Plan BO28407
IVRS/IWRSinteractive voice response system/interactive web response system; LVEFleft ventricular ejection fraction; MRImagnetic resonance imaging; 
MUGAmultiple-gated acquisition; OBRPoptional biomarker research program; pacpaclitaxel; PKpharmacokinetic; PRprogesterone receptor; 
PROpatient-reported outcome; QLQ-BR23Quality of Life QuestionnaireBreast Cancer 23; QLQ-C30Quality of Life QuestionnaireCore 30; qwweekly; 
SAEserious adverse event; SoCstandard of care; TBILItotal bilirubin; ULNupper limit of normal.
a
Screening to be performed within 30 days prior to randomization.  The randomization visit may be combined with anthracycline Cycle 1 Day 1 visit.  Patients 
should receive their first dose of study treatment on the day of randomization, if possible, but no later than 7 days after randomization.  No more than 9 weeks 
(63 days) may elapse between definitive breast surgery (or the last surgery if additional resection required for breast cancer) and randomization.
b
End-of-treatment visit or early termination visits will optimally be scheduled within 28 to 42 days following the last dose of study treatment.
c
The follow-up period begins from the date of the end-of-treatment visit, with a duration of up to 10 years from the date of randomization of the first patient.
d
Informed consent may be obtained at any time (including prior to the 30-day screening period) but must be obtained prior to the performance of any screening 
assessments.  Results of screening tests or examinations performed as SoC prior to obtaining informed consent and within 30 days prior to randomization may 
be used rather than repeating required tests unless the tests are required to be within 7 days prior to randomization.
e
FFPE tumor tissue must be obtained for central laboratory assessment of HER2 status for eligibility.  ER/PR determination will also be evaluated by a central 
laboratory.  A tissue block (FFPE material) collected at definitive breast cancer surgery is acceptable.  Sections and/or slides are not acceptable.  Biomarker 
analysis will only be performed on tissue from randomized patients.  At recurrence, tumor biopsy sample should be taken if the tumor is accessible for biopsy 
sample collection without (in the investigator’s opinion) significant risk to the patient.  In case tissue becomes available at time of recurrence, this tissue will be 
used for exploratory biomarker analysis. If a biopsy is collected as part of routine medical practice at relapse/recurrence, a tissue block or up to five unstained 
slides should be sent for biomarker analysis in order to gain better understanding of resistance mechanisms.
f
Bilateral mammogram (or breast MRI if indicated) is to be performed within 6 months prior to randomization. If mammogram is not available, then it could be 
performed after surgery.  During treatment and follow-up, mammograms of any remaining breast tissue should be performed at least annually ( 28 days) since 
the previous mammogram.  If there is no remaining breast tissue, then mammograms are not mandated.
g
Disease status based on all available clinical assessments should be documented from the date of randomization at the following timepoints:  every 3 months 
( 3 days) during study treatment and for the first 2 years after study treatment completion/early termination, every 6 months ( 7 days) from Years 3 to 5 after 
study treatment completion, and annually ( 28 days) from Year 6 up to Year 10 after study treatment completion, unless a recurrence that is defined as an 
IDFS event in Section 3.4.1 has occurred.  Patients who have a diagnosis of in situ breast cancer or second non-breast cancer should be maintained on a 
regular follow-up schedule as described above wherever possible in order to fully capture any subsequent recurrent invasive disease events. Such patients 
should continue with adjuvant study treatment, if not yet completed and considered by the investigator to be in the patient’s best interest, whenever possible.  In 
addition to physical examinations and mammograms, liver function tests, bone scans, chest X-rays/diagnostic CT, liver imaging, or other radiographic modality 
may be considered when clinically indicated to exclude metastatic disease and within a timeline as per current local standard of practice.  Whenever possible, 
disease recurrence should be confirmed histopathologically.  In cases of first disease recurrence (an IDFS event as defined in Section 3.4.1) diagnosed at any 
time during the study, patients will be out of the study schedule and will be followed annually starting 1 year after first recurrence until Year 10 from FPI for 
survival, anti-cancer medications, and new relapse (recurrence or disease progression) events.
h
If a CT scan is already available within 2 months prior to randomization, it may be used in lieu of chest X-ray.


Appendix 2
Schedule of Assessments (Cont.)
Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
45/Statistical Analysis Plan BO28407
i
A complete physical examination, including height and weight, should be measured at baseline.  Throughout the study, limited symptom-directed physical 
examination focusing on organ systems related to AE or disease may be performed.  Weight is to be measured on Day 1 of the specified cycles and compared 
to baseline. If 10% or greater variation occurs, then study treatment doses will be recalculated.  Dose must be readjusted for 10% or greater weight change 
based on the previous weight used for dose recalculation. For anthracyclines and taxanes, local standards for dose calculations will be followed.
j
Vital signs include blood pressure, pulse rate, and body temperature.  Vital signs should be obtained and reviewed, but it is not required that they should always 
be entered into the eCRF.  Abnormal vital signs at any time during the course of study treatment should be recorded as AEs or SAEs if clinically significant.
k
Cardiac monitoring (ECHO/MUGA) will be performed to assess LVEF.  LVEF assessment by ECHO is preferred.  The same method should be used throughout 
the study for each patient and, preferably, performed and assessed by the same assessor.  At baseline, LVEF must be done within 14 days prior to 
randomization. At the end of anthracycline therapy, LVEF should be assessed to determine if patient can start HER2-targeted therapy. During HER2-targeted 
study treatment, ECHO/MUGA should be obtained at Cycle 2, and every 4 cycles thereafter (Cycles 6, 10, 14, and 18).  All assessments will be performed within 
the last week of the treatment cycle to allow evaluation of the results before the next treatment cycle.  ECHO/MUGA should be obtained at the end-of-treatment
visit if not performed within the previous 6 weeks and at 3, 6, 12, 18, 24, 36, 48, and 60 months of follow-up regardless of the occurrence of invasive disease 
recurrence.  Note:  Cardiac signs/symptoms and an additional LVEF assessment must be completed after the last cycle of anthracycline is administered, but prior 
to the first cycle of targeted therapy.  Patients treated with anthracyclines must have an LVEF 50% and must have not experienced any clinical symptoms 
suggesting heart failure or asymptomatic LVEF declines by an absolute point of 15% from baseline and below the lower limit of normal prior to commencing 
the HER2-targeted component of therapy.
l
The PRO questionnaires (EORTC QLQ-C30, modified QLQ-BR23) and EQ-5D will be completed by the patients at the investigational site.  Assessments are to 
be completed on Cycle 1 Day 1 of the anthracycline treatment period; Day 1 of Cycles 1 through 5, Cycle 9, and Cycle 14 of the HER2-targeted treatment period; 
at treatment completion/treatment discontinuation visit; and at the 6- and 12-month follow-up visits after the end-of-treatment visit regardless of the occurrence of 
invasive disease recurrence.  All PRO questionnaires are required to be completed by patients prior to administration of study drug and prior to any other study 
assessment(s) or health care provider interactions to ensure that the validity of the instrument is not compromised and to ensure that data quality meets 
regulatory requirements.  Study personnel should review all questionnaires for completeness before the patient leaves the investigational site, and the hard copy 
originals of the questionnaires must be maintained as part of the patient’s medical record at the site for source data verification.
m Hematology tests (complete blood count with differential) including hemoglobin, hematocrit, counts of WBCs, platelets, and differential including absolute 
neutrophils. Abnormal CBC, including platelet counts, will be followed until resolution, until they are stable as assessed by the investigator, until the patient is 
lost to follow-up, or until the patient withdraws consent. Only if abnormal platelets have not returned to 100,000/mm3 at the time of end-of-treatment visit, it
should be checked at a minimum of every four weeks (monthly) during the follow-up period until 100,000/mm3, until they are clinically stable as assessed by 
the investigator, until the patient is lost to follow-up, or until the patient withdraws consent, regardless of the occurrence of invasive disease recurrence.  
Clinicians should consider more frequent evaluation (qw, etc.) for increasing grade of toxicity. 
n Screening laboratory tests to be performed within 7 days prior to randomization.  Screening laboratory assessments may be done on the day of randomization, 
and their results may be used for randomization visit purposes.  Results must be reviewed and documented prior to administration of first dose of study treatment.  
(Local laboratory [hematology, biochemistry, INR, and aPTT assessments] to be used for these assessments.)
o Prior to the first dose of study treatment (i.e., antracycline treatment), screening tests within 7 days prior to randomization will be utilized.  Protocol-specified 
subsequent tests will be performed within 72 hours preceding administration of study treatment; results must be reviewed and documented prior to administration 
of study treatment.  (Local laboratory [hematology, biochemistry, INR, and aPTT assessments] to be used for these assessments.)


Appendix 2
Schedule of Assessments (Cont.)
Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
46/Statistical Analysis Plan BO28407
p For patients receiving paclitaxel, sample for hematology should be collected qw during treatment.  Paclitaxel will be administered every 73 days. 
q
Serum chemistry tests at baseline include sodium, potassium, chloride, glucose, BUN or urea, creatinine, TBILI (and direct bilirubin when TBILI ULN), total 
protein, albumin, ALT, AST, and ALP.  Patients who have positive HBV or HCV serology without known active disease must meet the eligibility criteria for ALT, 
AST, TBILI, INR, aPTT, and ALP on at least two consecutive occasions, separated by at least 1 week, within the 30 day screening period.  Assessments at each 
treatment and at the end-of-treatment visit include potassium, TBILI, ALT, AST, and ALP; other assessments may be obtained as clinically indicated.  For 
patients who have positive HBV or HCV serology without known active disease, ALT, AST, TBILI, INR, aPTT, and ALP need to be assessed within 72 hours prior 
to the first dose on C1D1.  Abnormal ALT, AST, and total and/or direct bilirubin will be re-tested at a minimum of every 4 weeks (monthly) until normalization (i.e.,
until they are clinically stable for at least 3 months, as assessed by the investigator), until the patient is lost to follow-up or until the patient withdraws consent, 
regardless of the occurrence of invasive disease recurrence.  Clinicians should consider more frequent evaluation (qw, etc.) for increasing grade of toxicity.  Note: 
positive serology markers that indicate immunity will not be considered as clinically meaningful positive serology to trigger these tests.
r
Documentation of HBV and HCV serologies is required:  This includes HBsAg and/or total HBcAb in addition to HCV antibody testing.  The most recent serologic 
testing must have occurred no more than 3 months prior to randomization.  If such testing has not been done, it must be performed during screening. For 
patients who are known carriers of HBV and/or HCV, active hepatitis B infection and active hepatitis C infection must be ruled out on the basis of negative 
serologic testing and/or determination of HBV DNA viral load/HCV RNA load per local guidelines.
s
For all women of childbearing potential and for those who do not meet the definition of postmenopausal status (see definition in Section 4.5.1.2) or who have not 
undergone surgical sterilization, a serum -HCG must be performed within 7 days prior to randomization.  During the treatment period, in all treatment arms, a 
urine pregnancy test must be performed in women of childbearing potential within 72 hours prior to C1D1 of HER2-targeted therapy, then every 3 cycles
thereafter during study treatment, at 3 and 6 months after the end-of-treatment visit, and as clinically indicated regardless of the occurrence of invasive disease 
recurrence.  All positive urine pregnancy tests must be confirmed by a serum -HCG test.  
t
A whole blood sample for DNA isolation will be collected at baseline or at any time (after randomization) during the conduct of the clinical study. 
u
Collection of serum and plasma samples for biomarker analysis is mandatory.  After the end-of-treatment visit, these samples will be collected once a year for 
5 years, whenever possible, unless a recurrence that is defined as an IDFS event in Section 3.4.1 has occurred.  Biomarker samples (or processed samples) will 
be stored for up to 5 years after final database lock unless the patient consents to long-term storage for 15 years.  
v
If the patient gives OBRP consent, the serum and plasma samples for biomarker analysis will undergo long-term storage in the study biosample repository for 
use in future exploratory biomarker analyses. For patients that consented to the OBRP, a whole blood sample for DNA analysis will be collected as well at
baseline if possible or any time after randomization.
w AE and SAEs will be recorded from the start of study screening procedures if related to protocol-mandated intervention.  All non-serious AEs occurring prior to 
Day 1 (administration of study treatment) will be reported in the medical history, unless AE reporting is deemed more appropriate.  AEs are to be monitored 
continuously during study treatment.  All AEs occurring during the study and until the end-of-treatment/treatment discontinuation visit 28 days after the last dose 
of study treatment are to be recorded; thereafter, only drug-related SAEs and AEs/SAEs that qualify for long-term reporting should continue to be collected. 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 treatment or study 
participation if the event is believed to be related to prior study drug treatment or study procedures.
x
Concomitant medication will be recorded in the interval beginning 7 days prior to the patient being randomized into the study until the end of the treatment period, 
except for medications that are also collected during follow-up (Section 4.6).


Appendix 2
Schedule of Assessments (Cont.)
Trastuzumab Emtansine — F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan BO28407
y
In cases of invasive disease recurrence (an IDFS event as defined in Section 3.4.1) diagnosed at any time during the study, patients will be out of the study 
schedule for disease status assessments and will be followed annually ( 28 days) starting 1 year after first recurrence until 10 years after FPI for survival, 
anti-cancer medications, and new relapse (recurrence or disease progression) events.  If a patient has a recurrence, any anti-cancer medication given after the 
date of diagnosis must be recorded on the post-treatment anti-cancer medication page.