A Phase 1b Study of Talimogene Laherparepvec in Combination With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal Cancer With Liver Metastases
Phase: PHASE1
Conditions: Metastatic Triple Negative Breast Cancer, Metastatic Colorectal Cancer
Sponsor: Amgen

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  08 July 2019 
Page 1 of 139 
CONFIDENTIAL 
 
Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination With 
Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal 
Cancer With Liver Metastases  
Amgen Protocol Number (Talimogene Laherparepvec):  20140299 
EudraCT number:  2015-005480-16 
NCT number:  03256344 
Clinical Study Sponsor: 
Amgen Inc. 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone:  +1-805-447-1000 
Key Sponsor Contact(s): 
, MD, PhD 
Clinical Research Medical Director 
One Amgen Center Drive 
Thousand Oaks, CA 91320-1799 
Telephone: 
Email: 
 
Date: 
26 January 2016 
Amendment 1: 
04 November 2016 
Amendment 2: 
21 February 2017 
Amendment 3: 
25 September 2017 
Superseding Amendment 3 
05 December 2017 
Amendment 4 
26 March 2018 
Amendment 5 
08 July 2019 
Confidentiality Notice 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics committee/institutional 
scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of 
Amgen Inc. 
If you have questions regarding how this document may be used or shared, call the 
Amgen Medical Information number:  US sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; for all other countries, 1-805-447-1000.  
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  08 July 2019 
Page 2 of 139 
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Investigator’s Agreement 
I have read the attached protocol entitled:  A Phase 1b Study of Talimogene 
Laherparepvec in Combination With Atezolizumab in Subjects With Triple Negative 
Breast Cancer and Colorectal Cancer With Liver Metastases, dated 08 July 2019, and 
agree to abide by all provisions set forth therein.   
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) and applicable national or regional 
regulations/guidelines.  
I agree to ensure that Financial Disclosure Statements will be completed by: 
 
me (including, if applicable, my spouse [or legal partner] and dependent 
children) 
 
my subinvestigators (including, if applicable, their spouses [or legal partners] 
and dependent children) 
at the start of the study and for up to one year after the study is completed, if there are 
changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc.  
 
 
 
Signature 
 
 
Name of Investigator 
 
Date (DD Month YYYY) 
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  08 July 2019 
Page 3 of 139 
CONFIDENTIAL 
 
Protocol Synopsis 
Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination With Atezolizumab in 
Subjects With Triple Negative Breast Cancer and Colorectal Cancer With Liver Metastases  
Study Phase:  Phase 1b 
Indication:  Triple negative breast cancer and colorectal cancer with liver metastases  
Primary Objective:   
To evaluate the safety, as assessed by incidence of dose limiting toxicities (DLTs), of intrahepatic 
injection of talimogene laherparepvec into liver metastases in combination with intravenously 
administered atezolizumab separately in subjects with triple negative breast cancer and colorectal 
cancer  
Secondary Objectives:   
To evaluate the efficacy of talimogene laherparepvec in combination with atezolizumab 
separately in subjects with triple negative breast cancer and colorectal cancer with liver 
metastases as assessed by: 
 
Objective response rate (ORR), best overall response (BOR), duration of response (DOR), 
lesion level responses in injected and uninjected tumor lesions (overall, hepatic, nonhepatic) 
disease control rate (DCR), durable response rate (DRR), progression-free survival (PFS), 
overall survival (OS) by cohort (triple negative breast cancer and colorectal cancer)  
Safety Objective: 
 
To evaluate the safety and tolerability of intrahepatic injection of talimogene laherparepvec 
into liver metastases in combination with intravenously administered atezolizumab separately 
in subjects with triple negative breast cancer and colorectal cancer  
Hypotheses: 
It is hypothesized that intrahepatic injection of talimogene laherparepvec in combination with 
intravenously administered atezolizumab in subjects with triple negative breast cancer and 
colorectal cancer with liver metastases will be safe and well tolerated with a DLT rate ≤ 10%.  
Primary Endpoint:   
 
Subject incidence of DLTs by cohort (triple negative breast cancer and colorectal cancer) 
Secondary Endpoints:  
 
ORR, BOR, DOR, lesion level responses (≥ 30% and 100% decrease) in injected and 
uninjected tumor lesions (overall, hepatic, nonhepatic), DRR, DCR, PFS, and OS by cohort 
(triple negative breast cancer and colorectal cancer) 
Safety Endpoint: 
 
Subject incidence of adverse events and clinically relevant laboratory abnormalities by 
tumor type (triple negative breast cancer and colorectal cancer) 
Study Design:  This is a phase 1b, multicenter, open-label study to evaluate the safety of 
intrahepatic injection of talimogene laherparepvec in combination with intravenously administered 
atezolizumab in subjects with triple negative breast cancer and colorectal cancer with liver 
metastases.  Talimogene laherparepvec will be injected intrahepatically in combination with 
intravenous atezolizumab to approximately 36 DLT-evaluable subjects in 2 parallel cohorts.  
Cohort 1 will comprise subjects with triple negative breast cancer with liver metastases 
(n =18 DLT-evaluable subjects).  Cohort 2 will comprise subjects with colorectal cancer with 
unresectable liver metastases (n =18 DLT-evaluable subjects).  The DLT evaluation period for a 
given subject will consist of the period between the initial 106 PFU/mL dose of talimogene 
laherparepvec and atezolizumab and 3 weeks following the initial 108 PFU/mL dose of talimogene 
laherparepvec and atezolizumab or the start of cycle 3, whichever occurs first.  DLTs will be 
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  08 July 2019 
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evaluated based on the first 18 DLT-evaluable subjects in each cohort separately.  A Dose Level 
Review Team (DLRT) will review the safety data to evaluate possible drug effects and DLT.  To 
be evaluable for a DLT, subjects must have had the opportunity to be on treatment for at least 
2 cycles from the initial dose of study treatment and have received at least 2 doses of talimogene 
laherparepvec and 2 doses of atezolizumab in combination, or have a DLT during the DLT 
evaluation period.  Subjects may be replaced if they are not evaluable for DLT in order to obtain 
18 DLT-evaluable subjects.  There will be a safety interim analysis after the first 4 to 
6 DLT-evaluable subjects have been enrolled in this study and a safety analysis after 
18 DLT-evaluable subjects have been enrolled in a cohort.  Enrollment will be suspended during 
the first safety interim analysis.  At the discretion of the DLRT, additional safety analyses may be 
conducted as warranted.  Treatment will continue until a subject experiences a DLT (during the 
DLT evaluation period), has complete response (CR), has need for an alternative anticancer 
therapy, or experiences an adverse event necessitating drug discontinuation.  In addition, 
treatment will be discontinued for talimogene laherparepvec if the subject has no injectable 
lesions, upon confirmed progressive disease (PD) per modified immune related response criteria 
Response Evaluation Criteria in Solid Tumors (irRC-RECIST) or rapid clinical deterioration.  
Atezolizumab will be discontinued upon symptomatic disease progression.  All subjects will 
complete a safety follow-up visit approximately 30 (+ 7) days after the last dose of study 
treatment.  After the safety follow-up visit, all subjects will enter the long-term follow-up.  Subjects 
will be followed for survival, subsequent anticancer therapies and treatment-related adverse 
events every 12 weeks (± 28 days) for approximately 24 months after the last subject is enrolled.  
Sample Size:  Approximately 36 subjects will be enrolled (18 DLT-evaluable subjects in each 
cohort). 
Summary of Subject Eligibility Criteria:  To be eligible for the study subjects must be age 
≥ 18 years and have a diagnosis of triple negative breast cancer or colorectal cancer with liver 
metastases.  Subjects must have disease progression during or after ≥ 1 prior standard of care 
systemic anti-cancer therapy for metastatic disease.  Subjects must have measurable liver 
lesions that are suitable for injection.  Subjects must have Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 or 1, adequate organ function and life expectancy ≥ 5 months.  
Female subjects of childbearing potential must have a negative serum pregnancy test.  Subjects 
will be excluded if they are candidates for hepatic surgery or locoregional therapy of liver 
metastases with curative intent, or if more than one-third of the liver is estimated to be involved 
with metastases or if they have macroscopic intravascular invasion into the main portal vein, 
hepatic vein, or vena cava.  Subjects will not be eligible if they are receiving or have received liver 
metastatic-directed therapy (eg, radiation, ablation, embolization), hepatic surgery, 
antibody-based therapy, or immunotherapy < 4 weeks prior to enrollment.  Subjects with a history 
of malignancy (other than the current malignancy) within the past 5 years will be excluded with 
some exceptions.  Subjects with active or untreated central nervous system (CNS) metastases, 
presence of leptomeningeal disease or spinal cord compression will be excluded.  Subjects with 
symptomatic autoimmune disease or who are immunosuppressed will be excluded.  Subjects with 
active herpetic skin lesions or prior complications of herpetic infection (eg, herpetic keratitis or 
encephalitis), or who require intermittent and chronic systemic treatment with an antiherpetic drug 
(other than intermittent topical use), will not be eligible for the study.  Subjects receiving 
concomitant treatment with warfarin are not eligible for the study. 
For a full list of eligibility criteria, please refer to Section 4.1 and 4.2. 
Investigational Products 
Amgen Investigational Product Dosage and Administration:  Talimogene laherparepvec will 
be manufactured and packaged by Amgen Inc.  Talimogene laherparepvec is supplied as a 
sterile frozen liquid in a single-use vial.  Each vial contains a minimum of 1.0 mL talimogene 
laherparepvec at either 106 plaque-forming unit (PFU)/mL or 108 PFU/mL concentrations.  The 
first cycle of talimogene laherparepvec will be 21 (+ 3) days.  Subsequent cycles of talimogene 
laherparepvec will be 21 days.  On cycle 1, day 1, the first dose of talimogene laherparepvec will 
be up to 4.0 mL of 106 PFU/mL.  During the second cycle, talimogene laherparepvec will be 
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Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  08 July 2019 
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administered up to 4.0 mL of 108 PFU/mL at week 4 of the study (± 3 days).  During subsequent 
cycles, talimogene laherparepvec will be administered up to 4.0 mL of 108 PFU/mL every 21 days 
(± 3 days) thereafter.  The maximum volume of talimogene laherparepvec to be administered at 
any dose is 4.0 mL for any individual tumor lesion or for all tumor lesions combined.  Talimogene 
laherparepvec will be administered by image guided injection (either ultrasound or computerized 
tomography [CT]) into injectable liver lesions.  After 6 cycles of intrahepatic talimogene 
laherparepvec are administered, there is an investigator option to continue talimogene 
laherparepvec injections for up to an additional 6 cycles (for a maximum of 12 total cycles of 
talimogene laherparepvec).  During this additional dosing period (cycles 7 to 12), talimogene 
laherparepvec may be administered by intralesional injection to liver metastases or cutaneous, 
subcutaneous, and nodal tumor lesions, or both.  For cycles 7 to 12, liver lesions do not need to 
be prioritized.  Refer to Section 6.2.1. 
Non-Amgen Investigational Product Dosage and Administration:  Atezolizumab will be 
manufactured by Genentech.  Atezolizumab is supplied as a single-use, 20-cc Pharmacopeia 
(USP)/European Pharmacopoeia (Ph. Eur.) type 1 glass vial as a colorless-to-slightly-yellow, 
sterile, preservative-free clear liquid solution intended for intravenous administration.  The vial is 
designed to deliver 20 mL (1200 mg) of atezolizumab solution but may contain more than the 
stated volume to enable delivery of the entire 20 mL volume.  The first cycle of atezolizumab will 
be 21 (+ 3) days.  Subsequent cycles of atezolizumab will be 21 (± 3) days.  Atezolizumab will be 
administered intravenously at a dose of 1200 mg.  Administration of atezolizumab will be 
performed in a setting with emergency medical facilities and staff who are trained to monitor for 
and respond to medical emergencies.  The initial dose of atezolizumab (day 1, cycle 1) will be 
delivered over 60 (± 15) minutes.  If the first infusion is tolerated without infusion-associated 
adverse events, the second infusion may be delivered over 30 (± 10) minutes.  If the 30-minute 
infusion is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes.  The 
subject’s vital signs should be determined up to 60 minutes before each atezolizumab infusion.  
Vital signs should also be obtained during or after the atezolizumab infusion if clinically indicated.  
Refer to Section 6.2.2. 
Procedures:  Written informed consent must be obtained from all subjects or legally acceptable 
representatives before any study specific screening procedures are performed.  The following 
procedures will occur per the Schedule of Assessments:  medical history, concomitant therapies, 
physical examination and vital signs, body weight, ECOG performance status, 12-lead 
electrocardiogram (ECG), recording of concomitant medications, survival assessment, review of 
adverse events, disease related events (serious or non-serious) and serious adverse events as 
well as reporting of potential or known unintended exposure to talimogene laherparepvec by a 
household member, caregiver, or healthcare provider.  Blood will be collected for local laboratory 
testing including:  urinalysis, chemistry, hematology, coagulation, thyroid function, hepatitis B 
surface antigen, hepatitis B core antibody, hepatitis C virus antibody and human 
immunodeficiency virus (HIV).  Tumor markers in the blood will be collected in subjects with triple 
negative breast cancer (cancer antigen 27.29 [CA 27.29], cancer antigen 15-3 [CA 15-3]) and 
subjects with colorectal cancer (carcinoembryonic antigen [CEA] and CA-19-9).  In females of 
childbearing potential serum pregnancy tests will be performed locally.  Central laboratory testing 
will include blood for herpes simplex virus type 1 (HSV-1) serostatus, and blood for biomarker 
analysis.  Liver tumor biopsies and clinical and radiological tumor assessments will also be 
performed. 
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments (Table 7-1).   
Statistical Considerations:   
The null hypothesis (H0) is that the combination of talimogene laherparepvec and atezolizumab 
has a DLT rate ≤ 10%.  An unacceptable alternative hypothesis (Ha) is a true DLT rate ≥ 33%.  
The sample size goal is to have ≥ 80% power for a 1-sided ≤ 10% significance level test to reject 
H0 when Ha is true (Goldman, 1987).  Eighteen DLT-evaluable subjects in each cohort will be 
required to test H0.  Assuming the incidence of DLTs is evaluated as specified by Table 3-1 in 
Section 3.1, this design achieves a 7.7% 1-sided significance level and 81.6% power.  The data 
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Date:  08 July 2019 
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will be analyzed by cohort.  In addition, a summary of the incidence of DLTs and descriptive 
statistics for demographic, safety, efficacy, and biomarkers will be provided as appropriate.  The 
DLT analysis set will be used to summarize the subject incidence of DLTs as defined in 
Section 6.2.1.2.  The safety analysis set will be used for all safety analyses.  The safety analyses 
include incidence of treatment-emergent and treatment-related adverse events (all adverse 
events, ≥ grade 3 adverse events, serious adverse events, fatal adverse events and adverse 
events defined as events of interest).  The efficacy analysis will be conducted using the safety 
analysis set unless otherwise specified.  ORR, BOR, DRR, and DCR will be summarized with the 
associated 95% confidence interval (CIs).  DOR, PFS, and OS will be summarized and estimated 
using the Kaplan-Meier method.  Interim safety analyses will be performed for evaluation of DLTs 
for DLRT meetings.  All available safety data will be considered at interim safety analysis.  For a 
full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc.   
Data Element Standards 
Version(s)/Date(s):  
 
5/20 March 2015 
Approved 
 
 

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Date:  08 July 2019 
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Study Design and Treatment Schema 
 
Footnotes defined on next page 
Screening (up to 4 weeks)
Cohort 1: Triple Negative Breast Cancer  a, b, c
Talimogene laherparepvec (106 PFU/mL at  day 1 [cycle 1]  and 108 PFU/mL every 21 days 
thereafter (cycle 2 and beyond) + Atezolizumab (1200 mg at day 1 (cycle 1) and then every 21 
days thereafter (cycle 2 and beyond) 
N = 18
Cohort 2: Colorectal Cancer a, b, c
Talimogene laherparepvec (106 PFU/mL at  day 1 [cycle 1]  and 108 PFU/mL every 21 days 
thereafter (cycle 2 and beyond) + Atezolizumab (1200 mg at day 1 (cycle 1) and then every 21 
days thereafter (cycle 2 and beyond) 
N = 18
Enrollment
Safety Follow-up
Long Term  Follow-up
Enrollment
 
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PFU= plaque-forming unit 
a Enrollment of cohort 1 and 2 will begin simultaneously.  The DLT evaluation period for a given subject will consist of the period between the initial 106 PFU/mL dose of 
talimogene laherparepvec and atezolizumab and 3 weeks following the initial 108 PFU/mL dose of talimogene laherparepvec and atezolizumab or the start of cycle 3, 
whichever occurs first.  DLTs will be evaluated based on the first 18 DLT-evaluable subjects in each cohort separately.  A Dose Level Review Team (DLRT) will 
review the safety data to evaluate possible drug effects and DLT.  To be evaluable for a DLT, subjects must have had the opportunity to be on treatment for at least 2 
cycles from the initial dose of study treatments and have received at least 2 doses of talimogene laherparepvec and two doses of atezolizumab in combination, or 
have a DLT during the DLT evaluation period.  For additional details see Section 3.1. 
b.Injection of non-hepatic lesions (nodal, cutaneous, or subcutaneous metastases) is permitted after the first tumor assessment (3 cycles) if volume remains after 
injecting liver lesions.  After the initial 6 intra-hepatic cycles, there is an option to continue treatment with talimogene laherparepvec for an additional 6 cycles.  During 
this additional dosing period (cycles 7 to 12), talimogene laherparepvec may be administered, by intralesional injection to liver metastases or cutaneous, 
subcutaneous, and nodal tumor lesions, or both.  For cycles 7 to 12, liver lesions do not need to be prioritized.  A maximum of 12 cycles 
of talimogene laherparepvec are allowed during the study.  In the absence of confirmed PD per modified irRC-RECIST, atezolizumab treatment can continue after 
talimogene laherparepvec treatment has ended provided patient is tolerating atezolizumab and receiving clinical benefit in the opinion of the investigator. 
c Treatment will continue until a subject experiences a DLT (during the DLT evaluation period), has CR, has need for an alternative anticancer therapy or experiences 
an adverse event necessitating drug discontinuation.  In addition, treatment will be discontinued for talimogene laherparepvec if the subject has no injectable tumor 
lesions or upon confirmed PD per modified irRC-RECIST or rapid clinical deterioration.  Atezolizumab will be discontinued upon symptomatic disease progression.  
 
 
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Study Glossary 
Abbreviation or Term Definition/Explanation 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AST  
aspartate aminotransferase   
ATA 
anti-atezolizumab antibodies 
BOR 
best overall response 
CA 19-9 
cancer antigen 19-9 
CA 27.29 
cancer antigen 27.29 
CEA 
carcinoembryonic antigen 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRF  
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
target trough concentration 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLRT 
Dose Level Review Team 
DLT 
dose limiting toxicity 
dMMR 
mismatch repair deficient 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DRR 
durable response rate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are conducted 
for an individual subject 
End of Study (primary 
completion) 
defined as the date when the last subject is assessed or receives an 
intervention for the final collection of data for the primary endpoint(s), for 
the purpose of conducting the primary analysis, whether the study 
concluded as planned in the protocol or was terminated early. 
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Abbreviation or Term Definition/Explanation 
End of Study (end of 
trial) 
defined as the date when the last subject across all sites is assessed or 
receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow up), 
as applicable.  This will occur when the last subject discontinues 
talimogene laherparepvec or atezolizumab, whichever comes later, and 
has had the opportunity to complete both the safety follow-up and the 
long-term survival follow-up. 
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 
FDA 
Food and Drug Administration 
FOLFIRI 
folinic acid-fluorouracil-irinotecan 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
Heart rate 
number of cardiac cycles per unit of time 
HCC 
hepatocellular carcinoma 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HSV, HSV-1 
herpes simplex virus, herpes simplex virus type-1 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
ICP 
infected cell protein 
Ig 
immunoglobulin 
IT 
intratumorally 
IV 
intravenous 
INR 
international normalization ratio 
IPIM 
Investigational Product Instruction Manual 
IRB/IEC 
institutional review board/independent ethics committee 
irRC-RECIST 
Immune Related Response Criteria simulating Response Evaluation 
Criteria in Solid Tumors  
IxRS 
interactive voice/web response system.  A telecommunication 
technology that is linked to a central computer in real time as an 
interface to collect and process information.   
LDH 
lactate dehydrogenase 
LAG-3 
lymphocyte activation gene-3 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMR 
mismatch repair 
MSI-H 
microsatellite instability-high 
MSS 
microsatellite stable 
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Abbreviation or Term Definition/Explanation 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death 1 
PD-L1 
programmed death ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PFU 
plaque-forming unit 
Ph. Eur. 
European Pharmacopoeia 
PK 
pharmacokinetics 
POR 
Proof of Receipts 
PR 
partial response 
PR Interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
PT 
prothrombin time 
aPTT 
activated partial thromboplastin time 
PTT 
partial thromboplastin time 
qPCR 
real-time polymerase chain reaction 
QRS interval 
QRS interval the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it takes 
for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the Q wave and 
the end of the T wave in the heart's electrical cycle as measured by 
ECG. 
QTc interval 
QT interval corrected for heart rate using accepted methodology  
RANKL 
nuclear factor-kappa B ligand 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
stable disease 
SEERS  
Surveillance, Epidemiology, and End Results  
Source Data 
information from an original record or certified copy of the original record 
containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies).  (ICH Guideline 
[E6]).  Examples of source data include subject identification, 
randomization identification, and stratification value. 
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Abbreviation or Term Definition/Explanation 
Study day 1 
defined as the first day that protocol-specified investigational products 
are administered to the subject 
T3 
triiodothyronine 
T4 
thyroxine 
tk 
thymidine kinase 
TSH 
thyroid stimulating hormone 
TNF 
tumor necrosis factor 
TNF-α 
tumor necrosis factor α 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
white blood cells 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................. 3 
Study Design and Treatment Schema .............................................................................. 7 
Study Glossary .................................................................................................................. 9 
1. 
OBJECTIVES ......................................................................................................... 19 
1.1 
Primary ....................................................................................................... 19 
1.2 
Secondary .................................................................................................. 19 
1.3 
Safety ......................................................................................................... 19 
1.4 
Exploratory ................................................................................................. 19 
2. 
BACKGROUND AND RATIONALE ........................................................................ 19 
2.1 
Disease ....................................................................................................... 19 
2.1.1 
Cancer and Immunotherapy ....................................................... 19 
2.1.2 
Metastatic Triple Negative Breast Cancer .................................. 21 
2.1.2.1 
Immunotherapy in Triple Negative Breast 
Cancer ..................................................................... 22 
2.1.3 
Metastatic Colorectal Cancer ..................................................... 24 
2.1.3.1 
Immunotherapy in Colorectal Cancer ...................... 25 
2.1.4 
Oncolytic Virus Studies With Intrahepatic 
Administration ............................................................................ 26 
2.2 
Amgen Investigational Product Background:  Talimogene 
Laherparepvec ............................................................................................ 27 
2.3 
Non-Amgen Investigational Product Background:  Atezolizumab .............. 32 
2.4 
Rationale .................................................................................................... 33 
2.5 
Clinical Hypotheses .................................................................................... 33 
3. 
EXPERIMENTAL PLAN ......................................................................................... 33 
3.1 
Study Design .............................................................................................. 33 
3.2 
Number of Sites .......................................................................................... 36 
3.3 
Number of Subjects .................................................................................... 36 
3.4 
Replacement of Subjects ............................................................................ 36 
3.5 
Estimated Study Duration ........................................................................... 36 
3.5.1 
Study Duration for Subjects ........................................................ 36 
3.5.2 
End of Study ............................................................................... 36 
4. 
SUBJECT ELIGIBILITY .......................................................................................... 37 
4.1 
Inclusion Criteria ......................................................................................... 37 
4.2 
Exclusion Criteria ........................................................................................ 39 
5. 
SUBJECT ENROLLMENT ..................................................................................... 43 
5.1 
Treatment Assignment ............................................................................... 43 
6. 
TREATMENT PROCEDURES ............................................................................... 44 
6.1 
Classification of Product(s) and/or Medical Device(s) ................................ 44 
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6.2 
Investigational Product ............................................................................... 44 
6.2.1 
Amgen Investigational Product:  Talimogene 
Laherparepvec ........................................................................... 44 
6.2.1.1 
Dosage, Administration, and Schedule .................... 44 
6.2.1.2 
DLT .......................................................................... 48 
6.2.1.3 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 50 
6.2.2 
Non-Amgen Investigational Product:  Atezolizumab .................. 52 
6.2.2.1 
Dosage, Administration, and Schedule .................... 53 
6.2.2.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 53 
6.3 
Other Protocol-required Therapies ............................................................. 54 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ........................................ 55 
6.4.1 
Criteria for Permanent Discontinuation of Talimogene 
Laherparepvec and/or Atezolizumab Due to Potential 
Hepatotoxicity ............................................................................. 58 
6.4.2 
Criteria for Conditional Withholding of Talimogene 
Laherparepvec and/or Atezolizumab Due to Potential 
Hepatotoxicity ............................................................................. 58 
6.4.3 
Criteria for Rechallenge of Talimogene Laherparepvec 
and/or Atezolizumab After Potential Hepatotoxicity ................... 59 
6.5 
Concomitant Therapy ................................................................................. 59 
6.6 
Other Treatment Procedures ...................................................................... 60 
6.7 
Medical Devices ......................................................................................... 61 
6.8 
Product Complaints .................................................................................... 61 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period ................................................................................... 61 
6.10 
Contraceptive Requirements ...................................................................... 62 
6.10.1 
Female Subjects ......................................................................... 63 
6.10.2 
Unacceptable Methods of Birth Control for Female 
Subjects ..................................................................................... 64 
7. 
STUDY PROCEDURES ......................................................................................... 64 
7.1 
Schedule of Assessments .......................................................................... 64 
7.2 
General Study Procedures ......................................................................... 69 
7.2.1 
Screening and Enrollment .......................................................... 69 
7.2.2 
Re-screening .............................................................................. 69 
7.2.3 
Treatment ................................................................................... 69 
7.2.4 
Follow-up .................................................................................... 70 
7.2.4.1 
Safety Follow-up ...................................................... 70 
7.2.4.2 
Long-Term Follow-up ............................................... 70 
7.3 
Description of Study Procedures ................................................................ 70 
7.3.1 
Informed Consent ....................................................................... 71 
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7.3.2 
Demographic Data ...................................................................... 71 
7.3.3 
Medical History ........................................................................... 71 
7.3.4 
Prior Therapies ........................................................................... 71 
7.3.5 
Concomitant Therapy ................................................................. 71 
7.3.6 
Adverse Events, Disease Related Events and Serious 
Adverse Events .......................................................................... 72 
7.3.7 
Physical Examination ................................................................. 72 
7.3.8 
Vital Signs ................................................................................... 72 
7.3.9 
Physical Measurements ............................................................. 72 
7.3.10 
ECG ............................................................................................ 72 
7.3.11 
ECOG ......................................................................................... 73 
7.3.12 
Reporting of Exposure to Talimogene Laherparepvec ............... 73 
7.3.13 
Tumor Assessments ................................................................... 73 
7.3.13.1 
Clinical Tumor Assessments .................................... 73 
7.3.13.2 
Radiographic Tumor Assessment ............................ 73 
7.4 
Laboratory Assessments ............................................................................ 74 
7.4.1 
qPCR for Talimogene Laherparepvec ........................................ 75 
7.5 
Biomarker Development ............................................................................. 76 
7.5.1 
Blood Samples ........................................................................... 76 
7.5.2 
Archival Tumor Samples ............................................................ 76 
7.5.3 
Liver Tumor Biopsies .................................................................. 76 
7.6 
Pharmacogenetic Studies ........................................................................... 77 
7.7 
Sample Storage and Destruction ................................................................ 77 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 78 
8.1 
Subjects’ Decision to Withdraw .................................................................. 78 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 79 
8.3 
Reasons for Removal From Treatment or Study ........................................ 79 
8.3.1 
Reasons for Removal From Treatment ...................................... 79 
8.3.2 
Reasons for Removal From Study ............................................. 80 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 80 
9.1 
Definition of Safety Events ......................................................................... 80 
9.1.1 
Disease Related Events ............................................................. 80 
9.1.2 
Adverse Events .......................................................................... 81 
9.1.3 
Serious Adverse Events ............................................................. 81 
9.1.4 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ........................................................ 82 
9.2 
Safety Event Reporting Procedures ........................................................... 83 
9.2.1 
Reporting Procedures for Disease Related Events .................... 83 
9.2.2 
Adverse Events .......................................................................... 84 
9.2.2.1 
Reporting Procedures for Adverse Events 
That Do Not Meet Serious Criteria ........................... 84 
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9.2.2.2 
Reporting Procedures for Serious Adverse 
Events and Adverse Events of Special 
Interest ..................................................................... 85 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 86 
9.3 
Pregnancy and Lactation Reporting ........................................................... 87 
9.4 
Reporting of Exposure to Talimogene Laherparepvec ............................... 88 
10. 
STATISTICAL CONSIDERATIONS ....................................................................... 88 
10.1 
Study Endpoints, Analysis Sets, and Covariates ........................................ 88 
10.1.1 
Study Endpoints ......................................................................... 88 
10.1.1.1 
Primary Endpoints .................................................... 88 
10.1.1.2 
Secondary Endpoints ............................................... 88 
10.1.1.3 
Safety Endpoint ........................................................ 88 
10.1.1.4 
Exploratory Endpoints .............................................. 88 
10.1.2 
Analysis Sets .............................................................................. 89 
10.1.2.1 
DLT Analysis Set ..................................................... 89 
10.1.2.2 
Safety Analysis Set .................................................. 89 
10.1.2.3 
Biomarker Analysis Sets .......................................... 89 
10.1.3 
Covariates and Subgroups ......................................................... 89 
10.2 
Sample Size Considerations ...................................................................... 90 
10.3 
Planned Analyses ....................................................................................... 90 
10.3.1 
Interim Analyses ......................................................................... 90 
10.3.2 
Dose Level Review Team ........................................................... 90 
10.3.3 
Primary Analysis ......................................................................... 91 
10.3.4 
Final Analysis ............................................................................. 91 
10.4 
Planned Methods of Analysis ..................................................................... 91 
10.4.1 
General Considerations .............................................................. 91 
10.4.2 
Primary Endpoint ........................................................................ 91 
10.4.3 
Efficacy Endpoints ...................................................................... 91 
10.4.4 
Safety Endpoints ........................................................................ 92 
11. 
REGULATORY OBLIGATIONS ............................................................................. 92 
11.1 
Informed Consent ....................................................................................... 92 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 93 
11.3 
Subject Confidentiality ................................................................................ 94 
11.4 
Investigator Signatory Obligations .............................................................. 94 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................... 95 
12.1 
Protocol Amendments and Study Termination ........................................... 95 
12.2 
Study Documentation and Archive ............................................................. 95 
12.3 
Study Monitoring and Data Collection ........................................................ 96 
12.4 
Investigator Responsibilities for Data Collection ........................................ 97 
12.5 
Language.................................................................................................... 97 
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12.6 
Publication Policy ....................................................................................... 97 
12.7 
Compensation ............................................................................................ 98 
13. 
REFERENCES ....................................................................................................... 99 
14. 
APPENDICES ...................................................................................................... 103 
List of Tables 
Table 3-1.  Cumulative Increments of DLT-evaluable Subjects and 
Corresponding Acceptable Maximum Number and Percentage 
of DLTs at Each Interim Safety Analysis .................................................. 35 
Table 6-1.  Talimogene Laherparepvec Injection Volume Guideline............................... 45 
Table 6-2.  Talimogene Laherparepvec Injection Volume Guideline Based on 
Tumor Size for Cutaneous, Subcutaneous, and Nodal Lesions .............. 46 
Table 6-3.  Guidelines for Management of Hepatic Events for Talimogene 
Laherparepvec and Atezolizumab ........................................................... 56 
Table 7-1.  Schedule of Assessments ............................................................................. 65 
Table 7-2.  Laboratory Analytes ...................................................................................... 75 
Table 14-1.  Definition of Measurable Tumor Response (Baseline Target and 
New, Measurable Lesions) .................................................................... 116 
Table 14-2.  Matrix for Determining the Overall Response at Each 
Assessment Point .................................................................................. 117 
Table 14-3.  Quantitative/Qualitative Reporting of Fully Resected Lymph 
Nodes ..................................................................................................... 119 
Table 14-4.  Management Guidelines for Pulmonary Events, Including 
Pneumonitis ........................................................................................... 123 
Table 14-5.  Management Guidelines for Hepatic Events ............................................. 124 
Table 14-6.  Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) .................................................................................................... 125 
Table 14-7.  Management Guidelines for Endocrine Events ......................................... 126 
Table 14-8.  Management Guidelines for Ocular Events .............................................. 129 
Table 14-9.  Management Guidelines for Immune-Related Myocarditis ....................... 130 
Table 14-10.  Management Guidelines for Infusion-Related Reactions ........................ 131 
Table 14-11.  Management Guidelines for Pancreatic Events, Including 
Pancreatitis ............................................................................................ 132 
Table 14-12.  Management Guidelines for Dermatologic Events .................................. 134 
Table 14-13.  Management Guidelines for Neurologic Disorders ................................. 135 
Table 14-14.  Management Guidelines for Immune-Related 
Meningoencephalitis .............................................................................. 136 
Table 14-15.  Management Guidelines for Renal Events .............................................. 137 
Table 14-16.  Management Guidelines for Immune-Mediated Myositis ........................ 138 
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List of Appendices 
Appendix A.  Additional Safety Assessment Information .............................................. 104 
Appendix B.  Sample Serious Adverse Event Report Form .......................................... 106 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................. 109 
Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response ............................................................................................... 111 
Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status ..................................................................................................... 121 
Appendix F.  Dose Medication Guidelines for Atezolizumab Related Adverse 
Events .................................................................................................... 122 
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1. 
OBJECTIVES 
1.1 
Primary 
To evaluate the safety, as assessed by incidence of dose limiting toxicities (DLTs), of 
intrahepatic injection of talimogene laherparepvec into liver metastases in combination 
with intravenously administered atezolizumab separately in subjects with triple negative 
breast cancer and colorectal cancer  
1.2 
Secondary 
To evaluate the efficacy of talimogene laherparepvec in combination with atezolizumab 
separately in subjects with metastatic triple negative breast cancer and metastatic 
colorectal cancer with liver metastases assessed by: 
 
objective response rate (ORR), best overall response (BOR) , duration of response 
(DOR), lesion level responses in injected and uninjected lesions (overall, hepatic, 
nonhepatic) disease control rate (DCR) , durable response rate (DRR), 
progression-free survival (PFS), overall survival (OS) by cohort (triple negative 
breast cancer and colorectal cancer) 
1.3 
Safety 
To evaluate the safety and tolerability of intrahepatic injection of talimogene 
laherparepvec into liver metastases in combination with intravenously administered 
atezolizumab separately in subjects with triple negative breast cancer and colorectal 
cancer 
1.4 
Exploratory 
The exploratory objectives of the study are as follows: 
- 
To evaluate changes in tumor inflammation markers in tumor biopsies,  such as 
programmed cell death ligand 1 (PD-L1) expression and  cluster of differentiation 
8 (CD8) density 
- 
To explore blood and tissue biomarkers that may correlate with or predict 
treatment effect and/or clinical outcomes separately in subjects in triple negative 
breast cancer and metastatic colorectal cancer. 
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
2.1.1 
Cancer and Immunotherapy 
Clinical study data have shown that immune therapies are valid approaches in cancer 
therapy.  Immune checkpoint blocking monoclonal antibodies can provide durable 
responses and improve OS in cancer patients (Hodi et al, 2010; Garon et al, 2014). 
Tumor-specific mutations may be an important stimulus of responsiveness to 
immune-based therapies and are currently being evaluated in different tumor types.  
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Human cancer cells are characterized by a multitude of genetic aberrations 
(Alexandrov et al, 2013; Lawrence et al, 2013), many of which may be associated with 
immunogenicity by presenting novel epitopes for immune-cell recognition 
(Segal et al, 2008).  The immune response, largely mediated by tumor-reactive T cells, 
can be rapid, durable, and adaptable.  A recent study demonstrated that novel epitopes 
generated from missense mutations may be the target of tumor-reactive T cells and may 
mediate response to T cell checkpoint inhibitors (van Rooij et al, 2013).  Moreover, the 
durable responses observed in a subset of patients long after completion of therapy 
suggest the generation of T cell memory, which has been associated with improved 
overall survival in cancer patients (Pages et al, 2005; Kilinc et al, 2009). 
The immune system recognizes and is poised to eliminate cancer but is held in check by 
inhibitory receptors and their ligands.  These immune checkpoint pathways, which 
normally maintain self-tolerance and limit collateral tissue damage during anti-microbial 
immune responses, can be co-opted by cancer cells to evade immune destruction 
(Topalian et al, 2012).  Monoclonal antibodies have been developed that will block 
specific immune checkpoint proteins and unleash anti-tumor activity.  Available approved 
immune checkpoint inhibitors include ipilimumab, nivolumab, pembrolizumab, and 
atezolizumab.  Ipilimumab blocks cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
thereby prolonging T cell activation, restoring T cell proliferation, and amplifying 
T cell-mediated immunity.  Nivolumab and pembrolizumab are antibodies that will block 
programmed cell death 1 (PD-1) on the surface of the T cells preventing them from 
interacting with PD-L1.  Atezolizumab blocks PD-L1.  Immune-based therapies are only 
effective in a proportion of patients with cancer, and combination approaches are being 
explored to improve therapeutic efficacy.   
PD-1 is an inhibitory receptor expressed on T cells following T cell activation, which is 
sustained in states of chronic stimulation such as in chronic infection or cancer 
(Blank et al, 2005; Keir et al, 2008).  Ligation of PD-L1 with PD-1 inhibits T cell 
proliferation, cytokine production, and cytolytic activity, leading to the functional 
inactivation of T cell responses.  Aberrant expression of PD-L1 on tumor cells has been 
reported to impede anti-tumor immunity, resulting in immune evasion 
(Blank and Mackensen, 2007).  Therefore, interruption of the PD-L1/PD-1 pathway 
represents an attractive strategy to reinvigorate tumor-specific T cell immunity. 
PD-L1 expression is prevalent in many human tumors, and elevated PD-L1 expression 
is associated with a poor prognosis in patients with non–small cell lung cancer 
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(Mu et al, 2011) and other solid tumors (Hino et al, 2010; Hamanishi et al, 2007; 
Thompson et al, 2006).   
The field of cancer immunotherapy is expanding beyond checkpoint inhibition to include 
such categories as T cell growth factors/stimulators, cancer vaccines, inhibitors of 
cancer cell and immune cell suppression, dendritic cell growth factors and activators.  
Oncolytic immunotherapy is an emerging treatment modality which uses replication 
competent oncolytic viruses that will selectively infect and damage cancerous tissues 
without causing harm to normal tissues.  Each oncolytic virus has a specific cellular 
tropism that determines which tissues are preferentially infected and genetic engineering 
can be used to make them cancer specific while rendering them nonpathogenic to 
normal host cells (Russell et al, 2014).  Ongoing studies are using a variety of 
engineered viruses, including but not limited to herpes simplex virus (HSV), vaccinia, 
and reovirus.  
2.1.2 
Metastatic Triple Negative Breast Cancer   
The incidence rate of breast cancer varies worldwide and the mortality rate is between 
10 and 20 per 100,000 women across most global regions (Youlden et al, 2012).  
Annually in the United States, approximately 232,000 women are diagnosed with and 
40,290 women die from breast cancer according to the Surveillance, Epidemiology, and 
End Results (SEER) Program.  Triple negative tumors account for about 15% of all 
invasive breast cancers (Foulkes et al, 2010).  Among metastatic triple negative cases, 
the first distant site is lung (40%), brain (30%), liver (20%), and bone (10%) 
(Foulkes et al, 2010).  With subsequent metastases, the liver will be diagnosed as a 
metastatic site in up to 50% of women with metastatic triple negative breast cancer 
(Lin et al, 2008).  The estimated 5-year survival rate for metastatic triple negative breast 
cancer is approximately 22% according to the SEER database.  Incidence of triple 
negative breast cancer is increased in patients with germline breast cancer susceptibility 
gene 1 (BRCA1) mutations and African ancestry.  Triple negative breast cancers are 
generally, aggressive tumors with a high rate of distant metastases and worse 
disease-specific survival than other breast cancer subtypes (Dent et al, 2007; 
Haffty et al, 2006).  Tumors with the triple negative phenotype have specific features that 
are potential therapeutic targets (eg, they show an impaired deoxyribonucleic acid (DNA) 
repair mechanism and increased expression of basal-associated and proliferation 
associated markers).  Currently, the main treatment modality used is chemotherapy but 
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other targets are currently being investigated including the DNA repair pathway, 
angiogenesis and epidermal growth factor receptor (Rakha et al, 2011).  
There is significant heterogeneity within triple negative breast cancer.  A study analyzing 
gene expression profiling identified 6 subtypes, one of which was an immunomodulatory 
subtype enriched for genes involved in immune cell processes including immune cell 
signaling, cytokine signaling, antigen processing and presentation, and signaling through 
core immune signal transduction pathways (Lehmann et al, 2011).  In addition, the 
clinical importance of tumor immune infiltrates has been an emerging area of research in 
triple negative breast cancer, where an increased number of immune infiltrates seems to 
predict both response to chemotherapy and improved survival in the neoadjuvant setting 
and is a prognostic factor in the adjuvant setting (Adams et al, 2014; Dieci et al, 2014, 
Ono et al, 2012).  
2.1.2.1 
Immunotherapy in Triple Negative Breast Cancer 
Clinical studies in breast cancer to date have focused on countering immune 
suppression by targeting the lymphocyte activation gene-3 (LAG-3), CTLA-4 or PD-L1 
pathways.  PD-L1 is expressed in approximately 20% of patients with triple negative 
breast cancer and treatment with anti PD-1 and anti PD-L1 agents (eg, pembrolizumab, 
atezolizumab, nivolumab) is currently under investigation in several ongoing trials. 
Data indicate that PD-1/PD-L1 pathway blockade has clinical activity in patients with 
metastatic triple negative breast cancer.  Atezolizumab (anti-PD-L1) is being evaluated 
in an ongoing phase 1a study exploring its safety and efficacy, as well as biomarkers of 
response in a variety of cancers.  One expansion cohort has enrolled patients with both 
PD-L1 positive and PD-L1 negative triple negative breast carcinoma 
(Emens et al, 2015).  Tumors were considered to be PD-L1 positive if ≥ 5% of infiltrating 
immune cells stained for PD-L1 expression by immunohistochemistry.  Among 
prescreened patients, 23% were PD-L1 positive at first report.  Enrolled patients were 
heavily treated, with 89% having received more than 4 lines of systemic therapy.  
Atezolizumab was given at 15 or 20 mg/kg of a 1,200 mg flat intravenous dose every 
3 weeks.  Atezolizumab was well tolerated in 54 patients with PD-L1 positive and 
PD-L1 negative disease who were evaluable for safety.  Low-grade adverse events, 
including fatigue, nausea, fever, anorexia, and asthenia, were observed in 63% of 
patients, while 11% of patients experienced grade 3 treatment-related adverse events.  
There was 1 case of grade 4 pneumonitis, and 2 deaths currently assessed as related 
by the investigator are under active investigation.  The ORR for 21 PD-L1 positive 
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patients with metastatic triple negative breast cancer evaluable for efficacy was 19%, 
including 2 CRs and 2 PRs; 3 of 4 of these responses were ongoing at the time of data 
cutoff.  Three additional patients had clinical benefit in the setting of a nonclassical 
response, with durable regression of target lesions, even though new lesions developed.  
Pharmacodynamic changes associated with PD-L1 inhibition included transient 
increases in the number of activated, proliferating CD8+ T cells and increased levels of 
interleukin-18.  After initial evidence of activity in triple negative breast cancer subjects in 
a phase 1/2 study, atezolizumab was evaluated in combination with nab-paclitaxel in a 
randomized phase 3 trial (NCT02425891) of 902 patients with untreated metastatic 
triple negative breast cancer who were randomized 1:1 to atezolizumab plus 
nab-paclitaxel or placebo plus nab-paclitaxel.  Median OS in the atezolizumab plus 
nab-paclitaxel arm was 21.3 months, and in the placebo plus nab-paclitaxel arm 
was 17.6 months (Hazard ratio for death, 0.84; P = 0.08); in patients with PD-L1 
positive tumors, the median OS was 25.0 months for the atezolizumab plus nab-
paclitaxel arm and 15.5 months for the placebo plus nab-paclitaxel arm (Hazard 
ratio 0.62).  The rate of grade 3 or 4 adverse events was 48.7% in the atezolizumab 
plus nab-paclitaxel group and 42.2% in the placebo plus nab-paclitaxel group, with 
the most common being neutropenia, decreased neutrophil count, peripheral 
neuropathy, fatigue, and anemia.  57.3% in the atezolizumab plus nab-paclitaxel 
group and 41.8% in the placebo plus nab-paclitaxel group had an adverse event of 
special interest, suggestive of a potential immune-related etiology.  Grade 3 or 4 
adverse events of special interest occurred in 7.5% in the atezolizumab plus 
nab-paclitaxel group and 4.3% in the placebo plus nab-paclitaxel group.  One 
grade 5 event of special interest (autoimmune hepatitis) occurred in the 
atezolizumab plus nab-paclitaxel group, and one grade 5 event of special interest 
(hepatic failure) occurred in the placebo plus nab-paclitaxel group.  Adverse 
events that led to discontinuation of any agent occurred in 15.9% of subjects who 
received atezolizumab plus nab-paclitaxel, and in 8.2% of subjects who received 
placebo plus nab-paclitaxel.  6.4% discontinued atezolizumab because of adverse 
events, and 1.4% discontinued placebo because of adverse events.  Based on the 
results of this trial, on March 8, 2019, the United States (US) Food and Drug 
Administration (FDA) granted accelerated approval for atezolizumab in 
combination with nab-paclitaxel for initial treatment of adult patients with 
unresectable locally advanced or metastatic triple negative breast cancer whose 
tumors express PD-L1, as determined by an FDA-approved test. 
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Pembrolizumab was evaluated in 32 patients with advanced PD-L1 positive triple 
negative breast carcinoma.  (Nanda et al, 2014).  Of all patients screened, 58% had 
PD-L1 staining in the tumor stroma or in ≥ 1% of tumor cells.  Most patients treated with 
pembrolizumab had received 1 to 3 prior chemotherapy regimens for metastatic disease, 
and 21.9% had received 5 or more.  Patients received pembrolizumab at a dose of 
10 mg/kg intravenously (IV) every 2 weeks.  Adverse events were generally 
manageable, with 5 grade 3/4 toxicities.  There was also 1 treatment-related death due 
to disseminated intravascular coagulation.  The ORR for 27 evaluable patients was 
18.5%, including 1 CR and 2 partial response (PR).  The median time to response was 
18 weeks (range, 7 to 32 weeks), with the median DOR not reached.  The 6-month PFS 
rate was 23.3%. 
Preclinical data with engineered oncolytic viruses have shown efficacy in breast cancer 
tumor models (Cody et al, 2015).  Fourteen patients with breast cancer were treated in 
the first-in-human study with talimogene laherparepvec (Hu et al, 2006).  Overall safety 
and evidence of efficacy (evidenced by tumor necrosis with HSV antigen detection in 
necrotic areas) in biopsy specimens was demonstrated.  Some breast cancer patients 
showed stable disease (SD) in the injected lesions and/or shrinkage of both injected and 
adjacent uninjected tumor lesions.  Additionally, the oncolytic herpes simplex virus 
type 1 (HSV-1) mutant (HF10) has been used in a pilot study involving direct 
intratumoral injection in 6 patients with recurrent breast cancer and was shown to be well 
tolerated (Kimata et al, 2006).  A follow-up study showed histological evidence of viral 
replication and CD8+ lymphocyte infiltration in injected tumors (Sahin et al, 2012).  
A phase 2 study of reolysin for patients with advanced/metastatic breast cancer is 
ongoing (NCT01656538).  
2.1.3 
Metastatic Colorectal Cancer 
Colorectal cancer incidence rates vary worldwide, with rates per 100,000 among males 
ranging from 4 in India to 59 in the Czech Republic (Center et al, 2009).  Annually in the 
United States, approximately 132,700 people are diagnosed with and 49,700 people die 
from colorectal cancer (SEER).  The proportion of patients with synchronous liver 
metastases at initial diagnosis is about 15% and the 5-year cumulative metachronous 
liver metastasis rate has been reported to be 4% for stage I tumors, 13% for stage II, 
and 30% for stage III (Manfredi et al, 2006).  For 3 of 4 cases at diagnosis of liver 
metastasis, the liver is the only metastatic site (Manfredi et al, 2006). 
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Microsatellite instability-high (MSI-H) colorectal cancer comprises approximately 15% of 
sporadic colorectal cancer and most familial colorectal cancer, whereas the remainder 
are microsatellite stable (MSS) (Smyrk et al, 2001).  Cells with abnormal mismatch 
repair function accumulate DNA replication errors.  The high mutational load in MSI-H 
tumors also creates many tumor-specific neoantigens, typically 10 to 50 times those of 
MSS tumors (Llosa et al, 2015).  Llosa and colleagues analyzed surgically resected 
primary sporadic colorectal cancer tissue and found that a subset displayed high 
infiltration of activated CD8+ cytotoxic T lymphocytes as well as activation of additional 
cytokines where nearly all of the tumors of this subset demonstrated microsatellite 
instability.  Compared with MSS tumors, MSI-H tumors highly upregulate expression of 
multiple immune checkpoints, including PD-1 and CTLA-4, PD-L1, LAG-3, and 
indolamine 2, 3-dioxygenase in either tumor infiltrating lymphocytes, stroma or both.  
Because most MSI-H colorectal cancers typically present with lower-stage disease than 
MSS colorectal cancers, the MSI-H subtypes represent only 5% to 6% of the stage IV 
colorectal cancer population (Lochhead et al, 2013).  
2.1.3.1 
Immunotherapy in Colorectal Cancer 
Clinically, there is evidence of activity of PD-1 based therapy in colorectal cancer.  In a 
phase 1 study of nivolumab that included 39 patients with various solid tumors, 
1/14 patients with metastatic MSI-H colorectal cancer had a durable CR 
(Brahmer et al, 2012).  Interestingly, a pretreatment tumor specimen revealed 
membranous expression of PD-L1 on tumor-infiltrating macrophages and lymphocytes 
and on rare tumor cells, as well as PD-1-positive CD3+ T cells (Lipson et al, 2013).  
Additionally, a phase 2 investigator-initiated study with 41 patients demonstrated that the 
mismatch repair deficient (dMMR) phenotype is predictive of responses to 
PD-1 blockade.  Administration of pembrolizumab monotherapy resulted in objective 
response of 40% of patients with dMMR colorectal tumors compared with 0% in patients 
with MMR proficient colorectal cancer.  Median PFS and OS were not reached in the 
dMMR colorectal cancer cohort versus 2.2 and 5.0 months in the MMR proficient cohort, 
and somatic mutational burden correlated with PFS (Le et al, 2015).  Based on this and 
other data, the U.S. FDA has granted Breakthrough Therapy Designation to 
pembrolizumab for the treatment of patients with MSI-H metastatic colorectal cancer, 
and on 23 May 2017, granted accelerated approval to pembrolizumab for adult and 
pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that 
have progressed on prior therapy.   
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Although the exact mechanism of checkpoint inhibitors in colorectal cancer is still 
unknown, these agents function by releasing inhibition of the immune response, and 
therefore they likely act in large part by enhancing pre-existing antigenic responses.  
Preclinical data has suggested that administration of replication competent HSV-1 
oncolytic virus to nude rat tumors was successful in suppressing tumor growth and killing 
human colorectal cancer cells efficiently (Kooby et al, 1999).  A phase 1 study of 
intravenous reolysin (non-enveloped human reovius) in combination with folinic 
acid-fluorouracil-irinotecan (FOLFIRI) and bevacizumab in FOLFIRI-naive patients with 
KRAS mutant metastatic colorectal cancer is currently ongoing.  The primary endpoint is 
safety, and the secondary endpoint examines biomarkers and efficacy parameters 
(NCT01274624).  
2.1.4 
Oncolytic Virus Studies With Intrahepatic Administration 
The safety and activity of oncolytic viruses has been studied against various tumor types 
in the liver.  JX-594 (pexastimogene devacirepvec [Pexa-Vec]) is a modified vaccinia 
virus with a disrupted thymidine kinase (tk) gene to improve selectivity for cancer and 
insertions of human granulocyte-macrophage colony-stimulating factor (GM-CSF) for 
immune stimulation and β-galactosidase for assessment of replication.  It was 
administered intratumorally (IT) in a phase 1 trial to 14 subjects with primary 
hepatocellular carcinoma (HCC) or metastatic liver tumors (non-HCC) in a dose 
escalation study (Park et al, 2008).  DLT occurred at the highest dose of 3 x 109 plaque 
forming unit (PFU) with grade 3 hyperbilirubinemia due to tumor swelling and obstruction 
of the intrahepatic bile duct and grade 3 anorexia and abdominal pain.  Thus, 109 PFU 
was determined as the maximum tolerated dose (MTD).  No treatment-related deaths 
occurred.  All subjects had grade 1 to 2 flu-like symptoms.  Of 10 evaluable subjects, 
3 had a PR (lung squamous cell carcinoma, HCC, and melanoma), and 6 had SD by 
Response Evaluation Criteria in Solid Tumors (RECIST).  By Choi response criteria 
(a criteria initially developed for gastrointestinal (GI) stromal tumors which assesses 
change in size and change in density of target lesions), an additional 5 subjects with SD 
by RECIST were found to also have a PR (colorectal cancer, 2 subjects and renal cell 
carcinoma, thymic squamous cell carcinoma, and extragonadal germ cell tumor).  In a 
subsequent dose-finding phase 2 study, 30 subjects with advanced HCC were 
randomized to either 108 or 109 PFU JX-594 injected IT into up to five HCC tumors on 
days 1, 15, and 29 (Heo et al, 2013).  Treatment was generally well tolerated at both 
doses, and there were no treatment-related deaths.  There was one treatment-related 
serious adverse event of nausea and vomiting at the 109 PFU dose.  Grade 1 to 2 flu-like 
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symptoms occurred in all subjects in the first 12 to 24 hours after treatment.  The only 
grade 3 event was pyrexia which occurred in 19% of subjects treated at the 109 PFU 
dose, and 1 grade 4 event of lymphopenia occurred at the 109 PFU dose.  The trial was 
stopped early due to significant survival benefit favoring the higher-dose group 
(14.1 months vs 6.7 months) with median OS at 9.0 months for the entire study 
population.  There was no significant difference, however, in either modified RECIST or 
modified Choi responses between the higher and lower dose (7% vs 23% and 57% vs 
67%, respectively).  A subsequent phase 2b study evaluating JX-594 for 6 treatments on 
days 1 (intravenous), 8 (IT), 22 (IT), and weeks 6 (IT), 12 (IT), 18 (IT) vs best supportive 
care in 120 second-line advanced subjects with HCC refractory or intolerant to sorafenib 
did not meet its primary endpoint of OS (Transgene, 2013).  However, a pivotal phase 3 
study evaluating sorafenib with or without JX-594 in the first line setting for 
approximately 600 subjects with HCC is ongoing (NCT02562755). 
NV1020, an attenuated derivative of HSV-1 that has deletions of the genes encoding 
infected cell protein (ICP) 34.5, UL56, UL24, and tk and reinsertion of a functional HSV-1 
tk gene, was administered into the liver intra-arterially for unresectable colorectal cancer 
liver metastases in a phase 1/2 study (Geevarghese et al, 2010).  Doses from 3 x 106 to 
1 x 108 PFU were administered for up to 4 infusions to 13 subjects in the dose-escalation 
phase 1 portion, and no DLTs were seen.  For phase 2, the 1 x 108 PFU dose was 
administered to 19 subjects.  The most common adverse events were transient chills, 
headache, nausea, vomiting, myalgia, body pains, and fatigue.  No treatment-related 
disturbances in liver function were seen.  An asymptomatic grade 3 lymphopenia 
occurred after infusions in 1 subject.  At the 1 x 108 PFU dose, 1 PR and 13 SD were 
seen in 22 evaluable subjects.  Mean time to progression was 6.4 months, and mean OS 
was 11.8 months at the highest treatment dose. 
2.2 
Amgen Investigational Product Background:  Talimogene 
Laherparepvec 
Talimogene laherparepvec is a virally-based oncolytic immunotherapy consisting of an 
immune-enhanced HSV-1 that selectively replicates in solid tumors.  In this genetically 
modified strain, the HSV-1 viral genes encoding ICP 34.5 (a neurovirulence factor) and 
ICP47 (which blocks viral antigen presentation to major histocompatibility complex 
class I) have been functionally deleted.  The coding sequence for GM-CSF has been 
inserted in place of ICP34.5 and is intended to enhance the immune response to tumor 
antigens released after virus replication and lytic tumor cell death.  Thus, talimogene 
laherparepvec has 2 mechanisms of action: (a) direct oncolysis of infected tumor cells 
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and (b) immune activation through tumor-associated antigen release, innate immune 
activation and local virus-mediated GM-CSF expression.  Talimogene laherparepvec is 
administered by direct injection into tumors. 
In the United States, talimogene laherparepvec (Imlygic®) is indicated for the local 
treatment of unresectable cutaneous, subcutaneous, and nodal lesions in patients with 
melanoma recurrent after initial surgery.  The indication also contains a limitation of use 
which states that talimogene laherparepvec has not been shown to improve overall 
survival or have an effect on visceral metastases.  Additionally, in the European Union, 
talimogene laherparepvec (Imlygic®) has been approved for the treatment of adults with 
unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC, and 
IVM1a) with no bone, brain, lung or other visceral disease.  
As of 26 April 2016, more than 1,000 patients have received talimogene laherparepvec 
with approximately 761 patients having received talimogene laherparepvec in research 
studies and approximately 350 people were prescribed talimogene laherparepvec 
(IMLYGIC®) after it was approved for sale in the United States. 
In the First-in-Human Study, 001/01, talimogene laherparepvec was administered in 
single ascending doses of 106, 107, or 108 plaque forming unit (PFU)/mL (up to 4 mL) to 
subjects with breast cancer, colorectal cancer, head and neck cancer, and melanoma 
with refractory cutaneous or subcutaneous metastases (Hu et al, 2006).  In the first 
2 single-dose cohorts, subjects who were HSV-1 seronegative at study entry 
experienced more adverse events, including febrile influenza-like syndromes associated 
with symptoms of fatigue, rigors, erythematous skin rashes and small vesicles in the 
skin.  At the highest dose (108 PFU/mL), only HSV-1 seropositive subjects received 
talimogene laherparepvec and no rashes or rigors were observed.  In the subsequent 
multidose part of the study, talimogene laherparepvec was well tolerated in HSV-1 
seronegative as well as seropositive subjects who received a first dose of 106 PFU/mL, 
followed by 2 doses of 108PFU/mL.  Febrile responses were minimal.  Of the 
17 subjects, 7 subjects were HSV-1 seronegative at baseline but within 21 days 
(3 weeks) after the initial dose of 106 PFU/mL was administered, 6 of the 7 subjects 
seroconverted.  Based on these findings, to facilitate tolerance, enable seroconversion, 
and ensure consistency in dosing, the recommended dose in adults (both HSV-1 
seropositive and seronegative groups) was established to be 106 PFU/mL followed by 
108 PFU/mL 21 days (3 weeks) later.  Subsequent dosing could safely be administered 
every 14 days (2 weeks).  
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In the melanoma setting, talimogene laherparepvec has been administered into 
cutaneous or subcutaneous lesions or lymph nodes accessible by ultrasound.  The 
largest study to evaluate the activity of talimogene laherparepvec in melanoma was the 
pivotal OPTiM study.  In this open-label, phase 3 study, 436 subjects with stages lllB to 
IV unresectable melanoma were randomized 2:1 to intralesional talimogene 
laherparepvec or subcutaneous GM-CSF.  Treatment was administered until complete 
response (CR), clinically significant disease progression, intolerable side effects, 
12 months of therapy without an objective response, or withdrawal of consent.  The 
primary endpoint of the OPTiM study was DRR, defined as the rate of subjects with an 
objective response by central review (CR or PR) lasting continuously for 6 months and 
starting any time within 12 months of initiating therapy.  Secondary endpoints included 
OS, BOR, modified PFS, and changes in tumor burden and safety. 
Primary analysis of the OPTiM study showed a statistically significant difference 
between the DRR among subjects treated with talimogene laherparepvec (16%; 
95% confidence interval [CI]:  12%, 21%) versus those treated with GM-CSF (2%; 
95% CI:  0%, 5%; p value < 0.0001).  Overall response rate was 26.4% (CR 10.8%) for 
talimogene laherparepvec vs 5.7% (CR 0.7%) for GM-CSF (p value < 0.0001 
descriptive).  Median OS among subjects treated with talimogene laherparepvec was 
23.3 months vs 18.9 months among subjects treated with GM-CSF with an OS hazard 
ratio (HR) of 0.79 and p value of 0.051 (Andtbacka et al, 2015b).  
In a lesion level analysis, 64% and 47% of injected lesions, 34% and 22% of uninjected 
non-visceral lesions, and 15% and 9% of uninjected visceral lesions regressed ≥ 50% 
and 100%, respectively, demonstrating the systemic effect of talimogene laherparepvec 
beyond injected lesions (Andtbacka et al, 2014, Andtbacka et al, 2015a). 
The most common side effects in the OPTiM study were chills (talimogene 
laherparepvec, 49%; GM-CSF, 9%), pyrexia (43%; 9%), injection-site pain (28%; 6%), 
nausea (36%; 20%), influenza-like illness (30%; 15%), and fatigue (50%; 36%).  Grade 
≥ 3 adverse events occurred in 36% of subjects receiving talimogene laherparepvec and 
21% of subjects receiving GM-CSF.  The only grade 3/4 adverse events occurring in 
≥ 5 subjects was cellulitis (talimogene laherparepvec, n=6 [2.1%]; GM-CSF, n=1 [<1%]).  
Of 10 fatal adverse events in the talimogene laherparepvec arm, eight were attributable 
to disease progression.  The remaining two fatal adverse events (sepsis in the setting of 
salmonella infection; myocardial infarction) were not considered treatment-related per 
investigator (Andtbacka et al, 2015a). 
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The injection of talimogene laherparepvec into visceral tumors has been studied in the 
005/04 phase 1 study for advanced pancreatic cancer in subjects who either failed 
standard therapy or could not receive/refused standard therapy (Chang et al, 2012).  
There were 17 subjects who received endoscopic US guided injections into their 
pancreatic tumors at either 1 dose of 104 PFU/mL followed by 2 doses of 105 PFU/mL 
every 3 weeks (cohort 1, n=3), 1 dose of 105 PFU/mL followed by 2 doses of 
106 PFU/mL every 3 weeks (cohort 2, n=4), or 1 dose of 106 PFU/mL followed by 
2 doses of 107 PFU/mL every 3 weeks (cohort 3, n=10).  A fourth dose schedule of 
106 PFU/mL followed by 2 doses of 108 PFU/mL every 3 weeks was planned but not 
opened because the study was terminated early.  The maximal volume that could be 
administered was 4 mL. 
The primary analysis of efficacy was an assessment of the change from baseline in the 
diameter of injected tumors.  Two of the 4 subjects in cohort 3 with post-dose computed 
tomography (CT) scans achieved substantial size reductions (-36% and -33%) in 
injected tumors.  No subjects in the lower dose cohorts (n = 2 evaluable subjects in each 
cohort) showed clinically relevant size reductions of the injected tumors, suggesting a 
dose trend for response of injected tumors.  Three subjects also showed decreases in 
the diameters of 1 or more uninjected tumors (in the liver, pancreas, kidney, and chest) 
at any point in the study, and 1 subject had complete disappearance of a 
non-measurable tumor in the liver.  A dose trend was not observed for size reductions of 
uninjected tumors.  In the evaluation of overall tumor burden per RECIST version 1.0, no 
subjects achieved an overall CR or PR; 3 subjects (2 in cohorts 1 and 1 in cohort 3) had 
an assessment of overall SD at 1 or more time points.  
Eight subjects (47%) had at least 1 treatment-emergent adverse event considered 
related to talimogene laherparepvec.  Treatment-related adverse events included 
pyrexia in 3 subjects; abdominal pain, ascites, influenza-like illness, and dehydration in 
2 subjects; and constipation, vomiting, chills, pain, headache, weight decrease, and 
diarrhea in 1 subject each.  Grade 3 treatment-related adverse events included 
abdominal pain (12%), ascites (12%), and dehydration (6%); all occurred in cohort 3.  
Eleven deaths were reported, mostly due to pancreatic cancer-related complications.  
One subject with a fatal outcome had an adverse event of ascites considered possibly 
related to study treatment by the investigator.  This subject was hospitalized for severe 
ascites 1 week after the first dose of talimogene laherparepvec, and later experienced 
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disease progression and received home hospice care; the event of ascites was ongoing 
at the time of the subject’s death approximately 1 month later. 
There are currently 4 ongoing combination immunotherapy studies with talimogene 
laherparepvec and a checkpoint inhibitor in advanced stage melanoma.  One is a phase 
1b/2 study of ipilimumab with or without talimogene laherparepvec in unresected 
melanoma (NCT01740297).  In the phase 1b portion, 18 of 19 subjects (more than half 
with visceral disease) received both talimogene laherparepvec and ipilimumab in 
combination.  Full dose of talimogene laherparepvec and ipilimumab 3 mg/kg every 
3 weeks starting week 6 were tolerable.  Per immune-related response criteria (data 
cutoff of 22 December 2014), the ORR in 18 evaluable subjects was 56% (33% CRs), 
and the DRR was 44%.  Median PFS was 10.6 months (2.6 to 19.3+ months).  Median 
OS was not reached; 12-month and 18-months survival rates were 72.2% and 67%, 
respectively.  On a lesion level, 8 and 5 of 16 uninjected index lesions regressed ≥ 50% 
and 100%, respectively.  Grade 3/4 treatment-emergent adverse events occurred in 32% 
of subjects, and grade 3/4 immune-related adverse events occurred in two subjects 
(grade 3 hypophysitis and adrenal insufficiency; and grade 4 amylase + lipase 
elevations).  There were no treatment-related deaths (Puzanov et al, 2014).  Another 
study is a phase 1b/3 multicenter open-label trial of talimogene laherparepvec in 
combination with pembrolizumab for treatment of unresected, stage IIb to IVM1c 
melanoma (NCT02263508).  In the phase 1b portion of the study, subjects with stage 
IIB-IV melanoma with injectable lesions and no prior systemic therapy received up to 
4.0 mL of talimogene laherparepvec monotherapy for 2 doses followed by talimogene 
laherparepvec and pembrolizumab every 2 weeks thereafter.  All 21 evaluable subjects 
had an adverse event:  29% grade 3, no grade 4 and one grade 5 (not treatment 
related).  The most common adverse events by preferred term were fatigue (52%), 
pyrexia (48%), chills (43%), and rash (38%).  Of 16 subjects evaluable for response, the 
unconfirmed response rate per investigator was 56%; DCR was 69% (12.5% CR, 
44% PR, 12.5% SD) (Long et al, 2015). 
The hepatotoxicity of talimogene laherparepvec administration in the liver has been 
evaluated in immunocompetent rats.  Up to 107 PFU of talimogene laherparepvec per 
animal or vehicle was administered via intrahepatic artery injection.  No differences in 
morbidity or mortality were noted between talimogene laherparepvec and vehicle treated 
groups (Amgen data on file).  Additionally, a dose escalating hepatic injection study with 
talimogene laherparepvec into HCC and metastatic liver tumors is currently ongoing 
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(NCT02509507).  In that study, talimogene laherparepvec was shown to be safe when 
administered intrahepatically into non-HCC liver metastases at up to 4 mL of 
106 PFU/mL initial dose followed 3 weeks later by up to 4 mL of 108 PFU/mL every 
3 weeks (Hecht et al, 2018). 
The current study combining talimogene laherparepvec and atezolizumab will use the 
dose of talimogene laherparepvec that has been demonstrated to be safe in the 
monotherapy setting.  
Refer to the specific section of the talimogene laherparepvec Investigator’s Brochure for 
additional information related to the physical, chemical, and pharmaceutical properties 
and formulation(s). 
2.3 
Non-Amgen Investigational Product Background:  Atezolizumab 
Atezolizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets 
PD-L1 and inhibits the interaction between PD-L1 and its receptors , PD-1 and B7-1 
(also known as CD80), both of which function as inhibitory receptors expressed on 
T cells.  Therapeutic blockade of PD-L1 binding by atezolizumab has been shown to 
enhance the magnitude and quality of tumor-specific T-cell responses, resulting in 
improved anti-tumor activity (Fehrenbacher et al, 2016; Rosenberg et al, 2016).  
Atezolizumab has minimal binding to Fc receptors, thus eliminating detectable 
Fc-effector function and associated antibody-mediated clearance of activated effector 
T cells. 
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies.  
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab is approved in the United States and other countries for the treatment of 
urothelial carcinoma and is approved in the United States for the treatment of nonsmall 
cell lung cancer.  It is also approved in the United States in combination with 
nab-paclitaxel for the treatment of PD-L1 positive triple negative breast cancer 
(refer to the prescribing information for specific indications). 
Refer to the Atezolizumab Investigator’s Brochure for details on nonclinical and clinical 
studies. 
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2.4 
Rationale 
Talimogene laherparepvec and atezolizumab blockade may play complementary roles in 
regulating adaptive immunity.  Talimogene laherparepvec likely augments dendritic 
cell-mediated tumor antigen presentation through local expression of GM-CSF 
(Kaufman et al, 2010) and local antigen release by direct tumor lysis.  Data indicate that 
the PD-L1/PD-1 pathway plays a role in triple negative breast cancer.  Its role in 
colorectal cancer is currently being explored.  Atezolizumab is a PD-L1 regulator and 
prevents T cell exhaustion in peripheral tissues. 
The combination of an agent that increases tumor-specific immune activation 
(talimogene laherparepvec) with one that blocks inhibitory T cell checkpoints 
(atezolizumab) could potentially produce greater antitumor activity than either agent 
alone in both triple negative breast cancer and colorectal cancer.  The aim of this study 
is to evaluate safety and explore efficacy of the two agents in combination. 
2.5 
Clinical Hypotheses 
It is hypothesized that intrahepatic injection of talimogene laherparepvec in combination 
with intravenously administered atezolizumab in subjects with triple negative breast 
cancer and colorectal cancer with liver metastases will be safe and well tolerated with a 
DLT rate ≤ 10%. 
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 1b, multicenter, open-label study to evaluate the safety of intrahepatic 
injection of talimogene laherparepvec in combination with intravenously administered 
atezolizumab in subjects with triple negative breast cancer and colorectal cancer with 
liver metastases.  Approximately 36 DLT-evaluable subjects will be enrolled in two 
parallel cohorts.  Cohort 1 will comprise triple negative breast cancer subjects with liver 
metastases (n = 18 DLT-evaluable subjects).  Cohort 2 will comprise subjects with 
colorectal cancer with unresectable liver metastases (n = 18 DLT-evaluable subjects).  
Subjects will be treated with up to 4.0 mL of 106 PFU/mL talimogene laherparepvec at 
cycle 1, day 1 followed by talimogene laherparepvec up to 4.0 mL of 108 PFU/mL 
21 ± 3 days later (cycle 2, day 1, week 4 of the study).  Subsequent cycles of up to 
4.0 mL of 108 PFU/mL talimogene laherparepvec will be given every 21 (+ 3 days).  The 
first cycle of atezolizumab will be 21 (+ 3) days.  Subsequent cycles of atezolizumab will 
be 21 (± 3) days.  Atezolizumab will be administered intravenously at a dose of 1200 mg.  
For further details see Section 6.2.1.1 and 6.2.2.1. 
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The DLT evaluation period for a given subject will consist of the period between the 
initial 106 PFU/mL dose of talimogene laherparepvec and atezolizumab and 3 weeks 
following the initial 108 PFU/mL dose of talimogene laherparepvec and atezolizumab or 
the start of cycle 3, whichever occurs first.  DLTs will be evaluated based on the first 
18 DLT-evaluable subjects in each cohort separately according to Table 3-1.  The 
definition of DLT is provided in Section 6.2.1.2.3. 
A Dose Level Review Team (DLRT) will review the safety data to evaluate possible drug 
effects and DLT.  To be evaluable for a DLT, subjects must have had the opportunity to 
be on treatment for at least 2 cycles from the initial dose of study treatments and have 
received at least 2 doses of talimogene laherparepvec and two doses of atezolizumab in 
combination, or have a DLT during the DLT evaluation period.  Subjects may be 
replaced if they are not evaluable for DLT in order to obtain 18 DLT-evaluable subjects.  
Safety will be evaluated considering the incidence of DLTs among all DLT-evaluable 
subjects enrolled in the study in each cohort.  A sequential stopping rule is derived 
based on a hypothesis testing approach (Goldman, 1987).  There will be one safety 
interim analysis after the first 4 to 6 DLT-evaluable subjects have been enrolled in this 
study and a safety analysis after 18 DLT-evaluable subjects have been enrolled in a 
cohort.  Enrollment will be suspended during the first safety interim analysis.  At the 
discretion of the DLRT, additional safety analyses may be conducted as warranted.  The 
cumulative increments of DLT-evaluable subjects and corresponding acceptable 
maximum number and percentage of DLTs at each analysis are shown in Table 3-1.  
The combination will not be declared safe if the number of DLTs exceeds the acceptable 
maximum number and enrollment will stop. 
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Table 3-1.  Cumulative Increments of DLT-evaluable Subjects and Corresponding 
Acceptable Maximum Number and Percentage of DLTs at Each Interim Safety 
Analysis 
Number of subjects 
Acceptable Maximum Number (%) of DLTs 
Stopping Number (%) of DLTs 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18a 
1 
(50) 
1 
(33) 
2 
(50) 
2 
(40) 
2 
(33) 
2 
(29) 
2 
(25) 
3 
(33) 
3 
(30) 
3 
(27) 
3 
(25) 
3 
(23) 
4 
(29) 
4 
(27) 
4 
(25) 
4 
(24) 
4 
(22) 
2 
(100) 
2 
(66) 
3 
(75) 
3 
(60) 
3 
(50) 
3 
(43) 
3 
(38) 
4 
(44) 
4 
(40) 
4 
(36) 
4 
(33) 
4 
(31) 
5 
(36) 
5 
(33) 
5 
(31) 
5 
(29) 
5 
(28) 
DLT = dose limiting toxicity 
The design achieves a 7.7% 1-sided significance level and 81.6% power to test the null hypothesis of a DLT 
rate ≤ 10% versus the alternative hypothesis of a rate ≥ 33%. 
a If > 18 subjects receive the combination they will contribute to the overall safety analysis, but only the first 
18 DLT-evaluable will be considered in the decision to declare the combination safe. 
Treatment will continue until a subject experiences a DLT (during the DLT evaluation 
period).  See Section 6.2.1.3 and Section 6.2.2.2 for other reasons for stopping 
treatment. 
All subjects will complete a safety follow-up visit approximately 30 (+ 7) days after the 
last dose of study treatment.  Adverse events and disease related events will be 
collected as described in Section 9.2.  After the safety follow-up visit, all subjects will 
enter the long-term follow-up.  Subjects will be followed for survival, subsequent 
anticancer therapies and treatment related adverse events every 12 weeks (± 28 days) 
for approximately 24 months after the last subject is enrolled.  
Subjects who have received talimogene laherparepvec and completed the 
protocol-specified long-term follow-up period for a reason other than death or withdrawal 
of full consent will be eligible to continue follow-up in a separate ongoing registry study 
which is in place for the long-term survival follow-up of subjects treated with talimogene 
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laherparepvec in clinical trials.  The registry study will also monitor for late and long-term 
adverse events thought to be potentially related to talimogene laherparepvec. 
The overall study design is described by a study schema at the end of the 
protocol synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
The study will be conducted at approximately 20 sites in the United States of America 
(USA), Europe, and Australia.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 36 DLT-evaluable subjects will be enrolled (18 DLT-evaluable subjects 
in each cohort).  Refer to Section 10.2 for sample size considerations. 
3.4 
Replacement of Subjects 
Subjects enrolled may be replaced if they are not evaluable for DLT (eg, a subject did 
not receive at least one dose of each investigational agent, or ended the study treatment 
before completion of DLT evaluation period for a reason other than experiencing a DLT).  
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The duration of screening for each subject will be up to 28 days (4 weeks).  The subject 
accrual period is planned to be approximately 12 months.  The duration of treatment will 
vary for each subject.  Subjects may receive a maximum of 12 cycles of talimogene 
laherparepvec.  All subjects will complete a safety follow-up visit approximately 
30 (+ 7) days after the last dose of study treatment.  After the safety follow-up visit 
subjects will enter the long-term follow-up.  During this period, subjects will be followed 
every 12 weeks (± 28 days) for survival for up to approximately 24 months after the last 
subject is enrolled.  The study duration for an individual subject may be up to 
approximately 3 years. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint(s), for the purpose of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early.   
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The primary completion date is the date when data for the primary endpoint are last 
collected for the purposes of conducting the primary analysis.   
End of Study:  The end of study date is defined as the date when the last subject across 
all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit), following additional parts in the study (eg, long-term follow-up), as 
applicable.   
4. 
SUBJECT ELIGIBILITY 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening).   
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).   
4.1 
Inclusion Criteria 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures 
102 
Male or female subject age ≥ 18 years at the time of informed consent  
103 
Histologically or cytologically confirmed diagnosis of triple negative breast cancer 
or colorectal cancer with liver metastases 
104 
Subjects with triple negative breast cancer with liver metastases, or subjects with 
colorectal cancer with liver metastases are eligible if they have had disease 
progression during or after ≥ 1 prior standard of care systemic anti-cancer 
therapy (eg, chemotherapy, targeted therapy) for metastatic disease or if they 
progress during or within 6 months of receiving adjuvant therapy.  If 
subjects, in the opinion of the investigator, are deemed not appropriate 
candidates for systemic anti-cancer therapy for metastatic disease or if 
they refuse systemic anti-cancer therapy for metastatic disease, they may 
be eligible after investigator discussion with sponsor medical monitor for 
approval. 
105 
Measurable disease as defined by:  
 
≥ 1 metastatic liver lesion that can be accurately and serially measured in 
≥ 1 dimension and for which the longest diameter is ≥ 1 cm as measured by 
multiphase CT scan or magnetic resonance imaging (MRI)  
 
Measureable metastatic liver lesion(s) must not be in an area of the liver that 
received prior localized therapies (eg, radiation, ablation, embolization), 
unless there is documented evidence of disease progression in the area that 
can be measured and distinguished from the effects of any anti-cancer 
therapy prior to enrollment  
Approved 
 
 

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106 
Candidate for intrahepatic injection as defined by:  
 
≥ 1 injectable metastatic liver lesion without necrosis ≥ 1 cm in longest 
diameter or ≥ 1 metastatic liver lesion with necrosis where the longest 
diameter of the necrotic region subtracted from longest diameter of the lesion 
is ≥ 1 cm  
 
metastatic liver lesions selected for injection must not be located where any 
potential tumor swelling after injection may lead to biliary tract obstruction 
(eg, < 1 cm adjacent to the left main, right main, or common biliary ducts) or 
where there may be risk of bleeding (eg, < 1 cm from the hepatic capsule)  
107 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
108 
Life expectancy ≥ 5 months 
109 
Adequate organ function determined within 4 weeks prior to enrollment, defined 
as follows: 
Hematological 
 
ANC  1500/mm3 (1.5 x 109/L) without granulocyte colony-stimulating factor 
support within 2 weeks prior to enrollment 
 
white blood cell counts (WBC) > 2500/µL(2.5 x 109/L) 
 
lymphocyte count ≥ 500/µL (0.5 x 109/L) 
 
platelet count  100,000/mm3 (100.0 x 109/L) 
 
hemoglobin  9 g/dL (90 g/L) (without need for hematopoietic growth factor or 
transfusion support within 2 weeks prior to enrollment) 
Renal 
 
serum creatinine  1.5 x upper limit of normal (ULN), OR creatinine clearance 
≥ 60 mL/min for a subject with serum creatinine levels > 1.5 x ULN.  (Note 
creatinine clearance need not be determined if the baseline serum creatinine 
is ≤ 1.5 x ULN.  Creatinine clearance should be determined per institutional 
standards). 
Hepatic 
 
serum albumin ≥ 2.5 g/dL (25 g/L) 
 
serum total bilirubin  1.5 x ULN 
 
aspartate aminotransferase (AST)  2.5 x ULN 
 
alanine aminotransferase (ALT)  2.5 x ULN 
 
alkaline phosphatase (ALP) ≤ 2.5 x ULN 
Coagulation  
 
prothrombin time (PT) or international normalization ratio (INR) ≤ 1.5 x ULN 
 
partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN 
110 
Female subjects of childbearing potential should have a negative serum 
pregnancy test within 1 week prior to enrollment. 
Approved 
 
 

Product:  Talimogene Laherparepvec 
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Page 39 of 139 
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4.2 
Exclusion Criteria 
Cancer Related 
201 
Subject is a candidate for any hepatic surgery or locoregional therapy of liver 
metastases with curative intent  
202 
Approximately more than one-third of the liver estimated to be involved with 
metastases 
203 
Has macroscopic intravascular invasion into the main portal vein, hepatic vein, or 
vena cava 
204 
Currently receiving, or < 4 weeks prior to enrollment since receiving liver 
metastatic-directed therapy (eg, radiation, ablation, embolization) or hepatic 
surgery  
205 
History of other malignancy within the past 5 years prior to enrollment with the 
following exceptions: 
 
malignancy treated with curative intent and with no known active disease 
present for ≤ 5 years before enrollment and felt to be at low risk for 
recurrence by the treating physician and approved by the Amgen medical 
monitor 
 
adequately treated non-melanoma skin cancer without evidence of disease at 
the time of enrollment 
 
adequately treated cervical carcinoma in situ without evidence of disease at 
the time of enrollment 
 
adequately treated breast ductal carcinoma in situ without evidence of 
disease at the time of enrollment 
 
prostatic intraepithelial neoplasia without evidence of prostate cancer at the 
time of enrollment 
 
adequately treated superficial or in-situ carcinoma of the bladder without 
evidence of disease at the time of enrollment  
 
adequately treated superficial or in-situ colorectal carcinoma without evidence 
of disease at the time of enrollment 
206 
Active or untreated central nervous system (CNS) metastases. CT or MRI 
evaluation required during screening for all triple negative breast cancer subjects.   
Brain imaging is only required for colorectal cancer subjects with signs or 
symptoms concerning for CNS metastases or with a history of previously treated 
CNS metastases. 
Subjects with previously treated CNS metastases may participate provided they 
are stable (no evidence of progression by imaging or requirement for 
corticosteroids for at least 8 weeks prior to the first dose of investigational 
product(s) and no ongoing neurologic symptoms).  Subjects with a history of 
treated CNS metastases are eligible, provided they meet the following criteria: 
 
No metastases to midbrain, pons, or medulla  
 
No history of intracranial or spinal cord hemorrhage  
Approved 
 
 

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Note:  anticonvulsant prophylaxis (eg, phenytoin, carbamazepine) is 
permitted  
207 
History or known presence of leptomeningeal disease  
208 
Spinal cord compression not definitively treated with surgery and/or radiation or 
previously diagnosed and treated spinal cord compression without evidence that 
disease has been clinically stable for ≥ 8 weeks prior to enrollment without 
ongoing requirement for corticosteroids 
209 
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent 
drainage procedures (once monthly or more frequently) 
Other Medical Conditions 
210 
History of active autoimmune disease including, but not limited to systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with antiphospholipid syndrome, Wegener's 
granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain Barré syndrome, 
multiple sclerosis, vasculitis, or glomerulonephritis 
Note:  Subjects with controlled autoimmune thyroid disease, type 1 diabetes 
mellitus on a stable insulin regimen or vitiligo may be eligible following 
consultation with the Amgen medical monitor.  
211 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (ie, bronchiolitis obliterans, cryptogenic 
organizing pneumonia), risk of pulmonary toxicity, or evidence of active 
pneumonitis on screening chest CT scan 
Note:  History of radiation pneumonitis in the radiation field (fibrosis) is permitted 
if there is no ongoing requirement for corticosteroids 
212 
Evidence of clinically significant immunosuppression such as primary 
immunodeficiency state such as Severe Combined Immunodeficiency Disease 
213 
Prior allogeneic bone marrow transplantation or prior solid organ transplantation 
214 
Active herpetic skin lesions or prior complications of herpetic infection 
(eg, herpetic keratitis or encephalitis). 
215 
Acute or chronic active hepatitis B infection 
216 
Acute or chronic active hepatitis C infection 
217 
Positive test for human immunodeficiency virus (HIV) infection 
218 
Active tuberculosis 
219 
Severe infections within 4 weeks prior to enrollment, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia 
and/or received therapeutic oral or intravenous antibiotics within 2 weeks prior to 
enrollment  
Approved 
 
 

Product:  Talimogene Laherparepvec 
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Page 41 of 139 
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Note:  Subjects receiving prophylactic antibiotics (eg, for prevention of a urinary 
tract infection or chronic obstructive pulmonary disease) are eligible 
220 
Signs or symptoms of infection within 2 weeks prior to enrollment 
221 
Significant cardiovascular disease, such as New York Heart Association cardiac 
disease (Class II or greater), myocardial infarction ≤ 3 months prior to the first 
dose of investigational product(s), unstable arrhythmias, or unstable angina 
222 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen medical monitor, if consulted, would pose a risk to subject 
safety or interfere with the study evaluation, procedures, or completion 
223 
Female subject is pregnant or breast-feeding, or planning to become pregnant 
during study treatment and through 5 months after the last dose of talimogene 
laherparepvec or atezolizumab 
224 
Female subject of childbearing potential who is unwilling to use acceptable 
method(s) of effective contraception during study treatment and through 
5 months after the last dose of talimogene laherparepvec or atezolizumab.  Refer 
to Section 6.10 for additional contraceptive information. 
225 
Sexually active subjects and their partners unwilling to use male or female latex 
condom to avoid potential viral transmission during sexual contact while on 
treatment and within 30 days after treatment with talimogene laherparepvec.  For 
those with latex allergies, polyurethane condoms may be used. 
226 
Subject who is unwilling to minimize exposure with his/her blood or other body 
fluids to individuals who are at higher risks for HSV-1 induced complications such 
as immunosuppressed individuals, individuals known to have HIV infection, 
pregnant women, or children under the age of 1 year, during talimogene 
laherparepvec treatment and through 30 days after the last dose of talimogene 
laherparepvec 
227 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject's and investigator's knowledge  
Exclusions Related to Medications 
228 
Prior therapy with talimogene laherparepvec, any other oncolytic virus, immune 
checkpoint inhibitor or immunostimulatory agent 
229 
Known sensitivity to talimogene laherparepvec or components to be administered 
during dosing 
230 
Requires intermittent or chronic treatment with an antiherpetic drug 
(eg, acyclovir), or other antiviral medication, other than intermittent topical use. 
231 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to 
chimeric or humanized antibodies or fusion proteins 
Approved 
 
 

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232 
Known hypersensitivity or allergy to Chinese hamster ovary cell products or any 
component of the atezolizumab formulation 
233 
Prior chemotherapy, targeted therapy (eg, bevacizumab), radiotherapy,  to treat 
cancer or major surgery within 4 weeks prior to enrollment.  Subjects who 
continue to experience > grade 1 Common Terminology Criteria for Adverse 
Events (CTCAE) toxicity due to cancer therapy within 4 weeks prior to enrollment 
will not be eligible.   
Note:  Subjects with ≤ Grade 2 neuropathy and alopecia are an exception to this 
criterion  
234 
Currently using an investigational device or receiving treatment with an 
investigational drug in another study, or less than 4 weeks since ending a study 
involving an investigational device or investigational drug(s)   
235 
Treatment with systemic immunosuppressive medications (including but not 
limited to prednisone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks 
prior to enrollment 
 
Subject who has received acute and/or low-dose systemic 
immunosuppressant medications including chronic oral or systemic steroid 
medication use at a dose of > 10 mg/day of prednisone or equivalent or has 
received > 10 mg/day of prednisone or equivalent within 7 days of enrollment.  
Subjects that require intermittent use of steroid inhalers, topical steroids, or 
local steroid injection will not be excluded from the study.  
 
The use of inhaled corticosteroids and mineralocorticoids 
(eg, fludrocortisone) is allowed. 
Note:  Replacement corticosteroid replacement therapy for adrenal or 
pituitary insufficiency is not considered a form of systemic 
immunosuppressive medication 
236 
Treatment with systemic immunostimulatory agents (including but not limited to 
interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, 
prior to enrollment  
237 
Administration of a non-cancer, live, attenuated vaccine within 4 weeks of 
enrollment or anticipation that such a live attenuated vaccine will be required 
during the study or 5 months after the last dose of atezolizumab 
238 
Requires concomitant treatment with warfarin.  Other anticoagulants (ie, low 
molecular weight heparins, non-steroidal anti-inflammatory drugs) that do not 
prolong the PT/INR may be allowed as long as the institutional guidelines 
requiring their withholding for interventional radiology procedures can be 
followed. 
Approved 
 
 

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5. 
SUBJECT ENROLLMENT 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written Institutional Review Board (IRB)/Institutional Ethics 
Committee (IEC) approval of the protocol, informed consent form, and all other subject 
information and/or recruitment material, if applicable (see Section 11.2).  All subjects or 
legally acceptable representatives must personally sign and date the IRB/IEC and 
Amgen approved informed consent form before commencement of study-specific 
activities/procedures.   
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF). 
Each subject who enters into the screening period for the study (defined when the 
subject signs the informed consent) receives a unique subject identification number 
before any study-related activities/procedures are performed.  The subject identification 
number will be assigned by the Interactive voice/web response system (IxRS).  This 
number will be used to identify the subject throughout the clinical study and must be 
used on all study documentation related to that subject.  Subjects who are determined 
not eligible after screening must be screen-failed in the IxRS system and the reason for 
the screen-failure provided.  Subjects who do not meet all eligibility criteria may be 
rescreened 1 time at the discretion of the investigator.  If a subject is being rescreened, 
he or she may need to reconsent to the study to ensure that the IRB/IEC approved main 
informed consent form is signed within 4 weeks prior to enrollment.  Subjects may only 
be enrolled once into this study.   
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened.   
5.1 
Treatment Assignment  
All subjects enrolled will receive open-label talimogene laherparepvec and atezolizumab.  
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF. 
Approved 
 
 

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6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s) and/or Medical Device(s) 
The Amgen Investigational Product used in this study includes:  talimogene 
laherparepvec.   
The Non-Amgen Investigational Product used in this study includes:  atezolizumab.  
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of talimogene laherparepvec and atezolizumab.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product:  Talimogene Laherparepvec  
Talimogene laherparepvec will be manufactured and packaged by Amgen Inc.  and 
distributed using Amgen clinical study drug distribution procedures.  Talimogene 
laherparepvec is supplied as a sterile frozen liquid in a single-use 2-cc Crystal Zenith vial 
with a gray Fluorotec®-coated chlorobutyl elastomer stopper, aluminum seal, and 
polypropylene cap.  Each vial contains a minimum of 1.0 mL talimogene laherparepvec 
at either 106 PFU/mL or 108 PFU/mL concentrations.  The supply for the 106 PFU/mL 
concentration will be packaged separately from the supply for the 108 PFU/mL 
concentration. 
6.2.1.1 
Dosage, Administration, and Schedule 
Talimogene laherparepvec must be prepared and administered by a qualified healthcare 
professional.  Subjects should be assessed clinically for adverse events/toxicity prior to 
each dose using the CTCAE version 4 (Appendix A).  Hematology, chemistry and 
coagulation panels should be obtained according to the Schedule of Assessments 
(Table 7-1) and the results should be checked before each treatment administration.  
Dosing will occur only if these test values are acceptable, per Section 6.2.2.2. 
Talimogene laherparepvec will be administered by image guided injection (either 
ultrasound or CT) into injectable liver lesions.  The first cycle of talimogene 
laherparepvec will be 21 (+ 3) days.  Subsequent cycles of talimogene laherparepvec 
will be 21(+/- 3 days).  On cycle 1, day 1, the first dose of talimogene laherparepvec will 
be up to 4.0 mL of 106 PFU/mL.  During the second cycle, talimogene laherparepvec will 
be administered up to 4.0 mL of 108 PFU/mL at week 4 of the study (± 3 days).  During 
subsequent cycles, talimogene laherparepvec will be administered up to 4.0 mL of 
108 PFU/mL every 21 days (± 3 days) thereafter.  
Approved 
 
 

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The maximum volume of talimogene laherparepvec to be administered at any treatment 
visit is 4.0 mL for any individual tumor lesion or for all tumor lesions combined.  
Investigators are encouraged to use the maximum amount when tumor lesions allow.   
The recommended volume of talimogene laherparepvec to be injected into the tumor(s) 
depends on the longest diameters of the tumor(s) and necrotic core of the tumor(s) 
(if applicable) and should be dosed according to the injection volume guideline in 
Table 6-1.  
Lesions With a Necrotic Core 
Lesions with a necrotic core contain less viable cancer cells for talimogene 
laherparepvec to infect.  Thus, there are two separate dosing guidelines depending on 
whether there is a significantly sized necrotic core (the longest diameter of the necrotic 
core is ≥ 75% of the longest diameter of the tumor) or not (Table 6-1).  When 
determining the percent of the tumor diameter that is necrotic, measurements from the 
most recent multiphase CT or MRI should be used.  However, the longest diameters of 
tumors assessed by ultrasound or CT in preparation for injection guidance of each 
treatment should be used to determine the maximum injection volumes as described in 
Table 6-1.  Talimogene laherparepvec should be injected into viable tissue and direct 
injection into necrotic tumor tissue should be avoided.  Tumors which do not have a 
large enough non-necrotic portion to reliably inject should not be injected with 
talimogene laherparepvec regardless of the overall tumor size. 
Table 6-1.  Talimogene Laherparepvec Injection Volume Guideline 
Individual Tumor Diametera 
 
< 75% tumor diameter 
necroticb 
≥ 75% tumor diameter 
necroticb 
Maximum Injection Volume 
≥ 4 cm 
≥ 5 cm 
4 mL 
≥ 2 to < 4 cm 
≥ 2.5 to < 5 cm 
2 mL 
< 2 cm 
< 2.5 cm 
1 mL 
a Longest tumor diameter assessed by ultrasound or CT in preparation for injection guidance. 
b Based on longest necrotic core diameter divided by longest tumor diameter from most recent multiphase 
computerized tomography (CT) or magnetic resonance imaging (MRI) 
Liver lesions  < 1 cm from the hepatic capsule (bleeding risk) or the right main, left main, 
or common hepatic bile ducts (biliary obstruction risk) should not be injected.  
When biopsies of metastatic liver lesions are scheduled on treatment days (Table 7-1), 
they should be performed prior to intrahepatic administration of talimogene 
Approved 
 
 

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Date:  08 July 2019 
Page 46 of 139 
CONFIDENTIAL 
 
laherparepvec.  Only metastatic liver lesions that have been visualized on screening CT 
or MRI multiphase scans used for tumor assessments should be injected prior to the first 
on study radiographic assessment at week 10 (cycle 4).   
New liver lesions that have been identified on injection guidance CT scans or ultrasound 
between scheduled tumor assessments should not be treated with talimogene 
laherparepvec until they have been visualized on tumor assessment CT or MRI scans 
and documented in the CRF.  
After the first radiographic assessment at week 10 (cycle 4), if all injectable liver lesions 
have been injected, but the 4.0 mL maximum volume has not been used, injection of 
clinically assessed non-hepatic cutaneous, subcutaneous, and nodal tumor lesions with 
or without ultrasound guidance will be permitted.  Liver lesions should be prioritized over 
cutaneous, subcutaneous and nodal lesions.  
After the initial 6 intrahepatic cycles, there is an option to continue treatment 
with talimogene laherparepvec for an additional 6 cycles.  During this additional 
dosing period (week 19 [cycle 7] to week 34 [cycle 12]), talimogene laherparepvec may 
be administered, by intralesional injection to liver metastases or cutaneous, 
subcutaneous and nodal tumor lesions, or both.  For weeks 19 to 34 (cycles 7 to 12), 
liver lesions do not need to be prioritized.  A maximum of 12 cycles (34 weeks) 
of talimogene laherparepvec are allowed during the study.  
The longest diameters of tumors assessed on the day of each treatment should be used 
to determine the maximum injection volumes per Table 6-2 for cutaneous, subcutaneous 
and nodal tumor lesions.   
Table 6-2.  Talimogene Laherparepvec Injection Volume Guideline Based on 
Tumor Size for Cutaneous, Subcutaneous, and Nodal Lesions 
Tumor Size (longest dimension) 
Maximum Injection Volume 
> 5.0 cm 
4.0 mL 
> 2.5 cm to 5.0 cm 
2.0 mL 
> 1.5 cm to 2.5 cm 
1.0 mL 
> 0.5 cm to 1.5 cm 
0.5 mL 
≤ 0.5 cm 
0.1 mL 
Approved 
 
 

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Prioritization for the first 6 cycles (16 weeks) of talimogene laherparepvec is as follows: 
 
Any new injectable metastatic liver lesion that has appeared on tumor assessment 
CT or MRI scans since the start of treatment (from newest to oldest).   
 
Metastatic liver lesions by tumor size, beginning with the largest tumor. 
 
Any metastatic liver lesion seen on tumor assessment that was previously too small 
to inject that has now become large enough to inject. 
 
Injection of non-hepatic lesions (cutaneous, subcutaneous, and nodal tumor lesions) 
is allowed after the first radiographic assessment at week 10 (ie, after 3 doses) if 
volume remains after injecting liver lesions.  
 
After the first 6 cycles (16 weeks), liver lesions do not need to be prioritized. 
It is recommended that each metastatic lesion should receive the maximum volume of 
talimogene laherparepvec possible to inject based on tumor properties at each visit 
before moving on to the next lesion, using the prioritization model above and injection 
volume guideline based on the size of the tumor lesion.  
Volumes of less than 0.05 mL should not be planned for administration into a tumor 
lesion.  Tumor lesions should be injected until the maximum volume per treatment day 
(4 mL) has been reached, or there are no further injectable tumor lesions, whichever 
comes first. 
The dose, start date, number of vials used per visit, concentration, and lot number of 
talimogene laherparepvec are to be recorded on each subject’s CRF. 
Subjects will undergo a 23-hour observation period following the first 3 doses of 
talimogene laherparepvec treatment with vital signs recorded every 30 minutes for the 
first 2 hours, hourly for the next 4 hours, then once every 4 to 6 hours.  Vital signs should 
also be recorded at the end of the observation period.  The observation period for the 
fourth dose and subsequent doses of talimogene laherparepvec may be reduced to a 
minimum of 6 hours at the investigator’s discretion with vital signs recorded every 
30 minutes for the first 2 hours and hourly for the next 4 hours and once at the end of the 
observational period.  The subjects should be observed for a longer duration or 
hospitalized, if needed, if there is clinical deterioration during the observation period.  
When possible, it is preferred that atezolizumab be administered prior to talimogene 
laherparepvec.  Talimogene laherparepvec should be administered within 23 hours of 
atezolizumab administration.  If atezolizumab is administered after talimogene 
laherparepvec, it should not be administered until the talimogene laherparepvec 
observation period has ended. 
Approved 
 
 

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Page 48 of 139 
CONFIDENTIAL 
 
Talimogene laherparepvec will be discontinued if a subject experiences a DLT (during 
the DLT evaluation period), achieves CR, has no injectable tumor lesions,  has 
confirmed PD per modified irRC-RECIST, needs alternative anticancer therapy, 
experiences an adverse event necessitating drug discontinuation, or if the investigator 
determines it is in the best interest of the subject to discontinue treatment due to rapid 
clinical deterioration, whichever occurs first.  
Due to the mechanism of action of immunotherapeutic agents, subjects may experience 
growth in existing tumors or the appearance of new tumors prior to maximal clinical 
benefit.  Therefore, talimogene laherparepvec dosing should continue, up to a maximum 
of 12 doses, provided that the subject has no evidence of confirmed PD per modified 
irRC-RECIST and is able to tolerate treatment. 
6.2.1.2 
DLT 
6.2.1.2.1 
DLT Evaluation Period 
The DLT evaluation period for a given subject will consist of the period between the 
initial 106 PFU/mL dose of talimogene laherparepvec and atezolizumab and 3 weeks 
following the initial 108 PFU/mL dose of talimogene laherparepvec and atezolizumab or 
the start of cycle 3, whichever occurs first.  To be evaluable for a DLT, subjects must 
have had the opportunity to be on treatment for at least 2 cycles from initial dose of 
study treatments and have received at least 2 doses of talimogene laherparepvec and 
two doses of atezolizumab in combination, or have a DLT during the DLT evaluation 
period after at least 1 dose of talimogene laherparepvec and atezolizumab in 
combination. 
6.2.1.2.2 
DLRT 
A DLRT composed of the investigator(s), Amgen medical monitor, Genentech 
representative, Amgen Global Safety Officer or designated safety scientist, Amgen 
Global Clinical Trial Manager and Amgen Biostatistics representative will review data 
and monitor safety, and make dose decisions (see Section 10.3.2).  
Approved 
 
 

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6.2.1.2.3 
Definition of DLT 
All toxicities will be graded using the CTCAE version 4.0 (see Appendix A).  
The occurrence of any of the following toxicities during the DLT evaluation period 
(see Section 3.1) will be considered a DLT, if judged by the investigator to be related to 
the administration of talimogene laherparepvec or atezolizumab: 
 
Grade  4 neutropenia (ANC  500/L) lasting  7 days 
 
Grade > 3 febrile neutropenia 
 
Grade > 4 thrombocytopenia 
 
Grade  4 anemia 
 
Grade  4 rash 
 
Serious herpetic events (eg, herpetic encephalitis, or disseminated herpetic infection) 
 
Grade  3 symptomatic hepatic toxicities that do not resolve to Grade  2 within 
48 hours or Grade  3 asymptomatic hepatic toxicities that do not resolve to Grade 
 1 within 3 weeks of onset with the following exception: 
o Asymptomatic grade 3 laboratory abnormality deemed clinically not 
significant by both the investigator and Amgen Medical Monitor will not be 
considered a DLT. 
 
Grade  3 non-hematologic, non-hepatic organ toxicity, excluding the following: 
o Grade 3 immune-related adverse event that resolves to Grade  1 with 
immunosuppressant therapy within 3 weeks of its onset  
o Grade 3 nausea or vomiting that resolves to Grade  1 within 72 hours of 
appropriate supportive therapy 
o Grade  3 fatigue that resolves to Grade  2 within 7 days  
o Grade 3 arthralgia that can be adequately managed with supportive care or 
that resolves to Grade  2 within 7 days 
o Grade 3 fever (in the absence of any clinically significant source of fever) that 
resolves to Grade  2 within 7 days with supportive care 
o Grade  3 laboratory abnormality that is asymptomatic and deemed by both 
the investigator and sponsor not to be clinically significant 
o Grade 3 autoimmune thyroiditis or other endocrine abnormality that can be 
managed by endocrine therapy or hormonal replacement 
o Grade 3 tumor flare defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor 
o Grade 3 infusion reaction that resolves within 6 hours to Grade  1 
 
Grade 5 toxicity (ie, death) 
 
Any other intolerable toxicity leading to permanent discontinuation of talimogene 
laherparepvec or atezolizumab 
If a subject experiences a DLT during the DLT evaluation period, study treatments will 
be discontinued for that subject.   
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6.2.1.3 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
Dose reduction for adverse events is not allowed.  However, if during the process of 
administering talimogene laherparepvec in the clinic, the subject cannot tolerate the full 
dose due to an injection-related adverse event such as pain, the total volume given 
should be recorded, and the reason for intolerance should be documented as an 
adverse event. 
If a subject experiences any of the following treatment-related toxicities, talimogene 
laherparepvec administration should be delayed until the toxicity has resolved to at least 
CTCAE grade 1 or baseline: 
 
grade 2 or greater immune-mediated adverse events, with the exception of vitiligo 
 
grade 2 or greater allergic reactions (Note:  a grade ≥ 4 rash is considered a DLT if it 
occurs during the DLT evaluation window and requires permanent discontinuation 
per Section 6.2.1.2.3) 
 
any other grade 3 or greater hematologic or non-hematologic toxicity unless deemed 
not clinically important per both investigator and sponsor.  For hepatotoxicity 
stopping and rechallenge rules see Section 6.4.  
For subjects that have an INR of > 1.5 or platelet < 50,000/mm3 (109/L) prior to injection, 
talimogene laherparepvec administration should be delayed until INR is ≤ 1.5 or platelet 
≥ 50,000/mm3 (109/L) without transfusion.  Any planned correction of INR or platelet 
count with transfusion prior to injection should be approved by the Amgen medical 
monitor. 
If a subject requires corticosteroid dosing of >10 mg prednisone daily (or equivalent), for 
treatment of atezolizumab adverse events or other reason, talimogene laherparepvec 
dosing must be withheld until the corticosteroid dose has decreased to ≤ 10 mg 
prednisone daily (or equivalent).  
If subject requires tumor necrosis factor alpha (TNF-) inhibitors for treatment of 
atezolizumab immune related adverse events, talimogene laherparepvec must be 
withheld until TNF- inhibitors are discontinued. 
All necessary supportive care shall be available to subjects except for those listed in 
Section 6.9.  Talimogene laherparepvec treatment should be continued based on the 
potential risk/benefit assessment of the subject. 
If either atezolizumab or talimogene laherparpevec is delayed due to toxicity, the cycle 
must be delayed until both investigational products can be administered safely in 
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combination.  If either atezolizumab or talimogene laherparpevec requires a delay of 
more than 2 cycles (ie, 6 weeks) because of drug toxicity, that agent should be 
permanently discontinued (see Section 6.2.2.2 dosage adjustments and delays for 
atezolizumab). 
If talimogene laherparepvec treatment was delayed by > 2 weeks, that dose will be 
deemed to have been missed and the subject will proceed to the next scheduled 
treatment visit. 
If talimogene laherparepvec dosing is withheld by > 2 cycles (ie, 6 weeks) 
(ie, approximately 9 weeks from the previous cycle) for reasons other than talimogene 
laherparepvec related adverse event (eg, delay due to necessitation of corticosteroids 
for management of atezolizumab adverse event), the investigator must contact the 
Amgen medical monitor, to determine if the subject can resume talimogene 
laherparepvec therapy without compromising the subject’s safety. 
Talimogene laherparepvec is to be permanently discontinued for subjects meeting any of 
the following criteria: 
 
Subject developed a DLT during the DLT evaluation period. 
 
Possible DILI requiring permanent withholding of talimogene laherparepvec as per 
Section 6.4. 
 
The subject, for any reason, requires treatment with alternative anti-cancer agent.  In 
this case, discontinuation from investigational product(s) should occur immediately 
upon introduction of the new agent. 
 
Confirmed PD occurs as defined per modified irRC-RECIST.   
 
A grade 2 or greater immune-mediated adverse event (with the exception of vitiligo) 
or allergic reactions attributed to talimogene laherparepvec that would require a dose 
delay of greater than 2 cycles (ie, 6 weeks) from the date of the planned dose 
(ie, approximately 9 weeks from the previous cycle). 
Note:  immune-mediated glomerulonephritis, vasculitis, and pneumonitis and 
exacerbation of psoriasis have been observed in subjects receiving talimogene 
laherparepvec in clinical trials.  Most of these subjects had a history of other 
autoimmune disease and/or prior treatment with agents that offered plausible 
alternative etiologies; however, immune-mediated adverse events can potentially 
involve any organ system. 
 
Any other talimogene laherparepvec-related non-hematologic or hematologic 
toxicities Grade 3 or greater occur that, in the opinion of the investigator, would 
require a dose delay of greater than 2 cycles (ie, 6 weeks) from the date of the 
planned dose (ie, approximately 9 weeks from the previous cycle). 
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 
A female subject becomes pregnant or fails to use acceptable method(s) of effective 
contraception (for those subjects who are able to conceive).  
 
A female subject breast feeds while on study treatment.  
 
Concurrent medical illness that, in the judgment of the investigator, would make 
continued treatment with talimogene laherparepvec dangerous for the subject. 
Dosing should be permanently discontinued if, at the discretion of the investigator, the 
subject develops clinical evidence of any serious herpes infection (such as, herpetic 
encephalitis or disseminated infection).  Systemic anti-herpetic drugs (eg, acyclovir, 
valacyclovir, or famciclovir) should only be reserved for suspected cases of severe 
herpetic infection.  Topically administered anti-herpetic drugs may be used for limited 
suspected herpetic skin lesions after they are swabbed and tested for talimogene 
laherparepvec DNA using real time polymerase chain reaction (qPCR). 
Subjects who discontinue talimogene laherparepvec are to continue to return for all other 
study procedures and measurements including the 30-day safety follow-up visit (ie, until 
30 [+ 7] days after the last dose of talimogene laherparepvec or atezolizumab, whichever 
is later) and long-term follow-up. 
For additional information related to special warnings and precautions for the use of 
talimogene laherparepvec please refer to the latest version of the talimogene 
laherparepvec Investigator’s Brochure. 
6.2.2 
Non-Amgen Investigational Product:  Atezolizumab  
The atezolizumab drug product is provided in a single-use, 20-cc United States 
Pharmacopeia (USP)/European Pharmacopoeia (Ph. Eur.) Type 1 glass vial as a 
colorless-to-slightly-yellow, sterile, preservative-free clear liquid solution intended for 
intravenous administration.  The vial is designed to deliver 20 mL (1200 mg) of 
atezolizumab solution but may contain more than the stated volume to enable delivery of 
the entire 20 mL volume.  The atezolizumab drug product is formulated as 60 mg/mL 
atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, 
pH 5.8.  Atezolizumab must be refrigerated at 2°C to 8°C (36°F to 46°F) upon receipt 
until use.  Atezolizumab vials should not be used beyond the expiration date provided by 
the manufacturer.  No preservative is used in atezolizumab drug product; therefore, the 
vial is intended for single use only.  Discard any unused portion of drug left in a vial.  Vial 
contents should not be frozen or shaken and should be protected from direct sunlight. 
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6.2.2.1 
Dosage, Administration, and Schedule 
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies.  
Atezolizumab is preferred to be given prior to talimogene laherparepvec. 
The first cycle of atezolizumab will be 21 (+ 3) days.  Subsequent cycles of atezolizumab 
will be 21 (± 3) days.  The dose level of atezolizumab is 1200 mg administered by 
intravenous infusion.  In the absence of confirmed PD per modified irRC-RECIST, 
atezolizumab treatment can continue after talimogene laherparepvec treatment has 
ended provided patient is tolerating atezolizumab and receiving clinical benefit in the 
opinion of the investigator. 
The initial dose of atezolizumab (day 1, cycle 1) will be delivered over 60 (± 15) minutes.  
If the first dose is tolerated without infusion-associated adverse events, the second dose 
(cycle 2) may be delivered over 30 (± 10) minutes.  If the 30-minute intravenous infusion 
is well tolerated, all subsequent doses may be delivered over 30 (± 10) minutes.  The 
subjects’ vital signs (heart rate, respiratory rate, blood pressure, and temperature) 
should be determined up to 60 minutes before each atezolizumab intravenous infusion.  
Vital signs should also be obtained during or after the atezolizumab intravenous infusion 
if clinically indicated. 
No premedication will be allowed for the first dose of atezolizumab.  Premedication per 
Section 6.5 may be administered for subsequent doses at the discretion of the 
investigator and should be documented in the CRF. 
6.2.2.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
There will be no dose reduction for atezolizumab in this study.   
If either atezolizumab or talimogene laherparpevec is delayed due to toxicity, the 
treatment cycle must be delayed until both investigational products can be administered 
safely in combination.  If either atezolizumab or talimogene laherparpevec requires a 
delay of more than 2 cycles (ie, 6 weeks), because of drug toxicity, that agent should be 
permanently discontinued.  
Dose interruptions for reason(s) other than toxicity, such as surgical procedures, may be 
allowed with Amgen medical monitor approval.  The acceptable length of interruption will 
depend on agreement between the investigator and the Amgen medical monitor. 
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Subjects must permanently discontinue atezolizumab treatment if they experience any of 
the following: 
 
Symptomatic deterioration attributed to disease progression as determined by the 
investigator after integrated assessment of radiographic data, biopsy results, and 
clinical status as applicable 
 
Intolerable toxicity related to study treatment, including development of an immune 
related adverse event determined by the investigator and Amgen medical monitor to 
be unacceptable given the individual subject’s potential response to therapy and 
severity of the event 
 
Any medical condition that may jeopardize the subject’s safety if he or she continues 
on study treatment 
 
Subject experiences a DLT during the DLT evaluation period 
 
Use of another non-study anti-cancer therapy  
Subjects will be permitted to continue atezolizumab after confirmed progression per 
modified irRC-RECIST criteria at the discretion of the investigators as long as the 
following criteria are met and written approval of the Amgen Medical Monitor is obtained: 
 
Evidence of clinical benefit as assessed by the investigator 
 
Absence of symptoms and signs (including worsening of laboratory values; eg, new 
or worsening hypercalcemia) indicating unequivocal progression of disease 
 
No decline in ECOG performance status that can be attributed to disease 
progression 
 
Absence of tumor growth at critical anatomical sites (eg, leptomeningeal disease).  If 
additional tumor growth occurs then it must be managed by study-allowed treatment 
procedures (refer to Section 6.6) 
 
Subjects for whom approved therapies exist must re-sign informed consent form to 
acknowledge deferring these treatment options in favor of continuing study treatment 
at the time of confirmed progression. 
Refer to the Dose Medication Guidelines for Atezolizumab Related Adverse Events in 
Appendix F and the latest Atezolizumab Investigator’s Brochure. 
6.3 
Other Protocol-required Therapies 
All other protocol-required therapies, including topical anesthetic or injectable local 
anesthetic medications used for pretreatment of the talimogene laherparepvec injection 
site and oral or systemic steroids for management of atezolizumab immune-related 
adverse events that are commercially available are not provided or reimbursed by 
Amgen (except if required by local regulation).  The investigator will be responsible for 
obtaining supplies of these other protocol-required therapies.  
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Additional details regarding these other protocol-required therapies are provided in the 
IPIM. 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with impaired liver tests (ie, ALP, AST, ALT, total bilirubin and/or international 
normalized ratio [INR] and/or signs/symptoms of hepatitis as described in Sections 6.4.1 
and 6.4.2) may meet the criteria for withholding or permanent discontinuation of 
investigational product(s) (talimogene laherparepvec and/or atezolizumab) as specified 
in the United States Food and Drug Administration Guidance for Industry Drug-Induced 
Liver Injury [DILI]:  Premarketing Clinical Evaluation, July 2009).  Immune-mediated 
hepatitis has been associated with the administration of atezolizumab.  In subjects with 
impaired liver tests, concurrent medications, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate.  Imaging of the liver, gall 
bladder, and biliary tree should be performed to rule out neoplastic or other causes for 
increasing liver test values.  Anti-nuclear antibody, perinuclear anti-neutrophil 
cytoplasmic antibody, anti-liver kidney microsomal antibodies, and anti-smooth muscle 
antibody tests should be performed if an autoimmune etiology is considered.  
Additionally, appropriate biopsies should be performed if appropriate whenever possible.  
See Table 6-3 and the latest Atezolizumab Investigator’s Brochure for management 
guidelines for subjects who develop impaired liver tests. 
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Table 6-3.  Guidelines for Management of Hepatic Events for Talimogene 
Laherparepvec and Atezolizumab 
Severity (CTCAE v4.0) 
Talimogene laherparepvec 
(withhold if atezolizumab is 
withheld) 
Atezolizumab 
(withhold if talimogene 
laherparepvec is withheld) 
Grade 1: 
ALT ≤ 3xULN; 
AST 
≤ 3xULN; 
Total bilirubin 
≤ 1.5xULN; 
ALP ≤ 2.5xULN. 
Continue 
Monitor liver function tests 
Continue 
Monitor liver function tests 
Grade 2: 
ALT > 3xULN and ≤ 5xULN; 
AST > 3xULN and ≤ 5xULN; 
Total bilirubin > 1.5xULN 
and ≤ 3xULN; 
ALP > 2.5xULN and 
≤ 5xULN. 
Continue 
Close observation of liver 
function tests (see 
Appendix A), check liver 
function tests prior to next 
dose. 
Permanently discontinue, if: 
AST or ALT > 3xULN; and 
Total bilirubin > 2xULN; and 
No other cause for the 
combination of laboratory 
abnormalities is immediately 
apparent (see 
Section 6.4.1). 
Continue if < 5 days duration 
Close observation of liver 
function tests (see 
Appendix A), check liver 
function test prior to next 
dose. 
Withhold for up to 12 weeks 
after event onset if > 5 days 
duration.  Initiate treatment 
with 1-2 mg/kg/day IV 
methylprednisolone, oral 
prednisone, or equivalent if 
deemed related to 
atezolizumab. 
Resume when liver function 
tests back to grade 1 or better 
within 12 weeks.  If steroids 
have been initiated, they must 
be tapered to < 10 mg daily of 
prednisone or equivalent 
before atezolizumab can be 
resumed. 
Permanently discontinue if the 
abnormal liver function test 
does not resolve to grade 1 or 
better within 12 weeks, or if: 
AST or ALT > 3xULN; and 
Total bilirubin > 2xULN; and 
No other cause for the 
combination of laboratory 
abnormalities is immediately 
apparent (see Section 6.4.1). 
Page 1 of 2 
Footnotes defined on last page of the table 
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Table 6-3.  Guidelines for Management of Hepatic Events for Talimogene Laherparepvec 
and Atezolizumab 
Severity (CTCAE v4.0) 
Talimogene laherparepvec 
Atezolizumab 
Grade 3: 
ALT > 5xULN and 
≤ 20xULN; 
AST > 5xULN and 
≤ 20xULN; 
Total bilirubin > 3xULN and 
≤ 10xULN; 
ALP > 5xULN and 
≤ 20xULN. 
Withhold 
if AST or ALT > 5xULN for 
≥ 2 weeks; or 
if AST or ALT > 5xULN and 
unable to adhere to 
enhanced monitoring 
schedule according to 
Appendix A, or 
if AST or ALT > 8xULN; or 
if Total bilirubin > 3xULN; or 
if ALP > 8xULN. 
Close observation of liver 
function tests (see 
Appendix A). 
Rechallenge may be 
considered if an alternative 
cause for impaired liver 
tests is discovered and the 
laboratory abnormalities 
resolve to normal/baseline. 
If signs/symptoms recur with 
rechallenge, permanent 
discontinuation. 
Permanently discontinue* 
Should be followed according 
to recommendations in 
Appendix A 
Consider starting therapy with 
1 to 2 mg/kg/day IV 
methylprednisolone, oral 
prednisone, or equivalent; if 
liver function tests do not 
decrease within 48 hours of 
initiating systemic steroids, 
addition of an alternative 
immunosuppressive agent 
may be considered. 
Taper steroids ≥ 1 month, 
when symptoms improve to 
G0/G1 
*Resumption of atezolizumab 
may be considered in subjects 
who are deriving benefit and 
fully recovered from event.  
Patient can be rechallenged 
only after discussion with and 
agreement of Amgen Medical 
Monitor. 
Grade 4: 
ALT > 20xULN; 
AST > 20xULN; 
Total bilirubin > 10xULN; 
ALP > 20xULN. 
Permanently discontinue 
Contact Amgen Medical 
Monitor 
Permanently discontinue 
Contact Amgen Medical 
Monitor 
Page 2 of 2 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; TNF-α = tumor necrosis 
factor α; ULN = upper limit of normal 
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6.4.1 
Criteria for Permanent Discontinuation of Talimogene 
Laherparepvec and/or Atezolizumab Due to Potential Hepatotoxicity 
Talimogene laherparepvec and/or atezolizumab, should be discontinued permanently 
and the subject should be followed according to the recommendations in Appendix A 
(Additional Safety Assessment Information and Drug-induced Liver Injury Reporting & 
Additional Assessments) for possible DILI, if ALL of the criteria below are met:  
 
Current total bilirubin > 2x ULN following baseline total bilirubin < ULN or INR > 1.5 
 
AND current AST or ALT > 3x ULN following baseline AST or ALT < ULN 
respectively 
 
AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
total bilirubin values include, but are not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.   
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms   
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation 
(eg, indinavir, atazanavir) 
 
Alpha-one antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis  
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic Fatty Liver Disease including Steatohepatitis  
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, determine (based on patient population and/or 
severity of the hepatotoxicity or event) if talimogene laherparepvec and/or atezolizumab 
should be withheld or permanently discontinued, as deemed appropriate for the safety of 
the subject. 
6.4.2 
Criteria for Conditional Withholding of Talimogene Laherparepvec 
and/or Atezolizumab Due to Potential Hepatotoxicity 
For subjects who do not meet the criteria for permanent discontinuation of talimogene 
laherparepvec outlined above and have no underlying liver disease, and eligibility criteria 
requiring normal transaminases and total bilirubin at baseline or subjects with underlying 
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liver disease and baseline abnormal transaminases, the following rules are 
recommended for withholding of Amgen investigational product:  
 
Elevation of either AST or ALT according to the following schedule: 
Baseline AST or ALT value 
AST or ALT elevation  
≤ 3 x ULN 
> 5 x ULN for ≥ 2 weeks 
≤ 3 x ULN 
> 5 x ULN and unable to adhere to enhanced monitoring 
schedule 
≤ 5 x ULN 
> 8 x ULN at any time 
 
OR:  total bilirubin > 3x ULN at any time 
 
OR:  ALP > 8x ULN at any time 
Talimogene laherparepvec and atezolizumab should be withheld pending investigation 
into alternative causes of DILI.  If investigational product(s)  is/are withheld, the subject 
is to be followed according to recommendations in Appendix A for possible DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP and/or elevated total bilirubin), is discovered and the laboratory abnormalities 
resolve to normal or baseline (Section 6.4.3).   
6.4.3 
Criteria for Rechallenge of Talimogene Laherparepvec and/or 
Atezolizumab After Potential Hepatotoxicity 
The decision to rechallenge the subject should be discussed and agreed upon 
unanimously by the investigator and Amgen medical monitor and between the 
investigator and patient. 
If signs or symptoms recur with rechallenge, then talimogene laherparepvec and/or 
atezolizumab should be permanently discontinued.  Subjects who clearly meet the 
criteria for permanent discontinuation (as described in Section 6.4.1) should never be 
rechallenged without discussing with the Amgen medical monitor. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.9. 
Subjects who experience atezolizumab infusion-associated symptoms may be treated 
symptomatically with acetaminophen, diphenhydramine, and/or famotidine or another 
H2 receptor antagonist, as per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice).  Serious atezolizumab 
related infusion associated events manifested by dyspnea, hypotension, wheezing, 
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bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should 
be managed with supportive therapies as clinically indicated (eg, supplemental oxygen 
and β2-adrenergic agonists).   
Systemic corticosteroids and TNF- inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician after consultation with the Amgen medical monitor.  If 
corticosteroids (prednisone > 10 mg or equivalent daily) or TNF- inhibitors are needed 
for treatment of atezolizumab immune related adverse events, talimogene laherparepvec 
must be withheld until the corticosteroid dose is ≤ 10 mg prednisone or equivalent daily 
or TNF- inhibitors are discontinued (see Section 6.2.1.3).  If feasible, alternatives to 
corticosteroids should be considered.   
Premedication may be administered for the second and all subsequent doses of 
atezolizumab at the discretion of the treating physician (see Section 6.2.2.1) The use of 
inhaled corticosteroids and mineralocorticoids (eg, fludrocortisone) for subjects with 
orthostatic hypotension or adrenocortical insufficiency is allowed. 
Inactivated influenza vaccination may be given but only during influenza season.  
However, subjects must not receive live, attenuated influenza vaccine (eg, FluMist®) 
within 4 weeks prior to the first dose of talimogene laherparepvec and atezolizumab  
(day 1) or at any time during the study and an additional 5 months after the last dose of 
talimogene laherparepvec or atezolizumab, whichever is later. 
All concomitant therapies are to be collected in the CRF from informed consent through 
30 (+ 7) days after the last dose of talimogene laherparepvec or atezolizumab, 
whichever comes later.  
For concomitant therapies collect therapy name, indication, dose, unit, frequency, route, 
start date, and stop date. 
6.6 
Other Treatment Procedures 
Local radiation treatment to the site of bone and other metastasis will be permitted for 
palliative pain management at any time during the study.  Subjects with local symptoms 
suggestive of disease progression should undergo tumor assessment prior to the 
administration of palliative radiotherapy.  If a subject undergoes local radiation, study 
treatment should be withheld, and the investigator or designee should notify the Amgen 
medical monitor. 
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If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld.  After discussion between the Amgen medical monitor 
and the investigator to determine the appropriateness of treatment resumption provided 
CNS metastases are adequately treated, subjects may be allowed to remain on study.  
In addition, in order to resume talimogene laherparepvec or atezolizumab, corticosteroid 
dose must not exceed 10 mg of prednisone or equivalent daily.  Re-exposure to 
talimogene laherparepvec and atezolizumab may occur only if the investigator and 
sponsor agree that the subject safety will not be compromised.  
6.7 
Medical Devices 
Medical devices (eg, syringes, sterile needles, alcohol prep pads) that are commercially 
available are not usually provided or reimbursed by the Sponsor (except, for example, if 
required by local regulation).  The investigator will be responsible for obtaining supplies 
of these devices. 
6.8 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s) or device(s) provisioned and/or repackaged/modified by 
Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) supplied by Amgen are to be reported according to the 
instructions provided in the IPIM. 
6.9 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
Subjects must not use any of the following therapies during treatment period: 
 
other investigational agents or procedures   
 
concurrent experimental or approved antitumor therapies other than protocol 
specified therapies and radiation therapy required for symptom palliation.   
 
immunosuppressive agents with the exception of treatment for adverse events 
o If the subject requires corticosteroid dosing for related toxicities 
(eg, prednisone >10 mg or equivalent), talimogene laherparepvec dosing 
must be withheld until the corticosteroid dose is able to be decreased to 
≤ prednisone 10 mg (or equivalent) daily.  
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 
Subjects who are receiving talimogene laherparepvec may not receive 
antiherpetic drugs (eg, acyclovir) with the exception of treatment for adverse 
events, but may receive a topically administered antiherpetic drug more than 
20 cm from a talimogene laherparepvec injection site. 
 
Subjects who are receiving a nuclear factor-kappa B ligand (RANKL) inhibitor 
prior to enrollment must be willing and eligible to receive a bisphosphonate 
instead; RANKL inhibitors could potentially alter the activity and the safety of 
atezolizumab. 
 
Immunostimulatory agents not part of study treatment, including but not limited to 
interferon-gamma or interleukin-2; these agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions.  In 
addition, subjects should not receive immunostimulatory agents for 10 weeks 
after the last dose of atezolizumab. 
 
azathioprine, methotrexate, and thalidomide; these agents could potentially alter 
the activity and the safety of atezolizumab.  Systemic corticosteroids, TNF- 
inhibitors, mycophenolate and other immune suppressants may be administered 
for the treatment of immune-related toxicities at the discretion of the treating 
physician after consultation with the Amgen medical monitor. 
 
Subjects must not schedule any elective non-cancer-related surgeries during the 
treatment period and for at least 30 days after the last administration of study 
treatment.  If a subject undergoes any unexpected surgery during the course of 
the study, study treatment must be withheld and the investigator or designee 
should notify the Amgen medical monitor as soon as possible.  A subject may be 
allowed to resume study treatment if both the investigator and Amgen medical 
monitor agree to restart. 
6.10 
Contraceptive Requirements 
Female of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Female in the following categories are not considered of child bearing potential: 
1. Premenopausal female with 1 of the following: 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is acceptable:  
1) review of subject medical records, 2) subject medical examination, or 3) subject 
medical history interview. 
2. Premenarchal female 
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3. Postmenopausal female 
a. A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state 
in women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
b. Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they 
wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
6.10.1 
Female Subjects 
Female subjects of childbearing potential must agree to use one acceptable method of 
effective contraception (as described in the table below) during treatment and for an 
additional 5 months after the last dose of talimogene laherparepvec or atezolizumab.   
Acceptable Methods of Effective Contraception for Female Subjects 
 
Combined (estrogen and progestogen) or Progestogen-only hormonal methods 
given via oral, transdermal, injectable, or implantable route) 
 
Intrauterine device (IUD) 
 
Intrauterine hormonal-releasing system (IUS) 
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (Provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (Defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments.  The reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject.) 
 
Double barrier method:  the male uses a condom and the female may choose either 
a cap, diaphragm, or sponge with spermicide.  (A female condom is not an option 
due to the risk of tearing when both partners use a condom.) 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.   
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6.10.2 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to fetus if they become pregnant during treatment and for 
5 months after the last dose of talimogene laherparepvec or atezolizumab.   
7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments  
For Schedule of Assessments please refer to Table 7-1. 
 
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Table 7-1.  Schedule of Assessments 
 Period 
Screening  
Treatment a 
Safety 
Follow- 
upb 
Long-term 
Follow-upc  
Cycles 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and 
beyond 
 
 
Weeks 
- 4 weeks 
1      
(day 1) 
4 
7 
10 
13 
16 
19 
22 
25 
28 
31 
34 
 Every 
3 weeks 
after 
week 34 
 
  
General Assessments 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical Historyd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signse 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Performance Status:  ECOG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Record disease related events, 
adverse events & serious adverse 
eventsf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
Survival Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xc 
Local Laboratory Tests 
Hepatitis B surface antigen and core 
antibody/Hepatitis C virus antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy testg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Thyroid function (TSH, Free T3 & 
Free T4h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 2 
Footnotes defined on next page of table 
 
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Table 7-1.  Schedule of Assessments 
 Period 
Screening  
Treatment a 
Safety 
Follow- 
upb 
Long-term 
Follow-upc  
Cycles 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 and 
beyond 
 
 
Weeks 
- 4 weeks 
1      
(day 1) 
4 
7 
10 
13 
16 
19 
22 
25 
28 
31 
34 
 Every 
3 weeks 
after 
week 34 
 
  
Local Laboratory Tests 
Tumor markers (eg. CA 27.29, CA 
15-3 or CEA and CA 19-9) as 
applicablei 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Xn 
X 
 
Central Laboratory Tests 
Archival tumor sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HSV-1 serostatus 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Swab for Herpetic tumor for qPCR 
Within 3 days of event if applicable 
 
Liver tumor biopsyj 
 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Blood for biomarker analysisk 
 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
 
Response Assessments 
Radiographic (CT, PET/CT, or MRI) 
Scans +/- bone scansl 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xn 
Xl 
Xl 
Clinical Tumor Assessmentsm 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xn 
 
X 
Treatment Administration 
Atezolizumab administration 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Talimogene laherparepvec 
administrationa 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Reporting Exposure to Talimogene Laherparepvec 
Exposure of Subject’s Healthcare 
Provider 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
X 
 
Exposure of Subject’s Household 
Member or Caregiver 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
X 
 
Page 2 of 2 
CA 19.9 = cancer antigen 19-9; CA 27.29 = cancer antigen 27.29; CA 15-3 = cancer antigen 15-3; CEA carcinoembryonic antigen; CNS = central nervous system; 
CT = computerized tomography; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; HIV = human immunodeficiency virus; HSV-1 = herpes 
simplex virus type 1; irRC-RECIST = immune-related response criteria simulating Response Evaluation Criteria in Solid Tumors; MRI = magnetic resonance imaging; 
PET = positron emission tomography; qPCR = real-time polymerase chain reaction; TSH =  thyroid stimulating hormone; T3 = triiodothyronine;T4 = thyroxine; 
ULN = upper limit of normal 
 
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a After the initial 6 intrahepatic cycles of talimogene laherparepvec, there is an option to continue treatment with talimogene laherparepvec for an additional 6 cycles.  
During this additional dosing period (cycles 7 to 12), talimogene laherparepvec may be administered, by intralesional injection to liver metastases or cutaneous, 
subcutaneous and nodal tumor lesion, or both.  For cycles 7 to 12, liver lesions do not need to be prioritized.  A maximum of 12 cycles 
of talimogene laherparepvec are allowed during the study.  In the absence of confirmed PD per modified irRC-RECIST, atezolizumab treatment can continue after 
talimogene laherparepvec treatment has ended provided patient is tolerating atezolizumab and receiving clinical benefit in the opinion of the investigator.  
b Safety follow-up will be performed approximately 30 (+ 7) days after the last dose of study treatment.  
c Subjects will be followed for survival every 12 weeks (± 28 days) from the date of the safety follow-up visit until up to approximately 24 months after the last subject is 
enrolled.  Subsequent cancer treatments will be collected as part of the long-term follow-up survival assessment.  In addition, talimogene laherparepvec related 
adverse events that occur after the safety follow-up visit through the end of the long-term follow-up will be reported.  
d For subjects with metastatic colorectal cancer, if known, KRAS, NRAS, BRAF, and MSI test results (including date of testing and assay used) are to be recorded in a 
separate eCRF at the time of enrollment or at the subsequent time that the results become available.  See Section 7.3.3. 
e Subjects will undergo a 23-hour observation period following the first 3 doses of talimogene laherparepvec treatment with vital signs recorded every 30 minutes for the 
first 2 hours, hourly for the next 4 hours, then once every 4 to 6 hours.  Vital signs should also be recorded at the end of the observation period.  After the fourth dose 
of talimogene laherparepvec, the observation period for subsequent doses may be reduced to a minimum of 6 hours at the investigator’s discretion with vital signs 
recorded every 30 minutes for the first 2 hours and hourly for the next 4 hours and once at the end of the observational period.  The subjects’ vital signs (heart rate, 
respiratory rate, blood pressure, and temperature) should be determined up to 60 minutes before each atezolizumab intravenous infusion.  Vital signs should also be 
obtained during or after the atezolizumab intravenous infusion if clinically indicated. 
f Serious adverse events are reportable 90 days after last treatment dose. 
g Serum pregnancy test must be done within 1 week prior to enrollment. 
h Thyroid function tests must be collected, but if there are no symptoms of hypothyroidism or hyperthyroidism study treatment can be initiated prior to the reporting of 
the laboratory results. 
i Tumor marker measurement is required to confirm CR if baseline level of tumor marker was above the ULN and criteria for CR per modified irRC-RECIST guidelines 
are met.  Blood samples for tumor biomarkers are to be collected prior to administration of investigational agent/s per Schedule of Assessments.  Tumor marker 
measurements should be performed according to institutional guidelines and availability.   
j Liver tumor biopsies:  screening biopsy should only be performed for those subjects who have no prior biopsy to confirm that their disease is one of the eligible tumor 
types.  Those that have had prior pathology reports supporting their diagnosis do not need screening biopsy.  During treatment liver tumor biopsies will be performed 
immediately prior talimogene laherparepvec administration at weeks 1, 7, and 16.  Screening biopsy may be used for baseline (week 1) biopsy if the subject is 
eligible, provided enough tissue has been obtained.  One injected lesion should be biopsied at each time point.  If there are uninjected lesions that are suitable for 
biopsy at week 7 and/or week 16, one uninjected lesion should also be biopsied at that time prior to talimogene laherparepvec administration. 
k Blood will be collected for biomarker analysis prior to any study drug (atezolizumab and talimogene laherparepvec) administration and approximately 4 hours 
(± 30 minutes) following talimogene laherparepvec administration. 
l CT/MRI brain required at screening for triple negative breast cancer subjects.  An MRI scan of the brain is required to confirm or refute the diagnosis of CNS 
metastases at baseline in the event of an equivocal scan.  Only colorectal cancer subjects with signs/symptoms for CNS metastases need to have brain imaging.  
During treatment, radiographic tumor imaging and clinical tumor assessments will be performed independent of treatment cycle at week 10 (± 1 week) and then every 
9 weeks (± 1 week) until confirmed disease progression (PD).  Of note, atezolizumab is permitted to continue beyond confirmed PD in which case radiographic tumor 
imaging should continue until the subject discontinues treatment.  Radiographic imaging is only required at the safety follow-up visit if subject ended treatment prior to 
documentation of confirmed PD per modified irRC-RECIST and has not had radiographic tumor imaging performed within 9 (± 1) weeks of the visit and has not 
started new anti-cancer therapy.  In the case that the subject discontinues therapy prior to documentation of confirmed PD per modified irRC-RECIST, every effort 
should be made to complete radiographic assessments during the long-term follow-up approximately every 12 weeks (+ 28 days) until documented confirmed PD per 
modified irRC-RECIST, start of new anticancer treatment, death, or end of study, whichever occurs first.   
 
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m Clinical measurements of cutaneous, subcutaneous, and palpable nodule tumor lesions by caliper should be measured at baseline as well as at subsequent tumor 
assessments.  For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is suggested. 
n Every 3 cycles (approximately 9 weeks) 
o Subjects should be monitored for potential exposure cases that occur after the last dose of talimogene laherparepvec through 30 (+ 7) days after the last dose of 
talimogene laherparepvec. 
 
 
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7.2 
General Study Procedures  
The procedures performed and timing of each study visit are outlined in the Schedule of 
Assessments (Table 7-1).  Details regarding each type of procedure are provided in 
subsequent subsections.  Procedures that are part of routine care are not considered 
study-specific procedures and may be used at screening to determine eligibility. 
Refer to the applicable supplemental central laboratory, IxRS, IPIM, and study manuals 
for detailed collection and handling procedures.   
7.2.1 
Screening and Enrollment 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy or any disallowed therapy.  After signing the written 
informed consent form, the site will register the subject in IxRS and screen the subject in 
order to assess eligibility for participation.  Screening procedures are to be completed 
during the screening period within 4 weeks prior to enrollment.  If a subject has not met 
all eligibility criteria at the end of the 4-week window, the subject will be registered as a 
screen fail.  Screen fail subjects may be eligible for re-screening once as described in 
Section 7.2.2.  Prior to enrollment, subject eligibility must be confirmed with screening 
procedures.  Subjects satisfying eligibility requirements will be enrolled.  The time points 
for the procedures to be completed during the screening period are designated in the 
Schedule of Assessments. 
7.2.2 
Re-screening 
Subjects who are unable to complete or meet eligibility on initial screening will be 
permitted to re-screen once.  Re-screen subjects must first be registered as screen 
failed in IxRS and subsequently registered as re-screened.  Subjects will retain the same 
subject identification number assigned at the original screening.  Once the subject is 
registered as re-screened, a new 4 week screening window will begin.  If the 
re-screening period begins more than 4 weeks after the original signing of the informed 
consent form, all screening procedures, including informed consent must be repeated.  If 
the re-screening occurs less than 4 weeks after the original signing of the informed 
consent, then only those criteria that were originally failed are required to be repeated  
provided the tests that meet criteria fall within the time frame of the screening window. 
7.2.3 
Treatment 
During the treatment period, visits will occur per the Schedule of Assessments 
(Table 7-1).  The date of the first dose of investigational products is defined as day 1 
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(week 1).  All subsequent doses and study visits will be scheduled based on the day 1 
date.  On-study visits may be completed within ± 3 days of the planned visit date.  
Investigational product administration should begin as soon as possible after enrollment 
via IxRS but no later than 5 days after enrollment.  Investigational products are to be 
administered after all other study procedures are completed, during each visit that it is 
required.  It is recommended that dosing occur on the same day of the week (eg, if first 
dose is administered on Monday, all subsequent doses should be administered on a 
Monday), however a ± 3 day dosing and study procedure window is allowed unless 
specified otherwise. 
7.2.4 
Follow-up 
7.2.4.1 
Safety Follow-up 
All subjects will complete a safety follow-up visit approximately 30 (+ 7) days after the 
last dose of study treatment.  The time points for the procedures to be completed during 
the safety follow-up period are designated in the Schedule of Assessments.   
7.2.4.2 
Long-Term Follow-up 
After the safety follow-up visit subjects will enter the long-term follow-up.  Subjects will 
be contacted to assess survival and initiation of additional anticancer therapy.   
Contact for all subjects will be attempted every 12 weeks (± 28 days) following the safety 
follow-up visit until death, subject or legally acceptable representative withdraws full 
consent/assent, or up to 24 months after the last subject is enrolled, whichever comes 
first.  Anticancer therapies and treatment related adverse events that occur through the 
end of the long-term follow-up will be reported. 
For subjects who discontinued treatment for any reason other than confirmed PD every 
effort should be made to perform radiographic scans for tumor assessments every 
12-weeks (± 28 days) until documentation of confirmed PD per modified irRC-RECIST, 
start of new anticancer therapy, or end of study, whichever occurs first. 
Subjects who are alive at the end of study and received talimogene laherparepvec, will 
be consented and followed for long term survival and safety on the registry study 
(see Section 3.1) 
7.3 
Description of Study Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 
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7.3.1 
Informed Consent 
All subjects or legally acceptable representative must sign and personally date the 
IRB/IEC approved informed consent and if required the subject has provided assent 
before any study specific procedures are performed.  
7.3.2 
Demographic Data 
Demographic data including sex, age, race, and ethnicity will be collected in order to 
study their possible association with subject safety and treatment effectiveness.  
Additionally, demographic data will be used to study the impact of the protocol-required 
therapy on biomarkers variability. 
7.3.3 
Medical History 
The investigator or designee will collect complete medical and surgical history.  Medical 
history will include information on the subject’s concurrent medical conditions, clinically 
significant diseases, surgeries, cancer history (including prior cancer procedures and 
assessment of tumor mutational status and tumor molecular characteristic), reproductive 
status, smoking history, use of alcohol and drugs of abuse.  For subjects with metastatic 
colorectal cancer, if known, KRAS, NRAS, BRAF, and MSI test results (including assay 
used) are to be recorded in a separate eCRF at the time of enrollment or at the 
subsequent time that the results become available.  The current severity will be collected 
for each condition that has not resolved.  Triple negative breast cancer and colorectal 
cancer history must date back to the original diagnosis.  Record all findings on the 
medical history CRF. 
7.3.4 
Prior Therapies 
Prior therapies (eg, prescription drugs, over-the-counter drugs, herbal or homeopathic 
remedies, nutritional supplements) that were being taken from 4 weeks prior to 
screening through informed consent should be collected.  
For prior therapies, therapy name, indication, dose, unit, frequency, and start and stop 
date will be collected for all prior therapies taken for current or prior malignancies. 
7.3.5 
Concomitant Therapy 
All concomitant medications that are administered after the subject has signed informed 
consent through 30 (+ 7) days after the last administration of study treatment will be 
recorded in the CRF (refer to Section 6.5).  Concomitant medications should be 
assessed on an ongoing basis and recorded at each subject visit.  Only subsequent 
anticancer therapy will be recorded during the long-term follow-up period. 
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7.3.6 
Adverse Events, Disease Related Events and Serious Adverse 
Events 
Safety event reporting procedures are described in Section 9.2.  
7.3.7 
Physical Examination 
A physical examination will be performed at screening per standard of care.  At 
subsequent visits (or as clinically indicated), limited, symptom-directed physical 
examinations should be performed.  Changes from baseline abnormalities should be 
recorded in patient notes.  New or worsened clinically significant abnormalities should be 
recorded as adverse events on the adverse event CRF.  Physical examination findings 
should be recorded on the appropriate CRF (eg, medical history, event).  
7.3.8 
Vital Signs 
Vital signs (including systolic/diastolic blood pressure, heart rate, respiratory rate, and 
temperature):  Subjects must be in a supine position in a rested and calm state for at 
least 5 minutes before blood pressure assessments are conducted.  If the subject is 
unable to be in the supine position, the subject should be in most recumbent position as 
possible.  The position selected and temperature location for a subject should be the 
same that is used throughout the study and documented on the vital sign CRF.  Record 
all measurements on the vital signs CRF. 
Vital signs should be obtained prior to investigational product administration and if 
necessary during and after administration of study treatment(Refer to Section 6.2.1.1 
and Section 6.2.2.1). 
7.3.9 
Physical Measurements 
Body weight will be recorded in kilograms. 
7.3.10 
ECG 
A 12-lead electrocardiogram (ECG) will be performed per standard of care.  Subject 
must be in supine position in a rested and calm state for at least 5 minutes before ECG 
assessment is conducted.  If the subject is unable to be in the supine position, the 
subject should be in most recumbent position as possible.  The ECG must include the 
following measurements:  heart rate, PR interval, QRS, QT and QTc intervals.  The 
investigator or designated site physician will review all ECGs.  Once signed, the original 
ECG tracing will be retained with the subject’s source documents.  At the request of the 
sponsor, a copy of the original ECG will be made available to Amgen. 
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7.3.11 
ECOG  
ECOG performance status will be collected as outlined in Appendix E. 
7.3.12 
Reporting of Exposure to Talimogene Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec on this study is suspected to have 
been exposed to talimogene laherparepvec (eg, have or who have had signs or 
symptoms suspected to be herpetic in origin or who have been accidentally exposed to 
talimogene laherparepvec), while the subject is taking talimogene laherparepvec, the 
exposure must be reported to Amgen.  Refer to Section 9.4. 
7.3.13 
Tumor Assessments 
7.3.13.1 
Clinical Tumor Assessments 
Clinical measurements of cutaneous, subcutaneous, and palpable nodal tumor lesions 
by caliper should be measured at baseline as well as at subsequent tumor assessments.  
For the case of skin lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested to aid tracking.  Photographs are not 
required for the study; therefore, photographic equipment will not be provided. 
Clinically applicable tumor measurements include but are not limited to cancer antigen  
27.29 (CA 27.29), cancer antigen 15-3 (CA 15-3), carcinoembryonic antigen (CEA), and 
cancer antigen 19-9 (CA 19-9).  Blood samples for tumor biomarkers are to be collected 
prior to administration of investigational agent/s per Schedule of Assessments 
(Table 7-1).  Tumor marker measurements should be performed according to 
institutional guidelines and availability.  Tumor marker measurement is required to 
confirm CR if screening level of tumor marker was above the ULN and criteria for CR per 
modified irRC-RECIST guidelines are met. 
7.3.13.2 
Radiographic Tumor Assessment 
All known sites of disease must be documented at screening and reassessed at each 
subsequent tumor evaluation. 
Screening assessments must include CT scans (with oral/IV contrast unless 
contraindicated) or MRI of the chest, abdomen, and pelvis.  A spiral CT scan of the chest 
may be obtained but is not a requirement.  An MRI or a non-contrast CT scan of the 
chest, abdomen, and pelvis may be used in subjects for whom CT scans with contrast 
are contraindicated (ie, subjects with contrast allergy or impaired renal clearance).  If a 
subject had imaging as part of standard of care, it does not need to be repeated 
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provided it is of adequate quality as outlined above and falls within the screening 
window. 
A CT (with contrast) or MRI scan of the brain must be done at screening to evaluate 
CNS metastasis in all subjects with triple negative breast cancer.  A brain scan is only 
required for colorectal cancer subjects if they present with signs/symptoms of CNS 
metastasis.  An MRI scan of the brain is required to confirm or refute the diagnosis of 
CNS metastases at baseline in the event of an equivocal scan.  Subjects with active or 
untreated CNS metastases are not eligible for this study.  
If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a 
full-contrast diagnostic CT scan. 
Bone scans should also be performed if clinically indicated.  At the investigator’s 
discretion, other methods of assessment of measurable disease as per modified 
irRC-RECIST may be used (Appendix D). 
The same radiographic procedure used to assess disease sites at screening should be 
used throughout the study (eg, the same contrast protocol for CT scans).  All known 
sites of disease must be documented at screening and re-assessed at each subsequent 
tumor evaluation.  Response will be assessed by the investigator using modified 
irRC-RECIST criteria (Appendix D).  Assessments should be performed by the same 
evaluator if possible to ensure internal consistency across visits. 
7.4 
Laboratory Assessments  
On-treatment tests can be performed within 3 days of the treatment visit.  Results should 
be reviewed prior to the administration of study treatment.  All tests (except for real-time 
polymerase chain reaction [qPCR], HSV-1 antibody, archival tumor sample, liver tumor 
biopsy and blood for biomarkers) are to be performed at the local laboratory.  Specific 
analytes for serum chemistry, coagulation, hematology, urinalysis, and other testing to 
be conducted on blood, urine and swabs are below (Table 7-2).  During treatment, 
assessments and procedures can be performed within 3 days of the planned visit unless 
specified in study procedures. 
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Table 7-2.  Laboratory Analytes 
Local Laboratory 
Serum Chemistry 
Local 
Laboratory 
Coagulation 
Local 
Laboratory 
Hematology 
Local Laboratory 
Urinalysis 
Other Labs 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
Magnesium 
Phosphorus 
Total protein 
Albumin 
BUN or Urea 
Creatinine 
Total bilirubin 
ALP 
AST 
ALT 
Glucose 
LDH 
TSH 
Free T3 
Free T4 
 
PT or INR 
aPTT or PTT 
Red blood cell 
count 
Hemoglobin 
Hematocrit 
Platelets 
White blood cell 
count 
Differential a 
 ANC 
 Eosinophilsd 
 Basophils 
 Lymphocytes 
 Monocytes 
 Total 
neutrophils 
or 
segmented 
neutrophils 
and bands 
Specific gravity 
pH 
glucose 
protein 
ketones 
blood 
Local Laboratory 
Serum pregnancy test 
Hepatitis B surface 
antigen and Hepatitis 
B core antibody 
Hepatitis C virus 
antibody 
HIV antibody 
Tumor markers CEA, 
tumor markers (if 
clinically applicable) 
CA 15-3b 
CA 27.29b 
CEA & CA 19-9c 
Central Laboratory 
Archival tumor sample 
qPCR for talimogene 
laherparepvec DNA 
HSV-1 antibody 
Liver tumor biopsy 
Biomarker analysis 
Biopsy Lab 
PD-L1 & CD8 IHC 
ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time ;AST = aspartate 
aminotransferase; ALT = alanine aminotransferase; BUN = blood urea nitrogen; CA 19-9 = cancer antigen 
19-9; CA 15-3 = cancer antigen 15-3; CA 27.29 =  cancer antigen 27.29; CEA = carcinoembryonic antigen; 
DNA = deoxyribonucleic acid; free T3=free triiodothyronine; free T4 = free thyroxine; HIV =  human 
immunodeficiency virus; HSV-1 = herpes simplex virus type-1; IHC = immunohistochemistry; 
INR = international normalization ratio; LDH = lactate dehydrogenase; PD-L1 = programmed cell death 
ligand-1; PT = prothrombin time; qPCR = real-time polymerase chain reaction; TSH = thyroid stimulating 
hormone 
a 3-part differential (neutrophils, eosinophils, basophils) acceptable if 5-part unable to be performed 
b only in subjects with triple negative breast cancer 
c only in subjects with colorectal cancer 
7.4.1 
qPCR for Talimogene Laherparepvec 
Swab of cold sore, vesicles and other lesions suspected to be herpetic in origin (if any) 
for qPCR testing of talimogene laherparepvec DNA must be collected.  Subject should 
return to the clinic within 3 days of the occurrence of a reportable lesion suspected to be 
herpetic in origin.  The lesion should be evaluated by the investigator and swabbed if 
HSV infection is suspected.  A qPCR analysis will be performed on the swab sample by 
the central laboratory to evaluate whether the talimogene laherparepvec DNA is 
detectable in the sample. 
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7.5 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to investigational product(s) or protocol-required therapies. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to investigational product(s) (eg, Amgen or non-Amgen 
investigational product or protocol-required therapies).  
7.5.1 
Blood Samples 
Blood samples are to be collected for biomarker development prior to any study drug 
(atezolizumab and talimogene laherparepvec) administration and approximately 4 hours 
(± 30 minutes) following talimogene laherparepvec administration per the schedule of 
assessments at the following time points:  at day 1 (week 1), week 4, week 7, week 16, 
and at the safety follow-up visit (baseline only). 
7.5.2 
Archival Tumor Samples 
For archival tumor samples that should be submitted within the first 4 weeks after 
enrollment, a block of formalin-fixed paraffin-embedded tumor tissue collected prior to 
the study is to be sent to the central laboratory along with the corresponding pathology 
report.  The tumor block is to be carefully selected by a pathologist or a skilled 
experienced histology associate to include generous tumor tissue using the pathology 
report as a guide.  In lieu of a block, approximately 20 unstained sections on charged 
slides from the same block can be submitted.  When the samples of tumor tissues are 
available, analyses of tumor specific mutations or epigenetic changes may be performed 
(eg, somatic mutations). 
7.5.3 
Liver Tumor Biopsies 
Liver tumor biopsies will be performed immediately prior to the talimogene 
laherparepvec administration at weeks 1, 7 and 16.  Screening biopsy may be used for 
baseline (week 1) biopsy if subject is eligible, provided enough tissue has been 
obtained.  A screening biopsy is only required if the subject does not have histologically 
or cytologically confirmed disease required to confirm eligibility. 
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One injected lesion should be biopsied at each time point.  If there are uninjected lesions 
that are suitable for biopsy at week 7 and/or week 16, one uninjected lesion should also 
be biopsied at that time prior to talimogene laherparepvec administration.  
Refer to Laboratory Manual for further detail on tumor biopsy procedures. 
7.6 
Pharmacogenetic Studies 
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  The goals of the optional studies 
include the use of genetic markers to help in the investigation of cancer and/or to identify 
subjects who may have positive or negative responses to talimogene laherparepvec 
and/or atezolizumab.  No additional samples are collected for this part of the study.  For 
subjects who consent to this/these analysis/analyses, DNA may be extracted. 
7.7 
Sample Storage and Destruction  
Any blood or tumor sample collected according to the Schedule of Assessments 
(Table 7-1) can be analyzed for any of the tests outlined in the protocol and for any tests 
necessary to minimize risks to study subjects.  This includes testing to ensure analytical 
methods produce reliable and valid data throughout the course of the study.  This can 
also include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples and associated results will be coded prior to being shipped from the site for 
analysis or storage.  Samples will be tracked using a unique identifier that is assigned to 
the samples for the study.  Results are stored in a secure database to ensure 
confidentiality.   
If informed consent is provided by the subject or legally acceptable representative, 
Amgen can do additional testing on remaining samples (ie, residual and back-up) to 
investigate and better understand the cancer, the dose response and/or prediction of 
response to talimogene laherparepvec and characterize aspects of the molecule 
(eg, mechanism of action/target, metabolites).  Results from this analysis are to be 
documented and maintained, but are not necessarily reported as part of this study.  
Samples can be retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of pharmacogenetic or other exploratory studies are not 
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placed in the subject’s medical record and are not to be made available to the subject, 
members of the family, the personal physician, or other third parties, except as specified 
in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
blood samples and any other components from the cells can be located and destroyed.  
Samples will be destroyed once all protocol-defined procedures are completed.  
However, information collected from samples prior to the request for destruction, will be 
retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or undergoing 
procedures at any time during the study but continue participation in the study.  If this 
occurs, the investigator is to discuss with the subject the appropriate processes for 
discontinuation from investigational product or other protocol-required therapies and 
must discuss with the subject the options for continuation of the Schedule of 
Assessments (Table 7-1), including different options for follow-up (eg, in person, by 
phone/email, through family/friends, in correspondence/communication with other 
treating physicians, the review of medical records) and collection of data, including 
endpoints and adverse events.  Subjects that have discontinued investigational product 
and/or protocol required therapies or procedures should not be automatically removed 
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from the study.  Whenever safe and feasible, it is imperative that subject remain on 
study to undergo safety surveillance and/or collection of outcome data.  The investigator 
must document the change to the Schedule of Assessments (Table 7-1) and the level of 
follow-up that is agreed to by the subject (eg, in person, by telephone/mail, through 
family/friends, in correspondence/communication with other physicians, from review of 
the medical records).   
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.   
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
The investigator and/or sponsor can decide to withdraw a subject(s) from investigational 
product and/or other protocol-required therapies, protocol procedures, or the study as a 
whole at any time prior to study completion.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1. 
8.3 
Reasons for Removal From Treatment or Study  
8.3.1 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
 
subject request   
 
ineligibility determined 
 
protocol deviation 
 
non-compliance 
 
adverse event necessitating drug discontinuation 
 
other protocol specified criteria (CR, no injectable lesions [talimogene laherparepvec 
only])  
 
death 
 
lost to follow-up 
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 
decision by Sponsor (other than subject request, adverse event necessitating drug 
discontinuation, lost to follow-up) 
 
disease progression (confirmed disease progression as per modified irRC-RECIST 
required for talimogene laherparepvec only unless subject has rapid clinical 
deterioration requiring withdrawal from treatment) 
 
pregnancy 
8.3.2 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by sponsor  
 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease Related Events 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  All serious disease related events 
will be recorded and reported to the sponsor or designee within 24 hours.  These 
could include events such as pain or discomfort caused by growing tumors due to overall 
worsening of disease.  Such events do not meet the definition of an Adverse Event 
unless assessed to be more severe than expected for the subject’s condition and/or if 
the investigator believes that the event is related to the investigational product(s)/study 
treatment/protocol-required therapies. 
Disease related events that would qualify as an adverse event or serious adverse 
event: 
 
An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the 
investigator believes there is a causal relationship between the 
investigational product(s)/study treatment/protocol-required therapies and 
disease worsening, this must be reported as an adverse event or serious 
adverse event. 
Disease related events that do not qualify as adverse events or serious adverse 
events: 
 
An event which is part of the normal course of disease under study (eg, 
disease progression in oncology or hospitalization due to disease 
progression) is to be reported as a disease-related event.    
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Further, any disease related event which meets any of the seriousness criteria in 
Section 9.1.3 should be reported as a Serious Disease Related Event.  
9.1.2 
Adverse Events 
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.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, 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.  A pre-existing condition that has not worsened more 
than anticipated (ie, 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 adverse event.   
Note:  For situations where adverse events are due to metastatic triple negative breast 
cancer or colorectal cancer, the primary tumor type (eg, metastatic cancer) should be 
used, rather than the term “disease progression”.   
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.   
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least one of the 
following serious criteria: 
 
fatal 
 
life threatening (places the subject at immediate risk of death) 
 
requires in-patient hospitalization or prolongation of existing hospitalization 
 
results in persistent or significant disability/incapacity 
 
congenital anomaly/birth defect 
 
other medically important serious event 
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A disease related event (eg, PD or pain or discomfort caused by growing tumors) is to 
be reported as a serious adverse event if:  
 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event  
 
and the event meets at least one of the serious criteria above 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
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 a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix A for 
DILI reporting criteria), or events that necessitate an emergency room visit, outpatient 
surgery, or urgent intervention. 
9.1.4 
Adverse Events of Special Interest (Immediately Reportable to the 
Sponsor) 
 
Pneumonitis 
 
Colitis 
 
Endocrinopathies:  diabetes mellitus, pancreatitis, adrenal insufficiency, 
hyperthyroidism, and hypophysitis 
 
Hepatitis, including AST or ALT  10  ULN 
 
Systemic lupus erythematosus 
 
Neurological disorders:  Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
 
Events suggestive of hypersensitivity, infusion-related reactions, cytokine-release 
syndrome, influenza-like illness, systemic inflammatory response syndrome, and 
systemic immune activation 
 
Nephritis 
 
Ocular toxicities (eg, uveitis, retinitis) 
 
Myositis 
 
Myopathies, including rhabdomyolysis 
 
Grade  2 cardiac disorders (eg, atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
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9.2 
Safety Event Reporting Procedures  
9.2.1 
Reporting Procedures for Disease Related Events 
Disease related events are defined in Section 9.1.1. 
The investigator is responsible for ensuring that all Disease Related Events (serious or 
non-serious) observed by the investigator or reported by the subject that occur after the 
first dose of talimogene laherparepvec or atezolizumab through the safety follow-up visit 
(ie, 30 [+7] days after the last dose of talimogene laherparepvec or atezolizumab), are 
recorded on the Event CRF as a Disease-Related Event.   
All serious disease related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious 
disease related event data to the sponsor within 24 hours of it being available. 
The investigator must assign the following attributes to each disease related event: 
 
Disease related event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms), 
 
Dates of onset and resolution (if resolved) 
 
Severity (and/or toxicity per protocol) 
 
Assessment of relatedness to talimogene laherparepvec and/or atezolizumab and 
 
Action taken 
CTCAE version 4 will be used to grade a disease related event.  The grading scale used 
in this study is described in Appendix A. 
Note:  If the event is more severe than expected for the subject’s condition or if the 
investigator believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol-required therapies and disease worsening, the event 
should be reported as an adverse event, not a disease related event. 
The investigator is expected to follow reported disease related events (serious or 
non-serious) until stabilization or reversibility. 
Disease-Related Events assessed by the investigator to be more severe than expected 
and/or related to the talimogene laherparepvec or atezolizumab, and determined to be 
serious, must be recorded on the Event CRF as Serious Adverse Events and be 
recorded and reported per Section 9.1.1. 
Additionally, the investigator is required to report a fatal Disease Related Event on the 
Event CRF.   
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9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That Do Not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of talimogene 
laherparepvec or atezolizumab through the safety follow-up visit (ie, 30 [+7] days after 
the last dose of talimogene laherparepvec or atezolizumab) are reported using the Event 
CRF.   
Additionally, talimogene laherparepvec or atezolizumab related adverse events that 
occur after the safety follow-up visit through the end of the long-term follow-up will be 
reported.  
The investigator must assign the following attributes to each adverse event: 
 
Adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms) 
 
Dates of onset and resolution (if resolved) 
 
Severity (and/or toxicity per protocol) 
 
Assessment of relatedness to talimogene laherparepvec and/or atezolizumab 
 
Action taken 
The adverse event grading scale used will be the CTCAE version 4.0.  The grading 
scale used in this study is described in Appendix A.   
The investigator must assess whether the adverse event is possibly related to the 
talimogene laherparepvec and/or atezolizumab.  This relationship is indicated by a “yes” 
or “no” response to the question:  Is there a reasonable possibility that the event may 
have been caused by the investigational product(s)? 
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, use of medical device(s) and/or procedure (including any screening 
procedure(s)).  This relationship is indicated by a “yes” or “no” response to the question:  
“Is there a reasonable possibility that the event may have been caused by a study 
activity (eg, administration of investigational product, protocol-required therapies, use of 
medical device(s)), and/or procedure”? 
The investigator is responsible for 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.  In general, abnormal laboratory 
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findings without clinical significance (based on the investigator's judgment) are not to be 
recorded as adverse events.  However, laboratory value changes that require treatment 
or adjustment in current therapy are considered adverse events.  Where applicable, 
clinical sequelae (not the laboratory abnormality) are to be recorded as the adverse 
event. 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Event CRF. 
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for Serious Adverse Events and Adverse 
Events of Special Interest 
The investigator is responsible for ensuring that all serious adverse events observed by 
the investigator or reported by the subject that occur after signing of the informed 
consent through 90 (+ 7) days following cessation of treatment, or if the subject initiates 
new anticancer therapy, whichever is earlier are recorded in the subject’s medical record 
and are submitted to Amgen.  Additionally, talimogene laherparepvec and/or 
atezolizumab related serious adverse events that occur after the safety follow-up visit 
through the end of the long-term follow-up will be reported.  
All serious adverse events and adverse events of special interest must be submitted to 
Amgen within 24 hours following the investigator’s knowledge of the event via the Event 
CRF.   
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is available again. 
The investigator must assess whether the serious adverse event is possibly related to 
the investigational product (talimogene laherparepvec and/or atezolizumab), medical 
devices, combination product(s), and/or other protocol-required therapies.  This 
relationship is indicated by a “yes” or “no” response to the question:  “Is there a 
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reasonable possibility that the event may have been caused by talimogene 
laherparepvec and/or atezolizumab, combination products, and /or other 
protocol-required therapies?  Relatedness means that there are facts or reasons to 
support a relationship between investigational product and the event. 
The investigator is expected to follow reported serious adverse events and adverse 
events of special interest until stabilization or reversibility.  
New information relating to a previously reported serious adverse event or adverse 
event of special interest must be submitted to Amgen.  All new information for serious 
adverse events or adverse events of special interest must be sent to Amgen within 
24 hours following knowledge of the new information.  If specifically requested, the 
investigator may need to provide additional follow-up information, such as discharge 
summaries, medical records, or extracts from the medical record.  Information provided 
about the serious adverse event and adverse event of special interest must be 
consistent with that recorded on the Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event or adverse event of special interest, this information must be 
submitted to Amgen. 
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and Good 
Clinical Practice (GCP).  
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local procedures and statutes. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge of the event. 
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Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases for the purposes of expedited 
reporting.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking talimogene laherparepvec or atezolizumab report the pregnancy to 
Amgen Global Patient Safety as specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur through 5 months after the last dose of talimogene 
laherparepvec or atezolizumab.  
The pregnancy should be reported to Amgen’s Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested. 
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 (eg, 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. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  
In addition to reporting a lactation case during the study, investigators should monitor for 
lactation cases that occur through 5 months after the last dose of talimogene 
laherparepvec or atezolizumab.  
Any lactation case should be reported to Amgen’s Global Patient Safety within 24 hours 
of the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 
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. 
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9.4 
Reporting of Exposure to Talimogene Laherparepvec 
If a household member, caregiver, or healthcare provider who has had close contact 
with a subject treated with talimogene laherparepvec on this study is suspected to have 
been exposed to talimogene laherparepvec (eg, have or who have had signs or 
symptoms suspected to be herpetic in origin or who have been accidentally exposed to 
talimogene laherparepvec), while the subject is taking talimogene laherparepvec, report 
the exposure to Amgen as specified below.  In addition to reporting an unintended 
exposure case during the study treatment, investigators should monitor for potential 
exposure cases that occur after the last dose of talimogene laherparepvec through 
30 (+ 7) days after the last dose of talimogene laherparepvec.  
Any potential or known unintended exposure should be reported to Amgen within 
24 hours of the investigator’s knowledge of the event of exposure.  Amgen will seek to 
follow-up with the exposed individual, if necessary, to collect more information about the 
exposed individual contact with clinical trial subject, signs and/or symptoms related to 
the exposure, medical history, and/or outcome of the exposure.  If the exposed individual 
is reporting sign or symptoms suspected to be related to talimogene laherparepvec 
exposure, the exposed individual may be asked to have a swab taken to evaluate for the 
presence of talimogene laherparepvec DNA in the lesion. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoints 
 
Subject incidence of DLTs by tumor type (triple negative breast cancer and colorectal 
cancer) 
10.1.1.2 
Secondary Endpoints 
 
ORR, BOR, DOR, lesion level responses (≥ 30% and 100% decrease) in injected 
and uninjected lesions (overall, hepatic, nonhepatic), DRR, DCR, PFS, and OS by 
tumor type (triple negative breast cancer and colorectal cancer) 
10.1.1.3 
Safety Endpoint 
 
Subject incidence of adverse events and clinically relevant laboratory abnormalities 
by tumor type (triple negative breast cancer and colorectal cancer) 
10.1.1.4 
Exploratory Endpoints 
 
Changes in tumor inflammation markers such as PD-L1 analysis and CD8 density 
 
Identification of potential blood and tumor biomarkers which correlate with or predict 
clinical outcomes 
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10.1.2 
Analysis Sets  
10.1.2.1 
DLT Analysis Set  
The DLT analysis set will include DLT-evaluable subjects who have had the opportunity 
to be on treatment for at least 6 weeks from the initial dose of study treatment and have 
received at least 2 doses of talimogene laherparepvec and 2 doses of atezolizumab in 
combination, or have a DLT during the DLT evaluation period as described in 
Section 3.1. 
10.1.2.2 
Safety Analysis Set 
The safety analysis set will include all subjects who received at least 1 dose of 
talimogene laherparepvec or atezolizumab.   
10.1.2.3 
Biomarker Analysis Sets 
Biomarker analysis sets will be defined separately for each individual candidate 
biomarker.  For predictive analyses, the analysis set will include all subjects in the safety 
analysis set with a baseline biomarker result and, for analyses of biomarker changes, 
the analysis set will include all subjects in the safety analysis set that have baseline and 
at least one subsequent biomarker result. 
10.1.3 
Covariates and Subgroups 
For each tumor type the following covariates may be used to examine efficacy and 
safety in subgroups or in multivariate analyses as appropriate: 
 
Region, if applicable (USA vs non-USA) 
 
Age at baseline: < 50, ≥ 50; < 65, ≥ 65; < 75, ≥ 75 years 
 
Sex (female vs male) 
 
Prior lines of cancer therapy in metastatic setting (0, 1, 2, >2) 
 
HSV-1 serostatus (positive versus negative) 
 
Baseline lactate dehydrogenase (LDH) ≤ ULN vs > ULN 
 
ECOG performance status (0 versus 1) 
 
Brain metastases for triple negative breast cancer (yes or no),  
 
Baseline overall tumor burden 
 
Baseline liver tumor burden 
 
Prior exposure to chemotherapy (yes or no) 
 
Extrahepatic visceral metastases at baseline (yes or no) 
 
PD-L1 status (positive versus negative) 
 
MSI phenotype (yes, no, or unknown) (colorectal cancer cohort only) 
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 
Receipt of non-hepatic talimogene laherparepvec (yes or no)  
 
Other covariates reported in the literature or from other Amgen/Genentech studies 
may be considered as appropriate at the time of analysis 
10.2 
Sample Size Considerations 
The null hypothesis (H0) is that the combination of talimogene laherparepvec and 
atezolizumab has a DLT rate ≤ 10%.  An unacceptable alternative hypothesis (Ha) is a 
true DLT rate ≥ 33%.  The sample size goal is to have ≥ 80% power for a 1-sided ≤ 10% 
significance level test to reject H0 when Ha is true 1.  Eighteen DLT-evaluable subjects 
in each cohort will be required to test H0.  Assuming the incidence of DLTs is evaluated 
as specified by Table 3-1 in Section 3.1, this design achieves a 7.7% 1-sided 
significance level and 81.6% power. 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
No formal interim efficacy analysis is planned for this study.  Interim safety analyses will 
be performed to support the evaluation of safety by the DLRT.  Enrollment will be 
suspended at the first safety interim analysis when the first 4 to 6 DLT-evaluable 
subjects have been enrolled in the study.  At the discretion of the DLRT, additional 
safety analyses may be conducted as warranted.  If the DLRT does not prematurely end 
enrollment, the safety of the combination will be evaluated on the first 18 DLT-evaluable 
subjects in each cohort. 
10.3.2 
Dose Level Review Team 
DLRT meetings will be held to review data, monitor safety, and make dose decisions.  
The review team will be composed of the investigator(s), Amgen Medical Monitor, 
Genentech representative, Amgen Global Safety Officer or designated safety scientist, 
Amgen Global Clinical Trial Manager, and Amgen Biostatistics representative.  
Additional members may be added as needed (eg, Global Development Leader).  A 
quorum, defined as > 50% of the participating investigators who have enrolled subjects 
in the study or their qualified designee [ie, sub-PI or research nurse or study coordinator 
possessing hard copy documentation (eg, email) of the PI’s vote regarding the dose 
level review], must be in attendance for each DLRT meeting.  The DLRT will be 
rescheduled if a quorum is not reached.  The DLRT members are responsible for dosing 
decisions, which may include continuation, delay, or termination of dosing.  All available 
study data, including demographics, investigational product administration, medical 
history, concomitant medications, adverse events, ECGs, vital signs, laboratory results 
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will be reviewed.  In addition to DLTs, all ≥ grade 3 treatment emergent toxicities not 
meeting DLT criteria will be reviewed by the team and can be considered in the DLRT’s 
decisions.  Data to be reviewed will be queried. 
10.3.3 
Primary Analysis 
The primary analyses will be performed separately for each cohort if the expected data 
cutoff dates for the two cohorts exceed 3 months.  The primary safety analyses will 
occur when the last DLT-evaluable subject in the cohort is enrolled and has had the 
opportunity to complete the DLT evaluation period. 
The primary efficacy analyses will occur 19 weeks after the last DLT-evaluable subject in 
the cohort is enrolled. 
10.3.4 
Final Analysis  
The final analyses will be performed separately for each cohort and will occur when the 
last subject in the cohort has discontinued study treatment and has had the opportunity 
to complete the long-term survival follow-up visit.  The final analyses will be performed 
separately for each cohort if the expected data cutoff dates for the two cohorts exceeds 
3 months.  
10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
The data will be analyzed by cohort.  Besides a summary of the incidence of DLTs, 
descriptive statistics will be provided for demographic, safety, efficacy, and biomarkers 
as appropriate. 
10.4.2 
Primary Endpoint 
The DLT analysis set will be used to summarize the subject incidence of DLTs for the 
study and the safety analysis set will be used for all other analyses of safety endpoints.  
The efficacy analysis will be conducted using the safety analysis set unless otherwise 
specified. 
10.4.3 
Efficacy Endpoints 
ORR, BOR, DRR, DCR will be summarized with the associated 95% CI.  The proportion 
of all evaluable injected and uninjected lesions with a response (≥ 30% and 100% 
decrease) will be summarized by lesion type (overall, hepatic, non-hepatic).  DOR, PFS 
and OS will be summarized and estimated using the Kaplan-Meier method. 
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10.4.4 
Safety Endpoints 
Subject incidence of treatment-emergent and treatment-related adverse events 
(including all adverse events, grade ≥ 3 adverse events, serious adverse events, 
adverse events of interest and events requiring the discontinuation of study drug, and 
local effects on the tumor [ie, pain, inflammation and ulceration]) will be summarized.  
Treatment-emergent adverse events are defined as adverse events with an onset from 
the first dose of study therapy up to 30 days after the last dose of study therapy. 
Subject incidence of disease-related events and fatal disease-related events will be 
tabulated by system organ class and preferred term.  A sensitivity analysis of 
treatment-emergent adverse events will be conducted that considers any 
disease-related event as an adverse event if the disease-related event was reported in 
the study for any subject as a treatment-emergent adverse event. 
Medical Dictionary for Regulatory Activities (MedDRA) will be used to code adverse 
events to a system organ class and a preferred term within the system organ class.  The 
CTCAE version 4.0 will be used to grade severity of adverse events.  Subject incidence 
of disease related events and fatal disease related events will be tabulated by system 
organ class and preferred term. 
Summary statistics will be provided for vital signs, physical measurements and 
laboratory data. 
Full details of the analysis will be provided in the statistical analysis plan. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Study Manager to the 
investigator.  The written informed consent form is to be prepared in the language(s) of 
the potential patient population. 
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational product(s) is/are administered.  A legally acceptable representative is an 
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individual or other body authorized under applicable law to consent, on behalf of a 
prospective subject, to the subject’s participation in the clinical study. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form is to be signed and personally dated by the 
subject or a legally acceptable representative and by the person who conducted the 
informed consent discussion.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or a legally acceptable representative. 
If a potential subject is illiterate or visually impaired and does not have a legally 
acceptable representative, the investigator must provide an impartial witness to read the 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 
The investigator must submit and, where necessary, obtain approval from the IRB/IEC 
for all subsequent protocol amendments and changes to the informed consent 
document.  The investigator is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
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The investigator is responsible for obtaining annual IRB/IEC approval/renewal 
throughout the duration of the study.  Copies of the investigator’s reports and the 
IRB/IEC continuance of approval must be sent to Amgen. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
 
Subjects are to be identified by a unique subject identification number.   
 
Where permitted, date of birth is to be documented and formatted in accordance 
with local laws and regulations.   
 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
 
For Serious Adverse Events reported to Amgen, subjects are to be identified by 
their unique subject identification number, initials (for faxed reports, in 
accordance with local laws and regulations), and date of birth (in accordance with 
local laws and regulations) 
 
Documents that are not submitted to Amgen (eg, signed informed consent forms) 
are to be kept in confidence by the investigator, except as described below. 
In compliance with governmental regulations and International Council for Harmonisation 
(ICH) GCP guidelines, it is required that the investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB/IEC direct 
access to review the subject’s original medical records for verification of study-related 
procedures and data.  Direct access includes examining, analyzing, verifying, and 
reproducing any records and reports that are important to the evaluation of the study.  
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
a recognized expert in the therapeutic area 
 
an Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
an Investigator contributing a high number of eligible subjects 
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12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 
Amgen reserves the right to terminate the study at any time.  Both Amgen and the 
Investigator reserve the right to terminate the Investigator’s participation in the study 
according to theClinical Trial Agreement.  The investigator is to notify the IRB/IEC in 
writing of the study’s completion or early termination and send a copy of the notification 
to Amgen.   
Subjects may be eligible for continued treatment with Amgen investigational product(s) 
by an extension protocol or as provided for by the local country’s regulatory mechanism.  
However, Amgen reserves the unilateral right, at its sole discretion, to determine 
whether to supply Amgen investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 
12.2 
Study Documentation and Archive 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence. 
In this study, the IxRS system captures the following data points and these are 
considered source data:  subject identification number. 
Case Report Form (CRF) entries may be considered source data if the CRF is the site 
of the original recording (ie, there is no other written or electronic record of data).   
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
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inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.   
Elements to include: 
 
Subject files containing completed CRFs, informed consent forms, and subject 
identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts (POR), 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable. 
 
Non-investigational product(s) and or medical device(s) documentation, as 
applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 
Clinical Monitor is to have access to subject medical records and other study-related 
records needed to verify the entries on the CRFs. 
The investigator agrees to cooperate with the Clinical Monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global R&D Compliance and Audit (or 
designees).  Inspection of site facilities (eg, pharmacy, protocol-required therapy storage 
areas, laboratories) and review of study-related records will occur to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements.  
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Data capture for this study is planned to be electronic: 
 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, the data queries, and agrees with the 
content. 
12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 7-1), the investigator can search publicly available 
records [where permitted]) to ascertain survival status.  This ensures that the data set(s) 
produced as an outcome of the study is/are as comprehensive as possible.   
12.5 
Language 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood.  CRFs must be 
completed in English.  Trade names® (if used) for concomitant medications may be 
entered in the local language.   
12.6 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff as appropriate as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
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not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the International Committee of Medical Journal Editors [ICMJE])Recommendations for 
the Conduct of Reporting, Editing, and Publication of  Scholarly Work in Medical 
Journals, which states: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the 
article or revising it critically for important intellectual content; (3) final approval of the 
version to be published; (4) agreement to be accountable for all aspects of the work 
in ensuring that questions related to the accuracy or integrity of any part of the work 
are appropriately investigated and resolved.  Authors should meet conditions 1, 2, 3, 
and 4. 
 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content. 
All publications (eg, manuscripts, abstracts, oral/slide presentations, book chapters) 
based on this study must be submitted to Amgen for review.  The Clinical Trial 
Agreement among the institution, investigator, and Amgen will detail the procedures for, 
and timing of, Amgen’s review of publications. 
12.7 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
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13. 
REFERENCES 
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Andtbacka RHI, Ross MI, Delman K, et al.  Responses of injected and uninjected lesions 
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Phoenix, Arizona March 12-15, 2014.  Abstract 52. 
Alexandrov LB, Nik-Zainal S, Wedge DC, et al.  Signatures of mutational processes in 
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Blank C, Gajewski TF, Mackensen A.  Interaction of PD-L1 on tumor cells with PD-1 on 
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immunotherapy.  Cancer Immunol Immunother.  2005;54:307314. 
Blank C, Mackensen A.  Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion:  
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Brahmer JR, Tykodi SS, Chow LQM, et al.  Safety and activity of anti-PD-L1 antibody in 
patients with advanced cancer.  N Eng J Med. 2012;366:2455-2465. 
Center MM, Jemal A, Smith RA, Ward E.  Worldwide variations in colorectal cancer.  
Cancer J Clin. 2009;59:366-378. 
Chang KJ, Senzer NN, Binmoeller K, et al.  Phase I dose-escalation study of talimogene 
laherparepvec (T-VEC) for advanced pancreatic cancer (ca).  J Clin Oncol. 2012; 
30(suppl; abstract e14546). 
Cody JJ, Hurst D.  Promising oncolytic agents for metastatic breast cancer treatment.  
Oncolytic Virother. 2015;4:63-73.  
Dent R, Trudeau M, Protchard KI, et al.  Triple-Negative Breast Cancer:  Clinical 
Features and Patterns of Recurrence.  Clin Cancer Res. 2007;13:4429-4434. 
Dieci MV, Criscitiello C, Goubar A et al.  Prognositic value of tumor-infiltrating 
lymphocytes on residual disease after primary chemotherapy for triple-negative breast 
cancer:  a retrospective multicenter study.  Annals of Oncology. 2014;25:611-618. 
Emens L, Braiteh F, Cassier P, et al.  Inhibition of PD-L1 by MPDL3280A leads to 
clinical activity in patients with metastatic triple-negative breast cancer (TNBC).  Cancer 
Res 2015;75(15 Suppl):Abstract nr 2859. 
Fehrenbacher L, Spira A, Ballinger M, et al.  Atezolizumab versus docetaxel for patients 
with previously treated non-small-cell lung cancer (POPLAR):  a multicenter, open-label, 
phase 2 randomised controlled trial.  The Lancet.  2016; 387:1837-1846. 
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FDA Guidance for Industry - Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009 www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory 
Information/Guidances/UCM174090.pdf 
Foulkes WD, Smith IE, Reis-Filho JS.  Triple-negative breast cancer.  N Engl J Med. 
2010;363(20):1938-1948. 
Garon EB, Rizvi AN, Hui R et al.  Pemborlizumab for the Treatment of Non-Small Cell 
Lung Cancer. 2014;372:2018-2028. 
Geevarghese SK, Geller DA, de Haan HA, et al.  Phase I/II study of oncolytic herpes 
simplex virus NV1020 in patients with extensively pretreated refractory colorectal cancer 
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Genenetech.  Atezolizumab Investigator’s Brochure. 
Goldman AI.  Issues in designing sequential stopping rules for monitoring side effects in 
clinical trials.  Control Clin Trials. 1987;8:327-337. 
Hamanishi J, Mandai M, Iwasaki M, et al.  Programmed cell death 1 ligand 1 and 
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Proc Natl Acad Sci USA 2007;104:33603365. 
Haffty BG, Yang Q, Reiss M, et al.  Locoregional relapse and Distant Metastasis in 
Conservatively Managed Triple Negative Early-Stage Breast Cancer.  J. Clin Oncol. 
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Hecht J, Pless M, Cubillo A, et al.  Early safety from a phase 1, multicenter, open-label 
clinical trial of talimogene laherparepvec (T-VEC) injected into liver tumors.  Poster 
presented at:  2018 Gastrointestinal Cancers Symposium; 19 January 2018; San 
Francisco, CA. 
Heo H, Reid T, Ruo L, et al.  Randomized dose-finding clinical trial of oncolytic 
immunotherapeutic vaccinia JX-594 in liver cancer.  Nat Med. 2013;19:329-336. 
Hino R, Kabashima K, Kato Y, et al.  Tumor cell expression of programmed cell death-1 
ligand 1 is a prognostic factor for malignant melanoma.  Cancer. 2010;116:17571766. 
Hodi FS, O'Day SJ, McDermott DF, et al.  Improved survival with ipilimumab in patients 
with metastatic melanoma.  N Engl J Med.  2010;363:711-723. 
Hu JC, Coffin RS, Davis CJ, et al.  A phase 1 study of OncoVEXGM-CSF, a 
second-generation oncolytic herpes simplex virus expressing granulocyte macrophage 
colony-stimulating factor.  Clin Cancer Res. 2006;12:6737-6747. 
Kaufman HL, Kim DW, DeRaffele G, et al.  Local and distant immunity induced by 
intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients 
with stage IIIc and IV melanoma.  Ann Surg Oncol. 2010;17(3):718-730. 
Keir ME, Butte MJ, Freeman GJ, et al.  PD-1 and its ligands in tolerance and immunity.  
Annual Rev Immunol. 2008;26:677704. 
Kilinc MO, Gu T, Harden JL, et al.  Central role of tumor-associated CD8+ T 
effector/memory cells in restoring systemic antitumor immunity.  J Immunol. 
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Kimata, Hm Tsuneo I, Kikumori T et al.  Pilot Study of Oncolytic Viral Therapy Using 
Mutant Herpes Simplex Virus (HF10) against recurrent metastatic breast cancer.  Ann 
Surg Oncol. 2006;13:1078-1084. 
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Kooby DA, Carew JF, Halternam MW et al.  Oncolytic viral therapy for human colorectal 
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Lawrence MS, Stojanov P, Polak P, et al.  Mutational heterogeneity in cancer and the 
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Deficiency.  N Eng J Med. 2015;372:2509-2520. 
Lehmann BD, Bauer JA, Chen X, et al.  Identification of human triple-negative breast 
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and Effective Re-induction Therapy with an Anti-PD-1 Antibody.  Clin Can Res. 
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Long GV, Reinhard D, Ribas A, et al.  Primary analysis of MASTERKEY-265 phase 1b 
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survival in colorectal cancer.  N Engl J Med. 2005;353:26542666. 
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multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) 
and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.  J Clin 
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Rosenberg JE, Hoffman-Censits J, Powles T, et al.  Atezolizumab in patients with locally 
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components of the tumor microenvironment in patients with recurrent breast cancer.  
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Van Rooij N, van Buuren MM, Philips D, et al.  Tumor Exome Analysis Reveals 
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Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD.  The descriptive 
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14. 
APPENDICES 
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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 is available 
at the following location: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments Reporting 
To facilitate appropriate monitoring for signals of Drug Induced Liver Injury (DILI), cases 
of concurrent aspartate aminotransferase (AST) or alanine aminotransferase (ALT), 
alkaline phosphatase (ALP), and total bilirubin and/or international normalization ratio 
(INR) elevation according to the criteria specified in Section 6.4 require the following: 
 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
 
The appropriate case report form (CRF) (eg, Event CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to the Amgen.  
Other events of hepatotoxicity and potential DILI are to be reported as serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.2.2.2. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) is/are withheld (either permanently or 
conditionally) due to potential DILI as specified in Section 6.4.1 and Section 6.4.2 or who 
experience AST or ALT elevations > 3 x upper limit of normal (ULN) are to undergo a 
period of “close observation” until abnormalities return to normal or to the subject’s 
baseline levels.  Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, alkaline phosphatase (ALP), bilirubin (total and direct), and INR 
within 24 hours  
 
In cases of total bilirubin > 2x ULN or INR > 1.5, retesting of liver tests, bilirubin (total 
and direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 
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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic. 
 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
total bilirubin: 
 
Obtain complete blood count with differential to assess for eosinophilia 
 
Obtain serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth 
Muscle Antibody, and Liver Kidney Microsomal antibody 1 to assess for 
autoimmune hepatitis 
 
Obtain serum acetaminophen (paracetamol) levels 
 
Obtain a more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Obtain Hepatitis A, B, C viral serologies and human immunodeficiency virus 
(HIV) 
 
Obtain creatinine phosphokinase (CPK), haptoglobin, lactate dehydrogenase 
(LDH), and peripheral blood smear 
 
Perform appropriate liver imaging if clinically indicated 
 
Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist) 
 
Follow the subject and the laboratory tests (ALT, AST, ALP, total bilirubin, INR) until 
all laboratory abnormalities return to baseline or normal.  The “close observation 
period” is to continue for a minimum of 4 weeks after discontinuation of all 
investigational product(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in corresponding CRFs. 
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Appendix B.  Sample Serious Adverse Event Report Form 
 
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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 
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Appendix D.  Modified irRC-RECIST Guidelines for Assessment of Disease 
Response  
The Immune-related Response Criteria (irRC) simulating Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1(irRC-RECIST) defined by Nishino et al, 2014, with 
modification will be employed to account for unique tumor response characteristics 
observed with immunotherapies to enable treatment beyond progression, if the subject is 
clinically stable. 
Method of Measurement of Tumor Lesions 
Computed Tomography Scans (or Magnetic Resonance Imaging):  
Computed tomography (CT) scans by contrast-enhanced or spiral scan (or magnetic 
resonance imaging [MRI] scan) will be performed to evaluate tumor response for visceral 
or nodal/soft tissue disease (including lymph nodes).  Measurability of lesions on CT 
scan is based on the assumption that CT slice thickness is 5 mm or less.  Scan slices 
should ideally be 3 to 5 mm.  MRI is acceptable to assess disease extent if used 
throughout the study. 
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.  A 
switch from contrast enhanced CT to noncontrast CT or to MRI (or vice versa) should 
not preclude response assessment if, in the judgment of the site radiologist, there is no 
significant difference in the assessment by changing modalities.  This may occur if a 
subject has developed a medical contraindication to intravenous contrast for CT scans 
while on trial.  This change would require the preapproval of the Amgen medical monitor. 
Positron Emission Tomography (PET)/CT Scans:   
If a combined PET/CT scan is performed at the discretion of the investigator, the CT 
portion of that exam should not be substituted for the dedicated CT exams required by 
this protocol.  The PET portion of the CT may introduce additional data which may bias 
the investigator assessment of response if it is not routinely or serially performed.  
However, if the investigator or the site radiologist can document that the CT performed 
as part of a PET/CT is of identical diagnostic quality to a diagnostic CT (with intravenous 
and oral contrast) then the CT portion of the PET/CT can be used for tumor 
measurements.  
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Ultrasound:  
Ultrasound should not be used as a primary method to assess lesion measurements in 
response to treatment.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is needed. 
Clinical Lesion Measurements 
Clinical lesions will only be considered measurable when they are superficial and 
>10 mm in diameter as assessed using calipers (eg, skin nodules).  For the case of skin 
lesions, documentation by color photography including a ruler to estimate the size of the 
lesion is suggested.  As noted above, when lesions can be evaluated by both clinical 
exam and imaging, imaging evaluation should be undertaken.  
At baseline, lesions are categorized as measurable or non-measurable according to the 
following definitions: 
Measurability of Tumor Lesions at Baseline 
Measurable Lesions 
Measurable lesions are defined at baseline as lesions that can be accurately measured 
in at least one dimension (ie, longest diameter for non-nodal lesions and short axis for 
lymph nodes will be measured and followed) with a minimum size of: 
 
≥ 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) or MRI  
 
 10 mm caliper measurement by clinical exam for superficial cutaneous or 
subcutaneous lesion as measured by caliper  
 
A lymph node must be ≥ 15 mm in short axis when assessed by CT scan or MRI 
Target lesions must not be chosen from a previously irradiated field unless there has 
been documented tumor progression in that field prior to enrollment.  The distribution of 
the target lesions should be representative of the subject’s overall disease (eg, largest 
lesions per organ). 
Non-Measurable Lesions: 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm but < 15 mm short axis) and other truly non-measurable 
lesions are considered non-measurable and characterized as non-target lesions.  This 
will include any measurable lesions beyond the maximum number of 10 total 
(maximum 5 per organ) at baseline and new measurable lesions that were not chosen 
as target lesions.  Only cancerous lesions should be selected as non-measurable 
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lesions and not indeterminate lesions and lesions that could be cancer.  Other examples 
of non-measurable lesions include some bone lesions, leptomeningeal disease, 
inflammatory breast disease, lymphangitic involvement of the skin or (lymphangitis 
cutis/pulmonis), and groups of lesions that are small and numerous. 
Fluid Collections 
Ascites, pleural effusion, or pericardial effusion should not be selected as 
non-measurable disease at baseline or, if new or increased, as evidence of progressive 
disease (PD).  These collections may occur with both benign and malignant conditions, 
and their etiology is often not clear.  These collections may be removed via 
interventional procedures, which can lead to a false interpretation of disease response.  
These fluid collections should not be used as baseline non-target lesions or as evidence 
of disease response. 
Bone Lesions 
 
Bone scans, PET scans or plain films are not considered adequate imaging 
techniques to measure bone lesions.  However, these techniques can be used to 
confirm the presence or absence of bone lesions. 
 
Osteolytic (lytic) bone lesions or mixed lytic-blastic lesions, with identifiable soft 
tissue components, that can be evaluated by cross-sectional imaging technique 
such as CT or MRI can be considered as measurable lesions if the soft tissue 
component meets the definition of measurability as described above.  Only the 
soft tissue component of the bone lesion should be measured. 
 
Many osteoblastic (blastic) bone abnormalities can be benign and should not be 
selected as baseline lesions.  An isolated new small blastic lesion should not be 
selected as a new lesion unless there is demonstrated growth on subsequent 
scans.  Multiple new blastic lesions that are clearly cancerous may be considered 
for new lesions. 
Cystic Lesions 
 
Lesions that meet the criteria for radiographically defined simple cysts should not 
be considered as malignant lesions (neither measurable or non-measurable) 
since they are, by definition, simple cysts. 
 
Cystic lesions thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same subject, these are 
preferred for selection as target lesions.  If a cystic lesion is clearly cancerous 
and has both cystic and solid components, then the complete lesion should be 
measured including both components without excluding the cystic portion of a 
cystic tumor lesion when measuring. 
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Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area, or an area subject to other 
localized therapies (eg, radiation, ablation, embolization), should not be considered 
measurable unless there has been demonstrated progression in the lesion. 
Baseline Documentation of “Target” and “Non-Target” Lesions 
Baseline evaluations will be used to prospectively identify all sites of disease present as 
close as possible to the enrollment and never more than 4 weeks before the enrollment 
date.  Sites of disease will be characterized as either target or non-target lesions. 
Baseline Documentation of Target Lesions 
Up to 10 target lesions (a maximum of 5 per organ) will be chosen to measure over the 
course of therapy.  Pathological lymph nodes that are defined as measurable must meet 
the criterion of a short axis of ≥ 15 mm by CT scan in order to be identified as target 
lesions.  
The distribution of these target lesions should be representative of the subject’s overall 
disease status.  Target lesions should be selected on the basis of their size (lesions with 
longest diameter) and suitability for accurate repeated measurements by imaging 
techniques.  In situations where larger lesions cannot be accurately measured 
repeatedly (eg, near the diaphragm where respiratory changes may affect 
measurements), smaller lesions that meet criteria for measurability may be selected 
instead. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum of diameters.   
Baseline Documentation of Non-Target Lesions  
All other lesions (or sites of disease), including any measurable lesions that were not 
chosen as target lesions and pathological lymph node with short axis ≥ 10 mm but 
< 15 mm, should be identified as non-target lesions.  Measurable non-target lesions 
(ie, lesions in an organ beyond the allowed maximum number of targets that would 
otherwise qualify as target lesions) should also be recorded and assessed qualitatively 
over the course of the study.  Non-measurable non-target disease measurements are 
not required, but these lesions are evaluated at each timepoint and will be evaluated as 
‘present’, ‘absent’, or in rare cases ‘unequivocal progression’.   
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Follow-up Assessment of Tumor Lesions 
At each subsequent tumor assessment, the sum of diameters of target lesions identified 
at baseline plus the sum of diameters of up to 10 (maximum 5 per organ) new 
measurable lesions (for which the longest diameter is ≥ 10 mm for non-nodal lesions or 
the short axis is ≥ 15 mm for nodal lesions) are added together to provide the total tumor 
burden.  If more than 10 new measurable lesions total (or 5 per organ) are present, the 
new measurable lesions should be selected on the basis of their size and suitability for 
accurate repeated measurements by imaging techniques (CT or MRI).  If there are 
lesions beyond the new measurable lesion limit during the course of the study for one 
subject, the additional lesions would be considered new non-measurable lesions. 
Tumor Burden = sum of diameter of target lesions + sum of diameter of up to 
10 (maximum 5 per organ) new, measurable lesions. 
Non-target disease measurements are not required and these lesions should be 
followed as “present”, “absent”, or “unequivocal progression”. 
For non-nodal target lesions that become too small to measure, a value of 5 mm will be 
assigned.  If the non-nodal lesion subsequently increases in size to greater than or equal 
to 5 mm in one dimension, its true size will be recorded.  If an actual measurement is 
able to be provided, this should be recorded even if it is <5 mm.  If it is in the opinion of 
the radiologist that the non-nodal lesion has likely disappeared, the measurement should 
be recorded as “0 mm”.  Nodal disease should always have the actual short axis 
measurement recorded even if the nodes regress to below 10 mm on study.  
Response Evaluation 
Evaluation of Objective Response 
The subject response will be assessed based on tumor burden (the sum of diameters of 
target lesions plus the sum of up to 10 [maximum 5 per organ] new measurable lesions), 
and, in the case of complete response (CR), the presence of any non-target and/or new 
non-measurable lesions.  The overall response is derived from timepoint response 
assessments as described in Table 14-1 and Table 14-2.   
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Table 14-1.  Definition of Measurable Tumor Response (Baseline Target and New, 
Measurable Lesions)  
Complete Response (CR): 
Disappearance of all lesions (whether measurable or not 
and whether baseline or new) and confirmation by a repeat, 
consecutive assessment no less than 4 weeks from the date 
first documented.  Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to 
< 10 mm.  If tumor markers are initially above the upper limit 
of normal, they must normalize to be considered CR.  
Partial Response (PR): 
Decrease in tumor burden* ≥ 30% relative to baseline 
confirmed by a consecutive assessment at least 4 weeks 
(28 days) after first documentation  
Progressive Disease (PD): 
Increase in tumor burden* ≥ 20 % and at least 5 mm 
absolute increase relative to nadir (minimum recorded tumor 
burden) confirmation by a repeat, consecutive assessment 
no less than 4 weeks (28 days) from the date first 
documented PD.  
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for CR or PR nor 
sufficient increase to qualify for PD. 
Unable to Evaluate (UE): 
Any lesion present at baseline which was not assessed or 
was unable to be evaluated leading to an inability to 
determine the status of that particular tumor for that time 
point. 
Not Applicable (NA) 
No target lesions were identified at baseline 
*Tumor Burden = sum of diameter of target lesions + sum of diameter of up to 10 (maximum 5 per organ) 
new, measurable lesions.  
Diameters used: 
 
For nodal disease, shortest axis 
 
For non-nodal disease, longest diameters 
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Table 14-2.  Matrix for Determining the Overall Response at Each Assessment 
Point 
Measurable Response 
Overall Response 
Target and new, measurable 
lesions (tumor burden)a, % 
Non-target 
(nonmeasurable and new 
nonmeasurable) 
Using irRC-RECIST 
↓100b 
Absent/NAc 
CRd 
↓100 
Present/ND 
PRd 
↓100 
Unequivocal progression 
PRd 
↓≥ 30 
Absent/Present NAc 
PRd 
↓≥ 30 
Unequivocal progression 
PRd 
↓< 30 to ↑< 20 
Absent/Present/NA/NDc 
SD 
↓< 30 to ↑< 20 
Unequivocal progression 
SD 
↑≥ 20e 
Any 
PDb, d 
UE 
Any 
UE 
ND 
Any 
UE 
NAf 
Any 
UE 
CR = complete response; irRC-RECIST = immune-related response criteria Response Evaluation Criteria in 
Solid Tumors; NA = not applicable; ND = not done; PD = progressive disease; PR = partial response; 
SD = stable disease; UE = unevaluable 
a Disease relative to baseline, including new measurable lesions only (> 10 mm). 
b Disappearance of all non-lymph node lesions and all lymph nodes < 10 mm in short axis would also be CR 
even if lymph node measurements prevent 100% tumor burden reduction. 
c No non-target lesions identified at baseline. 
d Assuming response (CR or PR) or progression are confirmed by a second, consecutive assessment at 
least 4 weeks (28 days) apart. 
e In addition to relative increase of ≥ 20%, the tumor burden must also demonstrate an absolute increase 
of ≥ 5 mm from nadir for PD. 
f No target lesions identified at baseline.  When a subject has only non-measurable disease (ie, no target 
lesions identified at baseline) the response will be unevaluable. 
Determination of BOR is based on changes in total tumor burden from the baseline 
(nadir, for PD) tumor assessment, regardless of any initial increase in baseline lesions or 
the appearance of new lesions. 
Subjects are considered to have PR or SD even if new lesions were present, as long as 
they met the respective thresholds of response as described in Table 14-2. 
The best overall response for an unconfirmed CR or PR will be SD, and it will be UE if 
the last overall response is PD in the absence of consecutive confirmation or clinical 
deterioration.  A best overall response of SD requires a visit response of SD or better no 
earlier than 63 days after the start of treatment; otherwise the overall response will be 
UE. 
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Confirmation of Response (CR or PR) 
To be assigned a BOR of CR or PR, a corresponding overall visit response of CR or PR  
must be confirmed by consecutive repeat assessments performed no less than 4 weeks 
(28 days) after the criteria for response are first met. 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue.  When the evaluation of CR depends on this determination, it is recommended 
that the residual lesion be investigated (ie, biopsy) to confirm the CR status. 
Confirmation of Disease Progression 
If a subject is classified as having PD at a post baseline tumor assessment, then 
confirmation of PD by a second assessment ≥ 4 weeks (28 days) later in the absence of 
rapid clinical deterioration (eg, rapid decline in performance status) or symptomatic 
disease requiring rapid initiation of alternative systemic anti-cancer therapy is required.  
The definition of confirmation of progression represents a ≥ 20% and at least 5 mm 
absolute increase in the total tumor burden (ie, the sum of diameters of target lesions 
plus up to 10 [maximum 5 per organ] new measurable lesions) compared to the nadir at 
2 consecutive time-points at least 4 weeks (28 days) apart (with the date of progression 
considered to be the time of the initial evaluation showing PD).   
Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of PD at the time should have the reason for 
treatment discontinuation specified.  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
Subjects who have had a procedure to completely/partially resect a lesion will be 
evaluated as follows: 
The procedure itself and all post-procedure lesion assessments should always be 
recorded in the CRF.  A completely resected lesion should be assigned a default code of 
0 mm (for target lesions) or “absent” (for non-target lesions).  A partially resected lesion 
should be assigned its measurement post-procedure (for target lesions) or “present” (for 
non-target lesions).  If the resected lesion contained no cancer under pathology 
evaluation, subsequent tumor assessments post-procedure may be used for tumor 
burden calculations and/or determination of response.  If the resected lesion contained 
cancer or pathology results were unknown, the recorded tumor assessments 
post-procedure may be used for tumor burden calculations, but determination of 
response will be considered unevaluable (UE) for response except in the case of PD.  
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If the new tumor burden post-procedure is lower than the nadir before the procedure, 
then the new nadir will be set to the post-procedure tumor burden.  Otherwise, the 
previous pre-procedure nadir will be retained as the nadir.  Subsequent assessments for 
PD will be determined from the nadir. 
For resected lymph nodes, refer to Table 14-3 below for pre-procedure 
measurements. 
Table 14-3.  Quantitative/Qualitative Reporting of Fully Resected Lymph Nodes 
Lymph Node 
Type/Presence 
Contained 
cancer under 
pathology 
evaluation? 
Quantitative/qualitative reporting 
Target lymph 
node 
previously 
present 
Yes/Unknown 
If measurement available:  Actual short axis 
If measurement not available:  10 mm short axis 
No 
If measurement available:  Actual short axis 
If measurement not available:  9 mm short axis 
Non-target 
lymph node 
previously 
present 
Yes/Unknown Present 
No 
Absent 
Lymph node 
not previously 
present 
Yes/Unknown 
If measurement available and short axis < 15 mm:  New 
non-measurable lymph nodea 
If measurement available and short axis ≥ 15 mm:  please 
enter actual measurements (do not default to 10 mm)a 
If measurement not available:  New non-measurable lymph 
nodea 
No 
Not to be recorded as target or non-target lesion.  Instead to 
be reported on Procedures eCRF. 
a The initial dimension of a new measurable lymph node or presence of a new non-measurable lymph node 
should be reported at all subsequent assessments. 
Merging Lesions 
When two or more target/new measurable lesions merge, the smaller lesion should have 
0 mm recorded for the current and all future assessments, and the larger lesion should 
have the longest diameter of the merged lesion recorded for the current assessment and 
be followed for future assessments.  When two or more non-target/new non-measurable 
lesions merge, the smaller lesion should be recorded as absent for the current and all 
future assessments, and the larger lesion should be recorded as present for the current 
assessment and followed for future assessments.  If a target/new measurable lesion and 
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a non-target/new non-measurable lesion merge, the non-target/new non-measurable 
lesion should be absent for the current and all future assessments while the target 
lesion/new measurable lesion should include both merged lesions for recording 
measurements. 
Separating Lesions 
When a target/new measurable lesion splits into 2 or more lesions, the largest 
measurable part of the split lesion should be considered to be the previously recorded 
target/new measurable lesion with measurements provided for the current assessment 
and followed for future assessments.  The dimensions of the split parts would still be 
considered measurable.  Any new lesions that result from separating should be 
documented as lesions that were generated by separating and not truly new lesions.  
When a non-target lesion splits into 2 or more lesions, the split parts remain non-target 
lesions for the duration of the study. 
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Appendix E.  Eastern Cooperative Oncology Group (ECOG) Performance Status  
Grade 
ECOG Performance Status 
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, eg, 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 self care; confined to a 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 
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Appendix F.  Dose Medication Guidelines for Atezolizumab Related Adverse 
Events 
Management of Atezolizumab-Specific Adverse Events 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
Although most immune-related AEs observed with immunomodulatory agents have been 
mild and self-limiting, such events should be recognized early and treated promptly to 
avoid potential major complications.  Discontinuation of atezolizumab may not have an 
immediate therapeutic effect, and in severe cases, immune-related toxicities may require 
acute management with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. 
The investigator should consider the benefit-risk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  In patients who have met 
the criteria for permanent discontinuation, resumption of atezolizumab may be 
considered if the patient is deriving benefit and has fully recovered from the 
immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor.  
Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of atezolizumab.  Patients will be assessed for 
pulmonary signs and symptoms throughout the study and will also have CT scans of the 
chest performed at every tumor assessment.   
All pulmonary events should be thoroughly evaluated for other commonly reported 
etiologies such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary 
embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension.  Management guidelines for pulmonary events are provided in Table 14-4. 
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Table 14-4.  Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary 
event, Grade 1  
 
Continue atezolizumab and monitor closely. 
 
Re-evaluate on serial imaging. 
 
Consider patient referral to pulmonary specialist. 
Pulmonary 
event, Grade 2  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
 
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 
For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary 
event, Grade 3 
or 4  
 
Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 
Bronchoscopy or BAL is recommended. 
 
Initiate treatment with 12 mg/kg/day oral prednisone or equivalent. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over  1 
month. 
BAL  bronchoscopic alveolar lavage; IVIG  intravenous immunoglobulin 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Hepatic Events 
Immune-related hepatitis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate liver function, as manifested by measurements of 
total bilirubin and hepatic transaminases, and liver function will be monitored throughout 
study treatment.  Management guidelines for hepatic events are provided in Table 14-5.  
. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have LFTs performed immediately and reviewed before administration 
of the next dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or 
neoplastic etiologies should be considered and addressed, as appropriate. 
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Table 14-5.  Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 

Continue atezolizumab.

Monitor LFTs until values resolve to within normal limits.
Hepatic event, 
Grade 2  
All events: 

Monitor LFTs more frequently until return to baseline values.
Events of   5 days’ duration: 

Withhold atezolizumab for up to 12 weeks after event onset. a

Initiate treatment with 12 mg/kg/day oral prednisone or
equivalent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding
atezolizumab, permanently discontinue atezolizumab and contact
Medical Monitor. c
Hepatic event, 
Grade 3 or 4 

Permanently discontinue atezolizumab and contact Medical
Monitor. c

Consider patient referral to gastrointestinal specialist for
evaluation and liver biopsy to establish etiology of hepatic injury.

Initiate treatment with 12 mg/kg/day oral prednisone or
equivalent.

If event does not improve within 48 hours after initiating
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over
 1 month.
LFTs  liver function tests. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Gastrointestinal Events 
Immune-related colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 14-6.   
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of 
systemic inflammation or acute-phase reactants (eg, increased CRP, platelet count, or 
bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, 
with 3 to 5 specimens for standard paraffin block to check for inflammation and 
lymphocytic infiltrates to confirm colitis diagnosis. 
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Table 14-6.  Management Guidelines for Gastrointestinal Events (Diarrhea or 
Colitis) 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
 
Continue atezolizumab. 
 
Initiate symptomatic treatment. 
 
Endoscopy is recommended if symptoms persist for  7 days. 
 
Monitor closely. 
Diarrhea or 
colitis, Grade 2  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Initiate symptomatic treatment. 
 
Patient referral to GI specialist is recommended. 
 
For recurrent events or events that persist  5 days, initiate 
treatment with 12 mg/kg/day oral prednisone or equivalent.  
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 3  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy. 
 
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 4  
 
Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 
Refer patient to gastrointestinal specialist for evaluation and 
confirmation biopsy. 
 
Initiate treatment with 12 mg/kg/day IV methylprednisolone or 
equivalent and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
IV  intravenous 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
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Endocrine Events 
Thyroid disorders, adrenal insufficiency, diabetes mellitus and pituitary disorders have 
been associated with the administration of atezolizumab.  Management guidelines for 
endocrine events are provided in Table 14-7.   
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of 
thyroid, pituitary, or adrenal endocrinopathies.  The patient should be referred to an 
endocrinologist if an endocrinopathy is suspected.  Thyroid-stimulating hormone (TSH) 
and free T3 and T4 levels should be measured to determine whether thyroid 
abnormalities are present.  Pituitary hormone levels and function tests (eg, TSH, growth 
hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, 
adrenocorticotropic hormone [ACTH] levels and ACTH stimulation test) and magnetic 
resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 
Table 14-7.  Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism 

Continue atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.
Symptomatic 
hypothyroidism 

Withhold atezolizumab.

Initiate treatment with thyroid replacement hormone.

Monitor TSH weekly.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and
thyroid function is improving.
Asymptomatic 
hyperthyroidism 
TSH  0.1 mU/L and  0.5 mU/L: 

Continue atezolizumab.

Monitor TSH every 4 weeks.
TSH  0.1 mU/L: 

Follow guidelines for symptomatic hyperthyroidism.
Symptomatic 
hyperthyroidism 

Withhold atezolizumab.

Initiate treatment with anti-thyroid drug such as methimazole
or carbimazole as needed.

Consider patient referral to endocrinologist.

Resume atezolizumab when symptoms are controlled and
thyroid function is improving.

Permanently discontinue atezolizumab and contact Medical
Monitor for life-threatening immune-related hyperthyroidism.c
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Footnotes defined on last page of table 
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Table 14-7.  Management Guidelines for Endocrine Events 
Event 
Management 
Symptomatic adrenal 
insufficiency, 
Grade 24  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to endocrinologist. 
 
Perform appropriate imaging. 
 
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
Hyperglycemia  
Grade 1 or 2 
 
Continue atezolizumab. 
 
Initiate treatment with insulin if needed. 
 
Monitor for glucose control. 
Hyperglycemia, 
Grade 3 or 4 
 
Withhold atezolizumab. 
 
Initiate treatment with insulin. 
 
Monitor for glucose control. 
 
Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
Hypophysitis         
pan-hypopituitarism),    
Grade 2-3  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to endocrinologist. 
 
Perform brain MRI (pituitary protocol). 
 
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement.a 
 
Initiate hormone replacement therapy if clinically indicated. 
 
If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
 
For recurrent hypophysitis, treat as a Grade 4 event. 
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Table 14-7.  Management Guidelines for Endocrine Events 
Event 
Management 
Hypophysitis       
(pan-hypopituitarism),  
Grade 4 

Permanently discontinue atezolizumab and contact Medical
Monitor.c

Refer patient to endocrinologist.

Perform brain MRI (pituitary protocol).

Initiate treatment with 12 mg/kg/day IV methylprednisolone
or equivalent and convert to 12 mg/kg/day oral prednisone
or equivalent upon improvement.a

Initiate hormone replacement therapy if clinically indicated.
Page 3 of 3 
MRI  magnetic resonance imaging; TSH  thyroid-stimulating hormone, IV  intravenous 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Ocular Events 
An ophthalmologist should evaluate visual complaints (eg, uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 14-8.  
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Table 14-8.  Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
 
Continue atezolizumab. 
 
Patient referral to ophthalmologist is strongly recommended. 
 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 
If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Patient referral to ophthalmologist is strongly recommended. 
 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
 
Refer patient to ophthalmologist. 
 
Initiate treatment with 12 mg/kg/day oral prednisone or 
equivalent.   
 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Immune-Related Myocarditis 
Immune-related myocarditis has been associated with the administration of 
atezolizumab.  Immune-related myocarditis should be suspected in any patient 
presenting with signs or symptoms suggestive of myocarditis, including, but not limited 
to, dyspnea, chest pain, palpitations, fatigue, decreased exercise tolerance, or syncope.  
Immune-related myocarditis needs to be distinguished from myocarditis resulting from 
infection (commonly viral, eg, in a patient who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of pre-existing cardiac 
conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines. A cardiologist should be consulted. An 
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endomyocardial biopsy may be considered to enable a definitive diagnosis and 
appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 14-9.   
Table 14-9.  Management Guidelines for Immune-Related Myocarditis 
Event 
Management 
Immune-related 
myocarditis, Grade 1 

Refer patient to cardiologist

Initiate treatment as per institutional guidelines.
Immune-related 
myocarditis, Grade 2 

Withhold atezolizumab for up to 12 weeks after event onset a
and contact Medical Monitor. 

Refer patient to cardiologist

Initiate treatment as per institutional guidelines and consider
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD
as appropriate.

Consider treatment with 12 mg/kg/day IV
methylprednisolone or equivalent and convert to
12 mg/kg/day oral prednisone or equivalent upon
improvement.a

If event resolves to Grade 1 or better, resume
atezolizumab. b

If event does not resolve to Grade 1 or better while
withholding atezolizumab, permanently discontinue
atezolizumab and contact Medical Monitor. c
Immune-related 
myocarditis, Grade 3-4 

Permanently discontinue atezolizumab and contact Medical
Monitor. c

Refer patient to cardiologist

Initiate treatment as per institutional guidelines and consider
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD
as appropriate.

Initiate treatment with 12 mg/kg/day IV methylprednisolone
or equivalent and convert to 12 mg/kg/day oral prednisone
or equivalent upon improvement. a,b

If event does not improve within 48 hours after initiating
corticosteroids, consider adding an immunosuppressive
agent.

If event resolves to Grade 1 or better, taper corticosteroids
over  1 month.
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device; IV  intravenous. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
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Infusion Related Reactions 
No premedication is indicated for the administration of cycle 1 of atezolizumab.  
However, patients who experience an infusion-related reaction with cycle 1 of 
atezolizumab may receive premedication with antihistamines or antipyretics/analgesics 
(eg, acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited in 
treating atezolizumab associated infusion-related reactions, due to its potential for 
causing agranulocytosis. 
Guidelines for medical management of infusion-related reactions during cycle 1 are 
provided in Table 14-10.  For subsequent cycles, infusion-related reactions should be 
managed according to institutional guidelines. 
Table 14-10.  Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1  
 
Reduce infusion rate to half the rate being given at the time of 
event onset. 
 
After the event has resolved, the investigator should wait for 30 
minutes while delivering the infusion at the reduced rate. 
 
If the infusion is tolerated at the reduced rate for 30 minutes after 
symptoms have resolved, the infusion rate may be increased to 
the original rate. 
IRR, Grade 2  
 
Interrupt atezolizumab infusion. 
 
Administer aggressive symptomatic treatment (eg, oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 
After symptoms have resolved to baseline, resume infusion at half 
the rate being given at the time of event onset. 
o 
For subsequent infusions, consider administration of oral 
premedication with antihistamines, anti-pyretics, and/or 
analgesics and monitor closely for IRRs. 
IRR, Grade 3 or 4  
 
Stop infusion. 
 
Administer aggressive symptomatic treatment (eg, oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor.a 
IRR  infusion-related reaction; IV  intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
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Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with the administration of 
atezolizumab.  The differential diagnosis of acute abdominal pain should include 
pancreatitis.  Appropriate work-up should include an evaluation for ductal obstruction, as 
well as serum amylase and lipase tests.  Management guidelines for pancreatic events, 
including pancreatitis, are provided in Table 14-11. 
Table 14-11.  Management Guidelines for Pancreatic Events, Including Pancreatitis 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
 
Continue atezolizumab. 
 
Monitor amylase and lipase weekly. 
 
For prolonged elevation (eg,  3 weeks), consider 
treatment with 10 mg/day oral prednisone or 
equivalent. 
Amylase and/or lipase 
elevation, Grade 3 or 4  
 
Withhold atezolizumab for up to 12 weeks after event 
onset. a 
 
Refer patient to gastrointestinal specialist. 
 
Monitor amylase and lipase every other day. 
 
If no improvement, consider treatment with 
12 mg/kg/day oral prednisone or equivalent. 
 
If event resolves to Grade 1 or better, resume 
atezolizumab. b 
 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
 
For recurrent events, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
Immune-related pancreatitis, 
Grade 2 or 3 
 
 
Withhold atezolizumab for up to 12 weeks after event 
onset. a 
 
Refer patient to gastrointestinal specialist. 
 
Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 
If event resolves to Grade 1 or better, resume 
atezolizumab.  
 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
 
For recurrent events, permanently discontinue 
atezolizumab and contact Medical Monitor. c  
Page 1 of 2 
Footnotes defined on last page of table 
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Table 14-11.  Management Guidelines for Pancreatic Events, Including Pancreatitis 
Event 
Management 
Immune-related pancreatitis, 
Grade 4 
 
Permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 
Refer patient to gastrointestinal specialist. 
 
Initiate treatment with 12 mg/kg/day IV 
methylprednisolone or equivalent and convert to 
12 mg/kg/day oral prednisone or equivalent upon 
improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 
If event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
Page 2 of 2 
IV  intravenous 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Dermatologic Events 
Treatment-emergent rash has been associated with atezolizumab.  The majority of 
cases of rash were mild in severity and self limited, with or without pruritus.  A 
dermatologist should evaluate persistent and/or severe rash or pruritus.  A biopsy should 
be considered unless contraindicated.  Management guidelines for dermatologic events 
are provided in Table 14-12. 
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Table 14-12.  Management Guidelines for Dermatologic Events 
Event 
Management 
Dermatologic 
event, Grade 1  
 
Continue atezolizumab. 
 
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (eg, antihistamines). 
Dermatologic 
event, Grade 2  
 
Continue atezolizumab. 
 
Consider patient referral to dermatologist. 
 
Initiate treatment with topical corticosteroids. 
 
Consider treatment with higher-potency topical corticosteroids if 
event does not improve 
Dermatologic 
event, Grade 3  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to dermatologist. 
 
Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 12 mg/kg/day if event does not improve within 
4872 hours. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Dermatologic 
event, Grade 4 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor.c 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Neurologic Disorders  
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor 
neuropathy.  Diagnostic work-up is essential for an accurate characterization to 
differentiate between alternative etiologies.  Management guidelines for neurologic 
disorders are provided in Table 14-13. 
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Table 14-13.  Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy, 
Grade 1 
 
Continue atezolizumab. 
 
Investigate etiology. 
Immune-related 
neuropathy, 
Grade 2  
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Investigate etiology. 
 
Initiate treatment as per institutional guidelines. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Immune-related 
neuropathy, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor. c  
 
Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor.c 
 
Refer patient to neurologist. 
 
Initiate treatment as per institutional guidelines. 
 
Consider initiation of 12 mg/kg/day oral or IV prednisone or 
equivalent. 
IV  intravenous 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to  10 mg/day oral prednisone or equivalent.  The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral prednisone 
or equivalent before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the 
administration of atezolizumab.  Immune-related meningoencephalitis should be 
suspected in any patient presenting with signs or symptoms suggestive of meningitis or 
encephalitis, including, but not limited to, headache, neck pain, confusion, seizure, motor 
or sensory dysfunction, and altered or depressed level of consciousness.  
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from 
potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) or 
progression of malignancy, or secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with 
a CT scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or 
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edema.  If deemed safe by the treating physician, a lumbar puncture should be 
performed and a neurologist should be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an 
identified alternate etiology, should be treated according to the guidelines in 
Table 14-14. 
Table 14-14.  Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor. a 
 
Refer patient to neurologist. 
 
Initiate treatment with 12 mg/kg/day IV methylprednisolone 
or equivalent and convert to 12 mg/kg/day oral prednisone 
or equivalent upon improvement. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
IV  intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be rechallenged with atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Immune-related Nephritis 
Immune-related nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function, and renal 
function, including serum creatinine, should be monitored throughout study 
treatment.  Patients with abnormal renal function should be evaluated and treated 
for other more common etiologies (including prerenal and postrenal causes, and 
concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer 
the patient to a renal specialist if clinically indicated.  A renal biopsy may be 
required to enable a definitive diagnosis and appropriate treatment.  If no 
alternative cause of acute kidney injury is identified, patients with signs and 
symptoms of acute kidney injury, in the absence of an identified alternate 
etiology, should be treated according to the management guidelines in 
Table 14-15. 
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Table 14-15.  Management Guidelines for Renal Events  
Event 
Management 
Renal event, 
Grade 1 
 Continue atezolizumab. 
 Monitor kidney function, including creatinine, closely until values 
resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset. a 
 Refer patient to renal specialist. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab, and contact 
Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 Permanently discontinue atezolizumab and contact Medical Monitor.  
 Refer patient to renal specialist and consider renal biopsy. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day oral 
prednisone. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 
month. 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute 
Note:  Management guidelines are presented by adverse event severity based on NCI CTCAE and are 
applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
a Atezolizumab may be withheld for a longer period of time (ie,  12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  
Immune-mediated Myositis 
Immune-mediated myositis has been associated with the administration of 
atezolizumab.  Myositis or inflammatory myopathies are a group of disorders 
sharing the common feature of inflammatory muscle injury; dermatomyositis and 
polymyositis are among the most common disorders.  Initial diagnosis is based 
on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging 
(electromyography/magnetic resonance imaging [MRI]) features, and is confirmed 
with a muscle biopsy. 
Patients with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 14-16. 
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Table 14-16.  Management Guidelines for Immune-Mediated Myositis 
Event 
Management 
Immune-
mediated 
myositis, 
Grade 1 
 Continue atezolizumab. 
 Refer patient to rheumatologist or neurologist.  
 Initiate treatment as per institutional guidelines. 
Immune-
mediated 
myositis, 
Grade 2 
 Withhold atezolizumab for up to 12 weeks after event onset a and contact 
Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines. 
 Consider treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone and convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement. 
 If corticosteroids are initiated and event does not improve within 48 hours 
after initiating corticosteroids, consider adding an immunosuppressive 
agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab, and contact Medical 
Monitor. c 
Immune-
mediated 
myositis, 
Grade 3 
 Withhold atezolizumab for up to 12 weeks after event onset a and contact 
Medical Monitor. 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory support may 
be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (eg, cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, resume atezolizumab. b 
 If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab, and contact Medical 
Monitor. c 
 For recurrent events, treat as a Grade 4 event. 
Immune-
mediated 
myositis, 
Grade 4 
 Permanently discontinue atezolizumab and contact Medical Monitor. c 
 Refer patient to rheumatologist or neurologist. 
 Initiate treatment as per institutional guidelines.  Respiratory support may 
be required in more severe cases. 
 Initiate treatment with corticosteroids equivalent to 12 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 12 mg/kg/day oral 
prednisone or equivalent upon improvement. 
 If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
 If event resolves to Grade 1 or better, taper corticosteroids over  1 month. 
Footnotes defined on next page 
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IV = intravenous 
\a Atezolizumab may be withheld for a longer period of time (i.e.,  12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
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CONFIDENTIAL
Amendment 5
Protocol Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination 
With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal 
Cancer With Liver Metastases
Amgen Protocol Number (Talimogene Laherparepvec):  20140299
Amendment Date:
08 July 2019
Rationale:
This protocol is being amended to:

Update to clarify the subjects enrolled in both cohorts 1 and 2 are “DLT-evaluable 
subjects”.

Update to include results from randomized phase 3 trial (NCT02425891).

Update approval status of atezolizumab in combination with nab paclitaxel.

Update number of sites to delete the statement on closing sites that do not enroll 
within 6 months of site initiation.

Delete disease related events section.

Delete Self Evident Text

Update immune-related response evaluation criteria in solid tumors ( irRC-RECIST)
to modified irRC-RECIST

Update to include management guidelines for Immune-related nephritis and 
Immune-mediated myositis

Make administrative and editorial changes
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Description of Changes
Section:  Global
Change:  Typographical and editorial changes throughout.
Section:  Global
Change:  Changed date from 13 April 2018 to 08 July 2019
Section:  Title Page
Section:  Title Page
Add:
Amendment 5
08 July 2019
Section:  Synopsis, Study Design
Add:
This is a phase 1b, multicenter, open-label study to evaluate the safety of intrahepatic 
injection of talimogene laherparepvec in combination with intravenously administered 
atezolizumab in subjects with triple negative breast cancer and colorectal cancer with 
liver metastases.  Talimogene laherparepvec will be injected intrahepatically in 
combination with intravenous atezolizumab to approximately 36 DLT-evaluable subjects 
in 2 parallel cohorts.  Cohort 1 will comprise subjects with triple negative breast cancer 
with liver metastases (n =18 DLT-evaluable subjects).  Cohort 2 will comprise subjects 
with colorectal cancer with unresectable liver metastases (n =18 DLT-evaluable 
subjects).  
Section:  Synopsis, Sample Size
Add:
Approximately 36 subjects will be enrolled (18 DLT-evaluable subjects in each cohort).
Section:  Synopsis, Amgen Investigational Product Dosage and Administration and 
6.2.1.1 Dosage, Administration, and Schedule, paragraph 2
Replace:
During the second cycle, talimogene laherparepvec will be administered up to 4.0 mL of 
108 PFU/mL at week 4 of the study (+ 3 days).  
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With:
During the second cycle, talimogene laherparepvec will be administered up to 4.0 mL of 
108 PFU/mL at week 4 of the study (± 3 days).  
Section:  Study Glossary
Add:
IV
intravenous
US
United States
Section:  Study Design and Treatment Schema, footnote b
Add:
In the absence of confirmed PD per modified irRC-RECIST, atezolizumab treatment 
can continue after talimogene laherparepvec treatment has ended provided patient is 
tolerating atezolizumab and receiving clinical benefit in the opinion of the investigator.
Section:  2.1.2.1 Immunotherapy in Triple Negative Breast Cancer, paragraph 3
Replace:
After initial evidence of activity in triple negative breast cancer subjects in a phase 1/2 
study, atezolizumab is now being further evaluated in combination with nab paclitaxel in 
a phase 3 trial (NCT02425891).
With:
After initial evidence of activity in triple negative breast cancer subjects in a phase 1/2 
study, atezolizumab was evaluated in combination with nab-paclitaxel in a randomized
phase 3 trial (NCT02425891) of 902 patients with untreated metastatic triple 
negative breast cancer who were randomized 1:1 to atezolizumab plus 
nab-paclitaxel or placebo plus nab-paclitaxel.  Median OS in the atezolizumab plus 
nab-paclitaxel arm was 21.3 months, and in the placebo plus nab-paclitaxel arm 
was 17.6 months (Hazard ratio for death, 0.84; P = 0.08); in patients with PD-L1 
positive tumors, the median OS was 25.0 months for the atezolizumab plus nab-
paclitaxel arm and 15.5 months for the placebo plus nab-paclitaxel arm (Hazard 
ratio 0.62).  The rate of grade 3 or 4 adverse events was 48.7% in the atezolizumab 
plus nab-paclitaxel group and 42.2% in the placebo plus nab-paclitaxel group, with 
the most common being neutropenia, decreased neutrophil count, peripheral 
neuropathy, fatigue, and anemia. 57.3% in the atezolizumab plus nab-paclitaxel 
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group and 41.8% in the placebo plus nab-paclitaxel group had an adverse event of 
special interest, suggestive of a potential immune-related etiology. Grade 3 or 4 
adverse events of special interest occurred in 7.5% in the atezolizumab plus 
nab-paclitaxel group and 4.3% in the placebo plus nab-paclitaxel group. One 
grade 5 event of special interest (autoimmune hepatitis) occurred in the 
atezolizumab plus nab-paclitaxel group, and one grade 5 event of special interest 
(hepatic failure) occurred in the placebo plus nab-paclitaxel group. Adverse 
events that led to discontinuation of any agent occurred in 15.9% of subjects who 
received atezolizumab plus nab-paclitaxel, and in 8.2% of subjects who received 
placebo plus nab-paclitaxel. 6.4% discontinued atezolizumab because of adverse 
events, and 1.4% discontinued placebo because of adverse events.  Based on the 
results of this trial, on March 8, 2019, the United States (US) Food and Drug 
Administration (FDA) granted accelerated approval for atezolizumab in 
combination with nab-paclitaxel for initial treatment of adult patients with 
unresectable locally advanced or metastatic triple negative breast cancer whose 
tumors express PD-L1, as determined by an FDA-approved test.
Section:  2.3 Non-Amgen Investigational Product Background:  Atezolizumab, 
paragraph 3
Add:
Atezolizumab is approved in the United States and other countries for the treatment of 
urothelial carcinoma and is approved in the United States for the treatment of non-small 
cell lung cancer.  It is also approved in the United States in combination with 
nab-paclitaxel for the treatment of PD-L1 positive triple negative breast cancer
(refer to the prescribing information for specific indications).
Section:  3.1 Study Design
Replace:
This is a phase 1b, multicenter, open-label study to evaluate the safety of intrahepatic 
injection of talimogene laherparepvec in combination with intravenously administered 
atezolizumab in subjects with triple negative breast cancer and colorectal cancer with 
liver metastases.  Approximately 36 subjects will be enrolled in two parallel cohorts.  
Cohort 1 will comprise triple negative breast cancer subjects with liver metastases
(n = 18).  Cohort 2 will comprise subjects with colorectal cancer with unresectable liver 
metastases (n = 18).  Subjects will be treated with up to 4.0 mL of 106 PFU/mL 
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 5 of 13
CONFIDENTIAL
talimogene laherparepvec at cycle 1, day 1 followed by talimogene laherparepvec up to 
4.0 mL of 108 PFU/mL 21+ 3 days later (cycle 2, day 1, week 4 of the study).  
With: 
This is a phase 1b, multicenter, open-label study to evaluate the safety of intrahepatic 
injection of talimogene laherparepvec in combination with intravenously administered 
atezolizumab in subjects with triple negative breast cancer and colorectal cancer with 
liver metastases.  Approximately 36 DLT-evaluable subjects will be enrolled in two 
parallel cohorts.  Cohort 1 will comprise triple negative breast cancer subjects with liver 
metastases (n = 18 DLT-evaluable subjects).  Cohort 2 will comprise subjects with 
colorectal cancer with unresectable liver metastases (n = 18 DLT-evaluable subjects).  
Subjects will be treated with up to 4.0 mL of 106 PFU/mL talimogene laherparepvec at 
cycle 1, day 1 followed by talimogene laherparepvec up to 4.0 mL of 108 PFU/mL 21 ± 3 
days later (cycle 2, day 1, week 4 of the study).  
Section:  3.2 Number of Sites
Delete:
Sites that do not enroll subjects within approximately 6 months of site initiation may be 
closed.
Section:  3.3 Number of Subjects, paragraph 2
Add:
Approximately 36 DLT-evaluable subjects will be enrolled (18 DLT-evaluable subjects 
in each cohort).  Refer to Section 10.2 for sample size considerations.
Section:  4.1 Inclusion Criteria, criterion 104
Add:
104
Subjects with triple negative breast cancer with liver metastases, or subjects with 
colorectal cancer with liver metastases are eligible if they have had disease 
progression during or after ≥ 1 prior standard of care systemic anti-cancer 
therapy (eg, chemotherapy, targeted therapy) for metastatic disease or if they 
progress during or within 6 months of receiving adjuvant therapy.  If
subjects, in the opinion of the investigator, are deemed not appropriate 
candidates for systemic anti-cancer therapy for metastatic disease or if 
they refuse systemic anti-cancer therapy for metastatic disease, they may 
be eligible after investigator discussion with sponsor medical monitor for 
approval.
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 6 of 13
CONFIDENTIAL
Section:  6.2.1.1 Dosage, Administration, and Schedule, Table 6-2, Talimogene 
Laherparepvec Injection Volume Guideline Based on Tumor Size for Cutaneous, 
Subcutaneous, and Nodal Lesions
Add:
Table 6-2.  Talimogene Laherparepvec Injection Volume Guideline Based on Tumor 
Size for Cutaneous, Subcutaneous, and Nodal Lesions
Tumor Size (longest dimension)
Maximum Injection Volume
> 5.0 cm
4.0 mL
> 2.5 cm to 5.0 cm
2.0 mL
> 1.5 cm to 2.5 cm
1.0 mL
> 0.5 cm to 1.5 cm
0.5 mL
≤0.5 cm
0.1 mL
Section:  6.2.1.1 Dosage, Administration, and Schedule, paragraph 16
Add:
The dose, start date, number of vials used per visit, concentration, and lot number of 
talimogene laherparepvec are to be recorded on each subject’s CRF.
Section:  6.2.2.1 Dosage, Administration, and Schedule, paragraph 2
Add:
Atezolizumab is preferred to be given prior to talimogene laherparepvec.
Section:  6.2.2.1 Dosage, Administration, and Schedule, paragraph 3
Replace:
The first cycle of atezolizumab will be 21 (+ 3) days.  Subsequent cycles of atezolizumab 
will be 21 (± 3) days.  The dose level of atezolizumab is 1200 mg administered by 
intravenous infusion.  In the absence of confirmed PD per irRC-RESIST, atezolizumab 
treatment can continue after talimogene laherparepvec treatment has ended provided 
patient is tolerating atezolizumab and receiving clinical benefit in the opinion of the 
investigator.
With:
The first cycle of atezolizumab will be 21 (+ 3) days.  Subsequent cycles of atezolizumab 
will be 21 (± 3) days.  The dose level of atezolizumab is 1200 mg administered by 
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 7 of 13
CONFIDENTIAL
intravenous infusion.  In the absence of confirmed PD per modified irRC-RECIST, 
atezolizumab treatment can continue after talimogene laherparepvec treatment has 
ended provided patient is tolerating atezolizumab and receiving clinical benefit in the 
opinion of the investigator.
Section:  6.5 Concomitant Therapy, paragraph 3
Add:
Systemic corticosteroids and TNF-inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician after consultation with the Amgen medical monitor.  If 
corticosteroids (prednisone > 10 mg or equivalent daily) or TNF-inhibitors are needed 
for treatment of atezolizumab immune related adverse events, talimogene laherparepvec 
must be withheld until the corticosteroid dose is ≤ 10 mg prednisone or equivalent daily
or TNF-. inhibitors are discontinued (see Section 6.2.1.3).  If feasible, alternatives to 
corticosteroids should be considered.
Section:  6.6 Other Treatment Procedures, paragraph 2
Add:
If a subject demonstrates evidence of new or worsening CNS metastases, all study 
treatments should be withheld.  After discussion between the Amgen medical monitor 
and the investigator to determine the appropriateness of treatment resumption provided 
CNS metastases are adequately treated, subjects may be allowed to remain on study.  
In addition, in order to resume talimogene laherparepvec or atezolizumab, corticosteroid 
dose must not exceed 10 mg of prednisone or equivalent daily.  Re-exposure to 
talimogene laherparepvec and atezolizumab may occur only if the investigator and 
sponsor agree that the subject safety will not be compromised.
Section:  6.9 Excluded Treatments, Medical Devices, and/or Procedures During Study 
Period, bullet 3, sub-bullet 1
Add:
o
If the subject requires corticosteroid dosing for related toxicities (eg, prednisone 
>10 mg or equivalent), talimogene laherparepvec dosing must be withheld until 
the corticosteroid dose is able to be decreased to ≤ prednisone 10 mg (or 
equivalent) daily.
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 8 of 13
CONFIDENTIAL
Section:  Table 7-1 Schedule of Assessments, footnote a
Add:
In the absence of confirmed PD per modified irRC-RECIST, atezolizumab treatment 
can continue after talimogene laherparepvec treatment has ended provided patient is 
tolerating atezolizumab and receiving clinical benefit in the opinion of the investigator.
Section:  9.1.1 Disease Related Events
Add:
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  All serious disease related events 
will be recorded and reported to the sponsor or designee within 24 hours.  These 
could include events such as pain or discomfort caused by growing tumors due to overall 
worsening of disease.  Such events do not meet the definition of an Adverse Event 
unless assessed to be more severe than expected for the subject’s condition and/or if 
the investigator believes that the event is related to the investigational product(s)/study 
treatment/protocol-required therapies.
Disease related events that would qualify as an adverse event or serious adverse 
event:

An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the 
investigator believes there is a causal relationship between the 
investigational product(s)/study treatment/protocol-required therapies and 
disease worsening, this must be reported as an adverse event or serious 
adverse event.
Disease related events that do not qualify as adverse events or serious adverse 
events:

An event which is part of the normal course of disease under study (eg, 
disease progression in oncology or hospitalization due to disease 
progression) is to be reported as a disease-related event.   
Section:  9.2.1  Reporting Procedures for Disease Related Events, paragraphs 1 and 3
Add:
Disease related events are defined in Section 9.1.1.
The investigator is responsible for ensuring that all Disease Related Events (serious or 
non-serious) observed by the investigator or reported by the subject that occur after the 
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 9 of 13
CONFIDENTIAL
first dose of talimogene laherparepvec or atezolizumab through the safety follow-up visit 
(ie, 30 [+7] days after the last dose of talimogene laherparepvec or atezolizumab), are 
recorded on the Event CRF as a Disease-Related Event.  
All serious disease related events will be recorded and reported to the sponsor or 
designee within 24 hours.  The investigator will submit any updated serious 
disease related event data to the sponsor within 24 hours of it being available.
Section:  9.2.1  Reporting Procedures for Disease Related Events, paragraph 8
Add:
Disease-Related Events assessed by the investigator to be more severe than expected 
and/or related to the talimogene laherparepvec or atezolizumab, and determined to be 
serious, must be recorded on the Event CRF as Serious Adverse Events and be 
recorded and reported per Section 9.1.1.
Section:  12.3 Study Monitoring and Data Collection, paragraph 6
Delete:
Amgen (or designee) will perform Self-Evident Corrections (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF Standard Instructions 
and the CRF Specific Instructions, both of these will be available through the EDC 
system.  Examples of obvious data errors that may be corrected by Amgen (or designee) 
include deletion of obvious duplicate data (ie, same results sent twice with the same 
date with different visit, [eg, week 4 and early termination]) and updating a specific 
response if the confirming datum is provided in the  “other, specify” field (eg, for race, 
reason for ending study).
Appendix A, Additional Safety Assessment Information, bullet 5
Delete:

Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected 
Appendix D, Modified irRC-RECIST Guidelines for Assessment of Disease Response, 
Follow-up Assessment of Tumor Lesions, paragraph 1
Delete:
At each subsequent tumor assessment, the sum of diameters of target lesions identified 
at baseline plus the sum of diameters of up to 10 (maximum 5 per organ) new 
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 10 of 13
CONFIDENTIAL
measurable lesions (for which the longest diameter is ≥ 10 mm for non-nodal lesions or 
the short axis is ≥ 15 mm for non-nodal lesions) are added together to provide the total 
tumor burden.  
Appendix D, Modified irRC-RECIST Guidelines for Assessment of Disease Response, 
Response Evaluation, paragraph 11
Add:
For resected lymph nodes, refer to Table 14-3 below for pre-procedure 
measurements.
Section:  Appendix F, Dose Medication Guidelines for Atezolizumab Related Adverse 
Events Management of Atezolizumab-Specific Adverse Events, Immune-related 
Nephritis and Immune-mediated Myositis
Add:
Immune-related Nephritis
Immune-related nephritis has been associated with the administration of 
atezolizumab.  Eligible patients must have adequate renal function, and renal 
function, including serum creatinine, should be monitored throughout study 
treatment.  Patients with abnormal renal function should be evaluated and treated 
for other more common etiologies (including prerenal and postrenal causes, and 
concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer 
the patient to a renal specialist if clinically indicated.  A renal biopsy may be 
required to enable a definitive diagnosis and appropriate treatment.  If no 
alternative cause of acute kidney injury is identified, patients with signs and 
symptoms of acute kidney injury, in the absence of an identified alternate 
etiology, should be treated according to the management guidelines in 
Table 14-15.
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  08 July 2019 
Page 11 of 13 
CONFIDENTIAL 
 
Table 14-15.  Management Guidelines for Renal Events 
Event 
Management 
Renal event, 
Grade 1 
 
Continue atezolizumab. 
 
Monitor kidney function, including creatinine, closely until values 
resolve to within normal limits or to baseline values.  
Renal event, 
Grade 2 
 
Withhold atezolizumab for up to 12 weeks after event onset. a 
 
Refer patient to renal specialist. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 
If event resolves to Grade 1 or better, resume atezolizumab. b 
 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab, and contact 
Medical Monitor. c 
Renal event, 
Grade 3 or 4 
 
Permanently discontinue atezolizumab and contact Medical 
Monitor.  
 
Refer patient to renal specialist and consider renal biopsy. 
 
Initiate treatment with corticosteroids equivalent to 12 mg/kg/day 
oral prednisone. 
 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute 
Note:  Management guidelines are presented by adverse event severity based on NCI CTCAE and are 
applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. 
a Atezolizumab may be withheld for a longer period of time (ie.,  12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of  10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over  1 month to the equivalent of 
 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.  
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 12 of 13
CONFIDENTIAL
Immune-mediated Myositis
Immune-mediated myositis has been associated with the administration of 
atezolizumab.  Myositis or inflammatory myopathies are a group of disorders 
sharing the common feature of inflammatory muscle injury; dermatomyositis and 
polymyositis are among the most common disorders.  Initial diagnosis is based 
on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging 
(electromyography/magnetic resonance imaging [MRI]) features, and is confirmed 
with a muscle biopsy.
Patients with signs and symptoms of myositis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 14-16.
Table 14-16.  Management Guidelines for Immune-Mediated Myositis
Event
Management
Immune-mediated 
myositis, Grade 1

Continue atezolizumab.

Refer patient to rheumatologist or neurologist. 

Initiate treatment as per institutional guidelines.
Immune-mediated 
myositis, Grade 2

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.

Consider treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone and convert to 
12 mg/kg/day oral prednisone or equivalent upon improvement.

If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab, and 
contact Medical Monitor. c
Page 1 of 2
Footnotes defined on last page of table
Approved 
 
 

Product:  Talimogene Laherparepvec
Protocol Number:  20140299
Date:  08 July 2019
Page 13 of 13
CONFIDENTIAL
Table 14-16.  Management Guidelines for Immune Mediated Myositis (cont.)
Event
Management
Immune-mediated 
myositis, Grade 3

Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor.

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (eg, cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, resume atezolizumab. b

If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab, and 
contact Medical Monitor. c

For recurrent events, treat as a Grade 4 event.
Immune-mediated 
myositis, Grade 4

Permanently discontinue atezolizumab and contact Medical 
Monitor. c

Refer patient to rheumatologist or neurologist.

Initiate treatment as per institutional guidelines.  Respiratory 
support may be required in more severe cases.

Initiate treatment with corticosteroids equivalent to 
12 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 12 mg/kg/day oral prednisone or 
equivalent upon improvement.

If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent.

If event resolves to Grade 1 or better, taper corticosteroids over 
1 month.
Page 2 of 2
IV = intravenous
a Atezolizumab may be withheld for a longer period of time (i.e., 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of 10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor.
b If corticosteroids have been initiated, they must be tapered over 1 month to the equivalent of 
10 mg/day oral prednisone before atezolizumab can be resumed.
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor.
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  26 March 2018 
Page 1 of 55 
CONFIDENTIAL 
 
Amendment 4 
Protocol Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination 
With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal 
Cancer With Liver Metastases 
Amgen Protocol Number 20140299 
EudraCT number 2015-005480-16 
NCT number NCT03256344 
 
Amendment Date: 
26 March 2018 
 
Rationale: 
This protocol is being amended to: 
• 
Clarify the timing of the final analysis 
• 
Clarify that atezolizumab treatment can continue after talimogene laherparepvec 
treatment has ended 
• 
Update the end of study language and definitions 
• 
Update rules for talimogene laherparepvec and atezolizumab withholding with regard 
to management of hepatic events 
• 
Clarify that photographic equipment will not be provided by the sponsor, since 
photographs are not required for this study 
• 
Clarify when a screening biopsy is required 
• 
Add pharmacogenetics studies 
• 
Make editorial, typographical, and formatting changes throughout the document 
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  05 December 2017 
Page 1 of 5  
CONFIDENTIAL 
 
  
Amendment:  Superseding Amendment 3 
Protocol Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination 
With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal 
Cancer With Liver Metastases 
 
Amgen Protocol Number Talimogene Laherparepvec (TVEC) 20140299 
EudraCT number:  2015-005480-16 
NCT number:  03256344 
 
Amendment Date: 
05 December 2017 
 
Rationale: 
This superseding amendment is being done to correct minor errors from the last 
amendment. 
• 
Correct discrepancy between contraception language in the ICF and the protocol 
(polyurethane condom use allowed for those with latex allergies) 
• 
Correct a discrepancy with radiographic imaging time points at safety follow-up 
between the Schedule of Assessments and footnotes (clarify that radiographic 
imaging is only needed at safety follow-up if a subject does not have confirmed 
disease progression and has not been scanned for 9 weeks). 
Approved 
 
 

Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  25 September 2017 
Page 1 of 45 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination 
With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal 
Cancer With Liver Metastases 
Amgen Protocol Number 20140299 
EudraCT number:  2015-005480-16 
NCT number:  03256344 
Amendment Date: 
25 September 2017 
 
Rationale: 
The purpose of this protocol amendment is to: 
• 
Update guidance on atezolizumab background and toxicity information to align with 
most recently approved language as provided by Genentech. 
• 
Add guidance on the quantitative/qualitative reporting of resected lymph nodes. 
• 
Update disease related event language.  
• 
Address administrative, typographical, and formatting changes within the protocol. 
Approved 
 
 

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Product:  Talimogene Laherparepvec 
Protocol Number:  20140299 
Date:  04 November 2016  
Page 1 of 17 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 1b Study of Talimogene Laherparepvec in Combination 
With Atezolizumab in Subjects With Triple Negative Breast Cancer and Colorectal 
Cancer With Liver Metastases 
 
Amgen Protocol Number 20140299 
 
Amendment 1 Date: 
04 November 2016 
Rationale: 
This protocol is being amended to: 
• 
To update the required use of contraception for female patients to 5 months 
based on the latest update to the atezolizumab investigator brochure (IB) 
• 
This IB update also required the prohibited use of live vaccine after treatment for 
atezolizumab to be extended to 5 months 
• 
The language was updated to reflect the newest protocol template released: 
o The contraception language in the exclusion criteria was updated.  This 
resulted in an additional language in Section 6 (Section 6.10 
Contraceptive Requirements). 
o Table 6 Laboratory Analytes was updated 
o Section 9.2 Safety Event Reporting Procedures was updated 
o Section 9.3 Pregnancy and Lactation Reporting was updated 
o Section 12 Administrative and Legal Obligations was updated 
• 
The exposure language for talimogene laherparepvec was updated to reflect the 
newest language as of 26 April 2016 
• 
The End of Study language was updated for clarification 
• 
Update language regarding diameter of tumors to clarify they will be assessed by 
ultrasound or computerized tomography (CT) in preparation for injection 
guidance. 
• 
Clarify Grade ≥ 3 laboratory abnormality should be deemed to be not clinically 
significant by both the investigator and the sponsor. 
Approved