Phase II Trial of Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf (HP) Plus Enzalutamide for the Treatment of Selected Patients With Metastatic Castration-Resistant Prostate Cancer (TraPPer)
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Stage IVB Prostate Cancer AJCC v8
Sponsor: Mayo Clinic

 
 
 
 
 
MC210504 / 21-013057 
 
 
Phase II Trial of Pertuzumab, Trastuzumab, and Hyaluronidase-
zzxf (HP) Plus Enzalutamide for the Treatment of Selected 
Patients With Metastatic Castration-Resistant Prostate Cancer 
(TraPPer) 
 
 
NCT05730712 
 
 
Document Date: 02/26/2025 

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Table of Contents 
MC210504 Phase II Trial of Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf (HP) plus Enzalutamide 
for the Treatment of Selected Patients with Metastatic Castration-Resistant Prostate Cancer (TraPPer) .... 1 
Protocol Resources ........................................................................................................................................ 2 
Table of Contents .......................................................................................................................................... 3 
Schema .......................................................................................................................................................... 4 
1.0 
Background ................................................................................................................................... 5 
2.0 
Goals ............................................................................................................................................. 8 
3.0 
Patient Eligibility .......................................................................................................................... 9 
4.0  
Study Schedules .......................................................................................................................... 13 
5.0 
Grouping Factor .......................................................................................................................... 15 
6.0 
Registration Procedures .............................................................................................................. 15 
7.0 
Protocol Treatment ...................................................................................................................... 18 
8.0 
Dosage Modification Based on Adverse Events ......................................................................... 21 
9.0 
Ancillary Treatment/Supportive Care ......................................................................................... 23 
10.0 
Adverse Event (AE) Monitoring and Reporting ......................................................................... 24 
11.0 
Treatment Evaluation/Measurement of Effect ............................................................................ 44 
12.0 
Descriptive Factors: None ........................................................................................................... 50 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient ............................................................ 50 
14.0 
Body Fluid Biospecimens ........................................................................................................... 52 
15.0 
Drug Information ........................................................................................................................ 53 
16.0 
Statistical Considerations and Methodology ............................................................................... 60 
17.0 
Tissue Biospecimens ................................................................................................................... 65 
18.0 
Records and Data Collection Procedures .................................................................................... 66 
19.0 
Budget ......................................................................................................................................... 66 
20.0 
References ................................................................................................................................... 67 
Appendix I 
ECOG Performance Status .................................................................................................. 68 
Appendix II 
Patient Questionnaire Booklets ........................................................................................... 69 
Appendix III 
MC210504 Patient Medication Diary ............................................................................. 70 
Appendix IV 
Guidelines for Contraception .......................................................................................... 71 
Appendix V 
Genentech Safety Reporting Fax Cover Sheet .................................................................... 72 
 
.

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Schema 
Safety Run-in Only: Prior to discussing protocol entry with the patient,  
access the Mayo Clinic Research Registration Application  
to ensure a place on the protocol is open to the patient and reserve a slot 
 
Pre-Registration  
 
 
 
 
 
↓ 
 
 
 
 
 
Blood draw for NRG-1 Testing 
→ 
NRG-1 
<4ng/ml → 
Off 
study 
 
NRG-1 ≥4ng/ml↓ 
 
 
 
 
 
Registration 
 
 
 
 
 
↓ 
 
 
 
 
 
Biopsy  
 
 
 
 
 
↓ 
 
 
 
 
 
Pertuzumab, trastuzumab, and 
hyaluronidase-zzxf (HP) SC D1  
Enzalutamide PO D1-21 
→ 
Disease 
progression 
or 
alternative 
therapy 
 
 
 
↓ 
 
 
 
 
 
Events at any time: 
Intolerable adverse effects 
Patient refusal 
 
 
 
 
 
↓ 
 
 
 
 
 
Clinical Followup* 
 
 
 
 
 
↓ 
 
 
 
 
 
Extended Follow-up 
 
 
 
 
*CFU approximately every 3 months for up to one year 
Cycle = 21 ±3 days 
 
Generic name: pertuzumab, trastuzumab, and hyaluronidase-zzxf (HP) 
Brand name(s): PHESGO® 
Availability: Commercial agent supplied by Genentech 
Generic name: enzalutamide 
Brand name(s): XTANDI® 
Availability: Commercial supply 

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1.0 
Background  
1.1 
Prostate Cancer 
Treatment resistance is the single most pressing challenge in the treatment of prostate cancer. Castration-
resistant prostate cancer (CRPC) kills over 100,000 men each year (Centre 2020; Siegel et al. 2021). 
Androgen receptor (AR) signaling drives prostate cancer development and is the primary target for 
prostate cancer treatment (Huggins 1946). Unfortunately, most clinically significant prostate cancer 
develops resistance to androgen deprivation therapy (ADT) and is termed CRPC. Second-generation 
antiandrogens like enzalutamide (ENZ) have improved outcomes in CRPC, but this effect usually lasts 
only about 18 months (Beer et al. 2014; Hussain et al. 2018; Penson et al. 2016). After progression 
despite chemotherapy and second-generation antiandrogen therapy, additional resistance develops, and 
treatment becomes difficult. Thus, there is a critical need to investigate methods to overcome treatment 
resistance in prostate cancer. 
1.2 
NRG-1 as a marker or treatment resistance 
It is known that NRG-1 feeds CRPC cells to induce treatment resistance (Morris et al. 2002; Zhang et al. 
2020). However, previous attempts to block NRG-1 signaling with trastuzumab monotherapy have been 
disappointing in clinical trials (Ziada et al. 2004). We recently discovered that NRG-1 mediates a systemic 
“switch” between castration-sensitive prostate cancer (CSPC) and CRPC. NRG-1 is elevated in the plasma 
of patients with metastatic CRPC (Fig 1A-D) and is measured by ELISA. Paradoxically, high levels of 
NRG-1 predict superior outcomes in CSPC (Fig 1E-H) but inferior outcomes in CRPC (Fig 1I-L).  
 
Fig 1 – (A) High NRG-1 transcription predicts poor outcomes in the SU2C dataset. (B-C) High 
systemic NRG-1 readily identifies our CRPC cohort. (D) Treatment of CRPC cells with NRG-1 induces 
enzalutamide resistance. (E-H) High systemic NRG-1 predicts superior outcomes in CSPC. (I-L) High 
systemic NRG-1 predicts inferior outcomes in CRPC. 

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Similarly, treatment of CSPC cell line LNCaP with recombinant NRG-1 sensitizes these tumors to 
enzalutamide (ENZ)-mediated cell death (Fig 2A); conversely, treatment of CRPC cell lines Du145 and 
PC3 with recombinant NRG-1 induces resistance to ENZ (Fig 2B). 
 
This differential response to NRG-1 treatment appears to be through selective HER2/HER3 
heterodimerization in CRPC cells. Inducing HER2/HER3 heterodimerization with HER2 overexpression, 
HER3 suppression, or lapatinib leads to a CRPC phenotype (Fig 3A-C). Treatment of Du145 CRPC cells 
with pertuzumab, in contrast, re-sensitizes these cells to enzalutamide (Fig 3D).  
 
Fig 2 – (A) Treatment of CSPC (LNCaP) prostate cancer cells with increasing concentrations of NRG-
1 leads to cell death and sensitization to enzalutamide (ENZ). (B) In contrast, treatment of CRPC 
(Du145, PC3) prostate cancer cells leads to cell survival and resistance to ENZ. 
Fig 3 – Overexpression of HER2 (A), knockdown of HER3 (B), or lapatinib-induced HER2/HER3 
heterodimerization (C) leads to CSPC (LNCaP) resistance to enzalutamide. In contrast, blockade of 
HER2/HER3 heterodimerization in CRPC (Du145) cells (D) leads to resistant cancer cell death. 

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1.3 
HER2/HER3 Blockade 
In all, these data suggest that blockade of HER2/HER3 heterodimerization may sensitize CRPC cells to 
enzalutamide, resulting in improved treatment outcomes (Fig 4). 
 
1.4 
Trial Goals and Objectives 
Our long-term goal is to overcome prostate cancer treatment resistance. The overall objective in this 
application is to perform a pilot study of the combination of trastuzumab and pertuzumab, highly 
effective inhibitors of HER2/HER3 heterodimerization, in overcoming NRG-1-mediated prostate cancer 
resistance (Fig 4). Our central hypothesis is that the use of trastuzumab and pertuzumab in selected 
patients with high NRG-1 will prevent and overcome NRG-1-mediated HER2/HER3 heterodimerization 
and resultant enzalutamide (ENZ) resistance in a pilot study. 
We will objectively test our central hypothesis and thereby attain the objective of this application through 
the following specific aims: 
Aim 1. Evaluate the potential for dual HER2/HER3 and AR inhibition in NRG-1-selected 
castration-resistant prostate cancer progressing despite enzalutamide treatment. 
Aim 2. Determine the correlation between the CRPC gene expression signature and tumor response 
to the dual inhibition of HER2/HER3 and AR in advanced prostate cancer progressing despite 
enzalutamide treatment. 
We will enroll patients on the basis of NRG-1 plasma levels >4ng/ml by ELISA based on ELISA standard 
curve or comparison patient plasma at this cutoff from our previous cohort. In our previous cohort, 66.2% 
of patients would be eligible based on this cutoff. This cutoff was determined from the previous cohort 
with data presented in Figure 1. Receiver operating curve (ROC) analysis identified this cutoff as 
optimally sensitive and specific for resistant disease. 
We will use a commercial ELISA for this testing, which will be done after consent and pre-registration to 
the study. Historical control plasma at this cutoff or recombinant standard curve calculation will be used 
to determine which patients qualify. Patients whose NRG-1 levels match our criteria will enter screening 
for potential enrollment into the treatment phase. 
Since there are no data on the safety of this combination in prostate cancer, we will conduct a safety 
analysis among the initial cohort of patients. 
Fig 4. NRG-1 supports CRPC cell resistance through HER2/HER3 heterodimerization. 
Pertuzumab and trastuzumab prevent this signaling and we hypothesize that combined 
pertuzumab, trastuzumab, and enzalutamide treatment will overcome NRG-1-mediated CRPC 
resistance in selected patients with high baseline NRG-1 levels. 
 

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2.0 
Goals  
2.1 
Primary Goal 
Evaluate the preliminary efficacy of the combination of pertuzumab, trastuzumab, and 
hyaluronidase-zzxf plus enzalutamide with regard to objective response rate (PCWG 3.0) 
in enzalutamide-refractory metastatic castration-resistant prostate cancer . 
2.2 
Secondary Goals 
2.21 
Estimate the radiographic progression-free survival for this combination . 
2.22 
Estimate the overall survival for this combination . 
2.3 
Exploratory Goals 
2.31 
Assessment of this combination for adverse events according to clinical judgment 
and patient-reported outcomes (PRO-CTCAE - Prostate Cancer). 
2.32 
Assessment of patient quality of life using FACT-P questionnaire. 
2.4 
Correlative Goals 
2.41 
Determine the correlation between outcomes as above and systemic NRG-1 
levels at baseline and over time. 
2.42 
Determine the correlation between outcomes as above and change in 
HER2/HER3/AR gene signatures. 
 

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3.0 
Patient Eligibility 
Safety Run-in Only: Prior to discussing protocol entry with the patient, access the Mayo 
Clinic Research Registration Application to ensure a place on the protocol is open to the 
patient and reserve a slot. 
3.1 
Pre-registration – Inclusion Criteria 
3.11 
Age ≥18 years 
3.12 
Clinically or histologically confirmed diagnosis of second-generation 
antiandrogen-refractory metastatic castration-resistant prostate cancer. 
3.13 
Measurable disease as defined by the Prostate Cancer Working Group (PCWG3) 
criteria (See Section 11.0)  
3.14 
Prior treatment required: 
• 
Second generation anti-androgen (2GAA) therapy (e.g., enzalutamide, 
abiraterone) at any time prior registration 
3.15 
Provide written informed consent. 
3.16 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
3.17 
Ability to complete questionnaire(s) by themselves or with assistance. 
3.18 
Willingness to provide mandatory blood specimens for correlative research (see 
Section 14.0). 
3.19a 
Willingness to provide mandatory tissue specimens for correlative research (see 
Section 17.0). 
3.2 
Pre-registration - Exclusion criteria 
3.21 
History of myocardial infarction ≤6 months prior to pre-registration, or 
congestive heart failure requiring use of ongoing maintenance therapy for life-
threatening ventricular arrhythmias.  
3.22 
Failure to recover from acute, reversible effects of prior therapy regardless of 
interval since last treatment. 
EXCEPTION: Grade 1 peripheral (sensory) neuropathy that has been stable for 
at least 3 months since completion of prior treatment. 
3.23 
Uncontrolled intercurrent non-cardiac illness including, but not limited to:  
• 
Ongoing or active infection 
• 
Psychiatric illness/social situations  
• 
Dyspnea at rest due to complications of advanced malignancy or other 
disease that requires continuous oxygen therapy  
• 
Any other conditions that would limit compliance with study requirements 
3.24 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  
NOTE: Patients known to be HIV positive, but without clinical evidence of an 
immunocompromised state, are eligible for this trial. 
3.25 
Receiving any other investigational agent which would be considered as a 
treatment for the prostate cancer 

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3.26 
Thromboembolic event ≤60 days prior to pre-registration.  
3.27 
Serious cardiac illness or medical conditions including, but not confined to, the 
following: 
• 
History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart failure 
(CHF) or New York Heart Association (NYHA) Class ≥ II 
• 
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, such as second-
degree AV-block Type 2 [Mobitz II] or third-degree AV-block) 
• 
Serious cardiac arrhythmia or severe conduction abnormality not controlled 
by adequate medication 
• 
Angina pectoris requiring anti-angina medication 
• 
Clinically significant valvular heart disease 
• 
Evidence of transmural infarction on electrocardiogram (ECG) 
• 
Poorly controlled hypertension (e.g., systolic > 180 mm Hg or diastolic 
> 100mmHg) 
3.28 
History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, 
such as structural heart disease (e.g., severe left ventricular systolic dysfunction 
[LVSD], left ventricular hypertrophy), coronary heart disease (symptomatic or 
with ischemia demonstrated by diagnostic testing), clinically significant 
electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), 
or family history of sudden unexplained death or long QT syndrome 
3.3 
Registration - Inclusion Criteria 
3.31 
Plasma NRG-1 level ≥4 ng/ml 
3.32 
ECOG Performance Status (PS) 0, 1 or 2 (Appendix I) 
3.33 
The following laboratory values obtained ≤15 days prior to registration:  
• 
Hemoglobin ≥9.0 g/dL 
• 
Absolute neutrophil count (ANC) ≥1500/mm3 
• 
Platelet count ≥100,000/mm3 
• 
Total bilirubin ≤1.5 x ULN 
• 
Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3 x 
ULN (≤5 x ULN for patients with liver involvement) 
• 
PT/INR/aPTT ≤1.5 x ULN OR if patient is receiving anticoagulant therapy 
and INR or aPTT is within target range of therapy 
• 
Calculated creatinine clearance ≥45 ml/min using the Cockcroft-Gault 
formula below: 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males = 
(140 - age)(weight in kg) 
(72)(serum creatinine in mg/dL) 
Creatinine clearance for females = 
(140 - age)(weight in kg)(0.85) 
(72)(serum creatinine in mg/dL) 
3.34 
Left ventricular ejection fraction (LVEF) ≥50% ≤15 days prior to registration 

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3.35 
Provide written informed consent. 
3.36 
Ability to complete questionnaire(s) by themselves or with assistance. 
3.37 
Willingness to provide mandatory blood specimens for correlative research (see 
Section 14.0). 
3.38 
Willingness to provide mandatory tissue specimens for correlative research (see 
Section 17.0). 
3.39a 
Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study).  
3.39b Willing to use birth control during heterosexual intercourse while on treatment 
and for 7 months after last dose of study treatment. 
NOTE: See Section 9.0 for additional information. 
3.4 
Registration - Exclusion Criteria 
3.41 
Any of the following because this study involves an agent that has known 
genotoxic, mutagenic, and teratogenic effects: 
• 
Pregnant persons 
• 
Nursing persons 
• 
Persons of childbearing potential or able to father a child who are unwilling 
to employ adequate contraception during treatment and for seven months 
after last dose of study treatment 
3.42 
Failure to recover from any of the following therapies prior to registration:  
• 
Major surgery  
• 
Chemotherapy  
• 
Infection requiring systemic treatment 
3.43 
Co-morbid systemic illnesses or other severe concurrent disease which, in the 
judgment of the investigator, would make the patient inappropriate for entry into 
this study or interfere significantly with the proper assessment of safety and 
toxicity of the prescribed regimens. 
3.44 
Immunocompromised patients and patients known to be HIV positive and 
currently receiving antiretroviral therapy.  
NOTE: Patients known to be HIV positive, but without clinical evidence of an 
immunocompromised state, are eligible for this trial. 
3.45 
Uncontrolled intercurrent illness including, but not limited to:  
• 
ongoing or active infection 
• 
symptomatic congestive heart failure 
• 
unstable angina pectoris 
• 
cardiac arrhythmia 
• 
or psychiatric illness/social situations that would limit compliance with study 
requirements. 
3.46 
Currently receiving any other investigational agent which would be considered as 
a treatment for the primary neoplasm. 
 
 

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3.47 
Other active malignancy ≤3 years prior to registration.  
EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix.  
NOTE: If there is a history of prior malignancy, they must not be receiving other 
specific treatment (e.g., other hormonal therapy, chemotherapy) for their cancer.  
3.48 
History of myocardial infarction ≤6 months, or congestive heart failure requiring 
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias. 
3.49a 
Known hypersensitivity to pertuzumab, or trastuzumab, or hyaluronidase, or to 
any of its excipients 
3.49b Requirement for drugs or substances which can interfere with the actions of the 
study drugs (enzalutamide or pertuzumab/trastuzumab/hyaluronidase-zzxf). 
Consult pharmacist for review. 
 

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4.0 
Study Schedules 
4.1 
Test Schedule for Metastatic Castration-Resistant Prostate Cancer 
 
Screening 
Active Monitoring Phase 
Tests and procedures1 
After  
Pre-Reg 
≤15 days 
prior to 
Reg 
Prior to 
Cycle 1 
Day 1 
Prior to 
Cycle 2 
Prior to 
each cycle 
(Cycle 3+) 
 Every 
9 weeks for 
27 weeks, 
then every 
12 weeks 
End of 
treatment2 
Clinical 
Follow-up3 
Window 
 
 
 
±3 days 
 
 
 
 
History and exam, weight, PS  
 
X 
 
X 
X 
 
X 
X 
Height 
 
X 
 
 
 
 
 
 
Adverse event assessment 
 
X 
 
X 
X 
X 
X 
X 
CBC with 5-part diff  
 
X 
 
X 
X 
 
X 
X 
Chemistry group:4 
 
X 
X5 
X 
X 
 
X 
X 
Coagulation: PT/INR/aPTT 
 
X 
 
 
 
 
 
 
PSA 
 
X 
 
X 
 
 
X 
X 
Echocardiogram for LVEF (ejection fraction only)6 
 
X 
 
 
 
X 
 
 
Biopsy 
 
 
X7 
X8R 
 
 
X9 
 
Tumor measurement10 
X11 
 
 
 
 
X 
 
X 
Histologic review 
X 
 
 
 
 
 
 
 
Patient questionnaire PRO-CTCAE (Appendix II) 
 
 
X 
 
 
X 
X 
 
Patient questionnaire FACT-P (Appendix II) 
 
 
X 
 
 
X 
X 
 
 
Cycle = 21 ±3 days; R=research funded 
1 All tests may be done if clinically needed at any time 
2 End of treatment will be defined as disease progression, patient refusal, or adverse event(s) leading to cessation of therapy 
3 CFU every 3 months for 12 months or until disease progression or start of alternate therapy, whichever occurs first. 
4 CMP (80053) plus magnesium (83735) OR Hepatic Function Panel (80076) plus Renal Function Panel (80069) plus magnesium (83735) -Order additional testing as needed for 
clinical care 
5 Only repeat if most recent blood draw is ≥21 days prior to C1D1 
6 LVEF ejection fraction should be tested every 12 weeks during treatment with pertuzumab/trastuzumab/hyaluronidase-zzxf 
7 Mandatory biopsy can be done at any time after Registration and prior to treatment on C1D1. A recent (within 60 days) archival sample is also acceptable in lieu of a new biopsy. 
8 Optional research biopsy at end of Cycle 1; Patient may opt out of or delay this biopsy without deviation 
9 Optional clinical/research biopsy at End of Treatment; Patient may opt out of or delay this biopsy without deviation 
10 Tumor assessments per clinical standard of care will be performed every 9 weeks for the first  27 weeks (i.e., Weeks 9, 18, 27), then every 12 weeks (i.e., Weeks 39, 51, etc. ±1 
week) from the initiation of treatment regardless of treatment interruptions or holds until the PCWG3 or RECIST 1.1 criteria in Section 11.0 have been met. 
11 Baseline imaging should be ≤29 days prior to Registration 

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Screening 
Active Monitoring Phase 
Tests and procedures1 
After  
Pre-Reg 
≤15 days 
prior to 
Reg 
Prior to 
Cycle 1 
Day 1 
Prior to 
Cycle 2 
Prior to 
each cycle 
(Cycle 3+) 
 Every 
9 weeks for 
27 weeks, 
then every 
12 weeks 
End of 
treatment2 
Clinical 
Follow-up3 
Patient Medication Diary (Appendix III)12 
 
 
 
X 
 
 
 
 
Mandatory research tissue specimens (see Section 17.0) 13,R 
 
 
X 
X 
 
 
X 
 
Mandatory research blood specimens (see Section 14.0)14,R 
X 
 
X 
X 
 
X 
X 
 
 
12 The diary must begin the day the patient starts taking the medication and must be completed per protocol and returned to the treating institution OR compliance must be 
documented in the medical record by any member of the care or research teams. 
13 Tissue specimens must be collected and submitted per Section 17.0 
14 Blood specimens will be collected and submitted per Section 14.0. Kits are required 

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4.2 
Extended Follow-up 
 
Extended Follow-up1 
q. 3 months 
until PD 
At PD 
After PD  
q. 6 months 
Death 
New 
Primary 
Extended/Survival Follow-up2 
X 
X 
X 
X 
At each 
occurrence 
1. All timelines in this table are approximate and may vary by a month  
2. If a patient is still alive 2 years after registration, no further follow-up is required. 
5.0 
Grouping Factor: None 
6.0 
Registration Procedures 
6.1 
Pre-Registration (Step 0)  
6.11 
Pre-Registering a Patient 
To pre-register a patient, access the Mayo Clinic Research Registration 
Application at www.registration.mayo.edu. The Research Registration 
Application is available 24 hours a day, 7 days a week. Back up and/or system 
support contact information is available on the website. If unable to access the 
website, contact Research Registration Office at (507) 284-2753 or email 
random01@mayo.edu  between the hours of 8 a.m. and 4:30 p.m. Central Time 
(Monday through Friday). 
The instructions for the registration/randomization application are available on 
the Mayo Clinical Office of Clinical Trials web page 
(https://www.mayo.edu/research/centers-programs/center-clinical-translational-
science/offices/office-of-clinical-trials/research-registration-application) and 
detail the process for completing and confirming patient registration. Prior to 
initiation of protocol treatment, this process must be completed in its entirety and 
an MCCC subject ID number must be available as noted in the instructions. It is 
the responsibility of the individual registering the patient to confirm the process 
has been successfully completed prior to release of the study agent. Patient 
registration via the registration/randomization application can be confirmed in 
any of the following ways: 
• 
Contact Mayo Clinic Research Registration Office at (507) 284-2753 or 
email random01@mayo.edu. If the patient was fully registered, the 
Research Registration Office staff can access the information from the 
centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
6.12 
Verification of information 
Prior to accepting the pre-registration, the registration/randomization application 
will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient pre-registration eligibility  
• 
Existence of a signed consent form  
• 
Existence of a signed authorization for use and disclosure of protected health 
information. 

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6.13 
Pre-registration tests/procedures 
Pre-registration tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
6.2 
Registration (Step 1) 
Safety Run-in Only: Prior to discussing protocol entry with the patient, access the 
Mayo Clinic Research Registration Application to ensure that a place on the 
protocol is open to the patient and reserve a slot 
To register a patient, access the Mayo Clinic Research Registration Application at 
www.registration.mayo.edu. The Research Registration Application is available 24 hours 
a day, 7 days a week. Back up and/or system support contact information is available on 
the website. If unable to access the website, contact Research Registration by email 
random01@mayo.edu between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
The instructions for the registration/randomization application are available on the Mayo 
Clinical Office of Clinical Trials web page (https://www.mayo.edu/research/centers-
programs/center-clinical-translational-science/offices/office-of-clinical-trials/research-
registration-application) and detail the process for completing and confirming patient 
registration. Prior to initiation of protocol treatment, this process must be completed in its 
entirety and an MCCC subject ID number must be available as noted in the instructions. 
It is the responsibility of the individual registering the patient to confirm the process has 
been successfully completed prior to release of the study agent. Patient registration via 
the registration/randomization application can be confirmed in any of the following ways: 
• 
Contact Mayo Clinic Research Registration by email random01@mayo.edu. If the 
patient was fully registered, the Research Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section “Finding/Displaying 
Information about A Registered Subject.” 
6.3 
Verification of materials 
Prior to accepting the registration, registration/randomization application will verify the 
following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information  
6.4 
Documentation of IRB approval 
Documentation of IRB approval must be on file in the Research Registration Office 
before an investigator may register any patients.  
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) with Research Registration (email  
random01@mayo.edu). If the necessary documentation is not submitted in advance of 
attempting patient registration, the registration will not be accepted, and the patient may 
not be enrolled in the protocol until the situation is resolved. 
When the study has been permanently closed to patient enrollment, submission of annual 
IRB approvals to the Research Site Management Office is no longer necessary. 

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6.5 
Correlative Research 
6.51 
Mandatory 
A mandatory correlative research component is part of this study, the patient will 
be automatically registered onto this component (see Sections 3.3, 14.0, 17.0). 
6.52 
Optional 
An optional correlative research component is part of this study, there will be an 
option to select if the patient is to be registered onto this component (see Sections 
14.0 and/or 17.0). 
6.6 
Patient Permissions 
At the time of registration, the following will be recorded: 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research on cancer at Mayo Clinic. 
• 
Patient has/has not given permission to store and use his/her sample(s) for future 
research to learn, prevent, or treat other health problems. 
• 
Patient has/has not given permission for MCCC to give his/her sample(s) to 
researchers at other institutions. 
6.7 
Treatment on protocol 
Treatment on this protocol must commence at a Mayo Clinic institution under the 
supervision of a medical oncologist. 
6.8 
Treatment start 
Treatment cannot begin prior to registration and must begin ≤28 days after registration. 
6.9a 
Pretreatment 
Pretreatment tests/procedures (see Section 4.0) must be completed within the guidelines 
specified on the test schedule. 
6.9b 
Baseline symptoms 
All required baseline symptoms (see Section 10.6) must be documented and graded.  
6.9c 
Study drug 
Study drug is available on site for this patient. 
6.9d 
Blood draw kits 
Blood draw kit is available on site for this patient. 
6.9e 
Study Conduct 
The clinical trial will be conducted in compliance with regulations (21 CFR 312, 50, and 
56), guidelines for Good Clinical Practice (ICH Guidance E6), and in accordance with 
general ethical principles outlined in the Declaration of Helsinki; informed consent will 
be obtained from all participating patients; the protocol and any amendments will be 
subject to approval by the designated IRB prior to implementation, in accordance with 
21 CFR 56.103(a); and subject records will be stored in a secure location and subject 
confidentiality will be maintained. The investigator will be thoroughly familiar with the 
appropriate use of the study drug as described in the protocol and Investigator’s 
Brochure. Essential clinical documents will be maintained to demonstrate the validity of 
the study, and the integrity of the data collected. Master files should be established at the 
beginning of the study, maintained for the duration of the study and retained according to 
the appropriate regulations. 
 

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7.0 
Protocol Treatment 
7.1 
Treatment Schedule 
7.11 
Treatment medication table  
Agent 
Dose Level 
Route 
Day 
ReRx 
Pertuzumab/trastuzumab/
hyaluronidase-zzxf [HP] 
(given as a single dose) 
600 mg, 
600 mg, and 
20,000 units* 
Subcutaneous 
(thigh only) 
1 
Q3w 
Enzalutamide 
160 mg 
PO once daily 
1-21 
continuously 
Q3w 
*Cycle 1 loading dose of 1200 mg pertuzumab/600 mg trastuzumab/30,000 units 
hyaluronidase-zzxf 
Cycle = 21 days ±3 days 
7.2 
Pertuzumab/Trastuzumab/Hyaluronidase-zzxf (PHESGO™) [HP] 
Pertuzumab/trastuzumab/hyaluronidase-zzxf is administered by subcutaneous injection 
into the thigh once every 3 weeks as a combination injection. Loading dose should be 
given over approximately 8 minutes. Subsequent doses can be administered over 
approximately 5 minutes 
A loading dose is given Cycle 1, Day 1, and again if it has been more than 6 weeks since 
most recent previous dose. 
Patients must be observed for a minimum of 30 minutes after initial dose and at least 
15 minutes for subsequent doses for signs of hypersensitivity symptoms or 
administration-related reactions 
7.3 
Enzalutamide 
Enzalutamide is taken orally as a single dose once per day at the same time each day. 
Enzalutamide can be taken without regard for food.  
Enzalutamide is available as tablets or capsules. 
Patients should be instructed not to cut, crush, or chew tablets and not to chew, dissolve 
or open capsules. 
If a dose is missed the patient should take it as soon as they remember it. 
If an entire day is missed the patient should not make up the lost dose, just resume their 
normal dose the next day. 
7.4 
Biopsies 
An initial biopsy will be required prior to study treatment.  
A second, optional biopsy may be requested at end of Cycle 1 or any time if patient is 
willing. 
A third, required biopsy will be at time patient comes off treatment for any reason (e.g., 
at the time of disease progression or treatment change) (whichever comes first). 
NOTE: Patient may opt out of, or delay second or third biopsies without deviation. 

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7.5 
Safety Analysis 
7. 51 
Description 
Six patients will be enrolled at the planned starting dose level in Section 7.1 and 
observed for one cycle for evaluation of the safety analysis. See Section 16 for 
specifics. 
7.52 
Definitions of Significant Safety Events  
7.521 
For this protocol, significant safety events will be defined as the 
following events at least possibly related to treatment, occurring during 
Cycle 1 only: 
Any CTCAE Grade 5 event not definitely related to underlying 
disease, progression of disease, or intercurrent illness, and at least 
possibly related to the investigational product  
Grade 3 or higher seizure or cardiac disorder event (including heart 
failure, cardiac arrest, or myocardial infarction) 
Neutropenic fever (i.e., febrile neutropenia) 
Grade 4+ neutropenia or thrombocytopenia lasting >7 days  
Grade 3+ thrombocytopenia with bleeding 
Grade 3+ nausea/vomiting or diarrhea lasting >72 hours with adequate 
antiemetic and other supportive care 
Grade 3+ fatigue lasting ≥7 days 
Asymptomatic Grade 3+ electrolyte abnormality lasting >72 hours,  
Symptomatic Grade 3+ electrolyte abnormality regardless of duration 
Exception: Grade 3+ amylase or lipase elevation NOT associated 
with symptoms or clinical manifestations of pancreatitis does not 
need to be counted as a significant toxicity  
Grade 3+ non-laboratory events 
For patients with hepatic metastases: AST or ALT >8×ULN or  
AST or ALT >5×ULN for ≥14 days  
Meets or exceeds Hy's law:  
1. The drug causes hepatocellular injury, generally shown by a 
higher incidence of 3-fold or greater elevations above the ULN of 
ALT or AST than the (nonhepatotoxic) control drug or placebo  
2. Among trial subjects showing such aminotransferase (AT) 
elevations, often with ATs much greater than 3×ULN, one or more 
also show elevation of serum total bilirubin (TBL) to >2×ULN, 
without initial findings of cholestasis (elevated serum alkaline 
phosphatase [ALP])  
3. No other reason can be found to explain the combination of 
increased AT and TBL, such as viral hepatitis A, B, or C; 
preexisting or acute liver disease; or another drug capable of 
causing the observed injury All AEs of the specified grades should 
count as DLEs except those that are clearly and incontrovertibly 
due to disease progression or extraneous causes. 

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7.522 
Patients experiencing significant safety events requiring discontinuing 
study treatment will be monitored and treated as appropriate for these 
side-effects based on available evidence. 
7.6 
Return to consenting institution 
For this protocol, the patient must return to the consenting institution according to 
Section 4.0. 
7.7 
Treatment by local medical doctor (LMD) 
Treatment for this clinical trial by a local medical doctor (LMD) is not allowed. 
7.8 
Safety Follow-up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after 
the last dose of study treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first. This visit may be done by telephone call or virtual visit as needed. 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Participants 
with an AE of Grade >1 will be followed until the resolution of the AE to Grade 0-1 or 
until the beginning of a new anti-cancer therapy, whichever occurs first. SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment 
should also be followed and recorded. 
 
 

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8.0 
Dosage Modification Based on Adverse Events  
Strictly follow the modifications in this table for the first two cycles, until individual treatment 
tolerance can be ascertained. Thereafter, these modifications should be regarded as guidelines to 
produce mild-to-moderate, but not debilitating, side effects. If multiple adverse events are seen, 
administer dose based on greatest reduction required for any single adverse event observed. 
Reductions or increases apply to treatment given in the preceding cycle and are based on adverse 
events observed since the prior dose.  
The treating physician may hold, omit, or modify administration at any time based on discussion 
with Study Investigator or Co-Investigator. This information must be documented in the patient 
clinical record.  
→ ALERT: 
ADR reporting may be required for some adverse events (See Section 10.0) ← 
8.1 
Dose Levels 
Dose 
Level 
Enzalutamide 
Pertuzumab/ 
Trastuzumab/ 
Hyaluronidase-zzxf (HP) 
1* 
160mg 
600mg/600mg/20kU* 
-1 
120mg 
N/A 
-2 
80mg 
N/A 
*Dose level 1 refers to the starting dose 
**Loading dose = 1200 mg pertuzumab/600 mg trastuzumab/30,000 units 
hyaluronidase-zzxf 
NOTE: There are no dose reductions for the combination drug 
trastuzumab/pertuzumab/hyaluronidase-zzxf (HP). 
  Use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0* unless 
otherwise specified   
* 
Located at http:/ctep.cancer.gov/protocolDevelopment/electronic_applications.ctc.htm 
8.2 
Treatment Modification for Enzalutamide 
8.21 
Omit/adjust enzalutamide dose 
If a patient experiences a ≥Grade 3 event, withhold dosing for one week or until 
symptoms improve to ≤Grade 2, then resume at the same or a reduced dose 
(120 mg or 80 mg), if warranted 
• 
Fatigue 
• 
Falls and fractures 
• 
Lab abnormalities: 
Neutrophil count decreased 
White blood cell decreased 
Hyperglycemia 
Hypermagnesemia 
Hyponatremia 
Hypercalcemia 
• 
Hypertension 

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8.22 
Discontinue enzalutamide 
Permanently discontinue enzalutamide for any of the following events 
• 
Ischemic heart disease Grade 3-4 
• 
Seizures (any grade) 
• 
Hypersensitivity reactions (any grade) 
• 
Posterior reversible encephalopathy syndrome (PRES) 
8.3 
Treatment Modification for Pertuzumab, Trastuzumab, Hyaluronidase-xxzf (HP) 
8.31 
Hold pertuzumab, trastuzumab, hyaluronidase-xxzf (HP) 
Hold HP dose for up to 4 weeks or until event has resolved to ≤Grade 1, 
whichever is sooner. If event has not resolved within 4 weeks, patient will end 
study treatment. 
Hold HP until etiology is determined for the following Grade 2 events: 
• 
Left ventricular cardiac dysfunction (See 8.33 below) 
• 
Cardiac arrhythmias 
• 
Hypertension 
8.32 
Discontinue pertuzumab, trastuzumab, hyaluronidase-xxzf (HP) 
Discontinue HP for following events (any grade) 
• 
Clinically significant decrease in left ventricular function 
• 
Symptomatic CHF 
• 
Anaphylaxis or hypersensitivity 
• 
Angioedema 
• 
Interstitial pneumonitis or acute respiratory distress syndrome 
8.33 
HP Dose Modifications for Left Ventricular Dysfunction 
Pre-treatment 
LVEF 
Monitor 
LVEF every 
Withhold for at least 3 weeks 
for LVEF decrease to: 
Resume after 3 weeks if 
LVEF has recovered to: 
≥50% 
~12 weeks 
Either 
Either 
<40% 
40-45% with a 
fall of ≥10% 
points below 
pre-treatment 
value 
>45% 
40-45% with 
a fall of 
<10%-points 
below pre-
treatment 
value 
 
8.4 
Treatment Discontinuation for Adverse Events 
Patients will discontinue all treatment and go to Event Monitoring/Survival/Extended 
Follow-up if any of the following events occur which meet conditions for Hy’s Law: 
• 
ALT or AST >8xULN 
• 
ALT or AST >5xULN for more than 2 weeks 
• 
ALT or AST >3xULN and (TBL >2xULN or INR >1.5) 
• 
ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)  
Guidance Document https://www.fda.gov/media/116737/download  
 
 

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9.0 
Ancillary Treatment/Supportive Care 
9.1 
Full supportive care 
Patients should receive full supportive care while on this study. This includes blood 
product support, antibiotic treatment, and treatment of other newly diagnosed or 
concurrent medical conditions. All blood products and concomitant medications such as 
antidiarrheals, analgesics, and/or antiemetics received from the first day of study 
treatment administration until 30 days after the final dose will be recorded in the medical 
records. 
9.2 
Blood products and growth factors 
Blood products and growth factors should be utilized as clinically warranted and 
following institutional policies and recommendations. The use of growth factors should 
follow published guidelines of the Journal of Clinical Oncology, Volume 33, No 28 
(October 1), 2015: pp. 3199-3212 (WBC growth factors) AND Journal of Clinical 
Oncology, Volume 28, No 33 (November 20), 2010: pp. 4955-5010 
(darbepoetin/epoetin). 
9.3 
Antiemetics 
Antiemetics may be used at the discretion of the attending physician. 
9.4 
Diarrhea 
Diarrhea could be managed conservatively with loperamide. The recommended dose of 
loperamide is 4 mg at first onset, followed by 2 mg every 2-4 hours until diarrhea free 
(maximum 16 mg/day). 
In the event of Grade 3 or 4 diarrhea, the following supportive measures are allowed: 
hydration, octreotide, and antidiarrheals.  
If diarrhea is severe (requiring intravenous rehydration) and/or associated with fever or 
severe neutropenia (Grade 3 or 4), broad-spectrum antibiotics must be prescribed. 
Patients with severe diarrhea or any diarrhea associated with severe nausea or vomiting 
should be hospitalized for intravenous hydration and correction of electrolyte 
imbalances. 
9.5 
Concomitant Medications 
Please refer to the enzalutamide package insert for clinically relevant drug interactions. 
Medications that are listed as a “Risk X: Avoid Combination” are prohibited while 
patient is on trial unless approved by Principal Investigator. See also Section 15.26. 
9.6 
Contraception 
For biological males: agreement to remain abstinent (refrain from heterosexual 
intercourse) or use a condom, and agreement to refrain from donating sperm, as defined 
below:  
With female partners of childbearing potential or pregnant female partners, biological 
males must remain abstinent or use a condom during the study treatment periods and 
for seven months after the last dose of study treatment to avoid exposing the embryo. 
Biological males must refrain from donating sperm during this same period. 
 
 
 

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10.0 
Adverse Event (AE) Monitoring and Reporting  
10.1 
Definitions 
10.11 Roles 
Sponsor-Investigator 
An individual who both initiates and conducts, alone or with others, a clinical 
trial and under whose immediate direction the investigational product/study 
intervention is administered to, dispensed to, or used by a subject. This person 
holds the IND for the research study. 
Investigator 
An investigator includes the Site Principal Investigator (PI) or a designated Sub-
Investigator. 
Sub-Investigator 
A Sub-Investigator is a medically qualified delegate who has been identified and 
confirmed by the Site PI. Medically qualified designations may include, but are 
not limited to: 
• 
Medical Doctorate (M.D.), or equivalent medical school graduate degree 
• 
Physician Assistant (P.A.) 
• 
Certified Nurse Practitioner (C.N.P.) 
• 
Registered Nurse (R.N.) 
10.12 Adverse Event (AE) 
An adverse event is defined as any untoward medical occurrence in a clinical 
trial subject. The event does not necessarily have a causal relationship with study 
treatment. (FDA, 21 CFR 312.32; ICH E2A and ICH E6) 
The definition of AEs includes: 
• 
Worsening of a pre-existing medical condition. Worsening indicates that the 
pre-existing medical condition or underlying disease (e.g., diabetes, migraine 
headaches, gout) has increased in severity, frequency, and/or duration more 
than would be expected and/or has an association with a significantly worse 
outcome than expected.  
NOTE: A pre-existing condition that has not worsened more than anticipated 
(i.e., more than usual fluctuation of disease) during the study or involves an 
intervention such as elective cosmetic surgery or a medical procedure while 
on study, is not considered an AE. 
• 
Unintended or unfavorable sign or symptom 
• 
A disease temporally associated with participation in the protocol 
• 
An intercurrent illness or injury that impairs the well-being of the subject 
• 
AEs not previously observed in the subject that emerge during the protocol-
specified AE reporting period, including signs or symptoms associated with 
metastatic castration-resistant prostate cancer that were not present prior to 
the AE reporting period 
• 
Complications that occur as a result of protocol-mandated interventions (e.g., 
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In general, abnormal laboratory values or diagnostic test results constitute AEs 
only if they induce clinical signs or symptoms or require treatment or further 
diagnostic tests.  
Hospitalization for elective surgery or routine clinical procedures that are not the 
result of an AE (e.g., surgical insertion of central line) should not be recorded as 
an AE. 
Disease progression should not be recorded as an AE, unless it is attributable to 
the study regimen by the site investigator. 
The investigator is responsible for ensuring that any AEs observed by the 
investigator or reported by the subject are recorded in the subject’s medical record. 
10.13 Serious Adverse Event (SAE) 
A serious adverse event is defined as an adverse event that meets at least one of 
the following serious criteria (FDA, 21 CFR 312.32; ICH E2A and ICH E6): 
• 
Fatal 
• 
Life threatening (places the subject at immediate risk of death) 
• 
Requires inpatient hospitalization for ≥24 hours or prolongation of existing 
hospitalization. 
NOTE: Hospitalization for anticipated or protocol specified procedures such 
as administration of chemotherapy, central line insertion, metastasis 
interventional therapy, resection of primary tumor, or elective surgery, will 
not be considered SAEs. 
• 
Results in persistent or significant disability/incapacity. Congenital 
anomaly/birth defect.  
• 
Is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based 
upon appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention (e.g., medical, surgical) to prevent one of the 
other serious outcomes listed in the definition above). 
NOTE: Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions not resulting in hospitalization; or the development 
of drug dependency or drug abuse. (See Table 10.221) 
If an investigator considers an event to be clinically important, but it does not 
meet any of the serious criteria, the event could be classified as an SAE 
under the criterion of “other medically important serious event.” 
NOTE: Examples of such events could include allergic bronchospasm, 
convulsions, blood dyscrasias, drug induced liver injury (DILI), or events 
that necessitate an emergency room visit, outpatient surgery, or urgent 
intervention. 
10.14 Suspected Adverse Reaction 
Any AE for which there is a reasonable possibility that the drug caused the AE. 
10.15 Adverse Events of Special Interest (AESI) 
Events that would not typically be considered to meet the criteria for expedited 
reporting, but that for a specific protocol are being reported via expedited means 
in order to facilitate the review of safety data (may be requested by the FDA 
and/or the sponsor and/or pharmaceutical partner(s)).  

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10.16 Protocol Violation/Deviation 
Any change, divergence or departure from the study design or research 
procedures that has not been approved by the IRB.  
Major Protocol Violation/Deviation: Any change that affects the rights and 
welfare of subjects and others, increases risks to subjects and others, decreases 
potential benefits, compromises the integrity or validity of the research, or 
represents willful or knowing misconduct. 
Minor Protocol Violation/Deviation: Any change that did not increase the risk 
or decrease the benefit or significantly affect the subject’s rights, safety, or 
welfare and/or the integrity of research data (e.g., a routine lab missed at a visit 
and re-drawn, shortening the duration between a planned study visit, using an 
outdated HIPAA form or consent form when there are no differences between the 
two forms other than the approval date). 
10.17 Medication error 
A medication error is defined as any accidental incorrect administration or dosing 
of a medicinal product, 
10.18 Expedited Reporting 
Events immediately reported to sponsor/investigator and any pharmaceutical 
partner(s) using the appropriate iMedidata Rave SAE eCRF(s) once study team 
has become aware of the event. 
10.19a Routine Reporting 
Events reported to sponsor and any pharmaceutical partner(s) via the appropriate 
iMedidata Rave AE eCRF(s). 
10.19b Expected versus Unexpected Events  
Expected events are those described within the Section 15.0 of the protocol, the 
study specific consent form, package insert (if applicable), and/or the investigator 
brochure (IB), (if an investigator brochure is not required, otherwise described in 
the general investigational plan).  
Unexpected adverse events or suspected adverse reactions are those not listed in 
Section 15.0 of the protocol, the study specific consent form, package insert (if 
applicable), or in the investigator brochure (or are not listed at the specificity or 
severity that has been observed); if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general 
investigational plan. 
Unexpected also refers to AEs or suspected adverse reactions that are mentioned 
in the investigator brochure as occurring with a class of drugs but have not been 
observed with the drug under investigation. 
An investigational agent/intervention might exacerbate the expected AEs associated 
with a commercial agent. Therefore, if an expected AE (for the commercial agent) 
occurs with a higher degree of severity or specificity, expedited reporting is 
required. 
NOTE: Refer to protocol or IB for reporting needs. 

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10.19c Relatedness 
A problem or event is "related" if it is possibly related and/or attributed to the 
research procedures including (but not limited to) investigational product(s), 
assay process and/or study procedures or activity. 
Specifically, they will be categorized using the following terms: 
Unrelated 
AE is not related to study agent(s) or research procedure(s) 
Unlikely 
AE is doubtfully related to study agent(s) or research procedure(s) 
Possible 
AE may be related to study agent(s) or research procedure(s) 
Probable 
AE is likely related to study agent(s) or research procedure(s) 
Definite 
AE is clearly related to study agent(s) or research procedure(s) 
10.19d Severity Criteria 
An assessment of the Adverse Events severity grade will be made by the 
investigator according to the NCI CTCAE Version 5.0.  
A copy of this CTCAE version can be downloaded from the CTEP web site: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
10.2 
Site Reporting 
Subject data accrued on this study will be reported in accordance with 21CFR 312.32. 
All AEs and SAEs will be reported using iMedidata Rave electronic data capture system. 
Please refer to the “Mayo Clinic Cancer Center Electronic Case Report Form (eCRF) 
Completion Guidelines” for additional instructions. 
All AEs and SAEs must be evaluated, diagnosed, and assessed for safety reporting by an 
investigator.  
The AE grading scale for this study will be Common Terminology Criteria for AEs 
(CTCAE) version 5.0. All appropriate treatment areas must have access to this CTCAE 
version.  
10.21 Adverse Events 
10.211 
Site Requirements for Reporting AEs 
From the time of registration until ≤ 30 days after the administration of 
the last dose of study drug/agent or therapy, or until a new anti-cancer 
treatment starts, whichever occurs first, the Site Principal Investigator 
(PI) is responsible for ensuring that all AEs (observed by study team, 
provided by external sources, etc.) are reported to the 
sponsor/investigator and any pharmaceutical partner(s). 
After 30 days from last dose of administration of the last dose of study 
drug/agent or therapy, only adverse events that are attributed to the 
study drug (possible, probable, or definite) are required to be recorded 
on the adverse event forms. Also refer to Section 10.231 for the 
reporting of any possible SAEs as applicable.  
The investigator(s) is responsible for: 
• 
AE diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
• 
Dates of onset and resolution (if resolved), 
• 
Severity, 
• 
Assessment of the relationship to study treatment(s),  

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• 
As applicable, identify and clarify if an adjustment in treatment 
dose occurred due to an AE 
• 
Determine the relationship of the AE with any study mandated 
activity (e.g., administration of investigational product, protocol-
required therapies, and/or procedure (including any screening 
procedure(s)).  
• 
Reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a 
clinically significant change from the subject’s baseline values.  
o In general, abnormal laboratory findings without clinical 
significance (based on the Investigator's judgment) are not to 
be recorded as AEs. Exceptions may include but are not 
limited to: 
• 
AESI (Section 10.212) 
• 
Baseline and Adverse Events Evaluations (Section 10.213) 
o However, laboratory value changes that require treatment or 
adjustment in current therapy are considered AEs.  
o Where applicable, clinical sequelae (not the laboratory 
abnormality) are to be recorded as the AE.  
o Asymptomatic laboratory abnormalities that do not require 
treatment will not be collected as AEs. 
• 
Following reported AEs until resolution. 
The delegated study team member(s) must document and report AEs as 
follows: 
• 
All AEs must be documented in the subject’s medical record and 
recorded on the appropriate study specific iMedidata Rave 
“Adverse Events” eCRF. Information documented on the 
iMedidata Rave “Adverse Events” eCRF must be consistent with 
that recorded on the source document. 
o AEs will be recorded regardless of whether or not they are 
considered related to the study drug(s). AEs considered related 
to study drug(s) will be followed until resolution to ≤ Grade 1 
or baseline, deemed clinically insignificant, and/or until a new 
anti-cancer treatment starts, whichever occurs first. Exceptions 
may include non-clinically significant labs if they meet non-
critical reporting criteria. 
• 
If a subject is permanently withdrawn from protocol-required 
therapies because of an AE, the subject status must be submitted, 
via the appropriate iMedidata Rave eCRF. 
• 
If an AE results in adjustment in treatment dose (i.e., dose delay, 
dose reduction, etc.): 
o the individual AE needs to be documented on iMedidata Rave 
“Adverse Events” eCRF and,  
o the details of the dose adjustment due to the individual AE 
need to be documented on the iMedidata Rave “Treatment” 
(Intervention) eCRF. 

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10.2111 Additional Reporting per Genentech 
Eliciting Adverse Events 
A consistent methodology for eliciting AEs at all subject 
evaluation time points should be adopted. Examples of non-
directive questions include: 
• 
“How have you felt since your last clinical visit?” 
• 
“Have you had any new or changed health problems since 
you were last here?” 
Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts 
when reporting AEs or SAEs. Avoid colloquialisms and 
abbreviations. 
Diagnosis vs. Signs and Symptoms 
If known at the time of reporting, a diagnosis should be reported 
rather than individual signs and symptoms (e.g., record only liver 
failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases). However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single 
diagnosis or syndrome at the time of reporting, it is acceptable to 
report the information that is currently available. If a diagnosis is 
subsequently established, it should be reported as follow-up 
information. 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the start 
of the study. Such conditions should be reported as medical and 
surgical history. A preexisting medical condition should be re-
assessed throughout the trial and reported as an AE or SAE only 
if the frequency, severity, or character of the condition worsens 
during the study. When reporting such events, it is important to 
convey the concept that the preexisting condition has changed by 
including applicable descriptors (e.g., “more frequent 
headaches”). 
Adverse Event Reporting Period 
The study period during which AEs and SAEs where the patient 
has been exposed to Genentech product must be reported - 
reporting period begins after initiation of study treatment and 
ends 30 days following the last administration of study treatment 
or study discontinuation/termination, whichever is earlier. After 
this period, investigators should only report SAEs to Genentech 
that are attributed to prior study treatment 
For patients receiving combination therapy, causality will be 
assessed individually for each protocol-mandated therapy. 
Reporting Requirements for Adverse Events Originating 
from Patient Reported Outcomes 
Although sites are not expected to review the PRO data, if 
physician/study personnel become aware of a potential adverse 
event during site review of the PRO questionnaire data, he/she 
will determine whether the criteria for an adverse event have 

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been met and, if so, these must be reported using the Adverse 
Event and Special Situation Reporting Form or MedWatch form. 
10.212 
Adverse Events of Special Interest (AESIs) 
Selected non-serious and serious AEs are also known as Adverse 
Events of Special Interest (AESI) and must be recorded as such on the 
“SAE: Event Information” eCRF. AESIs (both non-serious and serious 
adverse events) identified from the date of first dose through 30 days 
following cessation of treatment, or 30 days after the initiation of a 
new anticancer therapy, whichever is earlier, will be reported by the 
site to Mayo Clinic within one business day. 
• 
Cases of potential drug-induced liver injury that include an 
elevated ALT or AST in combination with either an elevated 
bilirubin or clinical jaundice, as defined by Hy’s law: 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with 
total bilirubin > 2 × ULN 
• 
Treatment-emergent ALT or AST > 3 × ULN in combination with 
clinical jaundice 
• 
Data related to a suspected transmission of an infectious agent by 
the study drug (STIAMP), 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 that indicate an infection in a 
patient exposed to a medicinal product. This term applies only 
when a contamination of the study drug is suspected 
• 
Left ventricular dysfunction (asymptomatic decline in LVEF 
requiring treatment or leading to discontinuation of pertuzumab 
and trastuzumab) 
The following other Special Situations Reports should be collected 
even in the absence of an Adverse Event and transmitted to Genentech: 
• 
Data related to the Product usage during breastfeeding 
• 
Data related to overdose, abuse, misuse or medication error 
(including potentially exposed or intercepted medication errors) 
• 
In addition, reasonable attempts should be made to obtain and 
submit the age or age group of the patient, in order to be able to 
identify potential safety signals specific to a particular population 
• 
[This requirement, based on European Medicines Agency’s (EMA) 
Good Pharmacovigilance Practices (GVP) Module VI Section B.3, 
applies to Genentech because it is part of the larger Roche 
organization that operates in EU territories]: 
• 
Batch ID/lot ID for biologics associated with 
AE/SSR/PC/AESI must be included when submitting the case 
reports to Genentech. 
 
 

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10.213 
Baseline and Adverse Events Evaluations 
Pretreatment symptoms/conditions to be graded at baseline and adverse 
events to be graded at each evaluation.  
Grading is per CTCAE v5.0 unless alternate grading is indicated in the 
table below: 
CTCAE  
System/Organ/Class (SOC) 
Adverse event/Symptoms 
Baseline 
Each 
evaluation 
Cardiac disorders 
Left ventricular systolic dysfunction 
X 
X 
General disorders and 
administration site 
conditions 
Fatigue 
X 
X 
Investigations 
Neutrophil count decreased 
X 
X 
 
White blood cell decreased 
X 
X 
Metabolism and  
Hypercalcemia 
X 
X 
nutrition disorders 
Hyperglycemia 
X 
X 
 
Hypermagnesemia 
X 
X 
 
Hyponatremia 
X 
X 
Nervous system disorders 
Seizure 
X 
X 
Vascular disorders 
Thromboembolic event 
X 
X 
10.22 Serious Adverse Events 
10.221 
Site Requirements for Reporting SAEs  
From the time of registration until ≤ 30 days after the administration of 
the last dose of study drug/agent or therapy, or until a new anti-cancer 
treatment starts, whichever occurs first, the Site Principal Investigator 
(PI) is responsible for ensuring that all SAEs (observed by study team, 
provided by external sources, etc.) are reported immediately to the 
sponsor/investigator and any pharmaceutical partner(s). 
In addition to reporting to Mayo Clinic, the investigator is responsible 
for reporting to their appropriate IRB/IEC in accordance with local 
regulatory requirements and procedures.  
10.2211 Initial reporting: 
The investigator/study team must report SAEs as follows: 
• 
All SAEs must be immediately submitted to Mayo Clinic 
following the study team’s knowledge of the event via the 
iMedidata Rave “Adverse Events” eCRF.  
NOTES: This eCRF will generate the “SAE: Event Information” 
eCRF when the event is indicated as “serious.” Information 
documented on the iMedidata Rave “SAE: Event Information” eCRF 
must be consistent with that recorded on the source document.  
Once the SAE information has been captured and submitted in 
iMedidata Rave, a report can be generated. A copy of this completed 
report must be kept within the study file at the study site. 
• 
The investigator must assess whether the SAE is possibly related to 
the investigational product.  
• 
The investigator is expected to follow reported SAEs until 
stabilization, resolution, or patient death. (See section below on 
Follow-Up Reporting.) 

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10.2212 Follow-Up Reporting: 
New information relating to a previously reported SAE needs to be 
submitted to Mayo Clinic: 
• 
Immediately upon site becoming aware of updated information  
• 
Sites may be required to: 
o Provide additional information including but not limited to 
discharge summaries, medical records, etc.  
o Query external locations for additional information if events 
occurred outside the participating site (i.e., Hospitalization 
records)  
o Respond to sponsor/investigator and any pharmaceutical 
partner(s) query(ies) if additional information is needed  
• 
All SAEs regardless of relation to study drug will be followed until 
resolution to ≤ Grade 1 or baseline and/or deemed clinically 
insignificant, until a new anti-cancer treatment starts, or death 
whichever occurs first. 
• 
Revise the previously documented SAE on the appropriate 
iMedidata Rave eCRF.  
NOTE: Information documented on the iMedidata Rave eCRF must be 
consistent with that recorded on the source document.  
Once the updated SAE information has been captured and submitted in 
iMedidata Rave, a report can be generated. A copy of this updated 
report must be kept within the study file at the study site. 
NOTE: Refer to Section 10.23 for additional reporting regulatory 
authorities. 
 
 

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Table 10.222 
Expedited Reporting Requirements for Adverse Events/Serious Adverse Events 
EXPEDITED REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS 
(21 CFR Part 312) 
Investigators MUST immediately report to Mayo Clinic ANY Serious Adverse Events (SAE), whether 
or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64). 
Mayo Clinic Sponsor-Investigator will report as applicable 
Mayo Clinic will report to FDA, per regulations [21 CFR 312.32(c)(d)]. 
The definition of a SAE can be found in Section 10.13. 
Detailed site requirements for reporting SAEs can be found in Section 10.221. 
Initial Reporting 
Follow-Up Reporting 
Hospitalization 
>= 24 hours 
(any grade and/or 
attribution) 
 
Hospitalization  
>= 24 hours 
(any grade and/or 
attribution) 
 
GRADE 3 
Attribution of Possible, 
Probable, or Definite 
IMMEDIATELY, upon 
study team’s awareness of 
event. 
(Not to exceed 24 hours.) 
GRADE 3 
Attribution of Possible, 
Probable, or Definite 
IMMEDIATELY, upon 
receiving any updated 
information regarding 
initial event.  
(Not to exceed 24 hours.) 
GRADES 4 and 5 
Regardless of Attribution 
 
GRADES 4 and 5 
Regardless of Attribution 
 
Refer to Section 10.23 for detailed reporting requirements related to Important Medical Events 
(IME), Adverse Events of Special Interest (AESI), > 30 days post treatment, Dosing errors, 
Pregnancy, Fetal Death, Neonatal Death, and Lactation. 
Offline reporting when iMedidata Rave is unavailable: 
If the iMedidata Rave system is unavailable to the site staff to report the 
SAE, the information is to be reported to Mayo Clinic by completing, 
scanning, and submitting a hard copy of the “Adverse Events” CRF and 
related “SAE: Event Information” CRFs within 24 hours of the 
investigator’s knowledge of the event. See the study forms packet for 
printable copy of these forms. Completed forms are to be submitted to 
. 
For studies where the first notification of a SAE is reported to Mayo 
Clinic using the Offline reporting instructions, the data must be entered 
into iMedidata Rave when the system is again available. The originally 
submitted forms and the email correspondence must be kept within the 
study file at the study site. 
10.223 
Exceptions for Site(s) Regarding Expedited Reporting Timelines for 
SAEs  
For this protocol only, the following AEs/Grades are expected to occur 
within this population and do not require Expedited Reporting. These 
events must still be reported via iMedidata Rave (see Section 10.22): 
• 
Specific protocol exceptions to expedited reporting should be 
reported immediately by investigators ONLY if they exceed the 
expected grade of the event. 

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CTCAE 
System Organ Class 
(SOC) 
Adverse event/ Symptoms 
CTCAE Grade at which the event 
will not be reported in an expedited 
manner1 
Blood and lymphatic 
system disorders 
Anemia 
Grade 3 
General disorders and 
administration site  
Fatigue 
Grade 3 
conditions 
Malaise 
Grade 3 
Investigations 
Neutrophil count decreased 
≤Grade 4 
 
White blood cell decreased 
≤Grade 4 
Metabolism and nutrition  Hypercalcemia 
Grade 3 
disorders 
Hyperglycemia 
Grade 3 
 
Hypermagnesemia 
Grade 3 
 
Hyponatremia 
Grade 3 
*These exceptions only apply if the AE does not result in hospitalization. If the AE results in 
hospitalization, then the standard expedited AEs reporting requirements must be followed.  
The following hospitalizations are not considered to be SAEs because 
there is no “AE” (i.e., there is no untoward medical occurrence) 
associated with the hospitalization: 
• 
Hospitalizations for respite care. 
• 
Planned hospitalizations required by the protocol. 
• 
Hospitalization planned before informed consent (where the 
condition requiring the hospitalization has not changed post study 
drug administration). 
• 
Hospitalization for elective procedures unrelated to the current 
disease and/or treatment on this trial. 
• 
Hospitalization for administration of study drug or insertion of 
access for administration of study drug. 
• 
Hospitalization for routine maintenance of a device (e.g., battery 
replacement) that was in place before study entry. 
• 
Hospitalization or other serious outcomes for signs and symptoms 
of progression of the cancer. 
10.23 Other Reporting  
10.231 
>30 days post treatment 
Immediately, upon study team’s awareness of event, submit initial and 
follow-up (as applicable) reporting as follows: 
• 
SAEs that occur > 30 days after the last administration of 
investigational agent/intervention and have an attribution of 
possible, probable, or definite should be reported to Mayo Clinic 
(refer to Section 10.22). 
• 
For AEs occurring > 30 days after the last administration of 
investigational agent/intervention, refer to Section 10.211 for 
reporting requirements. 
10.232 
Medication Errors 
Medication Error: An error made in prescribing, dispensing, 
administration, and/or use of the study drug.  

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The following errors (including but not limited to) are to be reported as 
a deviation (refer to Section 10.237):  
• 
The dispensing, administration and/or use of the unassigned study 
drug. 
• 
The administration and/or use of an expired study drug. 
• 
Persistent or sporadic, intentional excessive use of medicinal 
products, which is accompanied by harmful physical or 
psychological effects. 
• 
Intentional and inappropriate use of a medicinal product not in 
accordance with the prescribed or authorized dose, route of 
administration, and/or the indication(s) or not within the legal 
status of its supply. 
• 
Administration of a quantity of study drug given per administration 
or per day, which is above the assigned dose. 
For Medication Errors that result in an AE or SAE, the event must be 
reported via the appropriate iMedidata Rave eCRF (refer to Sections 
10.21 and 10.22). 
10.233 
Pregnancy, Pregnant Partner, Fetal Death, Neonatal Death and 
Lactation 
If a female subject becomes pregnant, or a male subject fathers a child, 
while the subject is on protocol report the pregnancy to Mayo Clinic as 
specified below. 
NOTES:  
Pregnancies and/or lactations that occur after registration but before 
treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be ineligible from continued 
participation on the trial.  
Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 7 months following cessation of 
study drug/agent, or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  
10.2331 Pregnancy 
Immediately, upon the Investigator becoming aware of a 
pregnancy, the site must contact 
 for 
reporting instructions. Mayo Clinic Cancer Center FDA 
Coordination Team will follow-up with the investigator 
regarding additional information that may be required. 
If a female subject becomes pregnant during the study, the 
investigator should attempt 
to obtain information regarding the birth outcome and health 
of the infant. If the outcome of the pregnancy meets a 
criterion for immediate classification as a Serious Adverse 
Event (i.e., female subject experiences a spontaneous 
abortion, stillbirth, or neonatal death or there is a fetal or 
neonatal congenital anomaly) the investigator will report the 
event as a Serious Adverse Event. 

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Pregnancy must be reported in an expedited manner as Grade 
3 “Pregnancy, puerperium, and perinatal conditions - 
Other (pregnancy)” under the Pregnancy, puerperium, and 
perinatal conditions System Organ Class (SOC). Pregnancy 
should be followed until the outcome is known. 
10.2332 Pregnant Partner 
If a male subject's female partner becomes pregnant, the 
investigator should discuss 
obtaining information regarding the birth outcome and health 
of the infant from the pregnant partner. Prior to obtaining 
private information about a pregnant woman and her 
infant, the Investigator must obtain consent from the 
pregnant woman and the newborn infant’s parent or 
legal guardian before any data collection can occur. A 
consent form will need to be submitted to the IRB for 
these subjects if a pregnancy occurs.  
NOTE: If informed consent is not obtained, no 
information may be collected. 
The site must contact 
 for reporting 
instructions. Mayo Clinic Cancer Center FDA Coordination 
Team will follow-up with the investigator regarding 
additional information that may be required. 
10.2333 Lactation 
If a female breastfeeds while taking protocol-required 
therapies, report the lactation case to Mayo Clinic as 
specified below. 
Immediately upon the Investigator’s knowledge of any 
lactation case, the site must contact 
 
for reporting instructions. Mayo Clinic Cancer Center FDA 
Coordination Team will follow-up with the investigator 
regarding additional information that may be required. 
Investigators should report lactation cases that occur through 
180 days after the last dose of protocol-required therapies. 
10.2334 Pregnancy Loss/Fetal Death and Neo-Natal Death 
In cases of fetal death, miscarriage or abortion, the mother is 
the patient. In cases where the child/fetus experiences a SAE 
other than fetal death, the child/fetus is the patient. 
Pregnancy outcomes of: spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage, and stillbirth must be 
reported as serious events (Important Medical Events). If the 
pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
Pregnancy loss is defined in CTCAE as “A disorder 
characterized by death in utero.” 
Fetal loss at any gestational age must be reported 
expeditiously, as Grade 4 “Pregnancy loss” under the SOC 

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of “Pregnancy, puerperium and perinatal conditions.” 
Neonatal death, defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth” must be reported 
expeditiously as Grade 4 “Death neonatal” under the SOC 
of “General disorders and administration site conditions.” 
NOTE: When submitting Mayo Expedited Adverse Event 
Report reports for “Pregnancy”, “Pregnancy loss”, or 
“Neonatal loss”, the potential risk of exposure of the fetus to 
the investigational agent(s) or chemotherapy agent(s) must 
be documented in the “Description of Event” section. 
Include any available medical documentation.  
In addition to reporting to Mayo Clinic, sites are 
responsible to report any of the above instances to their 
IRB per Institutional guidelines. 
10.2335 Additional Reporting per Genentech 
For pregnancy, per PHESGO protocols, it is recommended 
that the patients (female and male) use contraceptive 
methods during the treatment on HER2 products and up to 
7 months after receiving the last dose. 
If a female subject (or female partner of a male subject) 
taking investigational product becomes pregnant or within 
7 months after the last dose of study drug, or if the female 
partner of a male study subject becomes pregnant while the 
study subject is receiving the study drug or within 7 months 
after the last dose of a study drug a report should be 
completed and expeditiously submitted to Genentech, Inc, 
Pregnancies will be followed-up until the outcome of the 
pregnancy is known, whenever possible, based upon due 
diligence taken to obtain the follow-up information. Abortion, 
whether accidental, therapeutic, or spontaneous, should 
always be classified as serious, and expeditiously reported as 
an SAE. Similarly, any congenital anomaly/birth defect in a 
child born to a female subject exposed to the study drug 
should be reported as an SAE.  
Additional information on any {PHESGO}-exposed 
pregnancy and infant will be requested by Genentech Patient 
Safety at specific time points (i.e., According to The Global 
Enhanced PV Pregnancy Program women exposed to 
PHESGO during pregnancy or within seven months prior to 
conception will be monitored and follow-up on the infant will 
be performed after birth, and at 3, 6, and 12 months of life.) 
10.234 
Death 
A death occurring between the time of registration and ≤30 days after 
last dose of study treatment requires iMedidata Rave reporting 
regardless of causality. Attribution to treatment or other cause must be 
provided. 
Reportable categories of Death  
• 
Death Not Otherwise Specified (NOS): A cessation of life that 

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cannot be attributed to a CTCAE term associated with Grade 5. 
• 
Sudden death NOS: A sudden (defined as instant or within one 
hour of the onset of symptoms) or an unobserved cessation of 
life that cannot be attributed to a CTCAE term associated with 
Grade 5. 
• 
Death due to progressive disease that cannot be attributed to a 
CTCAE term associated with Grade 5 should be reported as 
Grade 5 “Disease progression” under the SOC of General 
disorders and administration site conditions. Evidence that the 
death was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or progression: 
clinical deterioration associated with a disease process) should 
be submitted. 
• 
All other causes of “Death” must be attributable to a Grade 5 
CTCAE term. 
• 
Neonatal and Fetal Death: Refer to Section 10.2334. 
10.235 
Secondary Malignancy 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation, or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND will be reported. Three options are available to 
describe the event: 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
o Myelodysplastic syndrome (MDS) 
o Treatment-related secondary malignancy 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via iMedidata Rave. 
10.236 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy). Second 
malignancies require ONLY routine reporting via iMedidata Rave unless 
otherwise specified. 
10.237 
Protocol Violation/Deviation Reporting 
The Mayo Clinic 
 inbox must be notified 
immediately, of any Major Deviation (defined in Section 10.16).  
Mayo Clinic Sites: All Major and Minor deviations must be entered in 
PTrax immediately upon the study team becoming aware of the 
violation/deviation. Mayo Clinic staff are responsible for reporting to the 
Mayo Clinic IRB per IRB policy. 
External NON-Mayo Clinic Sites: All deviations must be entered into the 
appropriate iMedidata Rave eCRF. Non-Mayo Clinic Sites are responsible 
to report to their local IRB per IRB policy.  

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PC Hotline Number: 
 (M-F: 5 am to 5 pm PST) 
Transmission of these reports (initial and follow-up) will be either electronically or by 
fax and within the timelines specified below: 
Type of Report  
Timelines  
Serious Adverse Events (related and not related to 
the Product) 
30 calendar days from awareness date 
Special Situation Reports (With or without AE 
and pregnancy) 
Product Complaints (With or without AE) 
AESI 
Case Transmission Verification of Single Case Reports (Genentech): 
• 
The parties will verify that all single case reports have been adequately received by 
Genentech via the investigator emailing Genentech a Quarterly line-listing 
documenting single case reports sent by the investigator to Genentech in the 
preceding time period.  
• 
The periodic line-listing will be exchanged within seven (7) calendar days of the end 
of the agreed time period. Confirmation of receipt should be received within the time 
period mutually agreed upon. 
• 
If discrepancies are identified, the Sponsor and Genentech will cooperate in resolving 
the discrepancies. The responsible individuals for each party shall handle the matter 
on a case-by-case basis until satisfactory resolution.  The sponsor shall receive 
reconciliation guidance documents within the ‘Activation Package’. 
• 
Following Case Transmission Verification, single case reports which have not been 
received by Genentech shall be forwarded by the investigator to Genentech within 
five (5) calendar days from request by Genentech. 
At the end of the study, a final cumulative Case Transmission Verification report will be 
sent to Genentech 
Quarterly line-listings and final CTV should be sent to: 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
Sponsor-investigator, as the Sponsor of the Study, will be responsible for the expedited 
reporting of safety reports originating from the Study to the Regulatory Authorities 
(FDA) where it has filed a clinical trial approval, in compliance with local regulations. 
Sponsor-investigator or designee as the Sponsor of the Study, will be responsible for the 
expedited reporting of safety reports originating from the study to the European Medicine 
Agency (EMA) through Eudravigilance Clinical Trial Module (EVCTM), where 
applicable.  
Sponsor-investigator or designee will be responsible for the expedited reporting of safety 
reports originating from the Study to the Independent Ethics Committees/ Institutional 
Review Boards (IEC/IRB) of the Concerned Member States, where applicable. 
Sponsor-investigator or designee as the Sponsor of the Study, will be responsible for the 
preparation of six-monthly Suspected Unexpected Serious Adverse Reaction (SUSAR) 
reports and their submission to Investigators, Regulatory Authorities and the Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), where applicable 

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Aggregate Reports 
IND ANNUAL REPORTS 
Copies to Genentech: 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be 
copied to Genentech. Copies of such reports should be emailed to Genentech at: 
Genentech Patient Safety CTV mailbox: 
 
STUDY CLOSE-OUT 
Any study report submitted to the FDA by the Sponsor/Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final 
study report). Additionally, any literature articles that are a result of the study should be 
sent to Genentech. Copies of such reports should be mailed to the assigned Clinical 
Operations contact for the study: 
 
And to Genentech Patient Safety CTV oversight mailbox at: 
 
QUERIES 
Queries related to the Study will be answered by Sponsor-Investigator. However, 
responses to all safety queries from regulatory authorities, Ethics Committees, and 
Institutional Review Board, or for publications will be discussed and coordinated 
between the Parties. The Parties agree that Genentech shall have the final say and control 
over safety queries relating to the Product. Sponsor-Investigator agrees that it shall not 
answer such queries from regulatory authorities and other sources relating to the Product 
independently but shall redirect such queries to Genentech. 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent 
requests from Regulatory Authorities and/or IRB/IEC for information or review of data 
are met. The Parties will clearly indicate on the request the reason for urgency and the 
date by which a response is required. 
SIGNAL MANAGEMENT AND RISK MANAGEMENT 
Genentech is responsible for safety signal management (signal detection and/or 
evaluation) for their own Product. However, it is agreed that the sponsor-investigator as 
Sponsor of the Study, will be primarily responsible for assessment of the benefit-risk 
balance of the Study. 
If Sponsor-investigator issues a safety communication relevant for Genentech (i.e., a 
safety issue that notably impacts the benefit-risk balance of the Study and / or triggers 
any changes to the Study) this will be sent to Roche within five (5) business days of its 
internal approval. 
As needed, Genentech will reasonably assist the sponsor-investigator with signal and risk 
management activities related to the Product within the Study. 
Genentech will also provide the sponsor-investigator with any new relevant information 
that may modify or supplement known data regarding the Product (e.g., relevant Dear 
Investigator Letter).  
COMPLIANCE WITH PHARMACOVIGILANCE AGREEMENT / AUDIT 
The Parties shall follow their own procedures for adherence to AE reporting timelines.  
Each Party shall monitor and, as applicable, request feedback from the other Party 
regarding AE report timeliness in accordance with its own procedures. The Parties agree 
to provide written responses in a timely manner to inquiries from the other Party 
regarding AE reports received outside the agreed upon Agreement timelines. If there is 

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any detection of trends of increasing or persistent non-compliance to transmission 
timelines stipulated in this Agreement, both Parties agree to conduct ad hoc or institute a 
regular joint meeting to address the issue. 
In case of concerns related to non-compliance of processes, other than exchange 
timelines, with this Agreement, the Parties will jointly discuss and collaborate on 
clarifying and resolving the issues causing non-compliance. Every effort will be made by 
the non-compliant Party to solve the non-compliance issues and inform the other Party of 
the corrective and preventative actions taken. 
Upon justified request, given sufficient notice of no less than sixty (60) calendar days, an 
audit under the provisions of this Agreement can be requested by either Party. The Parties 
will then discuss and agree in good faith upon the audit scope, agenda and execution of 
the audit. The requesting Party will bear the cost of the audit. 
 

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11.0 
Treatment Evaluation/Measurement of Effect  
For the purposes of this study, patients should be reevaluated every 9 weeks for the first 
27 weeks, then every 12 weeks. The timing of scans should be based off the initiation date of 
protocol treatment. The restaging schedule should be adhered to regardless of treatment holds or 
interruptions. In addition to a baseline scan, confirmatory scans should also be obtained at least 
6 weeks following initial documentation of objective response. 
11.1 
Prostate Cancer Working Group 3 (PCWG3) response criteria 
This study makes use of the PCWG3 response criteria, which consists of the following 
three distinct evaluations:  
• 
Visceral lesions and lymph nodes will be assessed using a modified form of the 
RECIST 1.1 criteria as specified in Section 11.2.  
• 
Bone metastases will be assessed using the PCWG3 criteria specified below in 
Section 11.2.  
PCWG3 discourages the use of overall response criteria, and in this study, overall 
response criteria will only apply to soft tissue lesions, will not incorporate bone lesions, 
and will not incorporate changes in tumor markers.  
Tumor markers: Neither PSA nor any other tumor marker will be used in this study for 
either defining in part or in whole progression or response. PSA will not be used to make 
treatment decisions either.  
Bone lesions: Post-treatment changes will be described as "new lesions" or "no new 
lesions." There will be no descriptions of post-treatment "responses" for bone metastases. 
As such, only progression will be defined in regards to bone lesions, using the following 
table as a descriptor.  
Patients are defined as progressing when they meet bone or soft tissue progression (both 
are not required). 
11.11 Documentation for Radiographic Evidence of Disease Progression 
Date 
Progression 
Detected 
(Visit)a 
Criteria for Progression 
Criteria for 
Confirmation of 
Progression  
(requirement and 
timing)b 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 9 
Bone lesions: Two or more 
new lesions compared to 
baseline bone scan by 
PCWG3 
Consider bone flare 
phenomenon as a 
possibilityc 
Timing: at least 6 weeks 
after progression 
identified or at Week 18 
visitb 
Two or more new bone 
lesions on bone scan 
(compared to Week 9 
scan) 
Soft tissue lesions: 
Progressive disease on CT 
or MRI per Section 11.23 
Confirmation required for 
soft tissue disease (scan 
of same modality as 
demonstrated 
progression)b 
Confirmation of 
progressive soft tissue 
disease per Section 
11.23 

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Date 
Progression 
Detected 
(Visit)a 
Criteria for Progression 
Criteria for 
Confirmation of 
Progression  
(requirement and 
timing)b 
Criteria for 
Documentation of 
Disease Progression on 
Confirmatory Scan 
Week 18 
Bone lesions: Two or more 
new lesions on bone scan 
compared to Week 9 bone 
scan 
Timing: at least 6 weeks 
after progression 
identified or at Week 27 
Visit  
Required for bone lesions 
observed on bone scanb 
Persistentd or increase in 
number of bone lesions 
on bone scan compared 
to Week 18 scan 
Soft tissue lesions: 
Progressive disease on CT 
or MRI per Section 11.23 
No confirmatory scan 
required for soft tissue 
disease progression 
-------------- 
Week 27 or 
later 
Bone lesions: Two or more 
new lesions compared to 
Week 9 bone scan 
Timing: at least 6 weeks 
but no later than 12 
weeks after progression 
identified  
Required for bone lesions 
observed on bone scanb 
Persistentd or increase in 
number of lesions on 
bone scan compared to 
prior scan 
Soft tissue lesions: 
Progressive disease on CT 
or MRI per Section 11.23 
No confirmatory scan 
required for soft tissue 
disease 
-------------- 
a. Progression detected at an unscheduled visit either prior to Week 9 or between 
scheduled visits will require a confirmatory scan at least 6 weeks later and should 
follow confirmation criteria outlined in the table for the next scheduled scan. 
b. Confirmation must occur at the next available scan. 
c. Bone flare phenomenon can occur early in the course of antiandrogen therapy. If is 
defined as detection of new bone lesions(s) on first follow-up bone scan occurring 
due to flare of a pre-existing subclinical metastatic lesion(s) Assuming that the 
treatment is being tolerated well and there is no clinical or radiographic reason to 
discontinue it investigators are encouraged to continue treatment and obtain 
confirmatory imaging studies (including a bone scan) at least 6 weeks later. 
d. For confirmation, at least two of the lesions first identified as new must be present at 
that next available scan (confirmation scan). 
Note: For patients with a superscan (confluence of lesions across the axial skeleton 
such that distinguishing any new lesions is not possible), progression will be 
defined by clinical progression or progression by RECIST criteria. 
11.2  
Target Lesions 
Soft tissue (non-lymph nodal) lesions ≥10 mm in the longest diameter are considered 
measurable. Bone metastases are only considered measurable (i.e., target lesion) if they 
have a soft tissue component ≥10 mm. All other bone metastases are considered 
inevaluable per modified RECIST 1.1 criteria. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, and should be chosen based on their suitability for accurate repetitive 
measurements. Record individual sites of spread (lung, liver, adrenal, CNS, etc.) 
separately, up to 5 lesions per site. 

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Lymph nodes need to be ≥15 mm in the short axis to be considered target or evaluable 
lesions to assess changes in size. Record short axis dimensions of pelvic and extrapelvic 
(retroperitoneal, mediastinal, thoracic, other) nodal disease separately; and up to 5 nodes 
in total. 
Record new lesions versus growth of pre-existing lesions, and sites of new lesions. 
It may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
repeated measurements in which case the next largest lesion that can be measured 
reproducibly should be selected. A sum of the diameters (longest for all lesions, including 
nodes) for all target lesions will be calculated and reported as the baseline sum diameters. 
The baseline sum LD will be used as reference to further characterize the objective tumor 
response of the measurable dimension of the disease. 
11.21  Complete Response 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in long axis to <10 mm. 
11.22  Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameters of target lesions, 
taking as reference the baseline sum diameters. 
11.23  Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one 
or more new non-osseous lesions is also considered progression). Clinical lesions 
will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes) and at least 10 mm in diameter as assessed using calipers 
(e.g., skin nodules). 
Note: Per PCWG3, visceral (lung, liver adrenal) or extranodal lesions need to be 
≥10 mm in one dimension, using spiral CT. However, lymph nodes need to be 
≥15 mm in at least one dimension to be considered new. 
11.24  Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as references the smallest sum diameters while on study. 
11.3  
Non-target Lesions 
All other lesions (or sites of disease) including any measurable lesions over and above the 
5 target lesions should be identified as non-target lesions and should also be recorded at 
baseline. Bone metastases without a soft tissue component ≥10 mm (see Section 11.2) are 
considered inevaluable and should not be designated as non-target lesion(s). 
Measurements of these lesions are not required, but the presence, absence, or in rare 
cases unequivocal progression of each should be noted throughout follow-up. Non-target 
lesions include bone lesions. 
11.31  Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (<10 mm long axis). Note: If 

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tumor markers are initially above the upper normal limit, they must normalize for 
a patient to be considered in complete clinical response. 
11.32  Non-complete response (non-CR)/Non-progression (non-PD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
11.33  Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. Unequivocal progression should not normally trump 
target lesion status. It must be representative of overall disease status change, not 
a single lesion increase. 
Although a clear progression of non-target lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed later on by the review panel (or Study 
Chair). 
Whether new or pre-existing, lesions must be measurable per Section 11.23 to be 
used to measure progression. For new bone lesions, adhere to bone progression 
criteria specified in Section 11.1. 
11.4  
Evaluation of Best Overall Response 
Measurable disease will be evaluated using the PCWG3 criteria in Section 11.1. 
11.41 For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions  
Non-target Lesions  
New Lesions  
Overall Response  
 CR  
CR  
No  
CR  
CR  
Non-CR / Non-PD  
No  
PR  
CR  
Not evaluated   
No  
PR  
PR  
Non-CR / Non-PD / not 
evaluated  
No  
PR  
SD  
Non-CR / Non-PD / not 
evaluated  
No  
SD  
PD  
Any  
Yes or No  
PD  
Any  
PD*  
Yes or No  
PD  
Any  
Any  
Yes  
PD  
* In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 

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11.42 For Patients with Non-measurable Disease (Non-Target) Disease Only 
NOTE: This section is included for reference only. See Section 3.0. 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR / Non-PD 
No 
Non-CR / Non-PD* 
Not all evaluated 
No 
Not evaluated 
Unequivocable PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target 
disease since SD is increasingly used as an endpoint for assessment of 
efficacy in some trials so to assign this category when no lesions can be 
measured is not advised  
11.5  
Guidelines for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
11.51  Clinical Lesions  
Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules, palpable lymph nodes) and ≥ 10 mm diameter as assessed 
using calipers (e.g., skin nodules). For the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
11.52  Chest X-ray 
Use of Chest X-ray is not allowed for determination of measurable disease in this 
study. 
11.53  Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. If CT scans have slice 
thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness. Visceral (lung, liver, adrenal) or extranodal lesions need 
to be ≥ 10 mm in one dimension if slice thickness is ≤ 5 mm; however, lymph 
nodes need to be ≥ 20 mm in at least one dimension to be considered evaluable 
lesions to assess for changes in size. MRI is also acceptable in certain situations 
(e.g., for body scans). Use of MRI remains a complex issue. MRI has excellent 
contrast, spatial, and temporal resolution; however, there are many image 
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conspicuity, and measurement. Furthermore, the availability of MRI is variable 
globally. As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and 
site of disease. Furthermore, as with CT, the modality used at follow-up should 
be the same as was used at baseline and the lesions should be measured/assessed 
on the same pulse sequence. Ideally, the same type of scanner should be used and 
the image acquisition protocol should be followed as closely as possible to prior 
scans. Body scans should be performed with breath-hold scanning techniques, if 
possible. 
11.54  PET-CT 
The low dose or attenuation correction CT portion of a combined PET- CT is not 
always of optimal diagnostic CT quality for use with RECIST measurements. At 
present, there are insufficient data to allow use of PET-CT scans for assessment 
of measurable disease in this study. 
11.55  Ultrasound (US) 
Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator 
dependent, it cannot be guaranteed that the same technique and measurements 
will be taken from one assessment to the next. If new lesions are identified by 
ultrasound in the course of the study, confirmation by CT or MRI is advised. If 
there is concern about radiation exposure at CT, MRI may be used instead of CT 
in selected instances. 
11.56  Endoscopy and Laparoscopy 
The utilization of these techniques for objective tumor evaluation is not advised. 
However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an 
endpoint. 
11.57  Tumor Markers alone cannot be used to assess response 
If markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
11.6  
Confirmation Measurement/Duration of Response 
11.61  Confirmation 
Confirmatory scans should be performed per Section 11.1 after the initial 
documentation of disease progression. 
11.62  Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria 
are met for CR/PR (whichever is first recorded) until the first date that recurrent 
or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started). 

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The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that progressive 
disease is objectively documented. 
11.63  Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for 
progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
12.0 
Descriptive Factors: None 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient  
13.1 
Continuation of treatment 
Patients who are CR, PR, or SD will continue treatment per protocol. 
13.2 
Discontinuation of treatment 
Per the Schema, patients will discontinue treatment if any of the following occur: 
1) Adverse events per Section 8.0 
2) Disease progression 
3) Alternative therapy 
4) Patient refusal 
13.3 
Progressive disease (PD) 
Patients who develop PD while receiving therapy will go to the survival/extended follow-
up phase. 
13.4 
Off protocol treatment 
Patients who go off protocol treatment for reasons other than PD or alternative therapy 
will go to the clinical follow-up phase per Section 4.0. 
13.5 
Observation/Clinical Follow-up 
If the patient has achieved CR, PR, or SD, and stops treatment, the patient will be 
observed every 3 months for 1 year, and then go to survival/extended followup.  
13.6 
Unevaluable patients 
If a patient fails to complete the first cycle of treatment or does not undergo first post-
treatment imaging, the patient will be regarded as unevaluable and will be replaced.  
13.7 
Ineligible 
A patient enrollment is deemed ineligible if after registration, it is determined that at the 
time of registration, the patient did not satisfy each and every eligibility criterion for 
study entry. If the patient received treatment, the patient may continue treatment at the 
discretion of the physician as long as there are not safety concerns. The patient will 
continue in the Active Monitoring/Treatment phase of the study, per Section 4.0 of the 
protocol.  
• 
If the patient never received treatment, on-study and end of study material must be 
submitted.  

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13.8 
Major violation 
A patient enrollment is deemed a major violation, if protocol requirements regarding 
treatment in cycle 1 of the initial therapy are severely violated that evaluability for 
primary end point is questionable. If the patient received treatment, the patient may 
continue treatment at the discretion of the physician as long as there are not safety 
concerns. The patient will continue in the Active Monitoring/Treatment phase of the 
study, per Section 4.0 of the protocol. 
13.9a Cancel 
A patient enrollment is deemed a cancel if he/she is removed from the study for any 
reason before any study treatment is given. On-study material and the End of Active 
Treatment/Cancel Notification Form must be submitted. The patient will go off study. 
13.9b Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy 
initiated after the last dose of trial treatment. If a participant initiates a new anti-cancer 
therapy within 30 days after the last dose of trial treatment, the Safety Follow-up visit 
must occur before the first dose of the new therapy. Once new anti-cancer therapy has 
been initiated the participant will move into survival follow-up/event 
monitoring/extended follow-up per Section 4.0. 
 

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15.0 
Drug Information 
15.1 
Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf (PHESGO™) [HP] 
15.11  Background  
Pertuzumab and trastuzumab are monoclonal antibodies directed against 
HER2. Pertuzumab targets the extracellular dimerization domain (subdomain 
II) of HER2 and, thereby, blocks ligand-dependent heterodimerization of 
HER2 with other HER family members, including EGFR, HER3 and HER4. 
As a result, pertuzumab inhibits ligand-initiated intracellular signaling 
through mitogen-activated protein (MAP) kinase and phosphoinositide 3-
kinase (PI3K). Trastuzumab binds to subdomain IV of the extracellular 
domain of the HER2 protein to inhibit the ligand-independent, HER2 
mediated cell proliferation and PI3K signaling pathway in human tumor cells 
that overexpress HER2. Inhibition of these signaling pathways can result in 
cell growth arrest and apoptosis. Both pertuzumab and trastuzumab-mediated 
antibody-dependent cell-mediated cytotoxicity (ADCC) have been shown to 
be preferentially exerted on HER2 overexpressing cancer cells compared with 
cancer cells that do not overexpress HER2.  
Hyaluronidase (recombinant human) is an endoglycosidase used to increase 
the dispersion and absorption of co-administered drugs when administered 
subcutaneously. In the doses administered, hyaluronidase acts transiently and 
locally. The effects of hyaluronidase are reversible, and permeability of the 
subcutaneous tissue is restored within 24 to 48 hours.  
15.12 Formulation 
Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection is supplied as two 
different strengths: a 15 mL single-dose vial containing 1,200 mg of 
pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase; and a 
10 mL single-dose vial containing 600 mg of pertuzumab, 600 mg of 
trastuzumab, and 20,000 units of hyaluronidase. Pertuzumab, trastuzumab, 
and hyaluronidase-zzxf injection is supplied as a sterile, preservative-free, 
clear to opalescent, and colorless to slightly brownish solution in single-dose 
vials for subcutaneous administration. Each carton contains one single-dose 
vial. Pertuzumab and trastuzumab are produced by recombinant DNA 
technology in a mammalian cell (Chinese Hamster Ovary) culture. 
Hyaluronidase (recombinant human) is a glycosylated single-chain protein 
produced by mammalian (Chinese Hamster Ovary) cells containing a DNA 
plasmid encoding for a soluble fragment of human hyaluronidase (PH20). 
15.13 Preparation and storage 
Store vials in the refrigerator at 2°C to 8°C (36°F to 46°F) in the original 
carton to protect from light. Do not freeze. Do not shake. Do not use vial if 
particulates or discoloration is present. Discard any unused portion remaining 
in the vial. For both the initial and maintenance dose, each corresponding vial 
is ready-to-use for one subcutaneous injection and should not be diluted. To 
avoid needle clogging, attach the hypodermic injection needle to the syringe 
immediately prior to administration. If the dose is not to be administered 
immediately, and the solution has been withdrawn from the vial into the 

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syringe, replace the transfer needle with a syringe closing cap. Once transferred 
from the vial to syringe, the syringe may be stored in the refrigerator (2°C to 8°C 
(36°F to 46°F)) for up to 24 hours and at room temperature (20°C to 25°C (68°F 
to 77°F)) for up to 4 hours. Pertuzumab, trastuzumab, and hyaluronidase-zzxf 
injection is compatible with stainless steel, polypropylene, polycarbonate, 
polyethylene, polyurethane, polyvinyl chloride and fluorinated ethylene 
polypropylene. 
15.14 Administration 
Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection may be injected 
using 25G-27G (3/8”-5/8”) hypodermic injection needles. Pertuzumab, 
trastuzumab, and hyaluronidase-zzxf injection is for subcutaneous use only in 
the thigh. Do not administer intravenously. The subcutaneous injection site 
should be alternated between the left and right thigh only. New injections 
should be given at least 1 inch (2.5 cm) from the previous site on healthy skin 
and never into areas where the skin is red, bruised, tender, or hard. Doses 
should not be split between two syringes or between two sites of 
administration. Other medications for subcutaneous administration should 
preferably be injected at different sites.  
Inject 15 mL initial dose of pertuzumab, trastuzumab, and hyaluronidase-zzxf 
1,200 mg, 600 mg, 30,000 units subcutaneously over approximately 8 
minutes.  
Inject 10 mL maintenance dose of pertuzumab, trastuzumab, and 
hyaluronidase-zzxf 600 mg, 600 mg, 20,000 units subcutaneously over 
approximately 5 minutes.  
Observe patients for a minimum of 30 minutes after initial dose and 15 
minutes after each maintenance dose of pertuzumab, trastuzumab, and 
hyaluronidase-zzxf injection for signs or hypersensitivity symptoms or 
administration-related reactions. Medications to treat such reactions, as well 
as emergency equipment, should be available for immediate use. 
In patients receiving an anthracycline-based regimen, administer pertuzumab, 
trastuzumab, and hyaluronidase-zzxf injection following completion of the 
anthracycline. In patients receiving docetaxel or paclitaxel, administer 
docetaxel or paclitaxel after pertuzumab, trastuzumab, and hyaluronidase-
zzxf injection. 
15.15 Pharmacokinetic information 
Absorption –  
Absolute bioavailability – Pertuzumab: 0.7; Trastuzumab: 0.8 
Tmax – Pertuzumab and trastuzumab: 4 days 
Distribution – Pertuzumab: 2.8 L; Trastuzumab: 2.9 L 
Excretion (Linear Clearance) – Pertuzumab: 0.2 L/day; Trastuzumab: 0.1 L/day 
No clinically significant differences in the pharmacokinetics of pertuzumab 
and trastuzumab were observed based on age, and renal impairment. The 
effects of hepatic impairment on the pharmacokinetics of pertuzumab and 
trastuzumab are unknown. 

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15.16 Potential drug interactions 
Patients who receive anthracycline after stopping PHESGO may be at increased 
risk of cardiac dysfunction because of PHESGO’s long washout period. If 
possible, avoid anthracycline-based therapy for up to 7 months after stopping 
PHESGO. If anthracyclines are used, carefully monitor the patient’s cardiac 
function. 
15.17 Known potential adverse events 
Consult the Investigator’s Brochure and package insert for the most current and 
complete information. Refer to the package insert pertaining to the following 
boxed warnings: cardiomyopathy, embryo-fetal toxicity, and pulmonary toxicity. 
Common known potential adverse events, > 10%:   
Dermatologic: alopecia, skin rash, xeroderma 
Endocrine & metabolic: decreased serum albumin, decreased serum sodium hot 
flash, increase serum potassium, weight loss 
Gastrointestinal: constipation, decreased appetite, diarrhea, dysgeusia, dyspepsia, 
nausea, stomatitis, vomiting 
Hematologic & oncologic: anemia, decrease absolute lymphocyte count, 
neutropenia, thrombocytopenia 
Hepatic: Increase serum alanine aminotransferase, increase serum aspartate 
aminotransferase 
Local:  injection site reaction  
Nervous system: asthenia, paresthesia, dizziness, headache, insomnia 
Neuromuscular & skeletal: arthralgia, myalgia 
Renal: increase serum creatinine 
Respiratory: cough, epistaxis, upper respiratory tract infection 
Miscellaneous: fatigue, fever, radiation injury 
Less common known potential adverse events, 1% - 10%:  
Cardiovascular: cardiac failure, peripheral edema, reduced ejection fraction 
Dermatologic: dermatitis, erythema of skin, nail discoloration, nail disease, 
palmar-plantar erythrodysesthesia, pruritus 
Endocrine & metabolic: decreased serum glucose, hypokalemia, increase serum 
sodium 
Gastrointestinal: abdominal pain, hemorrhoids, upper abdominal pain 
Genitourinary:  urinary tract infection 
Hematologic & oncologic: febrile neutropenia, leukopenia 
Hepatic: increase serum albumin 
Hypersensitivity: hypersensitivity reaction 
Infection: neutropenic sepsis  
Local: pain at injection site 
Nervous system: malaise, paresthesia 
Neuromuscular & skeletal: back pain, limb pain, muscle spasm, musculoskeletal 
pain, ostealgia 
Ophthalmic: dry eye syndrome, increased lacrimation 
Respiratory: dyspnea, flu-like symptoms, nasopharyngitis, rhinorrhea 
Frequency not defined: 
Cardiovascular: cardiac arrhythmias, cardiomyopathy, hypertension, left 
ventricular dysfunction 
Respiratory: Pulmonary toxicity  

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15.18 Drug procurement 
Genentech will supply PHESGO free of charge for patients on this trial. 
Genentech will provide each site pharmacy with PHESGO. 
15.19 Nursing guidelines 
15.191 
Injection should only be given SQ in the thigh. Do not administer IV. 
Alternate between right/left thigh and separate new injections from 
previous injections by about 1 inch. 
15.192 
Allergic reactions are possible. Patients should be monitored for at 
least 30 minutes after initial dose and 15 minutes after subsequent 
doses. Have emergency medications readily available. 
15.193 
If patients are receiving anthracycline-based regimen administer the 
pertuzumab, trastuzumab, hyaluronidase following completion of 
anthracycline.  
15.194 
If patients are receiving paclitaxel or docetaxel-injection should be 
given before chemo. 
15.195 
GI side effects can be seen, including constipation, diarrhea, nausea, 
and vomiting. Treat symptomatically and monitor for effectiveness. 
15.196 
Monitor LFTs 
15.197 
Monitor electrolytes and correct as needed.  
15.198 
Patients may experience arthralgias and myalgias. Treat 
symptomatically and monitor for effectiveness.  
15.199a Cardiac side effects can be seen. Monitor EF per study/SOC 
parameters. Instruct patient to report LE edema, chest pain, or SOB to 
study team. 
15.199b Rash and dermatitis can be seen. 
 
 

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15.2 
Enzalutamide 
15.21 Background 
Enzalutamide competitively inhibits androgen binding to androgen receptors, 
preventing nuclear translocation of androgen receptors and their interaction with 
DNA. As a result, prostate cancer cell proliferation decreases, and cell death is 
induced. N-desmethyl enzalutamide, a major metabolite, exhibits similar in vitro 
activity. 
15.22 Formulation 
Enzalutamide is supplied as both 40 mg white to off-white oblong liquid-filled 
soft gelatin capsules and 40mg and 80mg tablets for oral administration. The 
capsules also contain caprylocaproyl polyoxylglycerides, butylated 
hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, 
glycerin, purified water, titanium dioxide and black iron oxide. The tablet 
formulation includes hypromellose acetate succinate, microcrystalline cellulose, 
colloidal silicone dioxide, croscarmellose sodium, and magnesium stearate. 
15.23 Preparation and Storage  
Store enzalutamide at 20º to 25ºC (68º to 77ºF) in a dry place and keep the 
container tightly closed. Excursions permitted to 15º to 30ºC (59º to 86º F).  
15.24 Administration 
Enzalutamide is administered orally once daily with or without food. Swallow 
capsules whole.  
15.25 Pharmacokinetics 
Absorption: rapid with time to peak concentration in 1 hour (range 0.5-3 hours). 
A high-fat meal did not alter the AUC to enzalutamide or N-desmethyl 
enzalutamide. 
Distribution: 110 L; protein binding of parent drug is 97-98% to primarily 
albumin; protein binding of active metabolite is 95% to plasma proteins 
Metabolism: Hepatic via CYP2C8 (formation of active metabolite N-desmethyl 
enzalutamide) and CYP3A4  
Excretion: Primarily eliminated by hepatic metabolism. Following single oral 
administration of 14C-enzalutamide 160 mg, 85% of the radioactivity is recovered 
by 77 days post dose: Urine (71%), feces (14%) primarily as inactive metabolite 
T1/2: Enzalutamide: 5.8 days (range 2.8-10.2 days); N-desmethyl enzalutamide: 
7.8-8.6 days 
15.26 Drug Interactions 
Enzalutamide is metabolized by CYP2C8 and CYP3A4. Co-administration of a 
strong CYP2C8 inhibitor, gemfibrozil) increased the area under the plasma 
concentration-time curve (AUC) of enzalutamide and N-desmethyl enzalutamide 
by 2.2-fold in healthy volunteers. Avoid the administration of strong CYP2C8 
inhibitors. If co-administration with a strong CYP2C8 inhibitor cannot be 
avoided, reduce the dose of enzalutamide. Co-administration of enzalutamide 
with strong or moderate CYP2C8 inducers (e.g., rifampin) may alter plasma 
exposure of enzalutamide and should be avoided if possible. Selection of a 

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concomitant medication with no or minimal CYP2C8 induction potential is 
recommended.  
Co-administration of itraconazole, a strong CYP3A4 inhibitor, increased the 
AUC of enzalutamide and N-desmethyl enzalutamide by 1.3-fold in healthy 
volunteers. Co-administration of enzalutamide with strong CYP3A4 inducers 
(e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine) 
may decrease the plasma exposure of enzalutamide and should be avoided if 
possible. Selection of a concurrent medication with no or minimal CYP3A4 
induction potential is recommended. Moderate CYP3A4 inducers (e.g., bosentan, 
efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce 
the plasma exposure of enzalutamide and should be avoided if possible.  
Enzalutamide is a strong CYP3A4 inducer and moderate CYP2C9 and CYP2C19 
inducer. Enzalutamide reduced plasma exposure of midazolam (CYP3A4 
substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). 
Concomitant use of enzalutamide with narrow therapeutic index drugs that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus), CYP2C9 
(e.g., phenytoin, warfarin), and CYP2C19 (e.g., S-mephenytoin) should be 
avoided, as enzalutamide may decrease their exposure. If co-administration with 
warfarin cannot be avoided, conduct additional INR monitoring. 
15.27 Known Potential Adverse Events 
Common >10%: 
Cardiovascular: Peripheral edema, hypertension 
Central Nervous System: Fatigue, falling, headache, dizziness 
Endocrine & Metabolic: Hot flash, weight loss 
Gastrointestinal: Constipation, diarrhea, decreased appetite 
Hematologic & Oncologic: Neutropenia 
Neuromuscular & Skeletal: Weakness (falls), back pain, arthralgia, 
musculoskeletal pain 
Respiratory: Upper respiratory tract infection, dyspnea 
Less Common 1 to 10%: 
Central Nervous System: Myasthenia, insomnia, anxiety, paresthesia, cauda 
equine syndrome, spinal cord compression, altered mental status, 
hypoesthesia, hallucination, restless leg syndrome 
Dermatologic: Pruritus, xeroderma 
Endocrine & Metabolic: Gynecomastia 
Gastrointestinal: Dysgeusia 
Genitourinary: Hematuria, pollakiuria 
Hematologic & Oncologic: Thrombocytopenia 
Hepatic: Increased serum bilirubin 
Infection: Infection 
Neuromuscular & Skeletal: Bone fracture, stiffness 
Respiratory: Lower respiratory tract infection, epistaxis 
Rare <1%Limited to important or life-threatening: Seizure, ischemic heart 
disease 
Post-Marketing Experience: vomiting, Posterior Reversible Encephalopathy 
Syndrome, hypersensitivity, skin and subcutaneous tissue disorders (rash, severe 
cutaneous adverse reactions including Stevens-Johnson syndrome (SJS), 

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erythema multiforme, toxic epidermal necrolysis (TEN), drug reaction with 
eosinophilia and systemic symptoms (DRESS) and acute generalized 
exanthematous pustulosis (AGEP)) 
15.28 Drug Procurement 
Commercial supplies 
15.29 Nursing guidelines 
15.291 
Instruct patients that enzalutamide can be taken either with or without 
food.  
15.292 
Assess patient’s concurrent medication including over the counter 
supplements. There are numerous drug-drug interactions as outlined in 
Section 15.26. 
15.293 
Patients may experience peripheral edema, instruct patients to report 
any swelling to the study team. 
15.294 
Warn patients of myalgias. These can be mild to severe. Treat 
symptomatically and monitor for effectiveness. 
15.295 
Rarely patients may experience seizures. Warn patients of this and 
instruct patients to seek out emergency medical attention if they 
experience a seizure.  
15.296 
Patients may experience fatigue. Instruct patient in an energy 
conserving lifestyle, encourage alternating rest and exercise as 
tolerated.  
 
 

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16.0 
Statistical Considerations and Methodology  
16.1 
Overview 
This is a studyof pertuzumab/trastuzumab/hyaluronidase-zzxf (HP) with enzalutamide in 
patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of 
this study is to determine any preliminary evidence to suggest that a larger scale clinical 
trial might be recommended. The study will not utilize a formal statistical design but will 
focus on estimation rather than hypothesis testing. The primary endpoint will be the 
confirmed overall objective response rate (ORR), defined as any confirmed radiographic 
complete response plus partial response according to the PCWG3 criteria. In addition to 
response, this study will also estimate progression-free survival (PFS), overall survival 
(OS), and adverse event rates as secondary endpoints. 
A safety assessment of HP with enzalutamide will be conducted to evaluate the safety of 
this regimen.  
Evaluable Population: The Evaluable Population comprises all patients who are eligible, 
consented, receive protocol treatment, and undergo first post-treatment imaging scan. 
Treated Population: The Treated Population comprises all patients who consent and are 
registered to the study and receive any protocol treatment. 
16.2 
Statistical Design 
16.21 Sample Size 
A maximum of 6 evaluable patients will be enrolled. We anticipate accruing 1-
2 additional patients to replace a patient who is ineligible or unevaluable per the 
definition of Evaluable Population above. Maximum projected accrual is 
therefore 6-8 patients. 
16.22 Accrual Time and Study Duration 
The anticipated accrual rate is approximately 1-2 patients per month. Therefore, 
the accrual period for this study is expected to be between 3 and 6 months. The 
final analysis can begin approximately 9-12 months after the trial begins, i.e., as 
soon as the last patient has been observed for 6 months.  
16.3 
Analysis Plan 
The analysis for this trial will commence at the time the patients have become evaluable 
for the primary endpoint. Such a decision will be made by the Statistician and Study 
Chair, in accordance with MCCCC Standard Operating Procedures, availability of data 
for secondary endpoints, and the level of data maturity. It is anticipated that the earliest 
date in which the results will be made available via manuscript, abstract, or presentation 
format is when patients have been on study for 6 months (i.e., received at least 8 cycles of 
treatment). 
16.31 Primary Endpoint 
16.311 
Definition 
The primary endpoint of this trial is confirmed overall response rate 
(ORR). Overall response rate is defined as the proportion of patients 
who experience either a partial response or complete response as 
defined by PCWG3 (success). The primary endpoint can be analyzed 
when data confirms that the necessary number of evaluable patients 
have reached one of the following trial milestones: 1. Patient has gone 

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off protocol treatment, or 2. Patient has achieved overall response, or 
3. Patient has reached their third re-staging scan (corresponding to 
~6 months of treatment). ORR will be estimated, and a 95% 
confidence interval will be reported.  
16.312 
Estimation 
The proportion of successes will be calculated by the number of 
successes divided by the total number of evaluable patients. 
Confidence intervals for the true success proportion will be calculated 
according to the approach of Clopper and Pearson. The Evaluable 
Population will be used for this endpoint. 
Based on accrual of 6 evaluable patients, two-sided 95% exact 
binomial confidence intervals for a range of success rates are provided 
in the following table: 
Number of 
patients with 
successes 
0 
1 
2 
3 
4 
5 
6 
Point 
estimate of 
success rate: 
0.0% 
16.7% 
33.3% 
50.0% 
66.7% 
83.3% 
100.0% 
Two-sided 
95% 
confidence 
interval 
(exact 
binomial) 
(0.0%, 
45.9%) 
(0.4%, 
64.1%) 
(4.3%, 
77.7%) 
(11.8%, 
88.2%) 
(22.3%, 
95.7%) 
(35.9%, 
99.6%) 
(54.1%, 
100.0%) 
16.313 
Decision Rule 
While this study will not utilize formal hypothesis testing, we will 
consider this regimen promising for a larger scale clinical trial if at 
least one success is observed out of the six evaluable patients. 
16.32 Secondary Endpoints  
The following endpoints will be evaluated: progression-free survival, overall 
survival, adverse events, and quality of life according to the FACT-P. 
16.321 
Progression-Free Survival 
Progression-free survival is defined as the time from study entry to the 
first of either confirmed radiographic disease progression or death from 
any cause, where radiographic disease progression will be determined 
based on PCWG3 criteria. Patients who do not experience disease 
progression or death while on protocol will be censored at their last 
disease assessment date. PFS will be estimated using the Kaplan-Meier 
method. The median PFS and 6-month PFS proportion and 
corresponding 95% confidence intervals (by Brookmeyer and 
Crowley) will be reported. The Treated Population will be used for this 
endpoint. 
16.322 
Overall Survival (OS) 
Overall survival is defined as the time from study entry to death from 
any cause. Patients will be censored at the date patient was last known 

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to be alive. OS will be estimated using the Kaplan-Meier method. The 
median OS and 12-month OS proportion and corresponding 95% 
confidence intervals (by Brookmeyer and Crowley) will be reported. 
The Treated Population will be used for this endpoint. 
16.323 
Adverse events 
The rate of patients experiencing any Grade 3 or higher adverse event 
deemed at least possibly related to treatment will be reported. The 
maximum grade for each type of adverse event by patient will also be 
summarized in an exploratory and hypothesis generating fashion by 
frequencies and percentages using CTCAE version 5.0. Adverse event 
outcomes assessed via PRO-CTCAE will be descriptively summarized 
and compared to the physician assessments. The Treated Population 
will be used for this endpoint. 
In addition, the number and proportion of patients experiencing a 
significant toxicity event in Cycle 1 as described in Section 7.5 will be 
reported. This proportion will be calculated as the number of patients 
experiencing a significant toxicity divided by the number of patients 
who are eligible and receive the expected dose of HP and at least 75% 
of the expected dose of enzalutamide for the first cycle OR experience 
a significant safety event in the first cycle of treatment. Confidence 
intervals for the proportion of patients experiencing a significant 
toxicity will be calculated according to the approach of Clopper and 
Pearson. 
16.324 
Quality of Life 
Patient responses to the FACT-P will be summarized descriptively. All 
patients with responses to one post-baseline survey will be used for this 
endpoint. 
16.4 
Data & Safety Monitoring: 
16.41 Review 
The study chair(s) and the study statistician will review the study at least twice a 
year to identify accrual, adverse event, and any endpoint problems that might be 
developing. The Mayo Clinic Cancer Center (MCCC) Data Safety Monitoring 
Board (DSMB) is responsible for reviewing accrual and safety data for this trial 
at least twice a year, based on reports provided by the MCCC Statistical Office. 
16.42 Adverse Event Stopping Rules 
The stopping rules specified below are based on the knowledge available at study 
development. We note that the Adverse Event Stopping Rule may be adjusted in 
the event of either (1) the study re-opening to accrual or (2) at any time during 
the conduct of the trial and in consideration of newly acquired information 
regarding the adverse event profile of the treatment(s) under investigation. The 
study team may choose to suspend accrual because of unexpected adverse event 
profiles that have not crossed the specified rule below. 
Accrual will be temporarily suspended to this study if at any time we observe 
events that satisfy either of the following, regardless of attribution to study 
treatment: 

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• 
 if 2 or more treated patients experience a Grade 3 or higher seizure or 
cardiac disorder event (including heart failure, cardiac arrest, or 
myocardial infarction). 
We note that we will review all other Grade 4 and 5 adverse events to monitor 
the emergence of a previously unrecognized treatment-related adverse event. 
16.5 
Subset Analyses for Minorities 
16.51 Study availability 
This study will be available to all eligible patients, regardless of gender, race, or 
ethnic origin.  
16.52 Statistical analysis by subset 
There is no information currently available regarding differential effects of this 
regimen in subsets defined by race, gender, or ethnicity, and there is no reason to 
expect such differences to exist. Therefore, although the planned analyses will 
look for differences in treatment effect based on racial groupings, the sample size 
is not increased in order to provide additional power for subset analyses.  
16.53 Regional population 
The geographical region served by MCCC has a population which includes 
approximately 3% minorities. Expected sizes of racial by gender subsets are 
shown in the following table: 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
0 
1 
1 
Not Hispanic or Latino 
0 
7 
7 
Ethnic Category: Total of all subjects 
0 
8 
8 
Racial Category 
American Indian or Alaskan Native 
0 
0 
0 
Asian 
0 
0 
0 
Black or African American 
0 
1 
1 
Native Hawaiian or other Pacific Islander 
0 
0 
0 
White 
0 
7 
7 
Racial Category: Total of all subjects 
0 
8 
8 
 
 

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Ethnic 
Categories: 
Hispanic or Latino – a person of Cuban, Mexican, Puerto Rican, South or Central 
American, or other Spanish culture or origin, regardless of race. The term “Spanish 
origin” can also be used in addition to “Hispanic or Latino.” 
Not Hispanic or Latino 
Racial 
Categories: 
American Indian or Alaskan Native – a person having origins in any of the original 
peoples of North, Central, or South America, and who maintains tribal affiliations or 
community attachment. 
Asian – a person having origins in any of the original peoples of the Far East, 
Southeast Asia, or the Indian subcontinent including, for example, Cambodia, China, 
India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, and 
Vietnam. (Note: Individuals from the Philippine Islands have been recorded as Pacific 
Islanders in previous data collection strategies.)  
Black or African American – a person having origins in any of the black racial 
groups of Africa.  
Native Hawaiian or other Pacific Islander – a person having origins in any of the 
original peoples of Hawaii, Guam, Samoa, or other Pacific Islands. 
White – a person having origins in any of the original peoples of Europe, the Middle 
East, or North Africa. 

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18.0 
Records and Data Collection Procedures  
18.1 
Submission Timetable 
Data submission instructions for this study can be found in the Data Submission 
Schedule. 
18.2 
Survival Follow-up 
See Section 4.  
18.3 
CRF completion 
This study will use Medidata Rave® for remote data capture (rdc) of all study data. Data 
collection for this study will be done exclusively through the Medidata Rave® clinical 
data management system. Access to the trial in Rave is granted through the iMedidata 
application to all persons with the appropriate roles assigned in Regulatory Support 
System (RSS). To access Rave via iMedidata, the site user must have an active account 
and the appropriate Rave role (Rave CRA, Read-Only, Site Investigator) on the 
organization roster at the enrolling site. 
18.4 
Site responsibilities 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.5 
Supporting documentation  
This study requires supporting documentation for diagnosis (e.g., pathology report) and 
progression (e.g., radiographic evidence) prior to study entry as well as for evidence of 
response to study therapy, and progression after study therapy. These documents should 
be uploaded within 14 days of registration (for prior to study entry materials) or within 
14 days after the visit at which response or progression is determined. 
If patient has genetic testing at any time, please upload to Rave when available. 
18.6 
Labeling of materials 
Each site will be responsible for ensuring that all materials contain the patient’s initials, 
MCCC registration number, and MCCC protocol number. Patient’s name must be 
removed. 
18.7 
Overdue lists 
A list of overdue forms and outstanding queries will be available in Rave through the 
Rave Task Summary. In addition, the Overdue Materials report will be distributed 
monthly by the data manager. 
19.0 
Budget 
19.1 
Costs charged to patient 
Routine clinical care including biopsies, imaging, exams 
19.2 
Tests to be research funded 
• 
Research biopsy (1 per patient)  
• 
Research testing on blood and tissue specimens 
19.3 
Other budget concerns: 
Mayo Clinic will support the costs of running this study.  
Genentech will provide study drug, pertuzumab, trastuzumab, hyaluronidase-zzxf (HP) 
(PHESGO™), for use in this study. 
 
 

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20.0 
References 
Beer, Tomasz M. et al. 2014. “Enzalutamide in Metastatic Prostate Cancer before Chemotherapy.” New 
England Journal of Medicine 371(5): 424–33. http://www.nejm.org/doi/10.1056/NEJMoa1405095. 
Centre, European Union Joint Research. 2020. “ECIS - European Cancer Information System.” 
https://ecis.jrc.ec.europa.eu/explorer.php. 
Huggins, C. 1946. “Prostatic Cancer Treated by Orchiectomy; the Five Year Results.” Journal of the 
American Medical Association 131: 576–81. http://www.ncbi.nlm.nih.gov/pubmed/20986021. 
Hussain, Maha et al. 2018. “Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate 
Cancer.” New England Journal of Medicine 378(26): 2465–74. 
http://www.nejm.org/doi/10.1056/NEJMoa1800536. 
Morris, Michael J. et al. 2002. “HER-2 Profiling and Targeting in Prostate Carcinoma.” Cancer 94(4): 
980–86. http://doi.wiley.com/10.1002/cncr.10339 (April 8, 2020). 
Penson, David F. et al. 2016. “Enzalutamide Versus Bicalutamide in Castration-Resistant Prostate 
Cancer: The STRIVE Trial.” Journal of Clinical Oncology 34(18): 2098–2106. 
https://ascopubs.org/doi/10.1200/JCO.2015.64.9285. 
Siegel, Rebecca L., Kimberly D. Miller, Hannah E. Fuchs, and Ahmedin Jemal. 2021. “Cancer Statistics, 
2021.” CA: A Cancer Journal for Clinicians 71(1): 7–33. 
https://onlinelibrary.wiley.com/doi/10.3322/caac.21654. 
Zhang, Zeda et al. 2020. “Tumor Microenvironment-Derived NRG1 Promotes Antiandrogen Resistance 
in Prostate Cancer.” Cancer Cell. https://linkinghub.elsevier.com/retrieve/pii/S1535610820303093 
(July 23, 2020). 
Ziada, Ali et al. 2004. “The Use of Trastuzumab in the Treatment of Hormone Refractory Prostate 
Cancer; Phase II Trial.” The Prostate 60(4): 332–37. 
https://onlinelibrary.wiley.com/doi/10.1002/pros.20065. 
 
 

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Appendix I 
ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair. 
5 
Dead 
*As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: 
Toxicity and Response Criteria of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-
655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the 
scale, please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis, 
M.D., Group Chair. 
From http://www.ecog.org/general/perf_stat.html 
 

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Appendix II 
Patient Questionnaire Booklets 
Patient booklets and related documents are posted separately as required by the Mayo Clinic IRB. 
There are two booklets each with a separate set of questions 
Both booklets are completed at the same timepoints: Baseline, End of Every 4th Cycle, End of 
treatment 
1. NCI PRO-CTCAE Questionnaire (11 questions):  
2. FACT-P Version 4 (39 questions):  
 

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Appendix III MC210504 Patient Medication Diary 
NOTE: Patient medication diary will be provided separately and must be approved by the IRB prior to 
use with a patient. 
 

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Appendix IV Guidelines for Contraception 
Your study doctor will discuss prohibited and acceptable birth control methods for use during your 
participation in this study. 
You should notify your study doctor if birth control methods other than those specified below are 
started during the course of this study or if you start any prescription drug or other medication 
(including herbal and over-the-counter medications) not prescribed by the study doctor.  
One of the two forms of birth control must be highly effective, and the second method may also be 
highly effective or selected from the list of other contraceptive methods.  
Highly 
Effective 
Methods of 
Contraception 
Progestogen only hormonal contraception associated with inhibition of 
ovulation (oral, injectable, or implantable) 
Hormonal methods of contraception including 
• 
combined oral contraceptive pills (that is, those that contain 
both estrogen and progestogen) 
• 
vaginal ring 
• 
injectables, implants and intrauterine devices (IUDs) 
Sometimes, hormonal levels of birth control can be affected by the 
study drug. Your doctor will tell you whether hormonal forms of birth 
control are allowed for this study. 
Non-hormonal IUDs 
Bilateral tubal occlusion 
Vasectomized partner 
Complete abstinence 
Less than 
Highly 
Effective 
Methods of 
Contraception 
Diaphragm with spermicide 
Cervical cap with spermicide 
Vaginal sponge with spermicide 
Progestin only pills 
Male condoms with or without 
spermicide* 
*A male and a female condom 
must not be used together 
Female Condoms* 
 
Unacceptable 
Methods of 
Contraception 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
Withdrawal (coitus interruptus) 
Spermicide only 
Lactation amenorrhea method (LAM) 
If you choose abstinence as a method of contraception, your doctor will discuss other methods of 
contraception with you in the case you choose not to continue abstinence.   
 

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Appendix V 
Genentech Safety Reporting Fax Cover Sheet 
 
 
SAFETY REPORTING FAX COVER SHEET  
 
Genentech Supported Research 
 
AE / SAE FAX No: (650) 238-6067 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
 
Subject Initials 
 
(Enter a dash if patient has no middle
name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Patient Safety: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET