Clinical trial NCT02541604
Conditions: Solid Tumor
Sponsor: Hoffmann-La Roche
Start date: 2015-11-30; Completion date: 2019-06-06
Enrollment: 87 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This early phase, multicenter, open-label, single-arm study evaluated the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of atezolizumab in pediatric and young adult participants with solid tumors for which prior treatment was proven to be ineffective.

Detailed description:

Arms: arm 1: Participants received intravenous (IV) infusion of atezolizumab (maximum 1200 milligrams \[mg\]) on Day 1 of each 21-day cycle.
Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: Atezolizumab was administered as IV infusion (maximum 1200 mg) on Day 1 of each 21-day cycle.

Protocol documents:
Prot_SAP_000.pdf: 
 
Official Title: 
 
AN EARLY-PHASE, MULTICENTER, OPEN-LABEL STUDY OF THE 
SAFETY AND PHARMACOKINETICS OF ATEZOLIZUMAB 
(MPDL3280A) IN PEDIATRIC AND YOUNG ADULT PATIENTS 
WITH PREVIOUSLY TREATED SOLID TUMORS 
NCT Number: 
NCT02541604 
Document Date: 
Protocol Version 5: 21-October-2016 
 
 


 
Title
21-Oct-2016 14:33:33
Date and Time (UTC)
Company Signatory
Approver's Name
PROTOCOL AMENDMENT APPROVAL 
 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
Atezolizumab—F. Hoffmann-La Roche Ltd 
Protocol GO29664, Version 5 
PROTOCOL 
TITLE: 
AN EARLY-PHASE, MULTICENTER, OPEN-LABEL 
STUDY OF THE SAFETY AND 
PHARMACOKINETICS OF ATEZOLIZUMAB 
(MPDL3280A) IN PEDIATRIC AND YOUNG ADULT 
PATIENTS WITH PREVIOUSLY TREATED SOLID 
TUMORS 
PROTOCOL NUMBER: GO29664 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-004697-41 
IND NUMBER: 
124026 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
DATE FINAL: 
Version 1:  20 December 2014 
DATES AMENDED: 
Version 2:  15 April 2015 
Version 3:  8 May 2015 
Version 4:  15 October 2015 
Version 5:  See electronic date stamp below. 
 


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PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Changes to the protocol, along with a rationale for each change, are summarized below. 
• 
The atezolizumab clinical safety information has been updated to reflect the most 
current available data (Section 1.2.2.1). 
• 
The International Neuroblastoma Response Criteria (INRC) used in this study is 
modified from the original INRC publication to clarify the definition of measurable 
(evaluable) disease on computed tomography and magnetic resonance imaging 
scans for malignant lymph nodes (Section 3.1 and Appendix 3).  Notations were 
made to clarify this. 
• 
The protocol was modified to include atypical teratoid rhabdoid tumor (ATRT) and 
rhabdoid tumor (RT) on the basis of a significant clinical response seen in a patient 
in the non-rhabdomyosarcoma soft tissue sarcoma cohort.  Associated changes 
(including the addition of Response Assessment in Neuro-Oncology criteria) were 
made to allow for these patients to be able to enroll safely (e.g., utilization of 
steroids, exclusion of tumors that involve the brainstem) and to ensure that 
consistent data are obtained.  Additional safety measures including but not limited 
to additional neurologic visits were added for patients enrolling in the ATRT cohort 
(Section 3.1, Section 3.3.7, Section 3.4.4, Section 4.1.1, Section 4.1.2, 
Section 4.5.2, Section 4.5.5.2, Section 5.3.5.10, Section 6.1, Section 6.6.1, and 
Section 6.6.2). 
• 
The safety monitoring and reporting period has been differentiated on the basis of 
the category of adverse events.  Serious adverse events and adverse events of 
special interest will be reported until 90 days after the last dose of study drug or 
initiation of new anti-cancer therapy, whichever occurs first.  All other adverse 
events, regardless of relationship to study drug, will be reported until 30 days after 
the last dose of study drug or initiation of new anti-cancer therapy, whichever 
occurs first.  The change was made for consistency with the atezolizumab program 
in adult studies and to better focus on the most relevant safety information 
(Section 3.1, Section 5.1, Section 5.3.1, Section 5.4.2.2, and Section 5.6). 
• 
Bone biopsy tissue samples are now part of the acceptable tissue samples 
because of operational and bioanalytical updates; these samples can now be 
analyzed in the setting of this study (Sections 4.1.1 and 4.5.6). 
• 
Contraception requirements were updated to require female patients to use 
two methods of birth control for at least 5 months after the last dose of study drug, 
which corresponds to five times the terminal half-life of atezolizumab and is 
expected to provide a complete washout of the drug from the body.  Male 
contraception requirements were removed in consistency with updated safety 
requirements reported in the Investigator’s Brochure (Version 8), provided that 
atezolizumab is not considered a genotoxic drug (Section 4.1.1). 
• 
The criterion that excludes patients under treatment with investigational therapy 
(except specific cancer therapies) within 4 weeks prior to initiation of study drug 
was modified (Section 4.1.2). The 4-week period of withholding treatment is, in 


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certain instances, considered too extensive in this impaired patient population.  If 
required, patients will be evaluated on the basis of their grade of recovery of 
toxicity. 
• 
Enrollment stopping rules (Section 3.1.2) were updated in accordance to the 
atezolizumab Pediatric Investigational Plan. 
 
In addition, this amendment incorporates changes as follows: 
• 
The overall target enrollment has been modified (from approximately 40−100 to 
approximately 100) and the expected enrollment period updated on the basis of the 
updated recruitment plan (Section 3.1.1, Section 4.1, Section 6.1, and Section 9.4). 
• 
For consistency with the atezolizumab program in adult studies, it was clarified that 
among adverse events requiring drug discontinuation is included any toxicity that 
requires interruption of treatment for > 105 days (previously > 42 days), which refers 
to no more than 105 days between infusions (Section 3.1.3, Section 4.6.2, and 
Section 5.1.1.1). 
• 
Clarification of the exclusion criteria referring to any non-hematologic toxicity 
(excluding alopecia) from prior treatment that has not resolved to Grade ≤ 1: 
long-term sequelae of prior treatment (hearing loss, iatrogenic hypothyroidism, 
infertility, etc.) are not considered non-hematologic toxicity and are instead 
considered chronic medical conditions (Section 4.1.2). 
• 
For consistency with the atezolizumab program in adult studies and updated safety 
requirements reported in the Investigator’s Brochure (Version 8), the following 
exclusion criteria were amended (Section 4.1.2): 
Allowed timing of treatment with chemotherapy, differentiation therapy, or 
immunotherapy (such as anti-GD2 antibody treatment) prior to initiation 
of study drug updated to within 3 weeks instead of 4 weeks. 
Allowed timing of treatment with thoracic or mediastinal radiotherapy to 
within 3 weeks prior to initiation instead of 6 weeks. 
Allowed timing of treatment with hormonal therapy or biologic therapy 
updated to 4 weeks or 5 half-lives, whichever is shorter, instead of 4 weeks. 
Allowed timing of treatment with herbal cancer therapy updated to within 
1 week prior to initiation of study drug instead of 4 weeks. 
Patients with a history of autoimmune-related hypothyroidism on a stable 
dose of thyroid-replacement hormone are now eligible for the study. 
Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen 
are now eligible for the study. 
Allowed timing of use of live vaccine or live attenuated vaccine updated to 
within 4 weeks prior to initiation of the study or 5 months after final dose of 
study drug, instead of the previously stated 90 days after final dose 
(Section 4.1.2, Section 4.4.2, and Section 5.1). 
• 
Pregnancy reporting was updated for female patients to a more extensive period of 
5 months (Section 5.4.3.1), which corresponds to five times the terminal half-life of 


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atezolizumab and is expected to provide a complete washout of the drug from the 
body.  In case of pregnancies in partners of male patients, the Sponsor will follow 
up the outcome of the pregnancy regardless of time after last dose 
(Section 5.4.3.2). 
• 
Guidelines for the management of specific adverse events (Section 5.1.1) were 
amended to remove endocrine events and clarify systemic immune activation.  
Instruction for management of atezolizumab-specific adverse events now refers to 
the Investigator’s Brochure. 
• 
Changes that aim to facilitate the operational feasibility of the study and 
clarifications were made in the sections related to dosage, administration and 
compliance, prohibited therapies, tumor assessments, laboratory-related sections, 
patient discontinuation, adverse events requiring drug discontinuation immediately 
reportable to the Sponsor, immediate reporting requirements, reporting 
requirements, and schedules of assessments (Section 4.3.2, Section 4.4.2, 
Section 4.5.5.1, Section 4.5.6, Section 4.6.1, Section 5.2.4, Section 5.4, Section 
5.4.2, Appendix 1, and Appendix 2). 
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


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PROTOCOL AMENDMENT, VERSION 5: 
SUMMARY OF CHANGES 
PROTOCOL SYNOPSIS 
The protocol synopsis has been updated to reflect the changes to the protocol, where 
applicable. 
SECTION 1.1:  PD-L1/PD-1 PATHWAY IN CANCER 
Encouraging clinical data emerging in the field of tumorcancer immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced solid tumors and 
hematologic malignancies. 
SECTION 1.2:  BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab (also referred to as TECENTRIQ®) is a humanized IgG1 monoclonal 
antibody that targets PD-L1 and inhibits its interaction with PD-1. 
SECTION 1.2.2.1:  Clinical Safety 
As of 10 May 20152016, atezolizumab has been administered to approximately 
32006000 adult patients with solid tumors and hematologic malignancies… 
…In Study PCD4989g, as of 11 May 201515 December 2015, there have been 
558629 adult patients treated with study drug for a median duration of treatment of 12.14 
weeks (range: 0.0 71.4).  The most common cancer types for these patients include 
non−small cell lung cancer (NSCLC; n = 9189), urothelial bladder cancer (n = 9495), 
triple-negative breast cancer (n = 78111), and renal cell carcinoma (n = 7072).  Of the 
558629 patients evaluable for safety enrolled, 376 444 patients (67.470.6%) reported at 
least one treatment-related adverse event while receiving study drug.  The most 
frequently observed adverse events (occurring in ≥ 10% of treated patients) included 
fatigue, nausea, decreased appetite, diarrhea, constipation, dyspnea, pyrexia, cough, 
vomiting, anemia, back pain, headache, asthenia, arthralgia, pruritus, rash, abdominal 
pain, peripheral edema, urinary tract infection, insomnia, and chillsdizziness.  
Grade ≥ 3 adverse events were reported by 260 of 558326 of 629 patients (46.651.8%), 
and 6989 patients (12.414.1%) experienced Grade ≥ 3 adverse events that were 
assessed as related to study drug by the investigators.  The most frequently reported 
related Grade 3 and 4 adverse events included dyspnea, pneumonitis, increased alanine 
aminotransferase, increased aspartate aminotransferase, increased gamma glutamyl 
transferase, lymphocyte count decreased, cardiac tamponade, asthenia, autoimmune 
hepatitis, pneumonia, influenza, and hypoxiafatigue, asthenia, increased aspartate 
aminotransferase, dyspnea, and hyponatremia. 
SECTION 1.3:  STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
The expression of PD-L1 by malignant cells has been reported in many pediatric tumor 
types, including high-grade glioma (Wintterle et al. 2003; Wilmotte et al. 2005; 
Parsa et al. 2007), rhabdomyosarcoma (Wiendl et al. 2003, Kim et al. 2008), 


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non-Hodgkin’s lymphoma (Yamamoto et al. 2009; Green et al. 2010; 
Andorsky et al. 2011), Hodgkin’s lymphoma (Yamamoto et al. 2008, 2009; 
Green et al. 2010), rhabdomyosarcoma (Kim et al. 2008), soft tissue sarcoma 
(Kim et al. 2008), osteosarcoma (Lussier et al. 2013), Ewing sarcoma (Kim et al. 2008), 
and Wilms tumor (Routh et al. 2008, 2013). 
SECTION 2.6:  EXPLORATORY OBJECTIVES 
• 
To evaluate potential relationships between detectable ATAs and other clinical 
relevant outcome measures (e.g., pharmacokinetics, safety, and efficacy) 
 
SECTION 3.1:  DESCRIPTION OF STUDY 
…An independent Data Monitoring Committee (iDMC) will review the safety data of the 
first 5 patients and make recommendations on the appropriateness of opening the study 
to patients < 2 years of age (see Section 3.1.4)…. 
Tumor assessments will be performed every two cycles from Cycle1 through Cycle 8 
and then every 4th cycle thereafter.  Response will be determined by the investigator 
through use of modified International Neuroblastoma Response Criteria (mINRC) for 
patients with neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant 
Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma 
(Cheson et al. 2007; see Appendix 4), Response Assessment in Neuro-Oncology 
(RANO) criteria (see Appendix 11) for patients with atypical teratoid rhabdoid tumor 
and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for 
patients with other solid tumors (see Appendix 5)… 
…All patients will be closely monitored for adverse events throughout the study and for 
at least 9030 days after the last dose of study treatment or initiation of a new anti-
cancer therapy, regardless of relationship to study drug (see Section 5.3.1).  Serious 
adverse events and adverse events of special interest, regardless of relationship to study 
drug, will be monitored for 90 days after the last dose of study drug or until initiation 
of new anti-cancer therapy.  All identified adverse events should be followed up until 
resolution, which may necessitate monitoring beyond 9030 days after the last dose of 
study drug. 
SECTION 3.1.1:  Number of Patients 
Approximately 40 100 patients are expected be enrolled in this study, at approximately 
50 investigative sites in Europe and North America…. 
Accrual is expected to last approximately 23 years. 
SECTION 3.1.2:  Enrollment Stopping Rules 
• 
The Sponsor has stopped the study. 
• 
At least two tumor type cohorts have enrolled the minimum number of patients 
needed for initial response assessment. 


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Some exceptions may apply to these general stopping rules, including but not limited to 
the following: 
• 
Enrollment in the study willmay be stopped if enrollment has been open for more 
than 2 years and at least 20 patients have been treated with the study. 
 
SECTION 3.1.3:  Adverse Events Requiring Drug Discontinuation 
• 
Grade ≥ 3 thrombocytopenia with a Grade ≥ 2 bleeding event 
• 
Grade ≥ 3 non-hematologic, non-hepatic adverse event, with the following 
exceptions: 
Grade 3 fevers will not mandate study drug discontinuation. 
Grade 3 mucositis or stomatitis that resolves to Grade ≤ 2 within 3 days will not 
mandate study drug discontinuation. 
Grade ≥ 3 nausea or vomiting that responds to standard-of-care therapy 
within 3 days will not mandate study drug discontinuation.  In the ATRT cohort, 
this may mandate study drug discontinuation if Grade ≥ 3 nausea and/or 
vomiting is subsequent to increased intracranial pressure (see Section 4.5.3.1 
for management guidelines)…. 
• 
Any toxicity that requires interruption of atezolizumab treatment for > 42105 days 
(e.g., no more than 105 days between infusions), except in patients who must be 
tapered off corticosteroids used to treat adverse events (see Section 5.1.1.1 for 
details).  Longer periods of treatment interruption may be considered after 
discussion with the Medical Monitor. 
 
SECTION 3.3.1:  Rationale for Atezolizumab Starting Dose and Dose 
Modification 
…For atezolizumab, the nonspecific elimination pathway appears to be primary, as 
evidenced by linear pharmacokinetics in the dose range of 1−20 mg/kg, which includes 
the approved dose (for treatment of adult patients with urothelial carcinoma) and 
recommended Phase II/III dose currently under investigation in multiple cancer types 
(1200 mg; equivalent to a weight-based dose of 15 mg/kg assuming an adult body 
weight of 80 kg)… 
Children aged < 18 years will receive the weight-based equivalent of the approved adult 
dose and recommended Phase II/III adult dose (15 mg/kg atezolizumab every 3 weeks, 
with a maximum of 1200 mg).  Patients who are ≥ 18 years old will receive a flatthe 
approved adult dose of 1200 mg.  Dose adjustments may be made, if necessary, to 
achieve exposures corresponding to those measured in adult patients and if the safety 
profile is acceptable. 
Dose levels for modification will be determined on the basis of the available information 
regarding PK exposure, based on interim PK analyses, and the emerging safety profile. 


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SECTION 3.3.2:  Rationale for Inclusion of Patients Over Aged > 18 Years 
SECTION 3.3.4:  Rationale for Treatment beyond Progression 
…Patients participation in the study should be discontinued for unacceptable toxicity or 
symptomatic deterioration attributed to disease progression as determined by the 
investigator after an integrated assessment of radiographic data and clinical status (see 
Section 4.5.5.2). 
SECTION 3.3.7:  Rationale for Separate Cohorts for Rhabdoid Tumor and 
Atypical Teratoid Rhabdoid Tumor 
Patients with atypical teratoid rhabdoid tumor (ATRT) and rhabdoid tumor will be 
enrolled into separate cohorts.  Although the two tumor types are often merged 
together, reflecting common genetic drivers, the differences in tumor microenvironment 
(CNS for ATRT and non-CNS for rhabdoid tumor) necessitate separating them in this 
protocol.  This will allow for a more thorough evaluation of atezolizumab in these 
tumor types and account for any differences in safety and efficacy that may occur 
because of differences in organ location or tumor microenvironment or the presence of a 
blood-brain barrier. 
SECTION 3.4.2:  Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Atezolizumab maximum serum concentration (Cmax) after the infusion on Day 1 of 
Cycle 1 and Cycle 4 
 
SECTION 3.4.4:  Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are as follows: 
• 
Objective response, defined as a complete or partial response for patients with 
measurable disease or neuroblastoma patients with evaluable disease at baseline, 
or a complete response for patients with non−measurable but evaluable disease at 
baseline (except patients with neuroblastoma) on two consecutive 
occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1 
for patients with solid tumors (see Appendix 6), mINRC for patients with 
neuroblastoma (see Appendix 3), and Revised Response Criteria for Malignant 
Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see 
Appendix 4), and RANO criteria (see Appendix 11) for patients with ATRT. 
• 
Clinical benefit response (CBR), defined as objective response or stable disease 
for at least 6 months, as determined by RECIST v1.1 for patients with 
osteosarcoma (see Appendix 6) 
• 
PFS, defined as the time from initiation of study drug to the first documented 
occurrence of progressive disease, as determined by the investigator using 
RECIST v1.1 for patients with solid tumors (see Appendix 6), mINRC for patients 
with neuroblastoma (see Appendix 3), and Revised Response Criteria for 
Malignant Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s 


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lymphoma (see Appendix 4), and RANO criteria (see Appendix 11) for patients 
with ATRT, or death from any cause, whichever occurs first 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
DOR, defined as the time from the first tumor assessment that supports the 
patient’s objective response to the time of progressive disease, as determined by 
the investigator using RECIST v1.1 for patients with solid tumors (see Appendix 5), 
mINRC for patients with neuroblastoma (see Appendix 3), and Revised Response 
Criteria for Malignant Lymphoma for patients with Hodgkin’s lymphoma or 
non-Hodgkin’s lymphoma (see Appendix 4), and RANO criteria (Appendix 11) for 
patients with ATRT, or death from any cause, whichever occurs first 
• 
OS, defined as the time from initiation of study drug to death from any cause 
• 
ORR, PFS, and DOR as determined by the investigator using and 
immune-modified RECIST v1.1 for patients with other solid tumors (see Appendix 5) 
and immune-related response criteria (irRC) for patients with neuroblastoma, 
Hodgkin’s lymphoma or non-Hodgkin’s lymphoma 
 
SECTION 4.1:  PATIENTS 
This study will enroll at least 40 approximately 100 pediatric or young adult patients with 
solid tumors with known or expected PD-L1 pathway involvement for which prior 
treatment has proven to be ineffective (i.e., relapsed or refractory disease) or intolerable 
and for whom there are no curative standard-of-care treatment options. 
SECTION 4.1.1:  Inclusion Criteria 
Non-Hodgkin’s lymphoma 
Rhabdoid tumor 
Note:  Patients who have synchronous rhabdoid tumor and ATRT with no 
clear primary should be enrolled into the rhabdoid tumor cohort, and they 
should complete the additional assessments scheduled for patients 
with ATRT. 
ATRT 
Other tumor types not included in the list above with documented expression of 
PD-L1 on either tumor cells or immune infiltrating cells with approval of the 
Medical Monitor… 
• 
Disease that is measurable as defined by RECIST v1.1, mINRC, Revised 
Response Criteria for Malignant Lymphoma, or RANO criteria (as appropriate) or 
evaluable by nuclear medicine techniques, immunocytochemistry techniques, 
tumor markers, or other reliable measures 
• 
Archival tumor tissue block or 15 freshly cut, unstained, serial slides available for 
submission or willingness to undergo a core or excisional biopsy prior to enrollment 
(fine-needle aspiration, brush biopsy, bone metastases samples, and lavage 
samples are not acceptable)… 


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• 
For patients of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including 
at least one method with a failure rate of < 1% per year, during the treatment period 
and for at least 90 days5 months after the last dose of study drug… 
• 
For male patients:  agreement to remain abstinent (refrain from heterosexual 
intercourse) or use contraceptive measures and agreement to refrain from donating 
sperm, as defined below: 
With female partners of childbearing potential or pregnant female partners, men 
must remain abstinent or use a condom during the treatment period and for at 
least 90 days after the last dose of study drug. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. 
Men must refrain from donating sperm during the treatment period and for at 
least 90 days after the last dose of study drug. 
 
SECTION 4.1.2:  Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known primary CNS malignancy or symptomatic CNS metastases, except ATRT 
Patients with ATRT must not have tumor brainstem involvement or tumors 
within 10 mm of the optic chiasm; they must not have a history of intracranial 
hemorrhage or spinal cord hemorrhage or have had neurosurgical resection, 
brain biopsy, or radiation to the primary brain tumor within 28 days 
of Cycle 1, Day 1. 
• 
Patients with asymptomatic untreated CNS diseasemetastases may be enrolled 
after consultation with the Medical Monitor, provided all of the following criteria are 
met: 
Evaluable or measurable outside the CNS.  (Note:  this is not required for 
patients with ATRT.) 
No metastases to brain stem, midbrain, pons, medulla, or cerebellum or 
within 10 mm of the optic apparatus (optic nerve or chiasm).  (Note: ATRT may 
have metastases in the cerebellum.) 
No history of intracranial hemorrhage or spinal cord hemorrhage 
No ongoing requirement for corticosteroids for CNS disease except in ATRT 
where steroids use is permitted with approval from the Medical Monitor.  
Patients with ATRT must receive a stable or decreasing dose for ≥ 5 days prior 
to the baseline magnetic resonance imaging [MRI] scan and at the time of drug 
initiation. 
Patients taking a stable dose of anticonvulsants are permitted… 


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• 
Treatment with chemotherapy (other than high-dose chemotherapy as described 
above) or differentiation therapy (such as retinoic acid) or immunotherapy (such as 
anti-GD2 antibody treatment) within 43 weeks prior to initiation of study drug or, if 
treatment included nitrosoureas, within 6 weeks prior to initiation of study drug 
This requirement may be waived at the investigator’s request if the patient has 
recovered from therapeutic toxicity to the degree specified in the protocol, with 
approval of the Medical Monitor. 
• 
Treatment with thoracic or mediastinal radiotherapy within 63 weeks prior to 
initiation of study drug 
• 
Treatment with hormonal therapy (except hormone replacement therapy or oral 
contraceptives) or biologic therapy or herbal cancer therapy within 4 weeks or 
5 half-lives, whichever is shorter, prior to initiation of study drug.  This requirement 
may be waived at the investigator’s request if the patient has recovered from 
therapeutic toxicity to the degree specified in the protocol, with approval of the 
Medical Monitor. 
• 
Treatment with herbal cancer therapy within 1 week prior to initiation of study 
drug 
• 
Treatment with investigational therapy (with the exception of cancer therapies as 
described above) within 4 weeks prior to initiation of study drug.  This requirement 
may be waived at the investigator’s request if the patient has recovered from 
therapeutic toxicity to the degree specified in the protocol, with approval of the 
Medical Monitor. 
• 
Treatment with a live vaccine or a live attenuated vaccine (e.g., nasal spray of live 
attenuated influenza vaccine or FluMist®) within 4 weeks prior to initiation of study 
drug or anticipation that such treatment will be required during the study or within 
90 days5 months after the final dose of study drug 
• 
Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor [TNF] agents) within 2 weeks prior toat the time of initiation of study 
drug, or anticipated requirement for systemic immunosuppressive medications 
during the study 
Patients with ATRT can be receiving concurrent treatment with 
corticosteroids with approval from the Medical Monitor as outlined in 
Section 4.4.2 and the ATRT-related exclusion criteria. 
• 
Current treatment with therapeutic anticoagulants 
• 
Any non-hematologic toxicity (excluding alopecia or hearing loss) from prior 
treatment that has not resolved to Grade ≤ 1 (per NCI CTCAE v4.0) at screening 
Note:  Long-term sequelae of prior treatment (e.g., hearing loss, iatrogenic 
hypothyroidism, infertility, etc.) are not considered non-hematologic toxicity 
and instead are considered chronic medical conditions…. 


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• 
Known hypersensitivity to any component of the study drug 
biopharmaceuticals produced in Chinese hamster ovary cells or any component of 
the atezolizumab formulation… 
• 
History of any autoimmune disease, including but not limited to Type 1 diabetes 
mellitus, autoimmune-related hypothyroidism, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid 
syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, 
multiple sclerosis, vasculitis, or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism who are 
receiving a stable dose of thyroid-replacement hormone are eligible for the 
study. 
Patients with controlled Type 1 diabetes mellitus who are receiving a stable 
dose of insulin regimen are eligible for the study…. 
SECTION 4.3.1:  Formulation, Packaging, and Handling 
The atezolizumab drug product is provided in a single use, 20 mL USP/Ph. Eur. Type 1 
glass vial as a colorless to slightly yellow, sterile, preservative free clear liquid solution 
intended for IV 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 8°C (36°F 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 the atezolizumab drug product; therefore, each 
vial is intended for single use only.  Discard any unused portion of drug remaining in a 
vial.  Vial contents should not be frozen or shaken and should be protected from direct 
sunlight.Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass 
vials.  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. 
For further information on the storageformulation and handling of atezolizumab, see the 
Pharmacy Manual and the Atezolizumab Investigator’s Brochure and Pharmacy Manual. 
SECTION 4.3.2:  Dosage, Administration, and Compliance 
Patients will be weighed at the beginning of each cycle (within 37 days of the Day 1 
dose), and the dose will be adjusted as needed.  Atezolizumab infusion may be delayed 
up to 35 days to accommodate holidays, weekends, and other patient obligations.  
Subsequent infusions should be rescheduled accordingly.  For patients who receive the 
15-mg/kg dose, the dose administered should be within 5% of the calculated dose to 
accommodate for any rounding that may need to occur.... 


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…The initial dose of atezolizumab will be deliveredadministered 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 deliveredadministered over 
30 (± 10) minutes…. 
Refer to the Pharmacy Manual for detailed instructions on drug preparation and 
administration.For more detailed information on drug preparation, storage, and 
administration, refer to the Investigator’s Brochure and Pharmacy Manual. 
SECTION 4.4.2:  Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
• 
Any concomitant therapy intended for the treatment of solid tumors, either 
approved by health authorities or experimental, including chemotherapy, 
radiotherapy (except palliative radiotherapy), hormonal therapy, immunotherapy, 
biologic therapy, or herbal therapy 
Patients with rhabdoid tumor and ATRT may receive local therapy (radiation 
or surgery) after at least four cycles of atezolizumab with approval of the 
Medical Monitor.… 
• 
Live vaccines and live attenuated vaccines (prohibited during the study and for 
90 days5 months after the last dose of study drug) … 
Patients with ATRT can be receiving concurrent treatment with corticosteroids with 
approval from the Medical Monitor.  Patients must be receiving a stable or decreasing 
dose for ≥ 5 days prior to the baseline MRI scan and at the time of drug initiation.  The 
Medical Monitor should be informed when steroid doses are increased because of 
declining patient status. 
In clinically indicated emergent situations (i.e., anaphylaxis), corticosteroids may be 
administered without notifying the Medical Monitor in advance, but the Medical Monitor 
should be notified within 24 hours of the event.  If feasible, alternatives to these agents 
should be considered.  Systemic steroids used as steroid replacement therapy for 
adrenal insufficiency are permitted. 
SECTION 4.5.3.1:  Neurologic Examinations (ATRT Only) 
For patients with ATRT, a complete neurologic examination should be completed at 
every patient visit, including at baseline (see Schedule of Assessments in Appendix 1).  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), changes from baseline abnormalities 
need to be reviewed carefully prior to administering the next atezolizumab dose.  
Atezolizumab should not be administered if there is any sign of increased intracranial 
pressure.  


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The neurologic examination should include age-appropriate evaluations of vision, 
including visual fields, coordination, cranial nerve function, strength and motor 
evaluations (including gait when appropriate), and reflexes.  Discussions with the 
parents and/or guardian should also occur to assess for new or worsening symptoms, 
including but not limited to changes in physical activity, irritability, headaches, 
changes in appetite and/or feeding, vomiting, and nausea. 
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
SECTION 4.5.5.1:  Tumor Assessments 
Response will be assessed by the investigator on the basis of physical examinations, 
CT scans, MRI scans, fluorodeoxyglucose-positron emission tomography (FDG-PET) 
scans, or MIBG scans, as appropriate.  CT or MRI scans should include chest, abdomen, 
and pelvic scans; CT scans of the neck should be included if clinically indicated.Tumor 
assessment imaging should include all areas of known disease.  A chest CT is also 
required to be performed at each assessment.  An objective response should be 
confirmed by repeat assessments ≥ 4 weeks after initial documentation.  The same 
imaging techniques andradiographic procedures used to assess disease sites at 
screening should be used throughout the study (e.g., the same contrast protocol for CT 
scans).  To the extent that is feasible, assessments should be performed by the same 
evaluator to ensure internal consistency across visits. 
SECTION 4.5.5.2:  Response Criteria 
All tumors will be evaluated for disease response and progressive disease with 
RECIST v1.1 (see Appendix 6) with the exception of those listed below. 
• 
Neuroblastoma:  mINRC (see Appendix 3) 
• 
Hodgkin’s lymphoma and non-Hodgkin’s lymphoma:  Revised Response Criteria 
for Malignant Lymphoma (see Appendix 4) 
• 
ATRT:  RANO criteria (see Appendix 11) 
Patients with synchronous ATRT and rhabdoid tumor with no clear primary 
should be enrolled into the rhabdoid tumor cohort.  These patients’ tumors 
will be evaluated with RECIST v1.1 criteria. 
 
SECTION 4.5.6:  Laboratory, Biomarker, and Other Biological Samples 
…In situations where the total amount will exceed the amount stated above, clinical 
laboratory assessments should be prioritized.  Any remaining blood should be sent for 
PK analysis and immunogenicity followed by biomarker and PD analyses. 
Laboratory tests results must meet the inclusion criteria and not meet the exclusion 
criteria at the time of screening.  If laboratory tests are performed again prior to the 
first dose, they must continue to meet the inclusion criteria and not meet the exclusion 
criteria. 


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…Patients without archival samples must be willing to undergo a core or 
excisional biopsy prior to enrollment.  Fine-needle aspiration, brush biopsy, 
bone marrow biopsy, and lavage samples are not acceptable.  Submission of 
bone biopsy specimens is strongly discouraged because of complications in the 
assessment of such tissue.  These specimens can be used only if no other tissue 
is available.… 
• 
Epstein Barr virus serology 
 
Samples will be destroyed when the final Clinical Study Report has been completed, 
with the following exceptions: 
• 
Any remaining samples collected for pharmacokinetics, biomarker assays, and 
ATA assays may be used for exploratory biomarker profiling, identification, and PD 
assay development purposes and for additional safety assessments (e.g., ATA 
assay) as appropriate.  These samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed.  The remainder of samples 
obtained for study-related procedures will be destroyed no later than 5 years after 
the date of final closure of the clinical database unless the patient gives specific 
consent for the remainder of the samples to be stored for optional exploratory 
research…. 
 
SECTION 4.6.1:  Patient Discontinuation 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  In situations where it is either unsafe or not in the best interest of 
the patient to complete follow-up assessments after study drug discontinuation, 
survival data only may be submitted during the follow-up period with approval of the 
Medical Monitor.  However, pPatients will not be followed up for any reason after 
consent has been withdrawn.  Patients who withdraw from the study will not be replaced. 
SECTION 4.6.2:  Study Drug Discontinuation 
• 
Interruption of study treatment for > 42105 days (e.g., more than 105 days between 
infusions) because of an atezolizumab-related adverse event, except in patients 
who must be tapered off corticosteroids used to treat adverse events (see 
Section 5.1.1.1 for details).  This duration may be extended after consultation with 
the Medical Monitor. 
 
SECTION 5.1:  SAFETY PLAN 
Atezolizumab is not approved for pediatric use and is currently in clinical development 
for different indications.  Human experience is currently limited, and the entire safety 
profile is not known at this time.  It has not been studied in patients younger than 
15 years old.  The following information is based on results from nonclinical and adult 
clinical studies and published data on similar molecules.  Refer to the Atezolizumab 
Investigator’s Brochure for a complete summary of safety information. 


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Measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Specifically, patients at risk for study-emergent autoimmune conditions or with a prior 
diagnosis of autoimmune disease (except patients with a history of autoimmune-related 
hypothyroidism receiving a stable dose of thyroid-replacement hormone or patients with 
controlled Type 1 diabetes mellitus receiving a stable dose of insulin regimen), patients 
with evidence of acute or chronic infections, and patients who have received a live 
vaccine or a live attenuated vaccine within 4 weeks prior to initiation of study drug will be 
excluded from the study (see Section 4.1.2).  Patients are also required to abstain from 
receiving a live or live attenuated vaccine during treatment and for 90 days5 months 
following the last atezolizumab dose.  In addition, patients will undergo safety monitoring 
during the study as described in Section 4.5, Section 5, and the schedules of 
assessments (see Appendix 1 and Appendix 2).  Patients with ATRT will be monitored 
with additional visits to assess neurologic function due to the possible risk of tumor 
progression and/or pseudoprogression in the CNS cavities.  Adverse events, laboratory 
values, and vital signs must be reviewed prior to each infusion…. 
…All Serious adverse events and adverse events of special interest will be recorded 
during the study and for 90 days after the last dose of study treatment or until the 
initiation of another anti-cancer therapy, whichever occurs first.  All other adverse 
events will be recorded during the study and for 9030 days after the last dose of study 
treatment or until the initiation of another anti-cancer therapy, whichever occurs first; 
treatment-related adverse events must be reported beyond this date (see Section 5.3.1).  
In addition, patients will continue to be followed up at defined time intervals (see 
schedules of assessments in Appendix 1 and Appendix 2) until termination of the study.  
Following discontinuation from this study, patients will be offered follow-up for adverse 
events and survival. 
SECTION 5.1.1.1:  Dose Modification and Treatment Interruption 
There will be no intrapatient atezolizumab dose reductions as a result of adverse events.  
Study drug may be temporarily withheld if patients experience an adverse event that is 
considered related to atezolizumab.  If study drug is withheld because of an 
atezolizumab-related adverse event for > 42 105 days, the patient will be discontinued 
from atezolizumab treatment.… 
…If patients must be tapered off corticosteroids used to treat adverse events, study 
treatment may be withheld for > 42 105 days.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor. 
SECTION 5.1.1.2:  Immune-Mediated Adverse Events 
Specific guidance for investigators regarding endocrine events and systemic immune 
activation (SIA) are described below.  For all other immune mediated adverse events 
(pulmonary events [pneumonitis]; hepatic events; GI events [diarrhea/colitis]; ocular 
events; infusion related reactions; pancreatic events; dermatologic events [rash]; and 


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neurologic disorders) refer to the Atezolizumab IB for guidance (Appendix 10 for 
precautions for anaphylaxis). 
Note: The Atezolizumab IB lists recommended steroid dosing for adult patients.  In the 
pediatric population weight based equivalent dosing adapted to children should be 
usedManagement of systemic immune activation is presented below.  Refer to the 
Atezolizumab Investigator’s Brochure for details on management of atezolizumab-
specific adverse events, including pulmonary events, hepatic events, gastrointestinal 
events, endocrine events, ocular events, infusion-related reactions, pancreatic events, 
dermatologic events, neurologic disorders, and immune-related meningoencephalitis. 
SECTION 5.1.1.3:  Endocrine Events 
Thyroid disorders or adrenal insufficiency has been associated with the administration of 
atezolizumab. 
Patients with unexplained symptoms such as fatigue, myalgia, polydipsia, polyuria, 
impotence, mental status changes, or constipation should be investigated for the 
presence of thyroid, pituitary, or adrenal endocrinopathies, as well as for hyponatremia 
or hyperkalemia.  An endocrinologist should be consulted if an endocrinopathy is 
suspected.  Tests such as TSH and free thyroxine (T4), prolactin, and a morning cortisol 
level will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. 
TABLE 1:  Management Guidelines for Endocrine Events 
Table 1 has been deleted.   Subsequent tables have been renumbered accordingly. 
SECTION 5.1.1.3:  Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternate etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and initial evaluation should include assessing the 
following: 
SECTION 5.1.1.4:  Central Nervous System Signs and Symptoms (ATRT 
Only) 
For the ATRT cohort only, signs and symptoms of disease progression and 
pseudoprogression of this CNS tumor should be assessed at each visit.  Study treatment 
should be interrupted immediately and patients should be treated with steroids and/or 
other medications to reduce intracranial pressure as per institutional guidelines in the 
case of signs and symptoms of increased intracranial pressure considered to be related 
to atezolizumab, including but not limited to vomiting, headache, changes in mental 
status, and vision changes.  The Medical Monitor should be contacted within 24 hours 


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if CNS signs and symptoms considered to be related to atezolizumab occur.  Patients 
should be treated with steroids and/or other medications to reduce intracranial pressure 
as per institutional guidelines. 
SECTION 5.2.4:  Adverse Events Requiring Drug Discontinuation 
(Immediately Reportable to the Sponsor) 
Adverse events requiring drug discontinuation (defined in Section 3.1.3), are required to 
be reported by the investigator to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2 for reporting instructions). 
SECTION 5.3.1:  Adverse Event Reporting Period 
After initiation of study drug, all serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  
All other adverse events, regardless of relationship to study drug, will be reported until 
30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment (see 
Section 5.6). 
SECTION 5.3.5.10:  Lack of Efficacy or Worsening of Cancer 
Events that are clearly consistent with the expected pattern of disease evolution should 
not be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  In most cases, the expected pattern of progression will be based on mINRC, 
Revised Response Criteria for Malignant Lymphoma, or RECIST v1.1, or RANO criteria 
as appropriate.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is a result of progressive disease, it should be reported as an adverse event. 
SECTION 5.4:  IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
• 
Adverse events requiring drug discontinuation 
 
SECTION 5.4.2:  Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest, and Adverse Events 
Leading to Drug Discontinuation 
SECTION 5.4.2.2:  Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  
All other adverse events, regardless of relationship to study drug, will be reported until 
30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first. 


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The investigator should also report any serious adverse events that are believed to be 
related to prior study drug treatment even if these occur after the abovementioned 
reporting periods.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
SECTION 5.4.3.1:  Pregnancies in Patients 
Patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 90 days 5 months after the last dose 
of study drug. 
SECTION 5.4.3.2:  Pregnancies in Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
90 days after the last dose of study drug. 
SECTION 5.6:  POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
90 days after the last dose of study drug or until initiation of new anti-cancer therapy 
for serious adverse events and adverse events of special interest and 30 days for all 
other adverse events), if the event is believed to be related to prior study drug treatment. 
The investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and e mailing the Serious Adverse Event/Adverse Event of 
Special Interest Reporting Form using the fax number or e mail address provided to 
investigators.These events should be reported through use of the Adverse Event eCRF.  
However, if the EDC system is not available, the investigator should report these events 
directly to the Sponsor or its designee, either by faxing or by scanning and emailing the 
Serious Adverse Event/Adverse Event of Special Interest Reporting Form using the fax 
number or email address provided to investigators. 
SECTION 6.1:  DETERMINATION OF SAMPLE SIZE 
TABLE 3:  Sample Size and Responder Requirements for Initial Response 
Assessment 
Table 3 heading of column 2 has been changed as follows:  Historical Control 
OverallObjective Response Rate.  The last 2 rows of text regarding rhabdoid tumor and 
atypical teratoid rhabdoid tumor were added. 
Overall, approximately 40 100 patients will be enrolled in the study. 


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SECTION 6.4:  PHARMACOKINETIC ANALYSES 
…Descriptive statistics will include mean, median, range, and standard deviation, 
coefficient of variation, geometric mean, and geometric mean coefficient of variation as 
appropriate…. 
SECTION 6.5:  IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one ATA assessment.  
The numbers and proportions of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized.  Patients are considered to 
be ATA positive if they are ATA negative or missing at baseline but develop an ATA 
response following study drug administration (treatment-induced ATA response), or if 
they are ATA positive at baseline and the titer of one or more post-baseline samples is 
at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample 
(treatment-enhanced ATA response).  Patients are considered to be ATA negative if 
they are ATA negative or missing at baseline and all post-baseline samples are negative, 
or if they are ATA positive at baseline but do not have any post-baseline samples with a 
titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected). 
SECTION 6.6.1:  Primary Efficacy Endpoint 
The primary endpoints for efficacy are ORR and PFS.  For patients with measurable 
disease or patients with neuroblastoma who have evaluable disease at baseline, an 
objective response is defined as a complete or partial response on two consecutive 
occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1 
for patients with solid tumors (see Appendix 6), mINRC for patients with neuroblastoma 
(see Appendix 3), Revised Response Criteria for Malignant Lymphoma for patients with 
Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see Appendix 4), and RANO criteria 
(see Appendix 11) for patients with ATRT. 
For patients with non-measurable but evaluable disease at baseline (except patients 
with neuroblastoma patients), an objective response is defined as a complete response 
on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator using 
RECIST v1.1 for patients with solid tumors (see Appendix 6), Revised Response Criteria 
for Malignant Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s 
lymphoma (see Appendix 4), and RANO criteria (see Appendix 11) for patients with 
ATRT. 
… PFS is defined as the time from initiation of study drug to the first documented 
occurrence of disease progression, as determined by the investigator using 
RECIST v1.1 for patients with solid tumors (see Appendix 6), mINRC for patients with 
neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant Lymphoma 
for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see Appendix 4), 
and RANO criteria (see Appendix 11) for patients with ATRT, or death from any cause, 
whichever occurs first. 


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SECTION 6.6.2:  Secondary Efficacy Endpoints 
For patients who achieve an objective response, DOR is defined as the time from the 
first tumor assessment that supports the patient’s objective response to the time of 
progressive disease, as determined by the investigator using mINRC for patients with 
neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant Lymphoma 
for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see Appendix 4), 
RANO criteria (see Appendix 11) for patients with ATRT, and RECIST v1.1 for 
patients with other solid tumors (see Appendix 6), or death from any cause, whichever 
occurs first. 
SECTION 9.4:  ADMINISTRATIVE STRUCTURE 
This study will be sponsored by Roche and managed with the support of a contract 
research organization, which will provide clinical monitoring, sample management, and 
project management support.  Approximately 40 100 patients are expected be enrolled 
in this study, at approximately 50 investigative sites in Europe and North America. 
SECTION 9.5:  PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to health care professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results.  For more information, refer to the Roche 
Global Policy on Sharing of Clinical Trials Data at the following Web site: 
http://www.rochetrials.com/pdf/RocheGlobalDataSharingPolicy.pdf 
APPENDIX 1:  Schedule of Assessments 
The schedule of assessments has been revised to reflect the changes to the protocol. 
APPENDIX 2:  Schedule of Pharmacokinetic, Pharmacodynamic, and 
Immunogenicity Assessments 
Appendix 2 has been updated to reflect changes in the protocol that update timepoints 
and sample types. 
APPENDIX 3:  Modified International Neuroblastoma Response Criteria 
Appendix 3 has been updated to reflect changes in the protocol that clarify the definition 
of measurable disease in malignant lymph nodes. 
APPENDIX 11:  Response Assessment in Neuro-Oncology Criteria 
Appendix 11 has been added to the protocol. 
SAMPLE INFORMED CONSENT FORM 
The sample Informed Consent Form has been revised to reflect the changes to the 
protocol. 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 29 
PROTOCOL SYNOPSIS .................................................................................... 30 
1. 
BACKGROUND .......................................................................................... 41 
1.1 
PD-L1/PD-1 Pathway in Cancer ............................................ 41 
1.2 
Background on Atezolizumab................................................ 41 
1.2.1 
Nonclinical Studies with Atezolizumab .................................. 42 
1.2.2 
Clinical Studies with Atezolizumab ........................................ 42 
1.2.2.1 
Clinical Safety........................................................................ 43 
1.2.2.2 
Clinical Activity....................................................................... 43 
1.3 
Study Rationale and Benefit-Risk Assessment...................... 44 
2. 
OBJECTIVES.............................................................................................. 45 
2.1 
Safety Objective .................................................................... 45 
2.2 
Pharmacokinetic Objective .................................................... 45 
2.3 
Immunogenicity Objective...................................................... 45 
2.4 
Efficacy Objectives ................................................................ 46 
2.5 
Dose Assessment Objective.................................................. 46 
2.6 
Exploratory Objectives........................................................... 46 
3. 
STUDY DESIGN ......................................................................................... 46 
3.1 
Description of Study .............................................................. 46 
3.1.1 
Number of Patients................................................................ 49 
3.1.2 
Enrollment Stopping Rules .................................................... 49 
3.1.3 
Adverse Events Requiring Drug Discontinuation................... 50 
3.1.4 
Independent Data Monitoring Committee .............................. 51 
3.2 
End of Study.......................................................................... 52 
3.3 
Rationale for Study Design.................................................... 52 
3.3.1 
Rationale for Atezolizumab Starting Dose and 
Dose Modification .................................................................. 52 
3.3.2 
Rationale for Inclusion of Patients Aged > 18 
Years ..................................................................................... 54 
3.3.3 
Rationale for Exploratory Analysis of 
Immunogenicity ..................................................................... 54 


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3.3.4 
Rationale for Treatment beyond Progression ........................ 54 
3.3.5 
Rationale for Mandatory Collection of Tumor 
Specimens............................................................................. 55 
3.3.6 
Rationale for Blood Sampling for Biomarkers........................ 55 
3.3.7 
Rationale for Separate Cohorts for Rhabdoid 
Tumor and Atypical Teratoid Rhabdoid Tumor...................... 55 
3.4 
Outcome Measures ............................................................... 56 
3.4.1 
Safety Outcome Measures .................................................... 56 
3.4.2 
Pharmacokinetic Outcome Measures.................................... 56 
3.4.3 
Immunogenicity Outcome Measure....................................... 56 
3.4.4 
Efficacy Outcome Measures.................................................. 56 
3.4.5 
Dose Assessment Outcome Measure ................................... 57 
3.4.6 
Exploratory Outcome Measures ............................................ 57 
4. 
MATERIALS AND METHODS .................................................................... 58 
4.1 
Patients.................................................................................. 58 
4.1.1 
Inclusion Criteria.................................................................... 58 
4.1.2 
Exclusion Criteria................................................................... 60 
4.2 
Method of Treatment Assignment and Blinding..................... 64 
4.3 
Study Treatment.................................................................... 64 
4.3.1 
Formulation, Packaging, and Handling.................................. 64 
4.3.2 
Dosage, Administration, and Compliance.............................. 64 
4.3.3 
Investigational Medicinal Product Accountability ................... 66 
4.3.4 
Post-Study Access to Atezolizumab ...................................... 66 
4.4 
Concomitant Therapy and Food ............................................ 67 
4.4.1 
Permitted Therapy ................................................................. 67 
4.4.2 
Prohibited Therapy ................................................................ 68 
4.5 
Study Assessments ............................................................... 69 
4.5.1 
Informed Consent Forms and Screening Log........................ 69 
4.5.2 
Medical History and Demographic Data ................................ 69 
4.5.3 
Physical Examinations and Assessments.............................. 70 
4.5.3.1 
Neurologic Examinations (ATRT Only).................................. 70 
4.5.4 
Vital Signs.............................................................................. 71 
4.5.5 
Tumor and Response Evaluations......................................... 71 


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4.5.5.1 
Tumor Assessments.............................................................. 71 
4.5.5.2 
Response Criteria.................................................................. 72 
4.5.6 
Laboratory, Biomarker, and Other Biological 
Samples................................................................................. 73 
4.5.7 
Samples for Roche Clinical Repository.................................. 76 
4.5.7.1 
Overview of the Roche Clinical Repository............................ 76 
4.5.7.2 
Approval by the Institutional Review Board or 
Ethics Committee .................................................................. 77 
4.5.7.3 
Sample Collection.................................................................. 77 
4.5.7.4 
Confidentiality........................................................................ 78 
4.5.7.5 
Consent to Participate in the Roche Clinical 
Repository ............................................................................. 78 
4.5.7.6 
Withdrawal from the Roche Clinical Repository..................... 79 
4.5.7.7 
Monitoring and Oversight....................................................... 79 
4.6 
Patient, Treatment, Study, and Site 
Discontinuation...................................................................... 79 
4.6.1 
Patient Discontinuation.......................................................... 79 
4.6.2 
Study Drug Discontinuation ................................................... 80 
4.6.3 
Study and Site Discontinuation.............................................. 80 
5. 
ASSESSMENT OF SAFETY....................................................................... 81 
5.1 
Safety Plan ............................................................................ 81 
5.1.1 
Management of Specific Adverse Events .............................. 82 
5.1.1.1 
Dose Modification and Treatment Interruption....................... 82 
5.1.1.2 
Immune-Mediated Adverse Events........................................ 83 
5.1.1.3 
Systemic Immune Activation.................................................. 83 
5.1.1.4 
Central Nervous System Signs and Symptoms 
(ATRT Only) .......................................................................... 84 
5.2 
Safety Parameters and Definitions ........................................ 84 
5.2.1 
Adverse Events ..................................................................... 84 
5.2.2 
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 85 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 86 
5.3 
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 87 


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5.3.1 
Adverse Event Reporting Period ........................................... 87 
5.3.2 
Eliciting Adverse Event Information ....................................... 87 
5.3.3 
Assessment of Severity of Adverse Events ........................... 87 
5.3.4 
Assessment of Causality of Adverse Events ......................... 88 
5.3.5 
Procedures for Recording Adverse Events............................ 89 
5.3.5.1 
Infusion-Related Reactions.................................................... 89 
5.3.5.2 
Diagnosis versus Signs and Symptoms................................. 89 
5.3.5.3 
Adverse Events That Are Secondary to Other 
Events.................................................................................... 90 
5.3.5.4 
Persistent or Recurrent Adverse Events................................ 90 
5.3.5.5 
Abnormal Laboratory Values ................................................. 91 
5.3.5.6 
Abnormal Vital Sign Values ................................................... 91 
5.3.5.7 
Abnormal Liver Function Tests.............................................. 92 
5.3.5.8 
Deaths ................................................................................... 92 
5.3.5.9 
Preexisting Medical Conditions.............................................. 93 
5.3.5.10 
Lack of Efficacy or Worsening of Cancer............................... 93 
5.3.5.11 
Hospitalization or Prolonged Hospitalization.......................... 93 
5.3.5.12 
Adverse Events Associated with an Overdose or 
Error in Drug Administration .................................................. 94 
5.4 
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 94 
5.4.1 
Emergency Medical Contacts................................................ 95 
5.4.2 
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 95 
5.4.2.1 
Events That Occur prior to Study Drug Initiation.................... 95 
5.4.2.2 
Events That Occur after Study Drug Initiation........................ 95 
5.4.3 
Reporting Requirements for Pregnancies.............................. 96 
5.4.3.1 
Pregnancies in Patients......................................................... 96 
5.4.3.2 
Pregnancies in Partners of Male Patients.............................. 96 
5.4.3.3 
Abortions ............................................................................... 97 
5.4.3.4 
Congenital Anomalies and Birth Defects ............................... 97 
5.5 
Follow-Up of Patients after Adverse Events .......................... 97 
5.5.1 
Investigator Follow-Up........................................................... 97 
5.5.2 
Sponsor Follow-Up ................................................................ 97 


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5.6 
Post-Study Adverse Events................................................... 98 
5.7 
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 98 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 98 
6.1 
Determination of Sample Size ............................................... 99 
6.2 
Summaries of Conduct of Study.......................................... 100 
6.3 
Safety Analyses................................................................... 100 
6.4 
Pharmacokinetic Analyses................................................... 101 
6.5 
Immunogenicity Analyses.................................................... 101 
6.6 
Efficacy Analyses ................................................................ 102 
6.6.1 
Primary Efficacy Endpoint.................................................... 102 
6.6.2 
Secondary Efficacy Endpoints............................................. 103 
6.7 
Exploratory Analyses........................................................... 103 
6.7.1 
Biomarker Analyses............................................................. 103 
6.8 
Interim Analyses.................................................................. 104 
6.8.1 
Planned Interim Analyses.................................................... 104 
6.8.2 
Optional Interim Analyses.................................................... 104 
7. 
DATA COLLECTION AND MANAGEMENT ............................................. 104 
7.1 
Data Quality Assurance....................................................... 104 
7.2 
Electronic Case Report Forms............................................. 105 
7.3 
Source Data Documentation................................................ 105 
7.4 
Use of Computerized Systems ............................................ 105 
7.5 
Retention of Records........................................................... 106 
8. 
ETHICAL CONSIDERATIONS.................................................................. 106 
8.1 
Compliance with Laws and Regulations .............................. 106 
8.2 
Informed Consent ................................................................ 106 
8.3 
Institutional Review Board or Ethics Committee.................. 107 
8.4 
Confidentiality...................................................................... 108 
8.5 
Financial Disclosure ............................................................ 108 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ................................................................................... 109 
9.1 
Study Documentation .......................................................... 109 


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9.2 
Protocol Deviations.............................................................. 109 
9.3 
Site Inspections ................................................................... 109 
9.4 
Administrative Structure....................................................... 109 
9.5 
Publication of Data and Protection of Trade 
Secrets ................................................................................ 110 
9.6 
Protocol Amendments ......................................................... 110 
10. REFERENCES ......................................................................................... 112 


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LIST OF TABLES 
Table 1 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in the NCI CTCAE ......................................... 88 
Table 2 
Causal Attribution Guidance ....................................................... 89 
Table 3 
Sample Size and Responder Requirements for Initial 
Response Assessment ............................................................. 100 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema:  Two Phases of Response Assessment ............ 47 
 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Assessments......................................................... 117 
Appendix 2 
Schedule of Pharmacokinetic, Pharmacodynamic, and 
Immunogenicity Assessments................................................... 123 
Appendix 3 
Modified International Neuroblastoma Response Criteria......... 124 
Appendix 4 
Revised Response Criteria for Malignant Lymphoma............... 128 
Appendix 5 
Modified Response Evaluation Criteria in Solid Tumors ........... 137 
Appendix 6 
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication ............................... 144 
Appendix 7 
Immune-Related Response Criteria.......................................... 156 
Appendix 8 
Lansky Performance Status Scale............................................ 159 
Appendix 9 
Karnofsky Performance Status Scale ....................................... 160 
Appendix 10 Recommended Anaphylaxis Management ............................... 161 
Appendix 11 Response Assessment in Neuro-Oncology Criteria.................. 162 


 
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PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
AN EARLY-PHASE, MULTICENTER, OPEN-LABEL 
STUDY OF THE SAFETY AND 
PHARMACOKINETICS OF ATEZOLIZUMAB 
(MPDL3280A) IN PEDIATRIC AND YOUNG ADULT 
PATIENTS WITH PREVIOUSLY TREATED SOLID 
TUMORS 
PROTOCOL NUMBER: GO29664 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-004697-41 
IND NUMBER: 
124026 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
MEDICAL MONITOR: 
, M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator’s Name  (print) 
 
 
 
 
 
Principal Investigator’s Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy as 
instructed by your local study monitor. 


 
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PROTOCOL SYNOPSIS 
TITLE: 
AN EARLY-PHASE, MULTICENTER, OPEN-LABEL STUDY OF 
THE SAFETY AND PHARMACOKINETICS OF ATEZOLIZUMAB 
(MPDL3280A) IN PEDIATRIC AND YOUNG ADULT PATIENTS 
WITH PREVIOUSLY TREATED SOLID TUMORS 
PROTOCOL NUMBER: 
GO29664 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2014-004697-41 
IND NUMBER: 
124026 
TEST PRODUCT: 
Atezolizumab (RO5541267) 
PHASE: 
Early Phase 
INDICATION: 
Solid tumors 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
Objectives 
Safety Objective 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of atezolizumab in pediatric and young adult patients, 
focusing on the nature, frequency, and severity of serious and non-serious adverse events, 
as well as effects on laboratory values and vital signs 
Pharmacokinetic Objective 
The pharmacokinetic (PK) objective for this study is as follows: 
• 
To characterize the pharmacokinetics of atezolizumab 
Immunogenicity Objective 
The immunogenicity objective for this study is as follows: 
• 
To evaluate the immune response to atezolizumab on the basis of the incidence 
of anti-therapeutic antibodies (ATAs) 
Efficacy Objectives 
The efficacy objectives for this study are as follows: 
• 
To evaluate the anti-cancer activity of atezolizumab, as measured by objective response 
rate (ORR), progression-free survival (PFS), duration of objective response (DOR), and 
clinical benefit response rate (only for osteosarcoma) 
• 
To evaluate the anti-cancer activity of atezolizumab, as measured by overall survival (OS) 
Dose Assessment Objective 
The dose-assessment objective for this study is as follows: 
• 
To assess the optimal dose of atezolizumab in pediatric and young adult patients on the 
basis of safety, PK, and efficacy outcome measures 
Exploratory Objectives 
The exploratory objectives for this study are as follows: 
• 
To explore if programmed death−ligand 1 (PD-L1) expression on tumor and/or 
tumor-infiltrating cells at baseline is predictive of response to atezolizumab 


 
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• 
To explore the relationship between atezolizumab exposure and changes in levels of 
pharmacodynamic (PD) biomarkers including but not limited to cytokines, circulating tumor 
DNA (ctDNA) concentration, and T-cell subpopulations 
• 
To explore non-inherited biomarkers that may be predictive of response to atezolizumab 
(i.e., predictive biomarkers), may be associated with progression to a more severe disease 
state (i.e., prognostic biomarkers), acquired resistance to atezolizumab, or susceptibility to 
developing adverse events; may provide evidence of atezolizumab activity; or may increase 
the knowledge and understanding of disease biology 
• 
To explore inherited biomarkers (i.e., variants in germline DNA) that may be predictive 
of response to atezolizumab (i.e., predictive biomarkers); may be associated with 
progression to a more severe disease state (i.e., prognostic biomarkers), acquired 
resistance to atezolizumab, or susceptibility to developing adverse events; or may increase 
the knowledge and understanding of disease biology 
• 
To evaluate potential relationships between detectable ATAs and other clinical relevant 
outcome measures (e.g., pharmacokinetics, safety, and efficacy) 
Study Design 
Description of Study 
The study is an early-phase, multicenter, open-label, single-arm study designed to evaluate the 
safety, tolerability, pharmacokinetics, immunogenicity, and preliminary efficacy of atezolizumab 
in pediatric and young adult patients with solid tumors with known or expected PD-L1 pathway 
involvement for which prior treatment has proven to be ineffective (i.e., relapsed or refractory) or 
intolerable and for whom no curative standard-of-care treatment options exist. 
Number of Patients 
Approximately 100 patients are expected be enrolled in this study, at approximately 
50 investigative sites in Europe and North America.  Of those who are enrolled, at least 
20 patients < 18 years of age will be treated with study drug, and at least 40 patients across all 
tumor type cohorts will be treated and available for response assessment (at least two tumor 
type cohorts must enroll a minimum of 10 patients). 
Target Population 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed solid tumor of a type listed below (tumor types with 
known or expected PD-L1 pathway involvement) (including Hodgkin’s and non-Hodgkin’s 
lymphoma), for which prior treatment had proven to be ineffective (i.e., relapsed or 
refractory) or intolerable.  Patients must have had histologic or cytologic confirmation of 
malignancy at the time of diagnosis or relapse. 
Neuroblastoma 
Rhabdomyosarcoma 
Non-rhabdomyosarcoma soft tissue sarcoma 
Osteosarcoma 
Ewing sarcoma 
Wilms tumor 
Hodgkin’s lymphoma 
Non-Hodgkin’s lymphoma 
Rhabdoid tumor 
Note:  Patients who have synchronous rhabdoid tumor and atypical teratoid 
rhabdoid tumor (ATRT) with no clear primary should be enrolled into the 
rhabdoid tumor cohort, and they should complete the additional assessments 
scheduled for patients with ATRT. 
ATRT 
Other tumor types not included in the list above with documented expression of PD-L1 
on either tumor cells or immune infiltrating cells with approval of the Medical Monitor 


 
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Other tumor types not included in the list above without documented expression of 
PD-L1 can be included with approval of the Medical Monitor and should not exceed 
20% of the total sample size. 
• 
Signed Informed Consent Form 
• 
Signed Child’s or Young Adult’s Assent Form when appropriate, as determined by patient’s 
age and individual site and country standards 
• 
Age at study entry < 30 years 
The first 5 patients must be ≥2 years of age (i.e., patients must have reached their 2nd 
birthday) to ensure safety and tolerability before patients <2 years of age receive their 
first dose of study drug.  These first 5 patients must be followed for either two cycles of 
treatment or until drug discontinuation, whichever is shorter, prior to enrolling younger 
patients. 
The Sponsor may decide to stop enrollment of patients who are ≥ 18 years old at any 
time during the study to ensure adequate enrollment of patients < 18 years old. 
Patients who are ≥ 18 years old and are eligible for an adult PD-L1 treatment protocol 
will be preferentially enrolled onto those adult studies. 
• 
In exceptional cases of relapsed pediatric tumors in patients ≥ 30 years of age, the Sponsor 
will consider waiving the age requirement with approval of the Medical Monitor.  This waiver 
is restricted to patients with pediatric-specific diseases (e.g., neuroblastoma), for whom 
clinical trials are unlikely to be available and will not be extended to patients with tumors 
that typically occur both in children and adults (i.e., high-grade glioma). 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Weight ≥ 3 kg 
• 
Disease that is measurable as defined by Response Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST v1.1), modified International Neuroblastoma Response Criteria 
(mINRC), Revised Response Criteria for Malignant Lymphoma, or Response Assessment in 
Neuro-Oncology (RANO) criteria (as appropriate) or evaluable by nuclear medicine 
techniques, immunocytochemistry techniques, tumor markers, or other reliable measures 
• 
Archival tumor tissue block or 15 freshly cut, unstained, serial slides available for 
submission or willingness to undergo a core or excisional biopsy prior to enrollment 
(fine-needle aspiration, brush biopsy, and lavage samples are not acceptable) 
Patients with fewer than 15 slides available may be eligible for study entry following 
discussion with the Medical Monitor. 
• 
Lansky Performance Status (patients < 16 years old) or Karnofsky Performance Status 
(patients ≥ 16 years old) ≥ 50 
• 
Life expectancy ≥ 3 months, in the investigator’s judgment 
• 
For patients of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including at least 
one method with a failure rate of < 1% per year, during the treatment period and for at least 
5 months after the last dose of study drug 
Examples of contraceptive methods with a failure rate of <1% per year 
include established, proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices (IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. 
Barrier methods must always be supplemented with the use of a spermicide. 
• 
Adequate hematologic and end organ function, defined by the following laboratory results 
obtained within 28 days prior to initiation of study drug: 
ANC ≥ 0.75 × 109/L (unsupported) 
Platelet count ≥ 75 × 109/L (unsupported) 


 
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Hemoglobin ≥ 8 g/dL (transfusion permitted) 
Bilirubin ≤ 1.5 × upper limit of normal (ULN) for age 
AST and ALT ≤ 2.5 × ULN for age 
Serum creatinine ≤ 1.5 × ULN for age or creatinine clearance (or radioisotope 
glomerular filtration rate) > 70 mL/min/1.73 m2 
INR and aPTT ≤ 1.5 institutional ULN for age 
Patients receiving therapeutic anticoagulants are excluded from the study. 
• 
Fractional shortening ≥ 30% or left ventricular ejection fraction ≥ 50% at baseline, as 
determined by echocardiography or multigated acquisition scan within 28 days prior to 
initiation of study drug 
 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known primary CNS malignancy or symptomatic CNS metastases, except ATRT 
Patients with ATRT must not have tumor brainstem involvement or tumors 
within 10 mm of the optic chiasm; they must not have a history of intracranial 
hemorrhage or spinal cord hemorrhage or have had neurosurgical resection, brain 
biopsy, or radiation to the primary brain tumor within 28 days of Cycle 1, Day 1. 
• 
Patients with asymptomatic untreated CNS metastases may be enrolled after consultation 
with the Medical Monitor, provided all of the following criteria are met: 
Evaluable or measurable outside the CNS.  (Note:  this is not required for patients 
with ATRT). 
No metastases to brain stem, midbrain, pons, medulla, or cerebellum or within 10 mm 
of the optic apparatus (optic nerve or chiasm).  (Note:  ATRT may have metastases in 
the cerebellum.) 
No history of intracranial hemorrhage or spinal cord hemorrhage 
No ongoing requirement for corticosteroids for CNS disease except in ATRT where 
steroids use is permitted with approval from the Medical Monitor.  Patients with 
ATRT must receive a stable or decreasing dose for ≥ 5 days prior to the baseline 
magnetic resonance imaging scan and at the time of drug initiation. 
Patients taking a stable dose of anticonvulsants are permitted 
No neurosurgical resection or brain biopsy within 28 days prior to Cycle 1, Day 1 
• 
Patients with asymptomatic treated CNS metastases may by enrolled after consultation with 
the Medical Monitor, provided all the criteria listed above in the above CNS-related 
exclusion criteria are met as well as the following: 
Radiographic demonstration of improvement upon the completion of CNS-directed 
therapy and no evidence of interim progression between the completion of 
CNS-directed therapy and the screening radiographic study 
No stereotactic radiation or whole-brain radiation within 28 days prior to Cycle 1, Day 1 
Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy and 
≥ 2 weeks from discontinuation of corticosteroids 
• 
For patients with lymphoma, known CNS lymphoma, or leptomeningeal disease 
• 
Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue within 
3 months prior to initiation of study drug 
This requirement may be waived at the investigator’s request if the patient has 
recovered from therapeutic toxicity to the degree specified in the protocol, with 
approval of the Medical Monitor. 
• 
Prior allogeneic hematopoietic stem-cell transplantation or prior solid-organ transplantation 


 
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• 
Treatment with chemotherapy (other than high-dose chemotherapy as described above) or 
differentiation therapy (such as retinoic acid) or immunotherapy (such as anti-GD2 antibody 
treatment) within 3 weeks prior to initiation of study drug or, if treatment included 
nitrosoureas, within 6 weeks prior to initiation of study drug 
This requirement may be waived at the investigator’s request if the patient has 
recovered from therapeutic toxicity to the degree specified in the protocol, with 
approval of the Medical Monitor. 
• 
Treatment with thoracic or mediastinal radiotherapy within 3 weeks prior to initiation of study 
drug 
• 
Treatment with hormonal therapy (except hormone replacement therapy or oral 
contraceptives), immunotherapy, or biologic therapy within 4 weeks or 5 half-lives, 
whichever is shorter, prior to initiation of study drug.  This requirement may be waived 
at the investigator’s request if the patient has recovered from therapeutic toxicity to the 
degree specified in the protocol, with approval of the Medical Monitor. 
• 
Treatment with herbal cancer therapy within 1 week prior to initiation of study drug 
• 
Treatment with investigational therapy (with the exception of cancer therapies as described 
above) within 4 weeks prior to initiation of study drug.  This requirement may be waived at 
the investigator’s request if the patient has recovered from therapeutic toxicity to the 
degree specified in the protocol, with approval of the Medical Monitor. 
• 
Treatment with a live vaccine or a live attenuated vaccine (e.g., nasal spray of live 
attenuated influenza vaccine or FluMist®) within 4 weeks prior to initiation of study drug or 
anticipation that such treatment will be required during the study or within 5 months after the 
final dose of study drug 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including 
anti−CTLA-4, anti−programmed death−1 (PD-1), or anti−PD-L1 therapeutic antibodies 
• 
Treatment with systemic immunostimulatory agents (including but not limited to interferons 
or interleukin 2) within 6 weeks or five drug elimination half-lives prior to Day 1 of Cycle 1, 
whichever is longer 
• 
Treatment with systemic corticosteroids or other systemic immunosuppressive medications 
(including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and anti−tumor necrosis factor agents) at the time of initiation of 
study drug, or anticipated requirement for systemic immunosuppressive medications during 
the study 
Patients with ATRT can be receiving concurrent treatment with corticosteroids with 
approval from the Medical Monitor and the ATRT-related exclusion criteria. 
• 
Current treatment with therapeutic anticoagulants 
• 
Any non-hematologic toxicity (excluding alopecia) from prior treatment that has not resolved 
to Grade ≤ 1 (per National Cancer Institute Common Terminology Criteria for Adverse 
Events Version 4.0) at screening 
Note:  Long-term sequelae of prior treatment (e.g., hearing loss, iatrogenic 
hypothyroidism, infertility, etc.) are not considered non-hematologic toxicity and 
instead are considered chronic medical conditions. 
• 
Evidence of progression of neurologic deficit, in the investigator’s judgment, within 1 week 
prior to initiation of study drug 
• 
Major surgical procedure, significant traumatic injury within 4 weeks prior to initiation of 
study drug, or anticipation of need for major surgical procedure during the course of the 
study 
Placement of a vascular access device is permitted if the site has healed prior to 
initiation of study drug. 
Biopsy tissue collections are permitted if all bleeding parameters (including PT/INR and 
aPTT) are within normal limits and procedure is safe in the judgment of the investigator. 
• 
Known active infection (excluding fungal infection of the nail beds) within 28 days prior to 
initiation of study drug that has not completely resolved 


 
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• 
Pregnant or lactating or intending to become pregnant during the study 
Patients of childbearing potential must have a negative serum pregnancy test result 
within 1 week prior to initiation of study drug. 
• 
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or 
any component of the atezolizumab formulation 
• 
Any other disease, metabolic or psychological dysfunction, physical examination finding, or 
clinical laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates use of an investigational drug or places the patient at unacceptable risk 
from treatment complications 
• 
Current drug or alcohol use or dependence that would interfere with adherence to study 
requirements, in the opinion of the investigator 
• 
History of severe allergic or anaphylactic reaction to monoclonal antibody therapies (or 
recombinant antibody−related fusion proteins) 
• 
History of clinically significant cardiac or pulmonary dysfunction 
• 
History of any autoimmune disease, including but not limited to Type 1 diabetes mellitus, 
autoimmune-related hypothyroidism, myasthenia gravis, myositis, autoimmune hepatitis, 
systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular 
thrombosis associated with anti-phospholipid syndrome, Wegener granulomatosis, 
Sjögren’s syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or 
glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism who are receiving a 
stable dose of thyroid-replacement hormone are eligible for the study. 
Patients with controlled Type 1 diabetes mellitus who are receiving a stable dose of 
insulin regimen are eligible for the study. 
• 
History of severe eczema 
• 
History of Kawasaki disease 
• 
History of Fanconi anemia, Beckwith-Wiedemann, ataxia telangiectasia, or other genetic 
syndromes that may have immune or hematologic susceptibilities 
• 
History of severe asthma or presence of uncontrolled asthma at time of screening 
evaluation 
Severe asthma is defined as presence of symptoms throughout the day, multiple 
nighttime awakenings during the week, use of a short-acting β2 agonist several times a 
day, and/or limitations with normal daily activity.  In addition, any asthma that does not 
meet the above definition but is felt to be severe in the eyes of the investigator should 
also be excluded. 
• 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), 
cystic fibrosis, or evidence of active pneumonitis on screening chest computed tomography 
scan 
• 
Dyspnea at rest or requirement for supplemental oxygen 
• 
Uncontrolled seizures 
 
End of Study 
The end of this study is defined as the date when last patient last visit occurs or 5 years after 
the last patient is enrolled, whichever occurs first.  The Sponsor reserves the right to present 
interim data to health authorities for compliance purposes. 
Outcome Measures 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Nature, frequency, severity, and timing of adverse events, including serious adverse events 
and adverse events of special interest 


 
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• 
Changes in vital signs, physical findings, and clinical laboratory results during and following 
administration of atezolizumab 
• 
Growth patterns (relative to age-specific standards for height and weight) 
• 
Development patterns (relative to onset of menarche [for females] and pubertal changes) 
• 
Change in tetanus toxoid antibody titers at study discontinuation as compared with 
pretreatment values 
 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Atezolizumab maximum serum concentration (Cmax) after the infusion on Day 1 of Cycle 1 
and Cycle 4 
• 
Atezolizumab minimum serum concentration (Cmin) prior to the infusion on Day 1 of Cycles 2, 
3, 4, 8, 12, and 16 and every 8 cycles thereafter 
• 
Atezolizumab serum concentration at washout (90 or more days after the last dose) 
• 
Atezolizumab area under the concentration-time curve for serum concentration-time profile 
in Cycle 1 will be estimated using a population PK model, as appropriate. 
 
Immunogenicity Outcome Measure 
The immunogenicity outcome measure for this study is as follows: 
• 
Incidence of ATAs during the study relative to the prevalence of ATAs at baseline 
 
Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are as follows: 
• 
Objective response, defined as a complete or partial response for patients with measurable 
disease or neuroblastoma patients with evaluable disease at baseline, or a complete 
response for patients with non-measurable but evaluable disease at baseline (except 
patients with neuroblastoma) on two consecutive occasions ≥ 4 weeks apart, as determined 
by the investigator using RECIST v1.1 for patients with solid tumors, mINRC for patients 
with neuroblastoma, Revised Response Criteria for Malignant Lymphoma for patients with 
Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, and RANO criteria for patients with 
ATRT. 
• 
Clinical benefit response, defined as objective response or stable disease for at least 6 
months, as determined by RECIST v1.1 for patients with osteosarcoma 
• 
PFS, defined as the time from initiation of study drug to the first documented occurrence of 
progressive disease, as determined by the investigator using RECIST v1.1 for patients with 
solid tumors, mINRC for patients with neuroblastoma, Revised Response Criteria for 
Malignant Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, 
and RANO criteria for patients with ATRT, or death from any cause, whichever occurs 
first 
The secondary efficacy outcome measures for this study are as follows: 
• 
DOR, defined as the time from the first tumor assessment that supports the patient’s 
objective response to the time of progressive disease, as determined by the investigator 
using RECIST v1.1 for patients with solid tumors, mINRC for patients with neuroblastoma, 
Revised Response Criteria for Malignant Lymphoma for patients with Hodgkin’s lymphoma 
or non-Hodgkin’s lymphoma, and RANO criteria for patients with ATRT, or death from 
any cause, whichever occurs first 
• 
OS, defined as the time from initiation of study drug to death from any cause 
• 
ORR, PFS, and DOR as determined by the investigator using immune-modified 
RECIST v1.1 for patients with other solid tumors and immune-related response criteria for 
patients with neuroblastoma, Hodgkin’s lymphoma, or non-Hodgkin’s lymphoma 
 


 
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Dose Assessment Outcome Measure 
The dose assessment outcome measure for this study is as follows 
• 
Assessment of atezolizumab dose using integrated data gathered from safety, PK, 
biomarker, and efficacy outcomes 
 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Descriptive analyses of PD-L1 expression (as defined by immunohistochemistry [IHC] 
score), infiltrating T-cell activity, T-cell subpopulations, B-cell and NK cell absolute counts in 
baseline tumor samples 
• 
Correlation between PD-L1 expression (both overall expression and by tumor type) at 
baseline, as defined by IHC score, and efficacy outcome measures 
• 
Levels of potential PD biomarkers (including but not limited to cytokines, ctDNA 
concentration, and T-cell subpopulations) measured in plasma and whole blood collected at 
baseline; at Cycles 1, 2, 3, 8, and 12 and every 8 cycles thereafter; and at the time of 
progressive disease 
• 
Correlation between non-inherited and inherited biomarkers in plasma, whole blood, or 
tumor tissue (including but not limited to PD-L1, PD-1, CD4, CD8, FoxP3, cytokines, ctDNA 
concentration, ctDNA mutations, and T-cell receptor sequencing) and safety, PK, or efficacy 
outcome measures 
• 
Changes in T, B, and NK cell numbers (TBNK assay) in whole blood 
• 
Correlation between ATA status and PK, PD, safety, or efficacy outcome measures 
• 
Descriptive analyses of PD-L1 expression (as defined by IHC score), infiltrating T-cell 
activity, T-cell subpopulations, B-cell and NK cell absolute counts in any available tumor 
samples obtained at the time of progressive disease 
 
Investigational Medicinal Products 
Patients will receive atezolizumab by intravenous (IV) infusion on Day 1 of each 3-week cycle.  
The dosing regimen in this study aims to achieve similar atezolizumab exposures in children 
and adolescents (< 18 years) to those of adults receiving the recommended Phase II/III dose of 
1200 mg every 3 weeks.  Patients who are <18 years old will receive 15 mg/kg atezolizumab 
(maximum dose 1200 mg) every 3 weeks.  Dose adjustments may be made if necessary to 
achieve exposures corresponding to those measured in adult patients and if the safety profile is 
acceptable.  Patients ≥ 18 years old who are enrolled will receive a flat dose of 1200 mg 
atezolizumab. 
Statistical Methods 
Primary Analysis 
No formal hypothesis testing is planned in this study.  Safety analyses will be performed on the 
safety-evaluable population, which is defined as patients who receive any amount of study drug.  
Subgroup safety analyses by tumor type will also be conducted as appropriate. 
Study treatment exposure (such as treatment duration, total dose received, and number of 
cycles and dose modifications) will be summarized with descriptive statistics.  Descriptive 
statistics (mean, median, standard deviation, 25th percentile, 75th percentile, and range) will be 
presented for continuous variables, and proportions will be presented for categorical variables. 
Determination of Sample Size 
A minimum of 40 patients will be enrolled in this study across all tumor types.  In addition, at 
least two tumor type cohorts must enroll a minimum of 10 patients.  To make a preliminary 
assessment of the efficacy of the study drug, two response assessments are planned:  an initial 
response assessment and an additional response assessment.  Taking into account historical 
control ORRs for each pediatric tumor type, the minimum number of patients in the initial 
response assessment and the minimum number of responders needed for cohort expansion 
and advancement to the additional response assessment were calculated and presented by 
tumor type.  The selection of expansion cohorts for additional response assessment, as well as 


 
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the number of patients needed for the additional response assessment, will also take into 
account practical considerations (e.g., enrollment feasibility), biomarker analysis, safety profiles, 
and any other relevant information.  The maximum number of patients per tumor type cohort will 
be 40.  Similar consideration will be given to other rare pediatric tumor types that are enrolled in 
the study. 
Overall, approximately 100 patients will be enrolled in the study. 
Interim Analyses 
Interim PK analyses will be conducted after the first 5 and 20 patients have completed Cycle 1, 
along with an ongoing evaluation of safety.  An additional interim PK analysis will be conducted 
after the first 5 patients < 6 years old (if available) have completed Cycle 1.  After a minimum of 
20 patients have completed Cycle 1, an interim PK and safety analysis will be conducted. 
Interim efficacy analyses will be conducted whenever a tumor type cohort has enrolled the 
number of patients required for initial response assessment and patients have been followed up 
for approximately 6 months. 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ATA 
anti-therapeutic antibody 
ATRT 
atypical teratoid rhabdoid tumor 
AUC 
area under the concentration−time curve 
Cmax 
maximum concentration 
Cmin 
minimum concentration 
CBR 
clinical benefit response 
CBRR 
clinical benefit response rate 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
DOR 
duration of objective response 
EC 
Ethics Committee 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
U.S. Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded 
FPI 
first patient in 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
IC 
tumor-infiltrating immune cell 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
IHC 
immunohistochemistry 
IL-2 
interleukin 2 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IFN 
interferon 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
irRC 
immune-related response criteria 
IUD 
intrauterine device 
IV 
intravenous 
IxRS 
interactive voice or Web response system 
LPLV 
last patient last visit 
LVEF 
left ventricular ejection fraction 
MIBG 
metaiodobenzoguanine 
mINRC 
modified International Neuroblastoma Response Criteria 


 
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Abbreviation 
Definition 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamic 
PD-L1 
programmed death−ligand 1 
PD-1 
programmed death−1 
PFS 
progression-free survival 
PK 
pharmacokinetic 
RCR 
Roche Clinical Repository 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SNP 
single-nucleotide polymorphism 
TAM 
tumor associated macrophage 
TNF 
tumor necrosis factor 
ULN 
upper limit of normal 


 
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1. 
BACKGROUND 
1.1 
PD-L1/PD-1 PATHWAY IN CANCER 
Encouraging clinical data emerging in the field of cancer immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced solid tumors and 
hematologic malignancies (Hodi et al. 2010; Kantoff et al. 2010; 
Schadendorf et al. 2013).  Therefore, immunomodulation represents a promising new 
strategy for cancer therapy that results in improved anti-tumor activity. 
Programmed death−ligand 1 (PD-L1) expression is prevalent in many human tumors 
(e.g., lung, ovarian, melanoma, colon carcinoma, non-Hodgkin’s lymphoma) and its 
overexpression on tumor cells has been associated with poor prognosis in patients with 
some cancers (Thompson et al. 2006; Hamanashi et al. 2007; Okazaki and Honjo 2007; 
Hino et al. 2010).  PD-L1 is one of two ligands (PD-L1 and PD-L2) that bind programmed 
death−1 (PD-1), an inhibitory receptor expressed on T cells following T-cell activation 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 cells.  
Aberrant expression of PD-L1 on tumor cells has been reported to impede anti-tumor 
immunity and results 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. 
Blockade of PD-L1 or PD-1 with monoclonal antibodies results in strong and often rapid 
anti-tumor effects in several mouse tumor models (Iwai et al. 2002; Strome et al. 2003).  
These data suggest that tumor-specific T cells may be present in the tumor 
microenvironment in an inactive or repressed state, and inhibition of the PD-L1/PD-1 
pathway reinvigorates tumor-specific T-cell responses.  Reports from Phase I oncology 
studies of molecules targeting either PD-L1 or PD-1 have demonstrated activity in 
patients with advanced stage and metastatic disease refractory to standard therapy 
(Brahmer et al. 2012; Topalian et al. 2012).  Immune-related adverse events (irAEs) 
reported from the two recent studies were consistent with the role of the PD-L1/PD-1 
pathway in regulating peripheral tolerance.  See the Atezolizumab Investigator’s 
Brochure for safety data. 
1.2 
BACKGROUND ON ATEZOLIZUMAB 
Atezolizumab (also referred to as TECENTRIQ®) is a humanized IgG1 monoclonal 
antibody that targets PD-L1 and inhibits its interaction with PD-1.  Atezolizumab also 
blocks the binding of PD-L1 to B7-1, an interaction that is reported to provide additional 
inhibitory signals to T cells (Butte et al. 2007).  Therapeutic blockade of PD-L1 binding 
by atezolizumab is expected to enhance the magnitude and quality of the tumor-specific 
T-cell responses, resulting in improved anti-tumor activity.  Atezolizumab was 
engineered to impair its binding to Fcγ receptors, to minimize depletion of tumor-specific 


 
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T cells that express high levels of PD-L1 (and PD-1).  Also, unlike PD-1 antibodies, 
atezolizumab preserves the PD-L2 and PD-1 interaction, potentially reducing the risk of 
host tissue injury from T-cell activation while still overcoming the immunosuppressive 
effect of tumor-specific PD-L1 signaling. 
Atezolizumab consists of two heavy chains (448 amino acids) and two light chains 
(214 amino acids) and is produced in Chinese hamster ovary cells.  Atezolizumab was 
engineered to eliminate Fc-effector function via a single amino acid substitution 
(asparagine to alanine) at position 298 on the heavy chain, which results in a non-
glycosylated antibody that has minimal binding to Fc receptors and consequently 
eliminates detectable Fc-effector function and depletion of cells expressing PD-L1.  
Atezolizumab targets PD-L1 and inhibits its interaction with its receptor, PD-1.  
Atezolizumab also blocks the binding of PD-L1 to B7.1, an interaction that is reported to 
provide additional inhibitory signals to T cells (Butte et al. 2007).  Atezolizumab is being 
investigated as a potential therapy against solid tumors and hematologic malignancies in 
humans. 
1.2.1 
Nonclinical Studies with Atezolizumab 
The nonclinical strategy of the atezolizumab program was to demonstrate in vitro and 
in vivo activity, to determine in vivo pharmacokinetic (PK) behavior, to evaluate the 
safety profile, and to identify a Phase I starting dose.  Comprehensive pharmacology, 
PK, and toxicology evaluations were performed with atezolizumab.  The safety, 
pharmacokinetics, and toxicokinetics of atezolizumab were investigated in mice and 
cynomolgus monkeys to support intravenous (IV) administration and to aid in projecting 
the appropriate starting dose in humans.  Given the similar binding of atezolizumab for 
cynomolgus monkey and human PD-L1, the cynomolgus monkey was selected as the 
primary and relevant nonclinical model for understanding the safety, pharmacokinetics, 
and toxicokinetics of atezolizumab. 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for atezolizumab 
supported entry into clinical studies, including providing adequate safety factors for the 
proposed Phase I starting doses.  The results of the toxicology program were consistent 
with the anticipated pharmacologic activity of downmodulating the PD-L1/PD-1 pathway; 
heightened immune responses and the potential to increase immune-associated 
inflammatory lesions were identified as possible safety risks in patients.  Refer to the 
Atezolizumab Investigator’s Brochure for details on the nonclinical studies. 
1.2.2 
Clinical Studies with Atezolizumab 
Clinical data for atezolizumab are currently available from five Phase I or II clinical trials 
in patients with solid tumors and hematologic malignancies.  For each of these studies, 
treatment and/or analyses are ongoing.  Three of these studies use atezolizumab as a 
single agent, and two use atezolizumab in combination. 


 
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1.2.2.1 
Clinical Safety 
As of 10 May 2016, atezolizumab has been administered to approximately 6000 adult 
patients with solid tumors and hematologic malignancies.  The safety profile is mainly 
based on the ongoing Study PCD4989g (GO27831), in which atezolizumab is being 
used as single-agent therapy in adult patients with locally advanced or metastatic solid 
tumors or hematologic malignancies.  Across all these patients, fatigue was the most 
frequently reported adverse event.  In studies that investigated atezolizumab in 
combination, the incidence of adverse events in the treatment arms with combined use 
was consistent with the known safety profiles of the individual study drugs.  Currently, no 
maximum tolerated dose, no dose-limiting toxicities, and no clear dose-related trends in 
the incidence of adverse events have been observed. 
In Study PCD4989g, as of 15 December 2015, there have been 629 adult patients 
treated with study drug.  The most common cancer types for these patients include 
non−small cell lung cancer (NSCLC; n = 89), urothelial bladder cancer (n = 95), 
triple-negative breast cancer (n = 111), and renal cell carcinoma (n = 72).  Of the 
629 patients evaluable for safety enrolled, 444 patients (70.6%) reported at least 
one treatment-related adverse event while receiving study drug.  The most frequently 
observed adverse events (occurring in ≥ 10% of treated patients) included fatigue, 
nausea, decreased appetite, diarrhea, constipation, dyspnea, pyrexia, cough, vomiting, 
anemia, back pain, headache, asthenia, arthralgia, pruritus, rash, abdominal pain, 
peripheral edema, urinary tract infection, insomnia, and dizziness.  Grade ≥ 3 adverse 
events were reported by 326 of 629 patients (51.8%), and 89 patients (14.1%) 
experienced Grade ≥ 3 adverse events that were assessed as related to study drug by 
the investigators.  The most frequently reported related Grade 3 and 4 adverse events 
included fatigue, asthenia, increased aspartate aminotransferase, dyspnea, and 
hyponatremia. 
No safety information has been established in pediatric populations. 
Refer to the Atezolizumab Investigator’s Brochure for details on adverse events 
observed in patients who were treated with atezolizumab. 
1.2.2.2 
Clinical Activity 
As of the data cutoff date of 1 January 2014, efficacy analyses were performed on 
291 efficacy-evaluable adult patients enrolled in Study PCD4989g (single-agent 
atezolizumab administered to patients with locally advanced or metastatic solid tumors 
or hematologic malignancies).  These patients had been treated by 1 July 2013 to 
ensure each patient had a minimum of 6 months’ follow-up.  Objective responses with 
atezolizumab monotherapy were observed in a broad range of malignancies, including 
NSCLC, renal cell carcinoma, melanoma, bladder cancer, colorectal cancer, head and 
neck cancer, gastric cancer, breast cancer, and sarcoma.  Altogether, there were 
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75.7 weeks.  The majority of these responses have been durable with 72.3% (34 of 
47 patients) of responses ongoing as of the clinical cutoff date. 
Analyses of tumor-infiltrating immune cells (IC) for PD-L1 expression on baseline tumor 
tissue have been performed for Study PCD4989g.  Preliminary results suggest that 
across multiple tumor types, PD-L1 expression in IC is likely to be associated with 
response to atezolizumab (Herbst et al. 2014). 
Refer to the Atezolizumab Investigator’s Brochure for additional details on clinical activity 
in patients who were treated with atezolizumab. 
1.3 
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT 
Pediatric cancer that is recurrent or refractory represents an area of high unmet medical 
need.  Despite the progress made after 40 years of clinical research that used 
combinations of chemotherapy, radiotherapy, and surgery, disease-free survival and 
overall survival rates have not significantly improved for children with relapsed or 
refractory tumors. 
The expression of PD-L1 by malignant cells has been reported in many pediatric tumor 
types, including high-grade glioma (Wintterle et al. 2003; Wilmotte et al. 2005; 
Parsa et al. 2007), rhabdomyosarcoma (Wiendl et al. 2003, Kim et al. 2008), 
non-Hodgkin’s lymphoma (Yamamoto et al. 2009; Green et al. 2010; 
Andorsky et al. 2011), Hodgkin’s lymphoma (Yamamoto et al. 2008, 2009; 
Green et al. 2010), soft tissue sarcoma (Kim et al. 2008), osteosarcoma 
(Lussier et al. 2013), Ewing sarcoma (Kim et al. 2008), and Wilms tumor 
(Routh et al. 2008, 2013). 
Although the functional role of PD-L1 expression in the pediatric tumor 
microenvironment is unknown, there are strong surrogate markers of putative sensitivity 
to PD-L1 blockade for pediatric cancers.  PD-L1 is highly expressed on tumor-infiltrating 
leukocytes and tumor-associated macrophages (TAMs) (Zou et al. 2008; 
Chen et al. 2012; Berghoff et al. 2013; Melero et al. 2013).  Pediatric tumors are highly 
infiltrated by TAMs and contain a paucity of dendritic cells compared with adult tumors 
(Vakkila et al. 2006).  These TAMs are reported to have a prognostic role in pediatric 
tumors, including malignant glioma (Nishie et al. 1999; Bloch et al. 2013), neuroblastoma 
(Asgharzadeh et al. 2012), Ewing sarcoma (Fujiwara et al. 2011), Hodgkin’s lymphoma 
(Barros et al. 2012), and high-grade osteosarcoma (Endo-Munoz et al. 2012), although 
the latter is controversial because of the complexity of identification between TAMs and 
osteoclasts (Buddingh et al. 2011).  In addition to roles in invasion, angiogenesis, and 
metastasis (Pollard 2004; Ono 2008; Wynn et al. 2013), TAMs have an important 
immunosuppressive role in the solid tumor microenvironment (Sica and Bronte 2007; 
Jaiswal et al. 2010; Ruhrberg and De Palma 2010).  Impeding the immunosuppressive 
activity of TAMs with an anti−PD-L1 antibody is therefore of therapeutic interest for 
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Encouraging clinical data emerging in the field of cancer immunotherapy have 
demonstrated that therapies focused on enhancing T-cell responses against cancer can 
result in a significant survival benefit in patients with advanced cancer (Hodi et al. 2010; 
Kantoff et al. 2010).  In addition, encouraging results are being reported in early-phase 
clinical trials targeting the PD-L1/PD-1 pathway in adult patients with refractory 
late-stage cancer (Berger et al. 2008; Brahmer et al. 2012; Topalian et al. 2012). 
The preliminary nonclinical data indicate that pediatric and young adult patients 
diagnosed with relapsed and refractory solid tumors may benefit from the addition of an 
immune checkpoint inhibitor like atezolizumab.  In addition, atezolizumab has an 
acceptable toxicity profile in adults, in line with other PD-L1/PD-1 blocking agents.  
Given the poor long-term survival of children and young adults diagnosed with relapsed 
and refractory solid tumors, the potential benefit of atezolizumab is expected to outweigh 
the risk in this population. 
2. 
OBJECTIVES 
This study will evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and 
preliminary efficacy of atezolizumab administered by IV infusion every 3 weeks to 
pediatric and young adult patients with solid tumors for which prior treatment has proven 
to be ineffective (i.e., relapsed or refractory) or intolerable and for whom there is no 
effective standard treatment available.  Specific objectives for the study are outlined 
below. 
2.1 
SAFETY OBJECTIVE 
The safety objective for this study is as follows: 
• 
To evaluate the safety and tolerability of atezolizumab in pediatric and young adult 
patients, focusing on the nature, frequency, and severity of serious and non-
serious adverse events, as well as effects on laboratory test values and vital signs 
 
2.2 
PHARMACOKINETIC OBJECTIVE 
The PK objective for this study is as follows: 
• 
To characterize the pharmacokinetics of atezolizumab 
 
2.3 
IMMUNOGENICITY OBJECTIVE 
The immunogenicity objective for this study is as follows: 
• 
To evaluate the immune response to atezolizumab on the basis of the incidence of 
anti-therapeutic antibodies (ATAs) 
 


 
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2.4 
EFFICACY OBJECTIVES 
The efficacy objectives for this study are as follows: 
• 
To evaluate the anti-cancer activity of atezolizumab, as measured by objective 
response rate (ORR), progression-free survival (PFS), duration of objective 
response (DOR; see Section 3.4.4 for information on response assessment tools), 
and clinical benefit response rate (CBRR, only for osteosarcoma⎯see 
Section 3.4.4 for definition). 
• 
To evaluate the anti-cancer activity of atezolizumab, as measured by overall 
survival (OS) 
 
2.5 
DOSE ASSESSMENT OBJECTIVE 
The dose-assessment objective for this study is as follows: 
• 
To assess the optimal dose of atezolizumab in pediatric and young adult patients 
on the basis of safety, PK, and efficacy outcome measures (see Section 3.4) 
 
2.6 
EXPLORATORY OBJECTIVES 
The exploratory objectives for this study are as follows: 
• 
To explore if PD-L1 expression on tumor and/or tumor-infiltrating cells at baseline 
is predictive of response to atezolizumab 
• 
To explore the relationship between atezolizumab exposure and changes in levels 
of pharmacodynamic (PD) biomarkers including but not limited to cytokines, 
circulating tumor DNA (ctDNA) concentration, and T-cell subpopulations 
• 
To explore non-inherited biomarkers that may be predictive of response to 
atezolizumab (i.e., predictive biomarkers); may be associated with progression to a 
more severe disease state (i.e., prognostic biomarkers), acquired resistance to 
atezolizumab, or susceptibility to developing adverse events; may provide evidence 
of atezolizumab activity; or may increase the knowledge and understanding of 
disease biology 
• 
To explore inherited biomarkers (i.e., variants in germline DNA) that may be 
predictive of response to atezolizumab (i.e., predictive biomarkers); may be 
associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), acquired resistance to atezolizumab, or susceptibility to developing 
adverse events; or may increase the knowledge and understanding of disease 
biology 
• 
To evaluate potential relationships between detectable ATAs and other clinical 
relevant outcome measures (e.g., pharmacokinetics, safety, and efficacy) 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF STUDY 
The study is an early-phase, multicenter, open-label, single-arm study designed to 
evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary 
efficacy of atezolizumab in pediatric and young adult patients with solid tumors with 


 
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known or expected PD-L1 pathway involvement for which prior treatment has proven to 
be ineffective (i.e., relapsed or refractory) or intolerable and for whom no curative 
standard-of-care treatment options exist. 
Figure 1 Study Schema:  Two Phases of Response Assessment 
Pediatric and 
young adult 
patients (birth 
to < 30 years) with 
previously treated 
solid tumors
Tumor Type
Cohort A
(≥ 10 patients)
Tumor Type
Cohort B
(≥ 10 patients)
Additional 
Tumor Type 
Cohorts 
as Appropriate 
(≥ 10 patients)
Cohort 
Expansion
Cohort 
Expansion
Cohort 
Expansion
Minimum number of responders 
needed for continued enrollment 
within tumor type cohort
Initial Response Assessment:
Performed after a minimum 
of 10 patients have been 
treated and followed for 
approximately 6 months
Additional Response 
Assessment
 
Pediatric and young adult patients with pediatric-type tumors with known or expected 
PD-L1 pathway involvement (age: birth to < 30 years) will be enrolled via an interactive 
voice or Web response system (IxRS).  The first 5 patients must be ≥ 2 years of age (i.e., 
the first 5 patients must have reached their second birthday at the time of enrollment) to 
ensure safety and tolerability prior to dosing in children < 2 years of age.  These 
first 5 patients must be followed for either two cycles of treatment or until drug 
discontinuation, whichever is shorter, prior to enrolling younger patients.  An 
independent Data Monitoring Committee (iDMC) will review the safety data of the 
first 5 patients and make recommendations on the appropriateness of opening the study 
to patients < 2 years of age (see Section 3.1.4). 
Patients will receive atezolizumab by IV infusion on Day 1 of each 3-week cycle.  
The dosing regimen in this study aims to achieve similar atezolizumab exposures in 
children and adolescents (< 18 years) to those of adults receiving the recommended 
Phase II/III dose of 1200 mg every 3 weeks.  Patients who are < 18 years old will receive 
15 mg/kg atezolizumab (maximum dose 1200 mg) every 3 weeks.  Dose adjustments 
may be made, if necessary to achieve exposures corresponding to those measured in 


 
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adult patients and if the safety profile is acceptable.  Patients ≥ 18 years old who are 
enrolled will receive a flat dose of 1200 mg atezolizumab.  There must be at least 
24 hours between the initial treatment doses of the first 5 patients regardless of tumor 
type to allow for evaluation of immediate immune activating events before additional 
patients are exposed to atezolizumab.  There must also be at least 24 hours between 
treatment doses for the first 3 patients within each tumor type cohort. 
Atezolizumab treatment may be continued for a maximum duration of 8 months as long 
as patients experience clinical benefit as assessed by the investigator⎯in the absence 
of unacceptable toxicity or symptomatic deterioration attributed to progressive 
disease⎯on the basis of an integrated assessment of radiographic data, biopsy results 
(if available), and clinical status.  Patients who continue to experience clinical benefit at 
8 months may continue treatment with approval of the Medical Monitor.  If an individual 
patient continues to experience clinical benefit beyond 2 years of radiologic progressive 
disease (see Section 3.3.4), the Sponsor and treating physician will apply for additional 
approval from health authorities for continued treatment. 
Tumor assessments will be performed every two cycles from Cycle1 through Cycle 8 
and then every 4th cycle thereafter.  Response will be determined by the investigator 
through use of modified International Neuroblastoma Response Criteria (mINRC) for 
patients with neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant 
Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma 
(Cheson et al. 2007; see Appendix 4), Response Assessment in Neuro-Oncology 
(RANO) criteria (see Appendix 11) for patients with atypical teratoid rhabdoid tumor 
and Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) for 
patients with other solid tumors (see Appendix 5). 
All patients will be closely monitored for adverse events throughout the study and for at 
least 30 days after the last dose of study treatment or initiation of a new anti-cancer 
therapy, regardless of relationship to study drug (see Section 5.3.1).  Serious adverse 
events and adverse events of special interest, regardless of relationship to study drug, 
will be monitored for 90 days after the last dose of study drug or until initiation of new 
anti-cancer therapy.  All identified adverse events should be followed up until resolution, 
which may necessitate monitoring beyond 30 days after the last dose of study drug.  In 
addition, the Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period, if the 
event is believed to be related to prior study drug treatment.  Adverse events will be 
graded according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  An iDMC will be established to monitor 
patient safety throughout the study (see Section 3.1.4). 
Safety assessments will include the incidence, nature, and severity of adverse events; 
changes in vital signs; and laboratory abnormalities graded per NCI CTCAE v4.0.  
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the presence of antibodies to atezolizumab.  PK sampling time points have been 
optimized on the basis of a preliminary population PK model using the adult data.  A 
sample of archived tumor tissues, as well as blood samples, will be collected for future 
exploratory biomarker assessments. 
Schedules of assessments are provided in Appendix 1 and Appendix 2. 
Patients with pediatric solid tumors, including Hodgkin’s and non-Hodgkin’s lymphoma, 
may be enrolled into the study (see Section 4.1 for patient inclusion and exclusion 
criteria).  Each tumor type will be considered a distinct tumor type cohort.  An initial 
response assessment will be performed after a minimum of 10 patients have been 
enrolled in a tumor type cohort and followed up for approximately 6 months, to determine 
whether further enrollment is needed within that tumor type cohort (cohort expansion) for 
additional response assessment.  A minimum number of responders will be needed for 
cohort expansion and advancement to the additional response assessment (see Table 3 
for more details).  Cohort expansion, including the number of patients needed for the 
additional response assessment, will also take into account practical considerations 
(e.g., enrollment feasibility), biomarker analysis, safety profiles, and any other relevant 
information.  The maximum number of patients enrolled in any tumor cohort will be 40. 
In addition to the planned efficacy analyses mentioned above, interim PK analyses will 
also be performed.  An initial interim PK analysis will be conducted after the first 
5 patients have completed Cycle 1, irrespective of age and tumor type cohort.  An 
additional interim PK analysis will be conducted after 5 patients who are < 6 years old (if 
available) have completed Cycle 1.  Following these analyses, dose modifications may 
be considered for all patients, if warranted, to match adult exposures and to ensure an 
optimal safety profile.  After a minimum of 20 patients have completed Cycle 1, PK and 
safety analyses will also be conducted. 
3.1.1 
Number of Patients 
Approximately 100 patients are expected be enrolled in this study, at approximately 
50 investigative sites in Europe and North America.  Of those who are enrolled, at least 
20 patients who are < 18 years of age will be treated with study drug, and at least 
40 patients across all tumor type cohorts will be treated and available for response 
assessment (at least two tumor type cohorts must enroll a minimum of 10 patients). 
Accrual is expected to last approximately 3 years. 
3.1.2 
Enrollment Stopping Rules 
Enrollment in a tumor type cohort may be stopped if any one of the following criteria is 
met: 
• 
The number of patients needed for initial response assessment is reached and the 
number of responders does not meet the requirement for additional tumor type 
cohort expansion. 


 
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• 
The number of patients needed for additional response assessment is reached. 
• 
The Sponsor has stopped the study. 
• 
At least two tumor type cohorts have enrolled the minimum number of patients 
needed for initial response assessment. 
 
Some exceptions may apply to these general stopping rules, including but not limited to 
the following: 
• 
Enrollment in the study may be stopped if enrollment has been open for more than 
2 years and at least 20 patients have been treated with the study. 
• 
Enrollment in a tumor type cohort may be extended if there is strong evidence of a 
positive efficacy signal in a slow-enrolling and rare tumor type cohort, thus allowing 
for additional data to be collected. 
 
3.1.3 
Adverse Events Requiring Drug Discontinuation 
Events that require study drug discontinuation reflect the known and expected toxicities 
of the mechanism of action of atezolizumab, in addition to accounting for serious 
unexpected adverse events that may occur.  The following events require 
discontinuation of study drug if they occur at any time while undergoing treatment and 
are considered by the investigator to be related to atezolizumab (see Table 1 for 
causality assessment).  For situations of unclear attribution to study drug, investigators 
are encouraged to perform additional tests to determine the underlying etiology and 
most appropriate attribution. 
Any one of the following events will require study drug discontinuation if they are 
assessed by the investigator to be related to atezolizumab: 
• 
Grade ≥ 4 neutropenia (ANC < 0.5 × 109/L) that lasts > 7 days 
• 
Grade ≥ 4 neutropenia with documented infection 
• 
Grade ≥ 3 febrile neutropenia that lasts > 5 days 
• 
Grade ≥ 4 thrombocytopenia that lasts > 48 hours or any thrombocytopenia 
requiring a platelet transfusion, with the following exception: 
For patients who have undergone autologous hematopoietic stem cell 
transplantation or 131I-MIBG (metaiodobenzoguanine) therapy, Grade ≥ 4 
thrombocytopenia that lasts > 7 days or any thrombocytopenia that requires a 
platelet transfusion on two or more separate dates will require study drug 
discontinuation. 
• 
Grade ≥ 3 thrombocytopenia with a Grade ≥ 2 bleeding event 
• 
Elevation of serum hepatic transaminase levels (ALT or AST) ≥ 5 × the upper limit of 
normal (ULN) 
For patients with elevated hepatic transaminase levels at baseline as a result of 
liver metastases, hepatic transaminase ≥ 5 × baseline and < 10 × baseline 


 
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for > 3 days, or any hepatic transaminase ≥ 10 × baseline will require study drug 
discontinuation. 
• 
Elevation of serum bilirubin level ≥ 3 × ULN 
• 
Grade ≥ 3 non-hematologic, non-hepatic adverse event, with the following 
exceptions: 
Grade 3 fevers will not mandate study drug discontinuation. 
Grade 3 mucositis or stomatitis that resolves to Grade ≤ 2 within 3 days will not 
mandate study drug discontinuation. 
Grade ≥ 3 nausea or vomiting that responds to standard-of-care therapy 
within 3 days will not mandate study drug discontinuation.  In the ATRT cohort, 
this may mandate study drug discontinuation if Grade ≥ 3 nausea and/or 
vomiting is subsequent to increased intracranial pressure (see Section 4.5.3.1 
for management guidelines). 
Grade 3 fatigue that lasts for ≤ 3 days will not mandate study drug 
discontinuation. 
Grade 3 laboratory test abnormalities that are asymptomatic and considered by 
the investigator not to be clinically significant will not mandate study drug 
discontinuation. 
Patients with Grade 3 rash may continue treatment with atezolizumab 
according to guidelines outlined in the Atezolizumab Investigator’s Brochure. 
• 
Conditions (regardless of grade) suggestive of an autoimmune disorder, including 
but not limited to rheumatoid arthritis, Type I diabetes, vasculitis, neuritis, and 
neuropathies including myasthenia gravis, Guillain-Barré syndrome, systemic lupus 
erythematosus, Sjögren’s syndrome, and multiple sclerosis. 
The following conditions may continue treatment with atezolizumab according 
to the guidelines outlined in Section 5.1.1 and the Atezolizumab Investigator’s 
Brochure: 
Hepatitis (elevation of transaminases), rash, pancreatitis (elevated 
amylase/lipase), pneumonitis/pulmonary toxicity, endocrinopathies, colitis 
(presence of diarrhea), eye toxicities, and systemic immune activation 
• 
Pericardial effusion (any grade) if not attributable to disease 
• 
Any toxicity that requires interruption of atezolizumab treatment for > 105 days (e.g., 
no more than 105 days between infusions), except in patients who must be tapered 
off corticosteroids used to treat adverse events (see Section 5.1.1.1 for details).  
Longer periods of treatment interruption may be considered after discussion with 
the Medical Monitor. 
 
3.1.4 
Independent Data Monitoring Committee 
An iDMC will be set up to evaluate safety data during the study.  The iDMC will evaluate 
study safety data on a periodic basis, approximately every 6 months from the point of 
first patient in (FPI).  They will also have a scheduled review following enrollment of the 


 
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first 5 patients (mandated to be ≥ 2 years old).  After this review, they will make 
recommendations on the appropriateness of enrolling patients who are < 2 years old.  
Members of the iDMC will be external to the Sponsor and the Investigator and will follow 
a charter that outlines their roles and responsibilities.  Following their review, the iDMC 
will provide a recommendation as to whether the study may continue, whether 
amendment(s) to the protocol should be implemented, or whether the study should be 
stopped.  The IDMC may also contribute to the selection of tumor types to be included in 
the cohort expansion.  Specific details, such as committee composition, communication 
plan, and member roles and responsibilities, will be detailed in an iDMC Charter. 
3.2 
END OF STUDY 
The end of this study is defined as the date when the last patient last visit (LPLV) occurs 
or 5 years after the last patient is enrolled, whichever occurs first.  The Sponsor reserves 
the right to present interim data to health authorities for compliance purposes. 
For an individual patient, the completion of the study (i.e., the last visit) will occur when 
the patient withdraws consent, has been lost to follow-up, or dies or when the study is 
stopped. 
The primary analysis will be conducted after the enrollment has been completed and all 
enrolled patients have been followed up for at least 6 months.  A Clinical Study Report 
will be submitted to health authorities. 
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for Atezolizumab Starting Dose and Dose 
Modification 
The pharmacokinetics of atezolizumab in the pediatric population are expected to be 
similar to those in adults on the basis of the observation of linear pharmacokinetics, 
suggestive of nonspecific elimination, in the clinically relevant dose range.  Therefore, a 
pediatric dosing scheme for atezolizumab that provides reliable and adequate exposure 
for maximal efficacy while minimizing the potential for adverse events may be 
predictable from PK data in adults, provided that effects of body size are well 
characterized. 
Few studies in the literature have investigated developmental changes in absorption, 
distribution, and elimination of therapeutic proteins.  Tissue distribution of therapeutic 
proteins occurs primarily through transvascular transport processes such as convection 
and diffusion, which are not expected to be significantly affected by differences in body 
composition as a function of age (Anderson and Lynn 2009; Tabrizi et al. 2010; 
Xu et al. 2013).  The distribution of a therapeutic protein may be influenced by binding to 
plasma proteins or tissue targets; however, differences in antigen production or 
degradation rates may not be sufficient to alter the distribution of an antibody-based 
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(Xu et al. 2013).  Therefore, clinically meaningful differences in monoclonal antibody 
distribution are not expected between adult and pediatric patients after taking into 
account differences in body size.  Monoclonal antibodies are metabolized by the same 
catabolic pathways as endogenous proteins and are eliminated by nonspecific 
Fc receptor−mediated catabolism and/or target-mediated disposition (Tabrizi et al. 2006; 
Mould and Green 2010).  For atezolizumab, the nonspecific elimination pathway appears 
to be primary, as evidenced by linear pharmacokinetics in the dose range of 1−20 mg/kg, 
which includes the approved dose (for treatment of adult patients with urothelial 
carcinoma) and recommended Phase II/III dose currently under investigation in multiple 
cancer types (1200 mg; equivalent to a weight-based dose of 15 mg/kg assuming an 
adult body weight of 80 kg).  Because infants and children are able to maintain 
homeostasis of immunoglobulins, it is presumed that they are able to break down 
therapeutic monoclonal antibodies if Fc receptor−mediated catabolism is the major 
pathway.  Thus, no age-related developmental differences in disposition are expected 
for therapeutic proteins with nonspecific elimination as the major pathway.  A primary 
elimination pathway for atezolizumab via Fc receptor−mediated catabolism suggests that 
the pharmacokinetics of monoclonal antibodies in pediatric patients can be predicted 
from adult data, particularly in children who are > 6 years of age (Xu et al. 2013). 
Of the potential covariates that may affect the pharmacokinetics of antibody-based 
therapeutic proteins, body size (weight or body surface area) is the most frequently 
identified and clinically relevant covariate (Dirks and Meibohm 2010).  A review of the 
PK characteristics of 12 approved therapeutic proteins showed comparable steady-state 
peak and trough concentrations and terminal half-life between pediatric and adult 
patients after adjustment for body size (Xu et al. 2013).  Age alone does not appear to 
affect the clearance of monoclonal antibodies (Dirks and Meibohm 2010; Xu et al. 2013).  
Because the total clearance of antibody-based therapeutic proteins does not increase in 
proportion to increasing body weight, a 2-fold increase in body weight usually results in a 
less than 2-fold increase in clearance (Bai et al. 2012; Xu et al. 2013).  Therefore, the 
lightest pediatric patients who received the same body weight−based dose level of 
atezolizumab may have a lower drug exposure than adults.  Furthermore, because the 
development of ATAs has been associated with changes in pharmacokinetics for some 
adult patients in the lower-dose cohorts of Study PCD4989g (i.e., 0.3, 1, and 3 mg/kg), 
the possibility for lower exposure may be exacerbated, particularly in the lightest children.  
Children aged < 18 years will receive the weight-based equivalent of the approved adult 
dose and recommended Phase II/III adult dose (15 mg/kg atezolizumab every 3 weeks, 
with a maximum of 1200 mg).  Patients who are ≥ 18 years old will receive the approved 
adult dose of 1200 mg.  Dose adjustments may be made, if necessary, to achieve 
exposures corresponding to those measured in adult patients and if the safety profile is 
acceptable. 
Dose levels for modification will be determined on the basis of the available information 
regarding PK exposure, interim PK analyses, and the emerging safety profile. 


 
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3.3.2 
Rationale for Inclusion of Patients Aged > 18 Years 
The Sponsor expects that the majority of enrolled patients will be < 18 years old.  
However, there may be young adult patients with “pediatric-type” tumors who are treated 
in pediatric oncology facilities.  In a specific analysis of adolescent and young adult 
patients in the United States, limited clinical trial participation correlated with the relative 
lack of improvement in survival prolongation and cancer death rates (Bleyer et al. 2006).  
The lower participation of adolescent and young adult patients in clinical trials has 
created significant knowledge gaps with respect to cancer biology, treatment, and other 
factors affecting the survival of adolescent and young adult patients with cancer.  As part 
of the Sponsor’s commitment to the development of personalized medicine, adolescent 
and young adult patients up to the age of 30 years (and in exceptional cases of relapsed 
pediatric tumors, beyond 30 years) will be included in this study. 
3.3.3 
Rationale for Exploratory Analysis of Immunogenicity 
ATAs to atezolizumab have been observed in adult patients in all dose cohorts in 
Study PCD4989g, and their development was associated with changes in 
pharmacokinetics for some patients in the lower-dose cohorts (0.3, 1, and 3 mg/kg).  
Patients who were treated at the 10-, 15-, and 20-mg/kg dose levels maintained the 
expected target trough levels of drug despite the detection of ATAs.  To date, no 
relationship has been observed between the development of measurable ATAs and the 
safety or efficacy of atezolizumab.  Monitoring and characterization of ATA responses 
and their potential impact on pharmacokinetics, safety, and activity are continuing in all 
clinical studies of atezolizumab. 
With respect to immunogenicity, patient-related factors such as disease, genetics, 
immune status, concomitant use of immunomodulators, and previous use of a 
monoclonal antibody or a structurally related therapeutic protein may vary considerably 
between pediatric and adult patients, resulting in differences in immunogenicity.  To date, 
there are no data addressing immunogenicity with immune checkpoint inhibitors in the 
pediatric population, and predictions based on adult data cannot therefore be made.  
Thus, the occurrence of ATAs will be closely monitored in this study. 
3.3.4 
Rationale for Treatment beyond Progression 
Conventional response criteria may not adequately assess the activity of 
immunotherapeutic agents because progressive disease (by initial radiographic 
evaluation) does not necessarily reflect therapeutic failure.  Because of the potential for 
pseudoprogression or tumor immune infiltration, this study will allow patients to continue 
to receive study treatment after apparent radiographic progression, provided the benefit-
risk ratio is judged to be favorable.  In Study PCD4989g, several patients with NSCLC 
who had disease progression according to RECIST v1.1 criteria continued to receive 
atezolizumab treatment and demonstrated durable anti-tumor activity.  In addition, in 
some patients who responded, the growth of known lesions or the appearance of new 
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the biopsy tissue sample.  Patient participation in the study should be discontinued for 
unacceptable toxicity or symptomatic deterioration attributed to disease progression as 
determined by the investigator after an integrated assessment of radiographic data and 
clinical status (see Section 4.5.5.2). 
It is recommended that radiological disease progression be confirmed at a subsequent 
tumor assessment to take into account the potential for pseudoprogression or tumor 
immune infiltration.  In addition, it is highly recommended that evidence of progressive 
disease in patients who respond should be confirmed by a biopsy tissue sample from the 
growing or new lesion when feasible. 
3.3.5 
Rationale for Mandatory Collection of Tumor Specimens 
Development of a predictive diagnostic assay that enables prospective identification of 
patients who are likely to respond to treatment with atezolizumab may allow for 
pre-selection of patients likely to benefit from treatment with atezolizumab in future 
clinical studies. 
Published results suggest that expression of PD-L1 in tumors correlates with response 
to anti−PD-1 therapy (Topalian et al. 2012).  This correlation was also observed with 
atezolizumab in preliminary data from Study PCD4989g (see Section 1.2.2.2; 
Herbst et al. 2014).  In this study, tumor specimens from patients meeting eligibility 
criteria will be retrospectively tested for PD-L1 expression by a central laboratory. 
Other exploratory markers, such as potential predictive and prognostic markers that are 
related to response or clinical benefit of atezolizumab, tumor immunobiology, and tumor 
type markers, may also be analyzed. 
3.3.6 
Rationale for Blood Sampling for Biomarkers 
An exploratory objective is to evaluate changes in surrogate PD biomarkers in blood 
samples that are relevant because of the target expression.  Changes in PD biomarkers 
such as cytokines, ctDNA concentration, and T-cell subpopulations may provide 
evidence for biological activity of atezolizumab in humans.  In addition, potential 
correlations of these PD markers with safety and anti-tumor activity of atezolizumab will 
be explored. 
3.3.7 
Rationale for Separate Cohorts for Rhabdoid Tumor and 
Atypical Teratoid Rhabdoid Tumor 
Patients with atypical teratoid rhabdoid tumor (ATRT) and rhabdoid tumor will be 
enrolled into separate cohorts.  Although the two tumor types are often merged 
together, reflecting common genetic drivers, the differences in tumor microenvironment 
(CNS for ATRT and non-CNS for rhabdoid tumor) necessitate separating them in this 
protocol.  This will allow for a more thorough evaluation of atezolizumab in these 
tumor types and account for any differences in safety and efficacy that may occur 


 
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because of differences in organ location or tumor microenvironment or the presence of a 
blood-brain barrier. 
3.4 
OUTCOME MEASURES 
3.4.1 
Safety Outcome Measures 
The safety outcome measures for this study are as follows: 
• 
Nature, frequency, severity, and timing of adverse events, including serious 
adverse events and adverse events of special interest 
• 
Changes in vital signs, physical findings, and clinical laboratory test results during 
and following administration of atezolizumab 
• 
Growth patterns (relative to age-specific standards for height and weight) 
• 
Development patterns (relative to onset of menarche [for females] and pubertal 
changes) 
• 
Change in tetanus toxoid antibody titers at study discontinuation as compared with 
pretreatment values 
 
3.4.2 
Pharmacokinetic Outcome Measures 
The PK outcome measures for this study are as follows: 
• 
Atezolizumab maximum serum concentration (Cmax) after the infusion on Day 1 of 
Cycle 1 and Cycle 4 
• 
Atezolizumab minimum serum concentration (Cmin) prior to the infusion on Day 1 of 
Cycles 2, 3, 4, 8, 12, and 16 and every 8 cycles thereafter 
• 
Atezolizumab serum concentration at washout (90 or more days after the last dose) 
• 
Atezolizumab area under the concentration-time curve (AUC) for serum 
concentration-time profile in Cycle 1 will be estimated using a population PK model, 
as appropriate. 
 
3.4.3 
Immunogenicity Outcome Measure 
The immunogenicity outcome measure for this study is as follows: 
• 
Incidence of ATAs during the study relative to the prevalence of ATAs at baseline 
 
3.4.4 
Efficacy Outcome Measures 
The primary efficacy outcome measures for this study are as follows: 
• 
Objective response, defined as a complete or partial response for patients with 
measurable disease or neuroblastoma patients with evaluable disease at baseline, 
or a complete response for patients with non−measurable but evaluable disease at 
baseline (except patients with neuroblastoma) on two consecutive 
occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1 
for patients with solid tumors (see Appendix 6), mINRC for patients with 
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Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see 
Appendix 4), and RANO criteria (see Appendix 11) for patients with ATRT. 
• 
Clinical benefit response (CBR), defined as objective response or stable disease 
for at least 6 months, as determined by RECIST v1.1 for patients with 
osteosarcoma (see Appendix 6) 
• 
PFS, defined as the time from initiation of study drug to the first documented 
occurrence of progressive disease, as determined by the investigator using 
RECIST v1.1 for patients with solid tumors (see Appendix 6), mINRC for patients 
with neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant 
Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see 
Appendix 4), and RANO criteria (see Appendix 11) for patients with ATRT, or 
death from any cause, whichever occurs first 
 
The secondary efficacy outcome measures for this study are as follows: 
• 
DOR, defined as the time from the first tumor assessment that supports the 
patient’s objective response to the time of progressive disease, as determined by 
the investigator using RECIST v1.1 for patients with solid tumors (see Appendix 5), 
mINRC for patients with neuroblastoma (see Appendix 3), Revised Response 
Criteria for Malignant Lymphoma for patients with Hodgkin’s lymphoma or 
non-Hodgkin’s lymphoma (see Appendix 4), and RANO criteria (Appendix 11) for 
patients with ATRT, or death from any cause, whichever occurs first 
• 
OS, defined as the time from initiation of study drug to death from any cause 
• 
ORR, PFS, and DOR as determined by the investigator using immune-modified 
RECIST v1.1 for patients with other solid tumors (see Appendix 5) and 
immune-related response criteria (irRC) for patients with neuroblastoma, Hodgkin’s 
lymphoma or non-Hodgkin’s lymphoma 
 
3.4.5 
Dose Assessment Outcome Measure 
The dose assessment outcome measure for this study is as follows: 
• 
Assessment of atezolizumab dose with the use of integrated data gathered from 
safety, PK, biomarker, and efficacy outcomes 
 
3.4.6 
Exploratory Outcome Measures 
The exploratory outcome measures for this study are as follows: 
• 
Descriptive analyses of PD-L1 expression (as defined by immunohistochemistry 
[IHC] score), infiltrating T-cell activity, T-cell subpopulations, and B-cell and NK cell 
absolute counts in baseline tumor samples 
• 
Correlation between PD-L1 expression (both overall expression and by tumor type) 
at baseline, as defined by IHC score, and efficacy outcome measures 
• 
Levels of potential PD biomarkers (including but not limited to cytokines, ctDNA 
concentration, and T-cell subpopulations) will be measured in plasma and whole 
blood collected at baseline; at Cycles 1, 2, 3, 8, and 12 and every 8 cycles 
thereafter; and at the time of progressive disease. 


 
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• 
Correlation between non-inherited and inherited biomarkers in plasma, whole blood, 
or tumor tissue (including but not limited to PD-L1, PD-1, CD4, CD8, FoxP3, 
cytokines, ctDNA concentration, ctDNA mutations, and T-cell receptor sequencing) 
and safety, PK, or efficacy outcome measures 
• 
Changes in T, B, and NK cell numbers (TBNK assay) in whole blood 
• 
Correlation between ATA status and PK, PD, safety, or efficacy outcome measures 
• 
Descriptive analyses of PD-L1 expression (as defined by IHC score), infiltrating 
T-cell activity, T-cell subpopulations, and B-cell and NK cell absolute counts in any 
available tumor samples obtained at the time of progressive disease 
 
4. 
MATERIALS AND METHODS 
4.1 
PATIENTS 
This study will enroll approximately 100 pediatric or young adult patients with solid 
tumors with known or expected PD-L1 pathway involvement for which prior treatment 
has proven to be ineffective (i.e., relapsed or refractory disease) or intolerable and for 
whom there are no curative standard-of-care treatment options. 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
• 
Histologically or cytologically confirmed solid tumor of a type listed below (tumor 
types with known or expected PD-L1 pathway involvement) (including Hodgkin’s 
and non-Hodgkin’s lymphoma), for which prior treatment had proven to be 
ineffective (i.e., relapsed or refractory disease) or intolerable.  Patients must have 
had histologic or cytologic confirmation of malignancy at the time of diagnosis or 
relapse. 
Neuroblastoma 
Rhabdomyosarcoma 
Non-rhabdomyosarcoma soft tissue sarcoma 
Osteosarcoma 
Ewing sarcoma 
Wilms tumor 
Hodgkin’s lymphoma 
Non-Hodgkin’s lymphoma 
Rhabdoid tumor 
Note:  Patients who have synchronous rhabdoid tumor and ATRT with no 
clear primary should be enrolled into the rhabdoid tumor cohort, and they 
should complete the additional assessments scheduled for patients 
with ATRT. 
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Other tumor types not included in the list above with documented expression of 
PD-L1 on either tumor cells or immune infiltrating cells with approval of the 
Medical Monitor 
Other tumor types not included in the list above without documented expression 
of PD-L1 can be included with approval of the Medical Monitor and should not 
exceed 20% of the total sample size 
• 
Signed Informed Consent Form 
• 
Signed Child’s or Young Adult’s Assent Form when appropriate, as determined by 
patient’s age and individual site and country standards 
• 
Age at study entry < 30 years 
The first 5 patients must be ≥2 years of age (i.e., patients must have reached 
their 2nd birthday) to ensure safety and tolerability before patients <2 years of 
age receive their first dose of study drug.  These first 5 patients must be 
followed for either two cycles of treatment or until drug discontinuation, 
whichever is shorter, prior to enrollment of younger patients. 
The Sponsor may decide to stop enrollment of patients who are ≥ 18 years old 
at any time during the study to ensure adequate enrollment of patients who 
are < 18 years old. 
Patients who are ≥ 18 years old and are eligible for an adult PD-L1 treatment 
protocol will be preferentially enrolled in those adult studies. 
• 
In exceptional cases of patients with relapsed pediatric tumors who are ≥ 30 years 
of age, the Sponsor will consider waiving the age requirement with approval of the 
Medical Monitor.  This waiver is restricted to patients with pediatric-specific 
diseases (e.g., neuroblastoma), for whom clinical trials are unlikely to be available, 
and will not be extended to patients with tumors that typically occur both in children 
and adults (i.e., high-grade glioma). 
• 
Able to comply with the study protocol, in the investigator’s judgment 
• 
Weight is ≥ 3 kg 
• 
Disease that is measurable as defined by RECIST v1.1, mINRC, Revised 
Response Criteria for Malignant Lymphoma, or RANO criteria (as appropriate) or 
evaluable by nuclear medicine techniques, immunocytochemistry techniques, 
tumor markers, or other reliable measures 
• 
Archival tumor tissue block or 15 freshly cut, unstained, serial slides available for 
submission or willingness to undergo a core or excisional biopsy prior to enrollment 
(fine-needle aspiration, brush biopsy, and lavage samples are not acceptable) 
Patients with fewer than 15 slides available may be eligible for study entry 
following discussion with the Medical Monitor.  See Section 4.5.6 for detailed 
tissue requirements. 
• 
Lansky Performance Status (patients who are < 16 years old) or Karnofsky 
Performance Status (patients who are ≥ 16 years old) ≥ 50 (see Appendix 8 and 
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• 
Life expectancy is ≥ 3 months, in the investigator's judgment 
• 
For patients of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use two adequate methods of contraception, including 
at least one method with a failure rate of < 1% per year, during the treatment period 
and for at least 5 months after the last dose of study drug 
Examples of contraceptive methods with a failure rate of < 1% per year 
include established, proper use of hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices (IUDs), and copper IUDs. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception.  
Barrier methods must always be supplemented with the use of a spermicide. 
• 
Adequate hematologic and end organ function, defined by the following laboratory 
results obtained within 28 days prior to initiation of study drug: 
ANC ≥ 0.75 × 109/L (unsupported) 
Platelet count ≥ 75 × 109/L (unsupported) 
Hemoglobin ≥ 8 g/dL (transfusion permitted) 
Bilirubin ≤ 1.5 × ULN for age 
AST and ALT ≤ 2.5 × ULN for age 
Serum creatinine ≤ 1.5 × ULN for age or creatinine clearance (or radioisotope 
glomerular filtration rate) > 70 mL/min/1.73 m2 
INR and aPTT ≤ 1.5 institutional ULN for age 
Patients receiving therapeutic anticoagulants are excluded from the study. 
• 
Fractional shortening ≥ 30% or left ventricular ejection fraction (LVEF) ≥ 50% at 
baseline, as determined by echocardiography or multigated acquisition (MUGA) 
scan within 28 days prior to initiation of study drug 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
• 
Known primary CNS malignancy or symptomatic CNS metastases, except ATRT 
Patients with ATRT must not have tumor brainstem involvement or tumors 
within 10 mm of the optic chiasm; they must not have a history of intracranial 
hemorrhage or spinal cord hemorrhage or have had neurosurgical resection, 
brain biopsy, or radiation to the primary brain tumor within 28 days 
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• 
Patients with asymptomatic untreated CNS metastases may be enrolled after 
consultation with the Medical Monitor, provided all of the following criteria are met: 
Evaluable or measurable outside the CNS.  (Note:  this is not required for 
patients with ATRT.) 
No metastases to brain stem, midbrain, pons, medulla, or cerebellum or 
within 10 mm of the optic apparatus (optic nerve or chiasm).  (Note: ATRT may 
have metastases in the cerebellum.) 
No history of intracranial hemorrhage or spinal cord hemorrhage 
No ongoing requirement for corticosteroids for CNS disease except in ATRT 
where steroids use is permitted with approval from the Medical Monitor.  
Patients with ATRT must receive a stable or decreasing dose for ≥ 5 days prior 
to the baseline magnetic resonance imaging [MRI] scan and at the time of drug 
initiation. 
Patients taking a stable dose of anticonvulsants are permitted 
No neurosurgical resection or brain biopsy within 28 days prior to 
Cycle 1, Day 1 
• 
Patients with asymptomatic treated CNS metastases may by enrolled after 
consultation with the Medical Monitor, provided all the criteria listed above in the 
above CNS-related exclusion criteria are met as well as the following: 
Radiographic demonstration of improvement upon the completion of 
CNS-directed therapy and no evidence of interim progression between the 
completion of CNS-directed therapy and the screening radiographic study 
No stereotactic radiation or whole-brain radiation within 28 days prior to 
Cycle 1, Day 1 
Screening CNS radiographic study ≥ 4 weeks from completion of radiotherapy 
and ≥ 2 weeks from discontinuation of corticosteroids 
• 
For patients with lymphoma, known CNS lymphoma, or leptomeningeal disease 
• 
Treatment with high-dose chemotherapy and hematopoietic stem-cell rescue 
within 3 months prior to initiation of study drug 
This requirement may be waived at the investigator’s request if the patient has 
recovered from therapeutic toxicity to the degree specified in the protocol, with 
approval of the Medical Monitor. 
• 
Prior allogeneic hematopoietic stem-cell transplantation or prior solid-organ 
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• 
Treatment with chemotherapy (other than high-dose chemotherapy as described 
above) or differentiation therapy (such as retinoic acid) or immunotherapy (such as 
anti-GD2 antibody treatment) within 3 weeks prior to initiation of study drug or, if 
treatment included nitrosoureas, within 6 weeks prior to initiation of study drug 
This requirement may be waived at the investigator’s request if the patient has 
recovered from therapeutic toxicity to the degree specified in the protocol, with 
approval of the Medical Monitor. 
• 
Treatment with thoracic or mediastinal radiotherapy within 3 weeks prior to initiation 
of study drug 
• 
Treatment with hormonal therapy (except hormone replacement therapy or oral 
contraceptives) or biologic therapy within 4 weeks or 5 half-lives, whichever is 
shorter, prior to initiation of study drug.  This requirement may be waived at the 
investigator’s request if the patient has recovered from therapeutic toxicity to the 
degree specified in the protocol, with approval of the Medical Monitor. 
• 
Treatment with herbal cancer therapy within 1 week prior to initiation of study 
drug 
• 
Treatment with a long-acting hematopoietic growth factor within 2 weeks prior to 
initiation of study drug or a short-acting hematopoietic growth factor within 1 week 
prior to initiation of study drug 
• 
Treatment with investigational therapy (with the exception of cancer therapies as 
described above) within 4 weeks prior to initiation of study drug.  This requirement 
may be waived at the investigator’s request if the patient has recovered from 
therapeutic toxicity to the degree specified in the protocol, with approval of the 
Medical Monitor. 
• 
Treatment with a live vaccine or a live attenuated vaccine (e.g., nasal spray of live 
attenuated influenza vaccine or FluMist®) within 4 weeks prior to initiation of study 
drug or anticipation that such treatment will be required during the study or 
within 5 months after the final dose of study drug 
• 
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, 
including anti−CTLA-4, anti−PD-1, or anti−PD-L1 therapeutic antibodies 
• 
Treatment with systemic immunostimulatory agents (including but not limited to 
interferons or interleukin 2 [IL-2]) within 6 weeks or five drug elimination half-lives 
prior to Day 1 of Cycle 1, whichever is longer 
• 
Treatment with systemic corticosteroids or other systemic immunosuppressive 
medications (including but not limited to prednisone, dexamethasone, 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti−tumor 
necrosis factor [TNF] agents) at the time of initiation of study drug, or anticipated 
requirement for systemic immunosuppressive medications during the study 
Patients with ATRT can be receiving concurrent treatment with 
corticosteroids with approval from the Medical Monitor as outlined in 
Section 4.4.2 and the ATRT-related exclusion criteria. 
• 
Current treatment with therapeutic anticoagulants 


 
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• 
Any non-hematologic toxicity (excluding alopecia) from prior treatment that has not 
resolved to Grade ≤ 1 (per NCI CTCAE v4.0) at screening 
Note:  Long-term sequelae of prior treatment (e.g., hearing loss, iatrogenic 
hypothyroidism, infertility, etc.) are not considered non-hematologic toxicity 
and instead are considered chronic medical conditions. 
• 
Evidence of progression of neurologic deficit, in the investigator’s judgment, 
within 1 week prior to initiation of study drug 
• 
Major surgical procedure, significant traumatic injury within 4 weeks prior to 
initiation of study drug, or anticipation of need for major surgical procedure during 
the course of the study 
Placement of a vascular access device is permitted if the site has healed prior 
to initiation of study drug. 
Biopsy tissue collections are permitted if all bleeding parameters (including 
PT/INR and aPTT) are within normal limits and procedure is safe in the 
judgment of the investigator. 
• 
Known active infection (excluding fungal infection of the nail beds) within 28 days 
prior to initiation of study drug that has not completely resolved 
• 
Pregnant or lactating or intending to become pregnant during the study 
Patients of childbearing potential must have a negative serum pregnancy test 
result within 1 week prior to initiation of study drug. 
• 
Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary 
cells or any component of the atezolizumab formulation 
• 
Any other disease, metabolic or psychological dysfunction, physical examination 
finding, or clinical laboratory finding giving reasonable suspicion of a disease or 
condition that contraindicates use of an investigational drug or places the patient at 
unacceptable risk from treatment complications 
• 
Current drug or alcohol use or dependence that would interfere with adherence to 
study requirements, in the opinion of the investigator 
• 
History of severe allergic or anaphylactic reaction to monoclonal antibody therapies 
(or recombinant antibody−related fusion proteins) 
• 
History of clinically significant cardiac or pulmonary dysfunction 
• 
History of any autoimmune disease, including but not limited to Type 1 diabetes 
mellitus, autoimmune-related hypothyroidism, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, 
inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid 
syndrome, Wegener granulomatosis, Sjögren’s syndrome, Guillain-Barré syndrome, 
multiple sclerosis, vasculitis, or glomerulonephritis 
Patients with a history of autoimmune-related hypothyroidism who are 
receiving a stable dose of thyroid-replacement hormone are eligible for the 
study. 


 
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Patients with controlled Type 1 diabetes mellitus who are receiving a stable 
dose of insulin regimen are eligible for the study. 
• 
History of severe eczema 
• 
History of Kawasaki disease 
• 
History of Fanconi anemia, Beckwith-Wiedemann, ataxia telangiectasia, or other 
genetic syndromes that may have immune or hematologic susceptibilities 
• 
History of severe asthma or presence of uncontrolled asthma at time of screening 
evaluation 
Severe asthma is defined as presence of symptoms throughout the day, 
multiple nighttime awakenings during the week, use of a short-acting β2 agonist 
several times a day, and/or limitations with normal daily activity.  In addition, 
any asthma that does not meet the above definition but is felt to be severe in 
the eyes of the investigator should also be excluded. 
• 
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced 
pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic 
organizing pneumonia), cystic fibrosis, or evidence of active pneumonitis on 
screening chest computed tomography (CT) scan 
• 
Dyspnea at rest or requirement for supplemental oxygen 
• 
Uncontrolled seizures 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
This is an open-label study.  Dose assignments will be based on age. 
4.3 
STUDY TREATMENT 
4.3.1 
Formulation, Packaging, and Handling 
Atezolizumab will be supplied by the Sponsor as sterile liquid in 20-mL glass vials.  
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. 
For information on the formulation and handling of atezolizumab, see the Investigator’s 
Brochure and Pharmacy Manual. 
4.3.2 
Dosage, Administration, and Compliance 
The dose of atezolizumab is 15 mg/kg (maximum, 1200 mg) for patients aged <18 years.  
An interim analysis will be performed after 5 patients of <6 years of age have completed 
the first cycle.  Dose adjustments may be made, if necessary, to achieve exposures 
corresponding to those measured in adult patients and if the safety profile is acceptable 
(see Section 5.1.1.1).  Patients aged ≥ 18 years will receive a flat dose of 1200 mg of 
atezolizumab.  Atezolizumab will be administered by IV infusion once every 3 weeks.  
Patients will be weighed at the beginning of each cycle (within 7 days of the Day 1 dose), 
and the dose will be adjusted as needed.  Atezolizumab infusion may be delayed up to 
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infusions should be rescheduled accordingly.  For patients who receive the 15-mg/kg 
dose, the dose administered should be within 5% of the calculated dose to accommodate 
for any rounding that may need to occur. 
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.  
In addition, there must be at least 24 hours between the initial treatment doses of the 
first 5 patients regardless of tumor type to allow for evaluation of immediate immune 
activating events before additional patients are exposed to atezolizumab.  There must 
also be at least 24 hours of treatment doses for the first 3 patients within each tumor 
type cohort. 
Atezolizumab will be delivered in variable-size 0.9% NaCl IV infusion bags.  The size of 
the infusion bag for each dose is listed below and will accommodate fluid restrictions 
needed for smaller patients. 
Dose 
(mg) 
Infusion Bag Size 
(mL) 
600−1200 
250 
240−599 
100 
45−239 
25 
 
The initial dose of atezolizumab will be administered 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 administered over 30 (± 10) minutes.  For the first infusion, 
the patient’s vital signs (heart rate, respiratory rate, blood pressure, temperature, 
and pulse oximetry) should be determined within 60 minutes before, during (every 
15 [± 5] minutes), and 30 (± 10) minutes after the end of infusion.  For subsequent 
infusions, vital signs will be collected within 60 minutes before infusion and at the end of 
the infusion (± 10 minutes).  Patients or their caregivers will be informed about the 
possibility of delayed post-infusion symptoms and instructed to contact their study 
physician if they develop such symptoms. 
No premedication will be allowed for the first dose of atezolizumab.  Premedication, 
including acetaminophen, diphenhydramine, or other standard-of-care medications, may 
be administered for Cycles ≥ 2 at the discretion of the treating physician after 
consultation with the Medical Monitor.  Corticosteroids cannot be administered as 
premedication.  Patients who are receiving acetaminophen, diphenhydramine, or other 
medications for symptom management may continue to receive their scheduled 
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Guidelines for dosage modification and treatment interruption and for the management 
of specific adverse events, including infusion-related reactions, are provided in 
Section 5.1.1. 
Any overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF. 
For more detailed information on drug preparation, storage, and administration, refer 
to the Investigator’s Brochure and Pharmacy Manual. 
4.3.3 
Investigational Medicinal Product Accountability 
All investigational medicinal product (IMP) required for completion of this study 
(i.e., atezolizumab) will be provided by the Sponsor where required by local health 
authority regulations.  The study site will acknowledge receipt of IMP, using the IxRS to 
confirm the shipment condition and content.  Any damaged shipments will be replaced. 
IMP will either be disposed of at the study site according to the study site’s institutional 
standard operating procedure or returned to the Sponsor with the appropriate 
documentation.  The site’s method of IMP destruction must be agreed to by the Sponsor.  
The site must obtain written authorization from the Sponsor before any IMP is destroyed, 
and IMP destruction must be documented on the appropriate form. 
Accurate records of all IMP received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the drug accountability log and IxRS. 
4.3.4 
Post-Study Access to Atezolizumab 
The Sponsor will offer post-study access to the study drug (atezolizumab) free of charge 
to eligible patients in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, as outlined below. 
A patient will be eligible to receive study drug after the end of the study if all of the 
following conditions are met: 
• 
The patient has a life-threatening or severe medical condition and requires 
continued study drug treatment for his or her well-being 
• 
There are no appropriate alternative treatments available to the patient 
• 
The patient and his or her doctor comply with and satisfy any legal or regulatory 
requirements that apply to them 
 


 
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A patient will not be eligible to receive study drug after the end of the study if any of the 
following conditions are met: 
• 
The study drug is commercially marketed in the patient’s country and is reasonably 
accessible to the patient (e.g., is covered by the patient’s insurance or wouldn’t 
otherwise create a financial hardship for the patient) 
• 
The Sponsor has discontinued development of the study drug or data suggest that 
the study drug is not effective for solid tumors 
• 
The Sponsor has reasonable safety concerns regarding the study drug as 
treatment for solid tumors 
• 
Provision of study drug is not permitted under the laws and regulations of the 
patient’s country 
 
The Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following Web site: 
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf 
 
4.4 
CONCOMITANT THERAPY AND FOOD 
4.4.1 
Permitted Therapy 
Concomitant therapy includes any medication (e.g., prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 
7 days prior to study drug initiation to the study drug discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF. 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic 
anticoagulation therapy, or maintenance therapies other than prohibited therapies listed 
in Section 4.4.2 should continue their use, including stress dosing as clinically indicated. 
Pain medications may be administered according to local standard practice guidelines 
while the patient is in the study. 
Patients who experience infusion-associated symptoms should receive supportive care 
with oxygen, β-agonists, antihistamines, antipyretics, or corticosteroids, as considered 
appropriate by the investigator (see the Atezolizumab Investigator’s Brochure, 
Section 5.1.1, and Appendix 10 for more information). 
Systemic corticosteroids may attenuate potential beneficial immunologic effects of 
treatment with atezolizumab; however, they may be administered, as described in 
Section 5.1.1.2, after consultation with the Medical Monitor.  If feasible, alternatives to 
corticosteroids should be considered.  Premedication, excluding corticosteroids, may be 
administered for Cycles ≥ 2 at the discretion of the treating physician after consultation 
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Palliative radiotherapy may be given to patients (e.g., treatment of known bone 
metastases) provided it does not interfere with assessment of tumor target lesions.  It is 
not required to withhold atezolizumab during palliative radiotherapy. 
Patients may receive inactivated vaccines if deemed necessary by the treating physician.  
Influenza vaccination can be given during influenza season (approximately October to 
March in the Northern Hemisphere).  Acceptable influenza vaccines include TIV and QIV 
(injection of trivalent or quadrivalent killed vaccine).  However, LAIV and Q/LAIV (nasal 
spray of live attenuated influenza vaccine such as FluMist®) must be avoided. 
4.4.2 
Prohibited Therapy 
Use of the following therapies is prohibited during the study: 
• 
Any concomitant therapy intended for the treatment of solid tumors, either 
approved by health authorities or experimental, including chemotherapy, 
radiotherapy (except palliative radiotherapy), hormonal therapy, immunotherapy, 
biologic therapy, or herbal therapy 
Patients with rhabdoid tumor and ATRT may receive local therapy (radiation 
or surgery) after at least four cycles of atezolizumab with approval of the 
Medical Monitor. 
• 
Traditional herbal or homeopathic or natural medicines 
Ingredients for such medicines have not been fully studied, and their use may 
result in unanticipated drug-drug interactions that may cause or confound 
assessment of toxicity. 
• 
Immunostimulatory agents, including but not limited to interferon (IFN)-α, IFN-γ, 
anti-TNF-α, or IL-2 (prohibited during the study and for 10 weeks after the last dose 
of atezolizumab) 
These agents, in combination with atezolizumab, could potentially increase the 
risk for autoimmune conditions. 
• 
Immunosuppressive medications, including but not limited to cyclophosphamide, 
azathioprine, methotrexate, and thalidomide 
These agents could potentially alter the activity and the safety of atezolizumab. 
• 
Live vaccines and live attenuated vaccines (prohibited during the study and for 
5 months after the last dose of study drug) 
 
Initiation of granulocyte colony-stimulating factors (e.g., granulocyte colony-stimulating 
factor, granulocyte/macrophage colony-stimulating factor, and/or pegfilgrastim) should 
be discussed with the Medical Monitor. 
Systemic corticosteroids 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 Medical Monitor, as described in Section 5.1.1.2. 


 
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Patients with ATRT can be receiving concurrent treatment with corticosteroids with 
approval from the Medical Monitor.  Patients must be receiving a stable or decreasing 
dose for ≥ 5 days prior to the baseline MRI scan and at the time of drug initiation.  The 
Medical Monitor should be informed when steroid doses are increased because of 
declining patient status. 
In clinically indicated emergent situations (i.e., anaphylaxis), corticosteroids may be 
administered without notifying the Medical Monitor in advance, but the Medical Monitor 
should be notified within 24 hours of the event.  If feasible, alternatives to these agents 
should be considered.  Systemic steroids used as steroid replacement therapy for 
adrenal insufficiency are permitted. 
4.5 
STUDY ASSESSMENTS 
See Appendix 1 and Appendix 2 for the schedules of assessments performed during the 
study. 
Unless otherwise stated, the baseline measurement for any given assessment will be 
defined as the last value obtained before the first dose of study drug.  After treatment 
initiation, changes from baseline abnormalities should be recorded in patient notes.  New 
or worsened clinically significant abnormalities should be recorded as adverse events on 
the Adverse Event eCRF.  Patients should be assessed for toxicity prior to each dose; 
dosing will occur only if the clinical assessment and local laboratory test values are 
acceptable. 
If the timing of a protocol-mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent, and assent when applicable, for participation in the study must 
be obtained before performing any study-specific screening tests or evaluations.  
Informed Consent Forms and Child’s Informed Assent Forms for enrolled patients and 
for patients who are not subsequently enrolled will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
4.5.2 
Medical History and Demographic Data 
Medical history includes clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies, current cancer stage, and procedures), menstrual 
history, fertility history, and puberty history.  In addition, all medications 
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nutritional supplements) used by the patient within 7 days prior to initiation of study drug 
will be recorded. 
Demographic data will include age, sex, and self-reported race/ethnicity as permitted by 
local regulatory authorities. 
4.5.3 
Physical Examinations and Assessments 
A complete physical examination should include an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at 
baseline should be recorded on the General Medical History and Baseline Conditions 
eCRF. 
The Lansky Performance Status should be performed for patients who are < 16 years old, 
and the Karnofsky Performance Status should be performed for patients who are ≥ 16 
years old. 
At subsequent visits (or as clinically indicated), changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF. 
Fractional shortening or LVEF should be determined within 28 days prior to initiation of 
study drug by either echocardiography or MUGA scan. 
During the treatment period, weight will be measured at the beginning of each cycle.  
During the follow-up period, weight should be measured every 3 months for the 
first 2 years, every 6 months during the 3rd year, and yearly thereafter. 
During the treatment period, height, head circumference (until the age of 3 years), and 
Tanner stage should be measured every four cycles (approximately every 3 months).  
During the follow-up period, height, head circumference, and Tanner stage should be 
measured every 3 months for the first 2 years, every 6 months during the 3rd year, and 
yearly thereafter.  Tanner staging should be performed until the patient has reached 
Tanner Stage V. 
4.5.3.1 
Neurologic Examinations (ATRT Only) 
For patients with ATRT, a complete neurologic examination should be completed at 
every patient visit, including at baseline (see Schedule of Assessments in Appendix 1).  
Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. 
At subsequent visits (or as clinically indicated), changes from baseline abnormalities 
need to be reviewed carefully prior to administering the next atezolizumab dose.  


 
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Atezolizumab should not be administered if there is any sign of increased intracranial 
pressure.  
The neurologic examination should include age-appropriate evaluations of vision, 
including visual fields, coordination, cranial nerve function, strength and motor 
evaluations (including gait when appropriate), and reflexes.  Discussions with the 
parents and/or guardian should also occur to assess for new or worsening symptoms, 
including but not limited to changes in physical activity, irritability, headaches, 
changes in appetite and/or feeding, vomiting, and nausea. 
New or worsened clinically significant abnormalities should be recorded as adverse 
events on the Adverse Event eCRF. 
4.5.4 
Vital Signs 
Age-appropriate equipment should be used to obtain vital signs and assessments and 
adjusted for growth.  Vital signs will include measurements of respiratory rate, pulse rate, 
systolic and diastolic blood pressures, oxygen saturation by pulse oximetry, and 
temperature. 
For the first infusion of atezolizumab, vital signs should be determined within 60 minutes 
before, every 15 (± 5) minutes during, and 30 (± 10) minutes after the end of infusion.  
For subsequent infusions, vital signs should be recorded within 60 minutes before 
infusion and at the end of infusion (± 10) minutes, but vital signs do not need to be 
obtained during the infusion if the prior infusion was tolerated without symptoms. 
4.5.5 
Tumor and Response Evaluations 
4.5.5.1 
Tumor Assessments 
All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  Baseline tumor assessments should be performed within 
28 days prior to initiation of study drug (Day 1 of Cycle 1).  Tumor assessments must be 
performed during the last week of Cycles 2, 4, 6, and 8 and every 4th cycle thereafter 
(i.e., within 7 days prior to Day 1 of the next cycle).  At the investigator’s discretion, 
unscheduled tumor assessments may be performed at any time if progressive disease is 
suspected.  For patients who continue treatment beyond radiographic progressive 
disease because of possible pseudoprogression, a follow-up scan must be performed 
after 2 cycles or earlier if clinically indicated. 
Response will be assessed by the investigator on the basis of physical examinations, 
CT scans, MRI scans, fluorodeoxyglucose-positron emission tomography (FDG-PET) 
scans, or MIBG scans, as appropriate.  Tumor assessment imaging should include all 
areas of known disease.  A chest CT is also required to be performed at each assessment.  
An objective response should be confirmed by repeat assessments ≥ 4 weeks after initial 
documentation.  The same imaging techniques and procedures used to assess disease 
sites at screening should be used throughout the study (e.g., the same contrast protocol 


 
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for CT scans).  To the extent that is feasible, assessments should be performed by the 
same evaluator to ensure internal consistency across visits. 
Patients with neuroblastoma must have a MIBG scan and bilateral bone marrow 
aspirates and/or biopsies done for disease evaluation.  If the enrollment bone marrow 
aspirates and/or biopsy tissue samples are negative for disease, subsequent bone 
marrow aspirates and/or biopsy tissue samples are not needed.  Patients with evidence 
of bone marrow disease at screening require bone marrow evaluation with scheduled 
disease evaluations until they have had two consecutive evaluations that are negative 
for disease.  Patients with neuroblastoma should also have urine catecholamine test 
results (including homovanillic acid and vanillylmandelic acid) sent at screening and with 
all responses assessments. 
Patients with lymphoma should undergo FDG-PET imaging at screening and with each 
response assessment.  For lymphoma patients with a clinical suspicion of bone marrow 
involvement, bilateral bone marrow aspirates and/or biopsies should be performed at 
screening.  Patients who have documented bone marrow involvement at screening 
should have subsequent bilateral bone marrow evaluations performed with each 
response assessment until the first negative bone marrow evaluation. 
Patients without neuroblastoma or lymphoma who have a clinical suspicion of bone 
marrow involvement should also have bilateral bone marrow aspirates and/or biopsies 
performed at screening.  Patients who have documented bone marrow involvement at 
screening should have subsequent bone marrow evaluations performed with each 
response assessment until the first negative bone marrow evaluation. 
4.5.5.2 
Response Criteria 
All tumors will be evaluated for disease response and progressive disease with 
RECIST v1.1 (see Appendix 6) with the exception of those listed below. 
• 
Neuroblastoma:  mINRC (see Appendix 3) 
• 
Hodgkin’s lymphoma and non-Hodgkin’s lymphoma:  Revised Response Criteria 
for Malignant Lymphoma (see Appendix 4) 
• 
ATRT:  RANO criteria (see Appendix 11) 
Patients with synchronous ATRT and rhabdoid tumor with no clear primary 
should be enrolled into the rhabdoid tumor cohort.  These patients’ tumors will 
be evaluated with RECIST v1.1 criteria. 
Patients who enroll with evaluable but not measurable disease will have a modified 
response assessment.  For such patients, partial response cannot be determined; 
therefore, response will be limited to complete response, stable disease, or progressive 
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During treatment, patients who show evidence of clinical benefit will be permitted to 
continue atezolizumab treatment after criteria for progressive disease for their specified 
response assessment are met, if they meet all of the following criteria: 
• 
Evidence of clinical benefit as assessed by the investigator and agreed upon by the 
Medical Monitor 
• 
Absence of symptoms or signs (including worsening laboratory test values) 
indicating unequivocal progression of disease 
• 
No decline in Lansky or Karnofsky Performance Status that can be attributed to 
disease progression 
• 
Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal 
disease) that cannot be managed by protocol-allowed medical interventions 
 
Patients and/or their parents or guardians must sign a consent acknowledging treatment 
continuation after possible worsening disease in order to continue to receive 
atezolizumab.  Patients for whom radiographic disease progression is confirmed at a 
subsequent tumor assessment may be considered for continued study treatment at the 
discretion of the investigator if they have evidence of clinical benefit and continue to 
meet the criteria above.  If an individual patient continues to experience clinical benefit 
beyond 2 years of radiologic progressive disease (see Section 3.3.4), the Sponsor and 
treating physician will apply for additional approval from health authorities for continued 
treatment. 
Collection of an optional tumor biopsy sample, if clinically feasible, at the time of first 
radiographic progression on atezolizumab treatment is encouraged in order to evaluate 
the utility of the biopsy tumor sample in distinguishing pseudoprogression or tumor 
immune infiltration from true progressive disease. 
4.5.6 
Laboratory, Biomarker, and Other Biological Samples 
Assessments that require blood draws should be monitored closely to ensure that 
institutional guidance regarding total blood volume taken for samples is maintained.  In 
situations where no institutional guidance is available, no more than 2.5% of the total 
blood volume should be taken at one time and no more than 5% of the total blood 
volume should be taken over a 30-day period (total blood volume is defined as 
80 mL/kg).  Institutions should use micro-sampling systems to minimize the amount of 
blood drawn when able.  In situations where the total amount will exceed the amount 
stated above, clinical laboratory assessments should be prioritized.  Any remaining 
blood should be sent for PK analysis and immunogenicity followed by biomarker and 
PD analyses. 
Laboratory tests results must meet the inclusion criteria and not meet the exclusion 
criteria at the time of screening.  If laboratory tests are performed again prior to the 
first dose, they must continue to meet the inclusion criteria and not meet the exclusion 
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Samples for the following laboratory tests will be sent to the study site’s local laboratory 
for analysis: 
• 
Hematology (WBC count, hemoglobin, platelet count, 3-cell differential count 
[absolute neutrophils, monocytes, and lymphocytes]) 
• 
Serum chemistry (sodium, potassium, magnesium, chloride, bicarbonate, glucose, 
BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total bilirubin 
[if abnormal, fractionate sample for direct and indirect], alkaline phosphatase, ALT, 
AST, LDH, amylase, and lipase) 
• 
Creatinine clearance should be done as clinically indicated.  If radioisotope 
glomerular filtration rate is routinely performed at the institution to measure 
patients’ creatinine clearance, this test can be used to assess renal function at 
screening, per the eligibility criteria.  Otherwise, serum creatinine is sufficient to 
document renal function at screening. 
• 
Coagulation panel (INR, aPTT, PT) 
• 
Urinalysis (specific gravity, glucose, protein, blood) in children who are  > 3 years of 
age 
• 
Pregnancy test 
All patients of childbearing potential will undergo a serum pregnancy test at 
screening (prior to Cycle 1) within 1 week prior to initial dose.  Urine or serum 
pregnancy test will be performed prior to all subsequent cycles. 
• 
Thyroid function testing (thyroid-stimulating hormone, free T3, free T4) 
• 
Viral serology at screening (hepatitis B surface antigen, hepatitis B surface 
antibody, total hepatitis B core antibody, hepatitis C antibody, human 
immunodeficiency virus (HIV)-1, and HIV-2 antibody) 
If a patient is positive for hepatitis B core antibody at screening, a test for 
hepatitis B virus DNA should be performed prior to Day 1 of Cycle 1. 
If a patient is positive for hepatitis C antibody at screening, a test for hepatitis C 
virus RNA should be performed prior to Day 1 of Cycle 1. 
 


 
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The following samples will be sent to a central laboratory or the Sponsor or selected 
designee for analysis: 
• 
Archival or fresh primary tumor tissue samples for exploratory research on 
candidate biomarkers, including but not limited to PD-L1, PD-1, and CD8 
For patients with archival samples:  Representative formalin-fixed 
paraffin-embedded (FFPE) tumor specimens in paraffin blocks or at least 
15 freshly cut, unstained, serial slides (blocks preferred), with an associated 
pathology report, are required for study entry.  The specimen should be of good 
tissue quality and have sufficient viable tumor content as determined by the 
institutional pathologist.  Patients with fewer than 15 slides available may be 
eligible for study entry following discussion with the Medical Monitor.  The tumor 
specimen and associated pathology report must be confirmed to be available 
prior to patient participation in any study-specific screening procedures and 
must be shipped within 30 days of first dosing. 
Patients will be encouraged to submit all available FFPE tumor specimens from 
prior surgeries and biopsies performed as part of routine medical care.  If a 
patient has multiple archival specimens available but wants to submit only one 
sample, the specimen obtained closest to the start of treatment should be used. 
Patients without archival samples must undergo a core or excisional biopsy 
prior to enrollment.  Fine-needle aspiration, brush biopsy, and lavage samples 
are not acceptable.  Submission of bone biopsy specimens is strongly 
discouraged because of complications in the assessment of such tissue.  These 
specimens can be used only if no other tissue is available. 
Unused archival tumor blocks will be returned to the sites at the end of the 
study or upon site request. 
• 
PK assay 
Serum samples will be assayed for atezolizumab concentration with use of a 
validated immunoassay.  Any residual PK samples can be used for additional 
ATA testing if needed. 
• 
ATA assays 
Serum samples will be assayed for the presence of ATAs to atezolizumab with 
use of a validated immunoassay. 
• 
In children who have been vaccinated, tetanus toxoid IgG antibody titers 
• 
Plasma samples for exploratory research on candidate biomarkers, including but 
not limited to the following:  cytokines (e.g., IL-2 and IFN-γ), ctDNA concentration, 
ctDNA mutations (e.g., KRAS, P53, PTEN) 
• 
Whole blood samples for analysis of immune cell expression of biomarkers, 
including but not limited to the following:  PD-L1, CD4, CD8, FoxP3, IFN-γ 


 
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• 
A whole blood sample for molecular analysis of mutations and single-nucleotide 
polymorphisms (SNPs) is required ONLY for patients who consent to submitting 
optional on-study tissue (tissue submission described in Section 4.5.7). This sample 
may be used for the analysis of novel mutations detected in tumor tissue in order to 
verify the somatic nature of this mutation and SNPs that might be associated with 
safety, efficacy, or pharmacokinetics of the drug. 
• 
Whole blood samples for TBNK cell enumeration 
 
Serum samples will be obtained at baseline and held for possible testing in patients who 
develop immune-related or inflammatory adverse events during the study.  The samples 
will be analyzed as needed to determine baseline values for the following: 
• 
Auto-antibody testing 
Anti-nuclear antibody 
Anti−double-stranded DNA 
Circulating anti-neutrophil cytoplasmic antibody 
Perinuclear anti-neutrophil cytoplasmic antibody 
 
For sampling procedures, storage conditions, and shipment instructions, see the 
Laboratory Manual. 
Samples will be destroyed when the final Clinical Study Report has been completed, 
with the following exceptions: 
• 
Any remaining samples collected for pharmacokinetics, biomarker assays, and 
ATA assays may be used for exploratory biomarker profiling, identification, and PD 
assay development purposes and for additional safety assessments (e.g., ATA 
assay) as appropriate.  These samples will be destroyed no later than 5 years after 
the final Clinical Study Report has been completed.  The remainder of samples 
obtained for study-related procedures will be destroyed no later than 5 years after 
the date of final closure of the clinical database unless the patient gives specific 
consent for the remainder of the samples to be stored for optional exploratory 
research.  If the patient provides consent for optional exploratory research, the 
samples will be destroyed no later than 15 years after the date of final closure of 
the clinical database. 
 
4.5.7 
Samples for Roche Clinical Repository 
4.5.7.1 
Overview of the Roche Clinical Repository 
The Roche Clinical Repository (RCR) is a centrally administered group of facilities used 
for the long-term storage of human biologic specimens, including body fluids, solid 
tissues, and derivatives thereof (e.g., DNA, RNA, proteins, peptides).  The collection and 
analysis of RCR specimens will facilitate the rational design of new pharmaceutical 
agents and the development of diagnostic tests, which may allow for individualized drug 
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Specimens for the RCR will be collected from patients who give specific consent to 
participate in this optional research.  RCR specimens will be used to achieve the 
following objectives: 
• 
To study the association of biomarkers with efficacy, adverse events, or 
progressive disease 
• 
To increase knowledge and understanding of disease biology 
• 
To study drug response, including drug effects and the processes of drug 
absorption and disposition 
• 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.7.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection and submission of biological samples to the RCR is contingent upon the 
review and approval of the exploratory research and the RCR portion of the Informed 
Consent Form by each site’s Institutional Review Board (IRB) or Ethics Committee (EC) 
and, if applicable, an appropriate regulatory body.  If a site has not been granted 
approval for RCR sampling, this section of the protocol (Section 4.5.7) will not be 
applicable at that site. 
4.5.7.3 
Sample Collection 
The following samples will be collected for research purposes, including but not limited 
to research on dynamic (non-inherited) biomarkers related to atezolizumab or solid 
tumors: 
• 
Fresh tissue from study biopsies and residual tissue from non−study-related 
procedures, will be collected from the primary tumor location, metastatic site, or 
site of local recurrence or advancement for analyses that may include DNA or RNA 
extraction.  Samples should be obtained at the following timepoints:  prior to drug 
initiation, 4−6 weeks after the first dose of drug, and at the time of progressive 
disease (if applicable).  Patient may choose to consent to any or all of these 
timepoints. 
A minimum of three fresh tissue cores should be acquired using an 18-gauge 
needle.  If not feasible, one or two cores may be acceptable after discussion 
with the Medical Monitor. 
 
Patients consenting to the optional study biopsy will also be required to provide a 
mandatory whole blood sample listed under the main protocol (Section 4.5.6). 
For all samples, dates of consent should be recorded on the associated RCR page of 
the eCRF.  For sampling procedures, storage conditions, and shipment instructions, see 
the Laboratory Manual. 


 
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RCR specimens will be destroyed no later than 15 years after the date of final closure of 
the associated clinical database.  The RCR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
The dynamic biomarker specimens will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.7.4 
Confidentiality 
Data generated from RCR specimens must be available for inspection upon request by 
representatives of national and local health authorities and Roche monitors, 
representatives, and collaborators, as appropriate. 
Patient medical information associated with RCR specimens is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Data derived from RCR specimen analysis on individual patients will generally not be 
provided to study investigators unless a request for research use is granted.  The 
aggregate results of any research conducted using RCR specimens will be available in 
accordance with the effective Roche policy on study data publication. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RCR data will become and remain the exclusive and unburdened property 
of Roche, except where agreed otherwise. 
4.5.7.5 
Consent to Participate in the Roche Clinical Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RCR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RCR.  Patients will be 
told that they are free to refuse to participate and may withdraw their specimens at any 
time and for any reason during the storage period.  A separate, specific signature will be 
required to document a patient’s agreement to provide optional RCR specimens.  
Patients who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate by completing the RCR Research Sample Informed Consent eCRF. 
In the event of an RCR participant’s death or loss of competence, the participant’s 
specimens and data will continue to be used as part of the RCR research. 


 
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4.5.7.6 
Withdrawal from the Roche Clinical Repository 
Patients who give consent to provide RCR specimens have the right to withdraw their 
specimens from the RCR at any time for any reason.  If a patient wants to withdraw 
consent to the testing of his or her specimens, the investigator must inform the Medical 
Monitor in writing of the patient’s wishes through use of the RCR Subject Withdrawal 
Form and, if the study is ongoing, must enter the date of withdrawal on the RCR 
Research Sample Withdrawal of Informed Consent eCRF.  The patient will be provided 
with instructions on how to withdraw consent after the study is closed.  A patient’s 
withdrawal from Study GO29664 does not, by itself, constitute withdrawal of specimens 
from the RCR.  Likewise, a patient’s withdrawal from the RCR does not constitute 
withdrawal from Study GO29664. 
4.5.7.7 
Monitoring and Oversight 
RCR specimens will be tracked in a manner consistent with Good Clinical Practice by a 
quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of specimens as specified in this protocol and in the 
Informed Consent Form.  Roche monitors and auditors will have direct access to 
appropriate parts of records relating to patient participation in the RCR for the purposes 
of verifying the data provided to Roche.  The site will permit monitoring, audits, IRB/EC 
review, and health authority inspections by providing direct access to source data and 
documents related to the RCR samples. 
4.6 
PATIENT, TREATMENT, STUDY, AND SITE DISCONTINUATION 
4.6.1 
Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study (or be withdrawn by their 
patients or caregivers, if the patient is a minor) at any time for any reason.  In addition, 
the investigator has the right to withdraw a patient from the study treatment at any time.  
Reasons for withdrawal from the study may include but are not limited to the following: 
• 
Patient withdrawal of consent (or withdrawal of consent by their patients or 
caregivers, if the patient is a minor) at any time 
• 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues in the study 
• 
Investigator or Sponsor determines it is in the best interest of the patient. 
• 
Patient non-compliance with the study procedures (e.g., dosing instructions, study 
visits) 
 
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  In situations where it is either unsafe or not in the best interest of 
the patient to complete follow-up assessments after study drug discontinuation, 
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Medical Monitor.  Patients will not be followed up for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced. 
4.6.2 
Study Drug Discontinuation 
Patients must discontinue study drug 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 
• 
Unacceptable toxicity despite per-protocol treatment interruptions 
• 
Pregnancy 
• 
Withdrawal of consent 
• 
Interruption of study treatment for > 105 days (e.g., more than 105 days between 
infusions) because of an atezolizumab-related adverse event, except in patients 
who must be tapered off corticosteroids used to treat adverse events (see 
Section 5.1.1.1 for details).  This duration may be extended after consultation with 
the Medical Monitor. 
 
Patients who discontinue study drug for any reason will be asked to return to the clinic 
for a study drug discontinuation visit and undergo follow-up assessments (see the 
schedule of assessments in Appendix 1).  If treatment with another anti-cancer treatment 
is scheduled to begin within 90 days after the last dose of atezolizumab, assessments at 
this visit should be performed before the patient starts the other treatment, if possible.  
Patients who discontinue for reasons other than progressive disease should continue 
follow-up assessments, including tumor assessments, using the long-term follow-up 
schedule (e.g., every 3 months for the first 2 years, every 6 months during Year 3, etc.) 
until radiographic documentation of progressive disease, they start another treatment, or 
consent is withdrawn.  For patients who continue receiving study drug beyond 
radiographic progressive disease, assessments should be continued until they stop 
taking study drug.  The primary reason for study drug discontinuation should be 
documented on the appropriate eCRF. 
4.6.3 
Study and Site Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include but are not limited to the following: 
• 
The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients. 
• 
Patient enrollment is unsatisfactory. 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study. 


 
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The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include but are not limited to the following: 
• 
Excessively slow recruitment 
• 
Poor protocol adherence 
• 
Inaccurate or incomplete data recording 
• 
Non-compliance with the International Conference on Harmonisation (ICH) 
guideline for Good Clinical Practice 
• 
No study activity (i.e., all patients have completed and all obligations have been 
fulfilled) 
 
5. 
ASSESSMENT OF SAFETY 
5.1 
SAFETY PLAN 
Atezolizumab is not approved for pediatric use and is currently in clinical development 
for different indications.  Human experience is currently limited, and the entire safety 
profile is not known at this time.  It has not been studied in patients younger than 
15 years old.  The following information is based on results from nonclinical and adult 
clinical studies and published data on similar molecules.  Refer to the Atezolizumab 
Investigator’s Brochure for a complete summary of safety information. 
Measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients at higher risk for toxicities.  
Specifically, patients at risk for study-emergent autoimmune conditions or with a prior 
diagnosis of autoimmune disease (except patients with a history of autoimmune-related 
hypothyroidism receiving a stable dose of thyroid-replacement hormone or patients with 
controlled Type 1 diabetes mellitus receiving a stable dose of insulin regimen), patients 
with evidence of acute or chronic infections, and patients who have received a live 
vaccine or a live attenuated vaccine within 4 weeks prior to initiation of study drug will be 
excluded from the study (see Section 4.1.2).  Patients are also required to abstain from 
receiving a live or live attenuated vaccine during treatment and for 5 months following 
the last atezolizumab dose.  In addition, patients will undergo safety monitoring during 
the study as described in Section 4.5, Section 5, and the schedules of assessments (see 
Appendix 1 and Appendix 2).  Patients with ATRT will be monitored with additional 
visits to assess neurologic function due to the possible risk of tumor progression and/or 
pseudoprogression in the CNS cavities.  Adverse events, laboratory values, and vital 
signs must be reviewed prior to each infusion. 
An iDMC will monitor patient safety throughout the study. 
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.  
In addition, there must be at least 24 hours between the initial treatment doses of the 
first 5 patients regardless of tumor type to allow for evaluation of immediate immune 


 
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activating events before additional patients are exposed to atezolizumab.  There must 
also be at least 24 hours of treatment doses for the first 3 patients within each tumor 
type cohort. 
Serious adverse events and adverse events of special interest will be recorded during the 
study and for 90 days after the last dose of study treatment or until the initiation of 
another anti-cancer therapy, whichever occurs first.  All other adverse events will be 
recorded during the study and for 30 days after the last dose of study treatment or until 
the initiation of another anti-cancer therapy, whichever occurs first; treatment-related 
adverse events must be reported beyond this date (see Section 5.3.1).  In addition, 
patients will continue to be followed up at defined time intervals (see schedules of 
assessments in Appendix 1 and Appendix 2) until termination of the study.  Following 
discontinuation from this study, patients will be offered follow-up for adverse events and 
survival. 
5.1.1 
Management of Specific Adverse Events 
The potential safety issues anticipated in this study, as well as measures intended to 
avoid or minimize such toxicities, are outlined in the following sections.  Toxicities 
possibly associated with atezolizumab treatment should be managed according to the 
management guidelines described in the Atezolizumab Investigator’s Brochure in 
conjunction with standard medical practice.  However, the guidelines are not intended to 
replace clinical judgment.  Additional tests, such as autoimmune serology or biopsies, 
should be used to determine a possible immunogenic etiology, in accordance with 
pediatric standard-of-care practice.  Guidelines for managing adverse events, including 
criteria for treatment interruption or discontinuation, are provided below and described in 
the Atezolizumab Investigator’s Brochure. 
5.1.1.1 
Dose Modification and Treatment Interruption 
There will be no intrapatient atezolizumab dose reductions as a result of adverse events.  
Study drug may be temporarily withheld if patients experience an adverse event that is 
considered related to atezolizumab.  If study drug is withheld because of an 
atezolizumab-related adverse event for > 105 days, the patient will be discontinued from 
atezolizumab treatment. 
Following the interim PK analyses, dose modifications may be considered if warranted 
for all patients on the basis of individual and population PK data to ensure patient safety 
and/or to match adult exposures.  Recommendations will be based on evaluations of PK, 
safety, efficacy, and biomarker data as available and appropriate. 
If patients must be tapered off corticosteroids used to treat adverse events, study 
treatment may be withheld for > 105 days.  The acceptable length of interruption will 
depend on agreement between the investigator and the Medical Monitor. 


 
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Dose interruptions for reasons other than toxicity, such as surgical procedures, may be 
allowed with Medical Monitor approval.  The acceptable length of interruption will depend 
on agreement between the investigator and the Medical Monitor. 
5.1.1.2 
Immune-Mediated Adverse Events 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to management guidelines described in the Atezolizumab 
Investigator’s Brochure in conjunction with standard medical practice.  These guidelines 
outline the general management in adult patients; therefore, recommended dosing may 
need to be adjusted appropriately for pediatric patients.  Additional tests, such as 
autoimmune serology or biopsies, should be used to determine a possible immunogenic 
etiology. 
Although most immune-mediated adverse events 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-mediated 
toxicities may require acute management with topical corticosteroids, systemic 
corticosteroids, mycophenolate, or TNF−α inhibitors. 
The investigator should consider the benefit-risk balance a given patient may be 
experiencing prior to further administration of atezolizumab.  Atezolizumab should be 
permanently discontinued in patients with life-threatening immune-mediated adverse 
events and per management guidelines described in the Atezolizumab Investigator’s 
Brochure. 
Management of systemic immune activation is presented below.  Refer to the 
Atezolizumab Investigator’s Brochure for details on management of atezolizumab-
specific adverse events, including pulmonary events, hepatic events, gastrointestinal 
events, endocrine events, ocular events, infusion-related reactions, pancreatic events, 
dermatologic events, neurologic disorders, and immune-related meningoencephalitis. 
5.1.1.3 
Systemic Immune Activation 
Systemic immune activation is a rare condition characterized by an excessive immune 
response.  Given the mechanism of action of atezolizumab, systemic immune activation 
is considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternate etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and initial evaluation should include assessing the 
following: 
• 
CBC with peripheral smear 
• 
PT, PTT, fibrinogen, and D-dimer 
• 
Ferritin 


 
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• 
Triglycerides 
• 
AST, ALT, and total bilirubin 
• 
LDH 
• 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the 
Medical Monitor for additional recommendations. 
5.1.1.4 
Central Nervous System Signs and Symptoms (ATRT Only) 
For the ATRT cohort only, signs and symptoms of disease progression and 
pseudoprogression of this CNS tumor should be assessed at each visit.  Study treatment 
should be interrupted immediately and patients should be treated with steroids and/or 
other medications to reduce intracranial pressure as per institutional guidelines in the 
case of signs and symptoms of increased intracranial pressure considered to be related 
to atezolizumab, including but not limited to vomiting, headache, changes in mental 
status, and vision changes.  The Medical Monitor should be contacted within 24 hours 
if CNS signs and symptoms considered to be related to atezolizumab occur.  Patients 
should be treated with steroids and/or other medications to reduce intracranial pressure 
as per institutional guidelines. 
5.2 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4. 
5.2.1 
Adverse Events 
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory test 
finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product 
• 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition), except as described in 
Section 5.3.5.10 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
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• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that 
is associated with symptoms or leads to a change in study treatment or 
concomitant treatment or discontinuation from study drug 
• 
Adverse events that are related to a protocol-mandated intervention, including 
those that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
• 
Is fatal (i.e., the adverse event actually causes or leads to death) 
• 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death. 
• 
Requires or prolongs inpatient hospitalization (see Section 5.3.5.11) 
• 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions) 
• 
Is a congenital anomaly and/or birth defect in a neonate or infant born to a mother 
exposed to study drug 
• 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize 
the patient or may require medical or surgical intervention to prevent one of the 
outcomes listed above) 
 
The terms “severe” and “serious” are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to 
NCI CTCAE v4.0 criteria; see Section 5.3.3); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
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5.2.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest, regardless of seriousness, are required to be 
reported by the investigator to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event; see Section 5.4.2 for reporting instructions).  Adverse events 
of special interest for this study include the following: 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies 
Diabetes mellitus 
Pancreatitis 
Adrenal insufficiency 
Hyperthyroidism 
Hypothyroidism 
• 
Hepatitis 
• 
Transaminitis Grade ≥ 2 (AST or ALT > 3 × ULN and bilirubin > 2 × ULN) or 
AST/ALT > 10 × ULN 
• 
Systemic lupus erythematosus 
• 
Neurological 
Guillain-Barré syndrome 
Myasthenia gravis 
Meningoencephalitis 
• 
Nephritis 
• 
Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome, systemic immune activation, or 
infusion reactions syndrome 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST 
level in combination with either an elevated bilirubin level or clinical jaundice, as 
defined by Hy’s law (see Section 5.3.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
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5.3 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4 and Section 5.6. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4). 
5.3.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events). 
After initiation of study drug, all serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  
All other adverse events, regardless of relationship to study drug, will be reported until 
30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first.  After this period, the investigator should report any serious 
adverse events that are believed to be related to prior study drug treatment (see 
Section 5.6). 
5.3.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
“How have you felt since your last clinic visit?” 
“Have you had any new or changed health problems since you were last here?” 
 
5.3.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v4.0) will be used for 
assessing adverse event severity.  Table 1 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 1 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in the NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v4.0), which can be found at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a “significant medical event,” it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2. 
 
5.3.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether or 
not an adverse event is considered to be related to the study drug, indicating “yes” or 
“no” accordingly.  The following guidance should be taken into consideration (see also 
Table 2): 
• 
Temporal relationship of event onset to the initiation of study drug 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable) 
• 
Known association of the event with the study drug or with similar treatments 
• 
Known association of the event with the disease under study 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
• 
Presence of non−treatment-related factors that are known to be associated with the 
occurrence of the event 
 


 
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Table 2 
Causal Attribution Guidance 
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment? 
YES 
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained 
by the patient’s clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and if applicable reappears upon re-challenge. 
NO 
An adverse event will be considered related, unless it fulfills the criteria specified 
below. 
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug). 
 
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy. 
5.3.5 
Procedures for Recording Adverse Events 
When adverse event terms do not already exist in NCI CTCAE, investigators should use 
correct medical terminology and concepts when recording adverse events on the 
Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF. 
5.3.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration 
should be captured as individual signs and symptoms on the Adverse Event eCRF 
rather than an overall diagnosis (e.g., record dyspnea and hypotension as separate 
events rather than a diagnosis of infusion-related reaction or anaphylactic reaction). 
5.3.5.2 
Diagnosis versus Signs and Symptoms 
For adverse events other than infusion-related reactions (see Section 5.3.5.1), a 
diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 


 
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report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.3.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should 
be reported separately on the eCRF. 
• 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
• 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.3.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should be recorded only once on the 
Adverse Event eCRF.  The initial severity (grade) of the event will be recorded at the 
time the event is first reported.  If a persistent adverse event becomes more severe, the 
most extreme severity (grade) should also be recorded on the Adverse Event eCRF.  
Details regarding any increases or decreases in severity will be captured on the Adverse 
Event Grade Changes eCRF.  If the event becomes serious, it should be reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning that the event became 
serious; see Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should 
be updated by changing the event from “non-serious” to “serious,” providing the date that 
the event became serious, and completing all data fields related to serious adverse 
events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF. 


 
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5.3.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment 
Note:  For oncology studies, certain abnormal test values may not qualify as 
adverse events. 
 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin levels 5 × ULN associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating if the test result is above or below the normal range (e.g., “elevated 
potassium,” as opposed to “abnormal potassium”.  If the laboratory abnormality can be 
characterized by a precise clinical term per standard definitions, the clinical term should 
be recorded as the adverse event.  For example, an elevated serum potassium level of 
7.0 mEq/L should be recorded as “hyperkalemia.” 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should be recorded only once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
• 
Results in a medical intervention or a change in concomitant therapy 
• 
Is clinically significant in the investigator’s judgment  
 


 
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It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should be recorded only once on the Adverse Event eCRF (see Section 5.3.5.4 for 
details on recording persistent adverse events). 
5.3.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST level (> 3 × ULN) in combination with either an 
elevated total bilirubin (> 2 × ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
• 
Treatment-emergent ALT or AST level > 3 × ULN in combination with total bilirubin 
> 2 × ULN 
• 
Treatment-emergent ALT or AST level > 3 × ULN in combination with clinical 
jaundice 
 
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2). 
5.3.5.8 
Deaths 
For this protocol, mortality is an efficacy endpoint.  Deaths that occur during the 
protocol-specified adverse event reporting period (see Section 5.3.1) that are attributed 
by the investigator solely to progression of cancer should be recorded only on the Study 
Discontinuation eCRF.  All other on-study deaths, regardless of relationship to study 
drug, must be recorded on the Adverse Event eCRF and immediately reported to the 
Sponsor (see Section 5.4.2). 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  The term “sudden death” should be used only for the occurrence of an 
abrupt and unexpected death due to presumed cardiac causes in a patient with or 
without preexisting heart disease, within 1 hour after the onset of acute symptoms or in 
the case of an unwitnessed death within 24 hours after the patient was last seen alive 


 
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and stable.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, “unexplained death” should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), “unexplained death” should 
be replaced by the established cause of death. 
During survival follow-up, deaths attributed to progression of cancer should be recorded 
only on the Study Discontinuation eCRF. 
5.3.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
5.3.5.10 
Lack of Efficacy or Worsening of Cancer 
Events that are clearly consistent with the expected pattern of disease evolution should 
not be recorded as adverse events.  These data will be captured as efficacy assessment 
data only.  In most cases, the expected pattern of progression will be based on mINRC, 
Revised Response Criteria for Malignant Lymphoma, RECIST v1.1, or RANO criteria 
as appropriate.  In rare cases, the determination of clinical progression will be based on 
symptomatic deterioration.  However, every effort should be made to document 
progression through use of objective criteria.  If there is any uncertainty as to whether an 
event is a result of progressive disease, it should be reported as an adverse event. 
5.3.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., in-patient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as outlined 
below. 
The following hospitalization scenarios are not considered to be adverse events: 
• 
Hospitalization for respite care (temporary hospitalization of a dependent that 
provides a period of rest for the caregiver) 


 
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• 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease. 
The patient has not experienced an adverse event. 
• 
Hospitalization due solely to progression of the underlying cancer 
 
The following hospitalization scenarios are not considered to be serious adverse events 
but should be reported as adverse events instead: 
• 
Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available 
 
5.3.5.12 
Adverse Events Associated with an Overdose or Error in Drug 
Administration 
An overdose is the accidental or intentional use of a drug in an amount higher than the 
dose being studied.  An overdose or incorrect administration of study treatment is not 
itself an adverse event, but it may result in an adverse event.  All adverse events 
associated with an overdose or incorrect administration of study drug should be 
recorded on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). 
No safety data related to overdosing of atezolizumab are available. 
5.4 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
• 
Serious adverse events (see Section 5.4.2 for further details) 
• 
Adverse events of special interest, regardless of seriousness (see Sections 5.3.2 
and 5.4.2 for further details) 
• 
Pregnancies (see Section 5.4.3 for further details) 
 
For these specific events, the investigator must report new significant follow-up 
information to the Sponsor immediately (i.e., no more than 24 hours after becoming 
aware of the information).  New significant information includes the following: 
• 
New signs or symptoms or a change in the diagnosis 


 
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• 
Significant new diagnostic test results 
• 
Change in causality based on new information 
• 
Change in the event’s outcome, including recovery 
• 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.4.1 
Emergency Medical Contacts 
Medical Monitor Contact Information for United States and Canada 
Medical Monitor: 
, M.D. (primary) 
Mobile Telephone No.: 
 
 
Medical Monitor: 
, M.D. (secondary) 
Mobile Telephone No.: 
 
 
Medical Monitor Contact Information for European Union and Israel 
Medical Monitor: 
, M.D. (primary) 
Telephone No.: 
 
 
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Monitor, and track all calls.  The Emergency Medical Call Center Help Desk will be 
available 24 hours per day, 7 days per week.  Toll-free numbers for the Help Desk, as 
well as Medical Monitor contact information, will be distributed to all investigators. 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.4.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Sponsor or its designee 
immediately (i.e., no more than 24 hours after learning of the event), either by faxing or 
by scanning and e-mailing the form with the use of the fax number or e-mail address 
provided to investigators. 
5.4.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest, regardless of relationship to study drug, will be reported until 90 days after the 
last dose of study drug or initiation of new anti-cancer therapy, whichever occurs first.  
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30 days after the last dose of study drug or initiation of new anti-cancer therapy, 
whichever occurs first. 
The investigator should also report any serious adverse events that are believed to be 
related to prior study drug treatment even if these occur after the abovementioned 
reporting periods.  Investigators should record all case details that can be gathered 
immediately (i.e., within 24 hours after learning of the event) on the Adverse Event eCRF 
and submit the report via the electronic data capture (EDC) system.  A report will be 
generated and sent to Roche Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours 
after learning of the event), either by faxing or by scanning and emailing the form with 
the use of the fax number or email address provided to investigators.  Once the EDC 
system is available, all information will need to be entered and submitted via the EDC 
system. 
Instructions for reporting post-study adverse events are provided in Section 5.6. 
5.4.3 
Reporting Requirements for Pregnancies 
5.4.3.1 
Pregnancies in Patients 
Patients of childbearing potential will be instructed to immediately inform the investigator 
if they become pregnant during the study or within 5 months after the last dose of study 
drug.  A Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
the Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), either by faxing or scanning and emailing the form using the fax number or 
email address provided to investigators.  Pregnancy should not be recorded on the 
Adverse Event eCRF.  The investigator should discontinue study drug and counsel the 
patient, discussing the risks of the pregnancy and the possible effects on the fetus.  
Monitoring of the patient should continue until conclusion of the pregnancy.  Any serious 
adverse events associated with the pregnancy (e.g., an event in the fetus, an event in 
the mother during or after the pregnancy, or a congenital anomaly or birth defect in the 
child) should be reported on the Adverse Event eCRF.  In addition, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available. 
5.4.3.2 
Pregnancies in Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or after the last 
dose of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or scanning and e-mailing the form using the 
fax number or e-mail address provided to the investigators.  Attempts should be made to 


 
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collect and report details of the course and outcome of any pregnancy in the partner of a 
male patient exposed to study drug.  The pregnant partner will need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for follow-
up on her pregnancy.  Once the authorization has been signed, the investigator will 
submit a Clinical Trial Pregnancy Reporting Form when updated information on the 
course and outcome of the pregnancy becomes available.  An investigator who is 
contacted by the male patient or his pregnant partner may provide information on the 
risks of the pregnancy and the possible effects on the fetus, to support an informed 
decision in cooperation with the treating physician and obstetrician. 
5.4.3.3 
Abortions 
Any abortion should be classified as a serious adverse event (because the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
5.4.3.4 
Congenital Anomalies and Birth Defects 
Any congenital anomaly or birth defect in a child born to a patient exposed to study drug 
or the partner of a male patient exposed to study drug should be classified as a serious 
adverse event, recorded on the Adverse Event eCRF, and reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2). 
5.5 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.5.1 
Investigator Follow-Up 
The investigator should follow up each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient is 
lost to follow-up, or the patient withdraws consent.  Every effort should be made to follow 
up all serious adverse events considered to be related to study drug or study-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed up until pregnancy 
outcome. 
5.5.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, e-mail, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 


 
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5.6 
POST-STUDY ADVERSE EVENTS 
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
90 days after the last dose of study drug or until initiation of new anti-cancer therapy 
for serious adverse events and adverse events of special interest and 30 days for all 
other adverse events), if the event is believed to be related to prior study drug treatment. 
These events should be reported through use of the Adverse Event eCRF.  However, if 
the EDC system is not available, the investigator should report these events directly to 
the Sponsor or its designee, either by faxing or by scanning and emailing the Serious 
Adverse Event/Adverse Event of Special Interest Reporting Form using the fax number 
or email address provided to investigators. 
5.7 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities on the basis of applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document: 
• 
Atezolizumab Investigator’s Brochure 
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator’s assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
The study is an early-phase, multicenter, open-label, single-arm study designed to 
evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary 
efficacy of atezolizumab in pediatric and young adult patients with solid tumors for which 
prior treatment has proven to be ineffective (i.e., relapsed or refractory disease) or 
intolerable and for whom there is no effective standard treatment available.  The primary 
analysis will be conducted after the enrollment has been completed and all enrolled 
patients have been followed up for at least 6 months.  A primary Clinical Study Report 
will be submitted to health authorities for information. 


 
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6.1 
DETERMINATION OF SAMPLE SIZE 
No formal hypothesis testing is planned in this study. 
A minimum of 40 patients will be enrolled in this study across all tumor types.  In addition, 
at least two tumor type cohorts must enroll a minimum of 10 patients.  To make a 
preliminary assessment of the efficacy of the study drug, two response assessments are 
planned:  an initial response assessment and an additional response assessment.  
Taking into account historical control ORRs for each pediatric tumor type, the minimum 
number of patients in the initial response assessment and the minimum number of 
responders needed for cohort expansion and advancement to the additional response 
assessment were calculated and are presented by tumor type in Table 3.  Given the 
bony nature of osteosarcoma, responses in osteosarcomas do not always result in tumor 
shrinkage as the extracellular matrix produced by the tumor cells does not always 
disappear even when the cells die (Benjamin RS 2015).  Thus, for osteosarcoma, CBR 
instead of objective response was considered in the response assessment.  Patients 
with osteosarcoma are considered to have CBR if they have objective response or 
stable disease for at least 6 months, as determined by RECIST v1.1. 
An initial response assessment will consider any available preclinical data in addition to 
any early efficacy or safety signals seen in the tumor type cohorts (enrollment may be 
closed while the response assessments are being conducted).  The selection of 
expansion cohorts for additional response assessment, as well as the number of 
patients needed for the additional response assessment, will also take into account 
practical considerations (e.g., enrollment feasibility), biomarker analysis, safety profiles, 
and any other relevant information.  The maximum number of patients per tumor type 
cohort will be 40.  Similar consideration will be given to other rare pediatric tumor types 
that are enrolled in the study and not included in Table 3. 


 
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Table 3 
Sample Size and Responder Requirements for Initial Response 
Assessment 
Initial Response Assessment 
Disease 
(Relapsed/Refractory) 
Historical Control 
Objective Response 
Rate (%) 
Minimum No. of 
Patients Enrolled
Minimum No. of Responders 
Needed for Tumor Type 
Cohort Expansion 
Hepatoblastoma 
10% 
10 
2 
Hodgkin’s disease 
60 a 
14 
10 
Wilms tumor 
10 
10 
2 
Neuroblastoma 
18 
10 
3 
Non-Hodgkin’s lymphoma 
40 a 
12 
6 
High-grade osteosarcoma 
20 b 
10 
3 
Rhabdomyosarcoma 
10 
10 
2 
Non-rhabdomyosarcoma 
tissue sarcoma 
10 
10 
2 
Ewing sarcoma 
10 
10 
2 
Rhabdoid tumor 
5 
6 
1 
Atypical teratoid 
rhabdoid tumor 
5 
6 
1 
a Combination therapy. 
b Clinical benefit response: objective response or stable disease for at least 6 months. 
 
Overall, approximately 100 patients will be enrolled in the study. 
6.2 
SUMMARIES OF CONDUCT OF STUDY 
Patient enrollment will be tabulated by study site.  Patient disposition and reasons for 
discontinuations will be summarized for all enrolled patients.  In addition, major protocol 
deviations will be summarized. 
Patient demographics and baseline characteristics, including age, sex, race/ethnicity, 
medical history, and prior cancer treatment, will be summarized overall and by tumor 
type cohort.  Descriptive statistics (mean, median, standard deviation, 25th percentile, 
75th percentile, and range) will be presented for continuous variables, and proportions 
will be presented for categorical variables. 
6.3 
SAFETY ANALYSES 
Safety analyses will be performed on the safety-evaluable population, which is defined 
as patients who receive any amount of study drug.  Subgroup safety analyses by tumor 
type cohort will also be conducted as appropriate. 


 
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Study treatment exposure (such as treatment duration, total dose received, and number 
of cycles and dose modifications) will be summarized with descriptive statistics. 
All adverse events, serious adverse events, adverse events leading to death, adverse 
events of special interest, and adverse events leading to study treatment discontinuation, 
occurring on or after the first dose of study treatment (i.e., treatment-emergent adverse 
events) will be summarized by mapped term, appropriate thesaurus level, and toxicity 
grade.  For events of varying severity, the highest grade will be used in the summaries.  
Deaths and cause of death will be summarized. 
Laboratory toxicities will be summarized by NCI CTCAE grade. 
6.4 
PHARMACOKINETIC ANALYSES 
Individual and mean Cmax of atezolizumab on Day 1 of Cycle 1 and Day 1 of Cycle 4 will 
be summarized.  In addition, Cmin of atezolizumab on Day 1 of Cycles 2, 3, 4, 8, 12, and 
16 and every 8 cycles thereafter, at study drug discontinuation, and after washout will be 
summarized.  Atezolizumab AUC for serum concentration-time profile in Cycle 1 will be 
estimated using a population PK model, as appropriate.  Descriptive statistics will 
include mean, median, range, standard deviation, coefficient of variation, geometric 
mean, and geometric mean coefficient of variation as appropriate.  After a minimum of 
20 patients have completed Cycle 1, interim PK and safety analyses will be conducted.  
Relationships between PK and PD biomarkers may be explored using population PK 
and/or PD modeling approaches, as appropriate.  Details regarding the modeling and 
simulations will be described in a separate Modeling and Simulations Data Analysis Plan 
prior to the modeling. 
6.5 
IMMUNOGENICITY ANALYSES 
The immunogenicity analyses will include patients with at least one ATA assessment.  
The numbers and proportions of ATA-positive patients and ATA-negative patients during 
both the treatment and follow-up periods will be summarized.  Patients are considered to 
be ATA positive if they are ATA negative or missing at baseline but develop an ATA 
response following study drug administration (treatment-induced ATA response), or if 
they are ATA positive at baseline and the titer of one or more post-baseline samples is 
at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample 
(treatment-enhanced ATA response).  Patients are considered to be ATA negative if 
they are ATA negative or missing at baseline and all post-baseline samples are negative, 
or if they are ATA positive at baseline but do not have any post-baseline samples with a 
titer that is at least 4-fold greater than the titer of the baseline sample (treatment 
unaffected). 
The relationship between ATA status and safety, efficacy, PK, and biomarker endpoints 
will be analyzed and reported descriptively via subgroup analyses. 


 
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6.6 
EFFICACY ANALYSES 
All efficacy analyses will be performed on the safety-evaluable population, which is 
defined as patients who receive any amount of study drug. 
6.6.1 
Primary Efficacy Endpoint 
The primary endpoints for efficacy are ORR and PFS.  For patients with measurable 
disease or patients with neuroblastoma who have evaluable disease at baseline, an 
objective response is defined as a complete or partial response on two consecutive 
occasions ≥ 4 weeks apart, as determined by the investigator using RECIST v1.1 
for patients with solid tumors (see Appendix 6), mINRC for patients with neuroblastoma 
(see Appendix 3), Revised Response Criteria for Malignant Lymphoma for patients with 
Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see Appendix 4), and RANO criteria 
(see Appendix 11) for patients with ATRT. 
For patients with non-measurable but evaluable disease at baseline (except patients 
with neuroblastoma), an objective response is defined as a complete response on two 
consecutive occasions ≥ 4 weeks apart, as determined by the investigator using RECIST 
v1.1 for patients with solid tumors (see Appendix 6), Revised Response Criteria for 
Malignant Lymphoma for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma 
(see Appendix 4), and RANO criteria (see Appendix 11) for patients with ATRT. 
ORR is the percentage of patients who are determined to have an objective response.  
Patients with no post-baseline tumor assessments will be counted as non-responders.  
ORR and corresponding 95% exact CI using the Blyth−Still−Casella method will be 
summarized overall and by tumor type cohort (except for the osteosarcoma tumor type 
cohort). 
CBR is defined as objective response or stable disease for at least 6 months, as 
determined by RECIST v1.1 for patients with osteosarcoma (see Appendix 6).  CBRR is 
the percentage of patients who are determined to have a CBR.  Patients with no post-
baseline tumor assessments will be counted as not having CBR.  CBRR and 
corresponding 95% CI will be summarized for the osteosarcoma tumor type cohort only. 
PFS is defined as the time from initiation of study drug to the first documented 
occurrence of disease progression, as determined by the investigator using 
RECIST v1.1 for patients with solid tumors (see Appendix 6), mINRC for patients with 
neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant Lymphoma 
for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see Appendix 4), 
and RANO criteria (see Appendix 11) for patients with ATRT, or death from any cause, 
whichever occurs first.  Data for patients without progressive disease or death will be 
censored at the date of the last tumor assessment at which the patient was known to be 
progression-free or, if no tumor assessment is performed after the baseline visit, at the 
date of initiation of study drug.  The Kaplan-Meier approach will be used to estimate 
median PFS.  The 95% CI of the median PFS will be estimated using the Brookmeyer 


 
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and Crowley method.  Subgroup analysis of PFS by tumor type cohort will be conducted 
as appropriate. 
6.6.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include DOR and OS. 
For patients who achieve an objective response, DOR is defined as the time from the 
first tumor assessment that supports the patient’s objective response to the time of 
progressive disease, as determined by the investigator using mINRC for patients with 
neuroblastoma (see Appendix 3), Revised Response Criteria for Malignant Lymphoma 
for patients with Hodgkin’s lymphoma or non-Hodgkin’s lymphoma (see Appendix 4), 
RANO criteria (see Appendix 11) for patients with ATRT, and RECIST v1.1 for 
patients with other solid tumors (see Appendix 6), or death from any cause, whichever 
occurs first.  The censoring method for DOR will be the same as that for PFS.  The 
Kaplan-Meier approach will be used to estimate median DOR.  The 95% CI of the 
median DOR will be estimated using the Brookmeyer and Crowley method.  Subgroup 
analysis of DOR by tumor type cohort will be conducted as appropriate. 
OS is defined as the time from initiation of study drug to death from any cause.  Patients 
who are alive at the data cutoff date will be censored at the date the patient was last 
known to be alive.  Patients with no post-baseline information will be censored at the 
date of initiation of study drug.  The Kaplan-Meier approach will be used to estimate 
median OS.  The 95% CI of the median OS will be estimated using the Brookmeyer and 
Crowley method.  Subgroup analysis of OS by tumor type cohort will be conducted as 
appropriate. 
In addition, analyses for ORR, PFS, and DOR using irRC for patients with 
neuroblastoma, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma, and 
immune-modified RECIST v1.1 for patients with other solid tumors will be conducted 
with the same approaches as explained above. 
6.7 
EXPLORATORY ANALYSES 
6.7.1 
Biomarker Analyses 
PD-L1 expression will be analyzed by IHC in tumor tissue samples collected at baseline. 
Levels of potential PD biomarkers (including but not limited to cytokines, ctDNA 
concentration, and T-cell subpopulations) will be measured in plasma and whole blood 
collected at baseline; at Cycles 1, 2, 3, 8, 12, and 16 and every 8 cycles thereafter; and 
at the time of progressive disease.  These samples will be analyzed for changes in 
biomarker levels in response to exposure to atezolizumab. 
Plasma, whole blood, and archival tumor tissue samples will be collected at baseline and 
analyzed for non-inherited and inherited biomarkers (including but not limited to PD-L1, 
PD-1, CD4, CD8, FoxP3, cytokines [e.g., IL-2 and IFN-γ], ctDNA concentration, ctDNA 


 
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mutations [e.g., KRAS, P53, PTEN], and T-cell receptor sequencing) that may be 
correlated with severity of adverse effects, PK parameters, or response to atezolizumab. 
Whole blood samples will be collected for TBNK cell enumeration.  Changes in cell 
numbers during the study will be correlated with exposure to atezolizumab. 
6.8 
INTERIM ANALYSES 
6.8.1 
Planned Interim Analyses 
Interim PK analyses will be conducted after the first 5 and 20 patients have completed 
Cycle 1, along with an ongoing evaluation of safety (see details in Section 6.3).  
An additional interim PK analysis will be conducted after the first 5 patients who 
are < 6 years old (if available) have completed Cycle 1. 
Interim efficacy analyses will be conducted whenever a tumor type cohort has enrolled 
the number of patients required for initial or additional response assessment and 
patients have been followed up for approximately 6 months. 
6.8.2 
Optional Interim Analyses 
Given the hypothesis-generating nature of this study, the Sponsor may choose to 
conduct additional interim efficacy and PK analyses.  The decision to conduct an 
optional interim analysis and the timing of the analysis will be documented in the 
Sponsor’s study master file prior to the conduct of the interim analysis.  The interim 
analysis will be performed and interpreted by Sponsor study team personnel. 
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for the data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data and IxRS data will 
be sent directly to the Sponsor with the use of the Sponsor’s standard procedures to 
handle and process the electronic transfer of these data. 
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures. 


 
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7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgment of receipt of the compact disc is required. 
7.3 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification to confirm that critical 
protocol data (i.e., source data) entered into the eCRFs by authorized site personnel are 
accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include but are not limited to hospital records, 
clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies of transcriptions 
that are certified after verification as being accurate and complete, microfiche, 
photographic negatives, microfilm or magnetic media, X-rays, patient files, and records 
kept at pharmacies, laboratories, and medico-technical departments involved in a clinical 
trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5. 
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor or its representative direct access to applicable source documents and reports 
for study-related monitoring, Sponsor audits, and IRB/EC review.  The study site must 
also allow inspection by applicable health authorities. 
7.4 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 


 
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as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change. 
7.5 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic patient-reported outcome data (if applicable), Informed 
Consent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for at least 15 years after completion or 
discontinuation of the study, or for the length of time required by relevant national or 
local health authorities, whichever is longer.  After that period of time, the documents 
may be destroyed, subject to local regulations. 
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) application will comply with U.S. Food and Drug 
Administration (FDA) regulations and applicable local, state, and federal laws.  Studies 
conducted in the European Union (E.U.) or European Economic Area will comply with 
the E.U. Clinical Trial Directive (2001/20/EC). 
8.2 
INFORMED CONSENT 
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Caregiver’s Informed Consent Form, 
if applicable) will be provided to each site.  If applicable, it will be provided in a certified 
translation of the local language.  The Sponsor or its designee must review and approve 
any proposed deviations from the Sponsor’s sample Informed Consent Forms or any 
alternate consent forms proposed by the site (collectively, the “Consent Forms”) before 
IRB/EC submission.  The final IRB/EC−approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes according to local requirements. 


 
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If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient’s agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient’s legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
Patients must be re-consented to the most current version of the Consent Forms (or to a 
significant new information/findings addendum in accordance with applicable laws and 
IRB/EC policy) during their participation in the study.  Young adult patients must 
re-consent to study when they reach age of adulthood in their home country.  For any 
updated or revised Consent Forms, the case history or clinical records for each patient 
shall document the informed consent process and that written informed consent was 
obtained using the updated/revised Consent Forms for continued participation in the 
study. 
A copy of each signed Consent Form must be provided to the patient or the patient’s 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient’s study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  If the site utilizes a 
separate Authorization Form for patient authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 


 
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Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site’s study file. 
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law. 
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes. 
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA and other national and local health authorities; Sponsor 
monitors, representatives, and collaborators; and the IRB/EC for each study site, as 
appropriate. 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (i.e., LPLV). 


 
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9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including but not limited to the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. 
9.3 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients’ medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.4 
ADMINISTRATIVE STRUCTURE 
This study will be sponsored by Roche and managed with the support of a contract 
research organization, which will provide clinical monitoring, sample management, and 
project management support.  Approximately 100 patients are expected be enrolled in 
this study, at approximately 50 investigative sites in Europe and North America.  Patients 
may be enrolled through the study groups Innovative Therapies for Children with Cancer 
and Pediatric Oncology Experimental Therapeutics Investigators’ Consortium.  Patients 
will be enrolled with the use of an IxRS. 
EDC will be used for this study.  Central facilities will be used for certain study 
assessments (e.g., specified biomarker tests, PK analyses).  Accredited local 
laboratories will be used for routine monitoring; local laboratory ranges will be obtained. 
An iDMC will monitor patient safety throughout the study. 


 
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9.5 
PUBLICATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a study, the Sponsor is dedicated to openly providing 
information on the study to health care professionals and to the public, both at scientific 
congresses and in peer-reviewed journals.  The Sponsor will comply with all 
requirements for publication of study results. 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
center data.  In this case, a coordinating investigator will be designated by mutual 
agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.6 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 


 
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eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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116/Protocol GO29664, Version 5 
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Rev Immunol 2008;8:467−77. 




Appendix 1  
Schedule of Assessments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
118/Protocol GO29664, Version 5 
Treatment Period 
Follow-Up Period b 
Screening 
Period a 
C1 
C2 
C3
C4
C5
C6
C7 C8 C9 C10
C11
C12+
ATRT Only 
Day –28 to –1 
1 
8 15
1 
8 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Study 
Drug 
Discont. c
Day 90 
Follow-
up c 
Long-
Term 
Follow-
Up d 
Coagulation (INR, 
aPTT, PT) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase/lipase q 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Thyroid function testing r 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
x 
 
x 
x 
x 
 
Virology testing s 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK/ATA blood samples t 
 
x 
x 
 
x 
 
 
x 
x 
 
 
 
x 
 
 
 
x 
x 
x u 
 
Whole blood for TBNK 
 
x 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
x 
x u 
 
Whole blood for 
biomarkers t 
 
x 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
x 
x u 
 
Plasma for biomarkers t 
 
x 
 
 
x 
 
 
x 
 
 
 
 
x 
 
 
 
x 
x 
x u 
 
Tumor assessments v, w 
x 
 
 
 
x 
 
 
 
x 
 
x 
 
x 
 
 
 
x 
x w 
x w 
x w 
Atezolizumab 
administration x 
 
x 
 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Concomitant 
medications y 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 


Appendix 1  
Schedule of Assessments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
119/Protocol GO29664, Version 5 
Treatment Period 
Follow-Up Period b 
Screening 
Period a 
C1 
C2 
C3
C4
C5
C6
C7 C8 C9
C10
C11 C12+
ATRT Only 
Day –28 to –1 
1 
8 15
1 
8 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Study 
Drug 
Discont. c
Day 90 
Follow-
up c 
Long-
Term 
Follow-
Up d 
Tetanus toxoid antibody 
titer z 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
Auto-antibody testing aa 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Optional RCR tumor 
tissue sample and 
corresponding blood 
sample bb, cc, dd 
 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
ATA = anti-therapeutic antibody; C = cycle; CT = computed tomography; discont. = discontinuation; eCRF = electronic Case Report Form; FDG-
PET = fluorodeoxyglucose-positron emission tomography; HIV = human immunodeficiency virus; MIBG = metaiodobenzoguanine; MUGA = multigated 
acquisition scan; MRI = magnetic resonance imaging; PK = pharmacokinetic; RCR = Roche Clinical Repository; TBNK = T, B, and natural killer (cells). 
Notes:  All assessments should be performed within 3 days of the scheduled date (excluding Day 1 of Cycle 1), unless otherwise specified.  On 
treatment days, all assessments should be performed prior to dosing, unless otherwise specified.  Cycles are 3 weeks in length.  Atezolizumab 
infusion may be delayed up to 5 days to accommodate holidays, weekends, and other patient obligations. 
Assessments shaded in gray should be performed as scheduled, but the associated data do not need to be recorded on the eCRF (except in the case 
of ATRT neurologic examinations, an adverse event, or a pregnancy). 
a Results of standard-of-care tests or examinations performed prior to obtaining informed consent and within 28 days prior to Day 1 of Cycle 1 may 
be used; such tests do not need to be repeated for screening.  Informed consent must be documented before any study-specific assessments are 
performed. 
b In situations where it is either unsafe or not in the best interest of the patient to complete follow-up assessments after study drug 
discontinuation, survival data only may be submitted during the follow-up period with approval of the Medical Monitor. 


Appendix 1  
Schedule of Assessments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
120/Protocol GO29664, Version 5 
c Patients who discontinue study drug should return to the clinic for study drug discontinuation visits within 28 days of the last dose of atezolizumab.  
This may be done at the clinical visit where clinical or radiographic progression is first noted).  A follow-up visit should also be done 
90 (± 10) days after the last dose of study drug.  If treatment with another anti-cancer treatment is scheduled to begin within 90 days after the last 
dose of study drug, this visit should be performed before the patient starts the other treatment, if possible.  If the day 90 visit is done after 
initiation of another anti-cancer treatment, only PK and/or ATA blood samples and those laboratory tests needed to monitor for the resolution of 
adverse events need to be drawn. 
d Long-term follow-up information will be collected every 3 months during the first two years (Years 1 and 2), every 6 months during Year 3, and 
yearly until study termination by Sponsor, death, loss to follow-up, or withdrawal of consent, whichever occurs first. 
e A tumor specimen and associated pathology report must be confirmed to be available prior to patient participation in any study-specific screening 
procedures and must be shipped within 30 days of first dosing.  See Section 4.5.6 for details on sample collection. 
f Medical history includes clinically significant diseases, surgeries, cancer history (including prior cancer therapies, current cancer stage, and 
procedures), menstrual history, fertility history, and puberty history.  Demographic data will include age, sex, and self-reported race/ethnicity as 
permitted by local regulatory authorities. 
g All females of childbearing potential must undergo a serum pregnancy test within one week of the initial dose.  Urine or serum pregnancy tests must 
be performed prior to the start of all subsequent cycles. 
h Includes respiratory rate, pulse rate, systolic and diastolic blood pressures, oxygen saturation by pulse oximetry, and temperature.  For the first 
infusion of atezolizumab, vital signs should be determined within 60 minutes before, every 15 (± 5) minutes during, and 30 (± 10) minutes after the 
infusion.  For subsequent infusions, vital signs do not need to be obtained during the infusion if the prior infusion was tolerated without symptoms.  
Record abnormalities observed at baseline on the General Medical History and Baseline Conditions eCRF.  At subsequent visits, record 
abnormalities on the Adverse Event eCRF. 
i Includes evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  For patients with ATRT, a complete neurologic examination will be conducted at the time specified in 
the schedule of assessments, which includes two additional visits in Cycle 2, on Day 8 and Day 15. Record abnormalities observed at baseline on 
the General Medical History and Baseline Conditions eCRF.  At subsequent visits, changes from baseline abnormalities should be recorded in 
patient notes.  Record new or worsened clinically significant abnormalities on the Adverse Event eCRF. 
j Weight should be measured within 7 days of Day 1 for each cycle. 
k During the treatment period, height, head circumference (until the age of 3), and Tanner stage should be measured every four cycles 
(approximately every 3 months).  During the follow-up period, height, head circumference (until the age of 3), and Tanner stage should be 
measured every 3 months for the first 2 years, every 6 months during the third year, and yearly thereafter.  Tanner staging and height should be 
performed until the patient has reached Tanner Stage V. 


Appendix 1  
Schedule of Assessments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
121/Protocol GO29664, Version 5 
l Perform Lansky Performance Status for patients < 16 years old and Karnofsky Performance Status for patients ≥ 16 years old. 
m Hematology includes WBC count, hemoglobin, platelet count, 3-cell differential count (absolute neutrophils, monocytes, and lymphocytes).  Starting 
with Cycle 8, these assessments should take place every other cycle (e.g., Cycles 8, 10, 12, etc.). 
n Laboratory tests should be performed ≤ 96 hours prior to Day 1 of each scheduled cycle.  Screening labs may be used for Cycle 1, Day 1 
hematology, chemistry, and urinalysis if drawn within two weeks of Cycle 1 Day 1. 
o Chemistry includes sodium, potassium, magnesium, chloride, bicarbonate, glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, 
calcium, total bilirubin (if abnormal, fractionate sample for direct and indirect), alkaline phosphatase, ALT, AST, LDH.  Starting with Cycle 8, these 
assessments should take place every other cycle (e.g., Cycles 8, 10, 12, etc.). 
p Urinalysis includes specific gravity, glucose, protein, and blood in patients > 3 years of age.  Starting with Cycle 4, urinalyses should take place 
every other cycle (e.g., Cycles 4, 6, 8, etc.).  Creatinine clearance should be done as clinically indicated.  If radioisotope glomerular filtration rate is 
routinely performed at the institution to measure patients’ creatinine clearance, this test can be used to assess renal function at screening, per the 
eligibility criteria.  Otherwise, serum creatinine is sufficient to document renal function at screening. 
q Amylase and lipase testing should be done at screening and then every two cycles (e.g., Cycles 2, 4, 6, etc.). 
r Thyroid function testing includes thyroid-stimulating hormone, free T3, and free T4.  Thyroid function testing should take place every two cycles 
(e.g., Cycles 2, 4, 6, etc.). 
s Includes hepatitis B surface antigen, hepatitis B surface antibody, total hepatitis B core antibody, hepatitis C antibody, HIV-1, and HIV-2 antibody.  If 
patient is positive for hepatitis B core antibody at screening, a test for hepatitis B virus DNA should be performed prior to Day 1 of Cycle 1.  If patient 
is positive for hepatitis C antibody at screening, a test for hepatitis C virus RNA should be performed prior to Day 1 of Cycle 1. 
t Blood samples will be obtained to characterize biomarkers, atezolizumab pharmacokinetics, and ATAs according to the schedule in Appendix 2. 
u Collect sample between 90 to 150 days after last dose of study drug. 
v The same imaging technique(s) and procedure(s) (CT, MRI, FDG-PET, and/or MIBG scan) used to assess disease sites at screening should be 
used throughout the study (e.g., the same contrast protocol for CT scans).  To the extent that is feasible, assessments should be performed by the 
same evaluator to ensure internal consistency across visits.  See Section 4.5.5 for detailed information on tumor and response evaluations. 
w Tumor assessments must be performed during the last week of Cycles 2, 4, 6, and 8 and every 4th cycle thereafter (i.e., within 7 days prior to Day 1 
of the next cycle).  At the investigator’s discretion, tumor assessments may be repeated at any time if progressive disease is suspected.  An 
objective response should be confirmed by repeat assessments ≥ 4 weeks after initial documentation.  Patients who discontinue study drug without 
progressive disease should continue follow up assessments, including tumor assessments, using the long-term follow up schedule (e.g., every 
three months for the first 2 years, every 6 months during year 3, etc.) until radiographic documentation of progressive disease, they start another 
treatment or consent is withdrawn.  Patients who continue to receive study drug beyond radiographic progressive disease should continue follow-up 
assessments until they stop taking study drug. 


Appendix 1  
Schedule of Assessments (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
122/Protocol GO29664, Version 5 
x Atezolizumab will be administered by IV infusion every 3 weeks.  Patients will be weighed at the beginning of each cycle, and the dose will be 
adjusted as needed. 
y Includes any medication (e.g., prescription drugs, over-the-counter drugs, herbal or homeopathic remedies, nutritional supplements) used by a 
patient from 7 days prior to screening to the study drug discontinuation visit. 
z Only required in children who have been vaccinated. 
aa Samples should be obtained prior to infusion of the first dose and will be held for possible testing in patients who develop immune-related or 
inflammatory adverse events during the study.  Auto-antibody testing to include at least anti-nuclear antibody, anti−double-stranded DNA, 
circulating anti-neutrophil cytoplasmic antibody, and perinuclear anti-neutrophil cytoplasmic antibody. 
bb Patients who are willing to participate must provide separate informed consent for collection of tumor tissue samples for the RCR.  Sample 
collection is not applicable if the site has not been granted approval for RCR sampling.  
cc Optional RCR tumor tissue samples will be collected prior to drug initiation, 4 weeks after the first dose of drug, and at the time of progressive 
disease or treatment discontinuation. 
dd Mandatory blood sample will be collected prior to drug initiation and is required as an experimental control ONLY if patients consent to optional 
tumor tissue samples. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
123/Protocol GO29664, Version 5 
Appendix 2  
Schedule of Pharmacokinetic, Pharmacodynamic, and 
Immunogenicity Assessments 
Visit 
Timepoint 
Sample Type 
Cycle 1, Day 1 
Prior to the infusion 
Serum for atezolizumab PK and ATA a
EDTA plasma and whole blood for PD 
 
30 (± 10) min after the 
end of the infusion 
Serum for atezolizumab PK 
Cycle 1, Day 8 
Any time during visit 
Serum for atezolizumab PK 
Cycle 2, Day 1 
Prior to the infusion b 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
Cycle 3, Day 1 
Prior to the infusion b 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
Prior to the infusion b 
Serum for atezolizumab PK and ATA a 
Cycle 4, Day 1 
30 (± 10) min after the 
end of the infusion 
Serum for atezolizumab PK 
Cycle 8, Day 1 
Prior to the infusion b 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
Cycle 12, Day 1 
Prior to the infusion b 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
Day 1 of Cycle 16 and 
every 8 cycles thereafter 
Prior to the infusion b 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
Study drug discontinuation 
visit 
Any time during visit 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
At least 90 days (but no 
more than 150 days) after 
last dose of study drug 
Any time during visit 
Serum for atezolizumab PK and ATA a
Plasma and whole blood for PD 
ATA = anti-therapeutic antibody; PD = pharmacodynamic; PK = pharmacokinetic. 
a Serum samples will be split into 2 × 500 μL serum aliquots, one for PK and one for ATA. 
b Blood draws can occur up to 2 days prior to infusion. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
124/Protocol GO29664, Version 5 
Appendix 3  
Modified International Neuroblastoma Response Criteria 
Below response assessment is modified from the original INRC publication in 1993. 
DEFINITION OF MEASURABLE (EVALUABLE) DISEASE ON CT/MRI SCAN 
The presence of at least one lesion that can be accurately measured in at least one 
dimension with the longest diameter at least 20 mm.  With a spiral CT scan, lesions must 
be at least 10 mm.  The investigator will identify up to 10 measurable target lesions to be 
followed for response.  Note that bone lesions will be considered as non-target lesions 
for evaluation of CT/MRI response since they will be evaluated with MIBG scans. 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be ≤ 5 mm).  At baseline and in follow-up, only the 
short axis will be measured and followed.  Serial measurements of lesions are to be 
done with CT or MRI.  The same method of assessment used to characterize each 
identified and reported lesion at baseline should be used during follow-up. 
RESPONSE CRITERIA FOR MEASURABLE DISEASE ON CT/MRI SCAN 
The sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the disease measurement.  The response of the CT/MRI lesions will be 
defined as outlined below: 
• 
Complete response (CR):  Disappearance of all target and non-target CT/MRI 
lesions 
• 
Very good partial response (VGPR):  Greater than 90% decrease of the disease 
measurement for CT/MRI lesions, taking as reference the disease measurement 
done to confirm measurable disease at study entry; non-target CT/MRI lesions 
stable to smaller in size 
• 
Partial response (PR):  At least a 30% decrease in the disease measurement for 
CT/MRI lesions, taking as reference the disease measurement done to confirm 
measurable disease at study entry; non-target CT/MRI lesions stable to smaller in 
size 
• 
Progressive disease (PD):  At least a 20% increase in the disease measurement, 
taking as reference the smallest disease measurement since the treatment started, 
or a new site of tumor; non-target CT/MRI lesions stable, smaller, or increased in 
size 
• 
Stable disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD taking as reference the smallest disease measurement 
since the treatment started; no new sites of disease 
 


Appendix 3  
International Neuroblastoma Response Criteria (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
125/Protocol GO29664, Version 5 
RESPONSE CRITERIA FOR MORPHOLOGIC BONE MARROW DISEASE 
Only those patients with morphologic evidence of neuroblastoma by routine H and E 
staining (NSE staining only is not evaluable) will be evaluable to assess bone marrow 
response. 
• 
CR:  No tumor cells detectable by routine morphology on two subsequent bilateral 
bone marrow aspirates and biopsies done at least three weeks apart after study 
entry. 
• 
PD:  Tumor seen on morphology on two consecutive bone marrows done at least 
3 weeks apart in patients who had no tumor in bone marrow at study entry 
Patient may be declared to have PD in bone marrow after only one diagnostic 
bone marrow at the discretion of the treating physician 
Patients who enter study with bone marrow tumor by morphology will be 
considered to have PD if there is a minimum of 25% tumor in the marrow by 
morphology and a doubling in the amount of tumor in the marrow compared 
with the level present at study entry.  For example, a patient entering with 5% 
tumor in marrow by morphology must increase to > 25% tumor to have PD; a 
patient entering with 30% tumor must increase to > 60% tumor. 
• 
SD:  Persistence of an amount of tumor in the bone marrow by morphology that 
does not meet criteria for either CR or PD 
Patients who clear morphologic tumor but have immunocytologic tumor will be 
called SD.  
 
RESPONSE CRITERIA FOR MIBG-POSITIVE LESIONS 
All patients with known MIBG-avid lesions will be evaluable for MIBG response following 
the first course of therapy.  The following criteria will be used to report MIBG response: 
• 
CR:  Complete resolution of all MIBG-positive lesions 
• 
PR:  Resolution of at least one MIBG-positive lesion, with persistence of other 
MIBG positive lesions 
• 
SD:  No change in MIBG scan in number of positive lesions (includes patients who 
have same number of positive lesions but decreased intensity) 
• 
PD:  Development of new MIBG-positive lesions  
 


Appendix 3  
International Neuroblastoma Response Criteria (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
126/Protocol GO29664, Version 5 
DEFINITION OF OVERALL RESPONSE FOR EACH PATIENT WITH 
NEUROBLASTOMA 
The International Neuroblastoma Response Criteria were developed to define responses 
in patients being treated with frontline therapy from diagnosis.1  These criteria were 
utilized as a basis for the following response criteria, which integrate response at all sites 
defined as measurable in this study, including CT/MRI lesions that meet RECIST criteria, 
MIBG-positive lesions, and bone marrow disease.  These criteria will be used to define 
the overall response for each patient.  
• 
CR:  Disappearance of all target lesions; no evidence of tumor at any site (chest, 
abdomen, liver, bone, bone marrow, nodes, etc.); homovanillic acid (HVA) and 
vanillylmandelic acid (VMA) normal 
• 
VGPR:  Greater than 90% decrease of the disease measurement for CT/MRI target 
lesions, taking as reference the disease measurement done to confirm measurable 
disease in target lesions at study entry; all preexisting bone lesions with CR by 
MIBG; MIBG scan can be  ± or CR in soft tissue lesions corresponding to lesions on 
CT/MRI; CR in bone marrow; no new sites of tumor; HVA/VMA normal 
• 
PR:  At least a 30% decrease in the disease measurement for CT/MRI target 
lesions, taking as reference the disease measurement done to confirm measurable 
disease in target lesions at study entry; bone marrow with CR; MIBG with either PR 
or CR in bone lesions; MIBG may be SD or CR in soft tissue lesions corresponding 
to lesions on CT/MRI; HVA/VMA may still be elevated.  
• 
PD:  Any one of the following: 
At least a 20% increase in the disease measurement for CT/MRI target lesions, 
taking as reference the smallest disease measurement recorded since the 
start of treatment 
Appearance of one or more new lesions or new sites of tumor 
PD as defined above for either bone marrow or MIBG lesions 
• 
SD:  Stable disease by either CT/MRI lesion, bone marrow, or MIBG criteria; no 
new lesions; no new sites of disease 
 
The overall response as assessed at any particular timepoint based on the various 
disease sites is summarized in the table below.  
                                            
 
1 Brodeur GM, Pritchard J, Berthold F, et al. Revisions of the international criteria for 
neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol 1993;11:1466−77. 


Appendix 3  
International Neuroblastoma Response Criteria (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
127/Protocol GO29664, Version 5 
Table 1 
Overall Response at Any Timepoint 
CT/MRI Lesions 
MIBG Lesions 
Bone Marrow 
Catechols 
Overall 
Response 
PD 
Any 
Any 
Any 
PD 
Any 
PD 
Any 
Any 
PD 
Any 
Any 
PD 
Any 
PD 
CR 
CR 
CR 
Normal 
CR 
VGPR 
CR in bone lesions ; May 
have SD/CR in soft tissue 
sites corresponding to lesions 
on CT/MRI 
CR 
Normal 
VGPR 
PR 
PR/CR in bone lesions; May 
have SD/CR in soft tissue 
sites corresponding to lesions 
on CT/MRI 
CR 
Any 
PR 
SD 
SD 
SD 
Any 
SD 
SD/PR/VGPR/CR 
SD 
SD/CR 
Any 
SD 
SD/PR/VGPR/CR 
SD/PR/CR 
SD 
Any 
SD 
CR = complete response; CT = computed tomography; MRI = magnetic resonance imaging; 
PD = progressive disease; PR = partial response; SD = stable disease; VGPR = very good partial 
response. 
 
 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
128/Protocol GO29664, Version 5 
Appendix 4  
Revised Response Criteria for Malignant Lymphoma 
SELECTION OF TARGET LESIONS 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
• 
Clearly measurable in at least two perpendicular dimensions 
All nodal lesions must measure: 
> 1.5 cm in greatest transverse diameter (GTD) regardless of short axis 
measurement, or 
> 1.0 cm in short axis regardless of the GTD measurement 
All extranodal lesions must measure ≥ 10 mm in the GTD and twice the 
reconstruction interval of the scan. 
Extranodal lesions within the liver or spleen must be at least 1.0 cm in 
two perpendicular dimensions 
• 
If possible, they should be from disparate regions of the body 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
 
Measurable extranodal disease should be assessed in a manner similar to that used 
for nodal disease. 
SELECTION OF NON-TARGET LESIONS 
Non-target lesions will be qualitatively assessed at each subsequent timepoint.  All of the 
sites of disease present at baseline and not classified as target lesions will be classified 
as non-target lesions, including any measurable lesions that were not chosen as target 
lesions.  Examples of non-target lesions include: 
• 
All bone lesions, irrespective of the modality used to assess them 
• 
Lymphangitis of the skin or lung 
• 
Cystic lesions 
• 
Splenomegaly and hepatomegaly 
• 
Irradiated lesions 
• 
Measurable lesions beyond the maximum number of six 
• 
Groups of lesions that are small and numerous 
• 
Pleural/pericardial effusions and/or ascites 
 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
129/Protocol GO29664, Version 5 
For this study, a significant increase in existing pleural effusions, ascites, or other fluid 
collections will be considered sufficient evidence of progression and will not require 
cytological proof of malignancy.  Effusions, ascites, or other fluid collections will be 
followed as non-target lesions. 
• 
Existing effusions/ascites:  Effusions, ascites, or other fluid collections will be 
followed as non-target lesions.  At each timepoint, radiologists will check for the 
presence or absence of effusions/ascites.  If there is a significant volume increase 
in the absence of a benign etiology, progression can be assessed. 
• 
New effusions/ascites:  Significant new effusions, ascites, or other fluid 
collections, which are radiographically suggestive of malignancy, should be 
recorded as new lesions. 
REPORTING CONVENTIONS 
UNABLE TO EVALUATE (UE) LESION CATEGORY 
This category is reserved for target and non-target lesions that are deemed unevaluable 
because 1) subsequent (post-baseline) examinations had not been performed, 2) lesions 
could not be evaluated because of poor radiographic technique or poorly defined margins, 
or 3) lesions identified at baseline were not at a subsequent timepoint. 
Examples of UE lesions are a lung lesion in the hilum obstructing the bronchus and 
causing atelectasis of the lobe or a hypodense liver lesion that becomes surrounded 
by fatty infiltration.  In both examples the boundaries of the lesion can be difficult to 
distinguish.  Every effort should be made to assign measurements to lesions that 
develop less distinct margins because they become much smaller.  Another example is 
the instance when lesions identified at baseline were not imaged at a subsequent 
timepoint.  Lesions that cannot be measured or evaluated will be classified for that 
timepoint as UE. 
If a target lesion is classified as UE post-baseline, the sum of the product of the 
diameters (SPD)/area (whichever applies) of the target lesions cannot accurately 
be determined for that timepoint, a response of complete response (CR), partial 
remission (PR), or stable disease (SD) cannot be assigned for that timepoint, and the 
response assessment will be UE unless unequivocal progression is determined on the 
basis of non-target or new lesions or the evaluable target lesions. 
Progressive disease (PD) can be determined without evaluation of all sites of disease 
based on the greatest transverse diameter (GTD), area or SPD for target lesions, 
evaluation of unequivocal progression in non-target lesions, or observation of a new 
lesion within the available radiographic or clinical assessments. 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
130/Protocol GO29664, Version 5 
TOO SMALL TO MEASURE (TSTM) LESION CATEGORY 
Any target lesion findings identified on baseline images, which at a subsequent timepoint 
decreases in size to < 5 mm in any dimension, should be categorized as TSTM.  The 
lesion, node, or mass should be assigned measurements of 5 × 5 mm (for the GTD and 
the short axis) on the source document for the purposes of calculating the area.  If that 
lesion increases in size to ≥ 5 mm in any dimension afterwards, its true size (GTD and 
short axis) should be recorded.  The purpose of the assigned value for the measurement 
is the acknowledgment that small findings are not accurately measured. 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
131/Protocol GO29664, Version 5 
Timepoint Response 
Target Lesions 
Non-Target Lesions 
New Lesions a 
Timepoint 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
CR 
UE 
No 
UE 
PR 
UE 
No 
UE 
PR 
CR 
No 
PR 
PR 
SD 
No 
PR 
SD 
UE 
No 
UE 
SD 
CR 
No 
SD 
SD 
SD 
No 
SD 
PD 
Any 
Yes/No 
PD 
Any 
PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
UE 
Non-PD 
No 
UE 
UE 
UE 
No 
UE 
CR 
NA c 
No 
CR 
PR 
NA c 
No 
PR 
SD 
NA c 
No 
SD 
NA b 
SD 
No 
SD 
NA b 
CR 
No 
CR 
NA b 
UE 
No 
UE 
NA b 
NA c 
No 
UE 
CR = complete response; NA = not applicable; PD = progressive disease; PR = partial 
response; SD = stable disease; UE = unable to evaluate. 
Note:  Modified from Cheson BD, Pfistner B, Juweid ME, et al. Revised response 
criteria for malignant lymphoma. J Clin Oncol 2007;25:579–86. 
a Identification of new lesions at a post-baseline time point will result in a response 
assessment of PD.  If an identified new lesion subsequently becomes UE, 
the timepoint response will be recorded as PD unless the new lesion has proven 
to have resolved. 
b No target lesions identified at baseline. 
c No non-target lesions identified at baseline. 
 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
132/Protocol GO29664, Version 5 
Response should be determined on the basis of radiographic and clinical evidence of 
disease.  For the end-of-treatment response assessment, an FDG-PET will be 
performed 6−8 weeks after the last study treatment.  Assessment of PET should follow 
the criteria described by Juweid et al. 2007, which is presented in the table Response 
Definitions for Clinical Trials. 
COMPLETE RESPONSE 
• 
Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy 
• 
Typically 18F-fleurodeoxyglucose (FDG)−avid lymphoma: in patients with no 
pre-treatment positron emission tomography (PET) scan or when the PET scan 
was positive before therapy, a post-treatment residual mass of any size is 
permitted as long as it is PET negative. 
• 
Variably FDG-avid lymphomas/FDG avidity unknown:  in patients without a 
pre-treatment PET scan, or if a pre-treatment PET scan was negative, all lymph 
nodes and nodal masses must have regressed on CT to normal size (≤ 1.5 cm in 
their greatest transverse diameter for nodes > 1.5 cm before therapy).  
Previously involved nodes that were 1.1 to 1.5 cm in their long axis and > 1.0 cm in 
their short axis before treatment must have decreased to ≤ 1.0 cm in their short axis 
after treatment. 
• 
The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear.  However, determination of splenic involvement is not 
always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma. 
• 
If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy.  The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core).  If 
the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry.  A sample that is negative by immunohistochemistry but that 
demonstrates a small population of clonal lymphocytes by flow cytometry will be 
considered a CR until data become available demonstrating a clear difference in 
patient outcome. 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
133/Protocol GO29664, Version 5 
PARTIAL RESPONSE 
• 
At least a 50% decrease in SPD of up to six of the largest dominant nodes or nodal 
masses.  These nodes or masses should be selected according to all of the 
following:  they should be clearly measurable in at least two perpendicular 
dimensions; if possible they should be from disparate regions of the body; and they 
should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved.  
• 
No increase should be observed in the size of other nodes, liver, or spleen.  
• 
Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for 
single nodules, in the GTD.  
• 
With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
• 
Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive before treatment.  However, if positive, the cell type should be specified (e.g., 
large-cell lymphoma or small neoplastic B cells).  Patients who achieve a CR by the 
above criteria but who have persistent morphologic bone marrow involvement will be 
considered partial responders.  If the bone marrow was involved before therapy and a 
clinical CR is achieved, but with no bone marrow assessment after treatment, patients 
should be considered partial responders.  
• 
No new sites of disease should be observed.  
• 
Typically FDG-avid lymphoma:  for patients with no pre-treatment PET scan or 
if the PET scan was positive before therapy, the post-treatment PET should be 
positive in at least one previously involved site.  
• 
Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a 
pre-treatment PET scan, or if a pre-treatment PET scan was negative, CT criteria 
should be used. 
 
In patients with follicular lymphoma or mantle-cell lymphoma, a PET scan is only 
indicated with one or at most two residual masses that have regressed by more 
than 50% on CT; those with more than two residual lesions are unlikely to be 
PET negative and should be considered partial responders. 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
134/Protocol GO29664, Version 5 
STABLE DISEASE 
• 
A patient is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR but does not fulfill those for progressive disease (PD) (see 
Relapsed Disease [after Complete Response] or Progressive Disease [after Partial 
Response or Stable Disease]). 
• 
Typically FDG-avid lymphomas:  the PET should be positive at prior sites of 
disease with no new areas of involvement on the post-treatment CT or PET.  
• 
Variably FDG-avid lymphomas/FDG-avidity unknown:  for patients without a 
pre-treatment PET scan or if the pre-treatment PET was negative, there must 
be no change in the size of the previous lesions on the post-treatment CT scan. 
 
RELAPSED DISEASE (AFTER COMPLETE RESPONSE) OR PROGRESSIVE 
DISEASE (AFTER PARTIAL RESPONSE OR STABLE DISEASE) 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm, 
regardless of the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should 
only be considered abnormal if its short axis is more than 1.0.  Lymph nodes ≤ 1.0 × ≤ 1.0 
cm will not be considered as abnormal for relapse or progressive disease. 
• 
Appearance of any new lesion > 1.5 cm in any axis during or at the end of therapy, 
even if other lesions are decreasing in size.  Increased FDG uptake in a previously 
unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities.  In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign.  Thus, a 
therapeutic decision should not be made solely on the basis of the PET without 
histologic confirmation.  
• 
At least a 50% increase from nadir in the SPD of any previously involved nodes, or 
in a single involved node, or the size of other lesions (e.g., splenic or 
hepatic nodules).  To be considered PD, a lymph node with a diameter of the short 
axis < 1.0 cm must increase by ≥ 50% and to a size of 1.5 × 1.5 cm or > 1.5 cm in 
the long axis.  
• 
At least a 50% increase in the longest diameter of any single previously identified 
node > 1 cm in its short axis.  
• 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be 
detected with current PET systems (< 1.5 cm in its long axis by CT). 
 
Measurable extranodal disease should be assessed in a manner similar to that for nodal 
disease.  For these recommendations, the spleen is considered nodal disease.  Disease 
that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as present 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
135/Protocol GO29664, Version 5 
or absent only, unless, while an abnormality is still noted by imaging studies or physical 
examination, it is found to be histologically negative. 
In clinical trials where PET is unavailable to the vast majority of participants, or where 
PET is not deemed necessary or appropriate for use (e.g., a study involving patients with 
mucosa-associated lymphoid tissue lymphoma), response should be assessed as above 
but only using CT scans.  However, residual masses should not be assigned unconfirmed 
complete response status but should be considered partial responses. 
 


Appendix 4  
Revised Response Criteria for Malignant Lymphoma (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
136/Protocol GO29664, Version 5 
Response Definitions for Clinical Trials (Revised International Working Group Criteria 2007) 
Response 
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
a) FDG-avid or PET positive prior to therapy; mass of 
any size permitted if PET negative 
b) Variably FDG-avid or PET negative; regression to 
normal size on CT 
No palpable, nodules; 
nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate on 
morphology and 
immunohistochemistry; 
bone marrow should be 
negative 
PR 
Regression 
of measurable 
disease and no 
new sites 
A ≥ 50% decrease in SPD of up to six largest 
dominant masses; no increase in size of other nodes 
a) FDG-avid or PET positive prior to therapy; one or 
more PET positive at previously involved site 
b) Variably FDG-avid or PET negative; regression on 
CT 
A ≥ 50% decrease in 
SPD of nodules 
(for single nodule in 
the greatest 
transverse diameter); 
no increase in size of 
liver or spleen 
Irrelevant if positive prior to 
therapy; cell type should be 
specified 
SD 
Failure to attain 
CR/PR or PD 
a) FDG-avid or PET positive prior to therapy; PET 
positive at prior sites of disease and no new sites on 
CT or PET 
b) Variably FDG-avid or PET negative; no change in 
size of previous lesions on CT 
 
 
Relapsed 
disease 
or PD 
Any new lesion or 
increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) > 1.5 cm in any axis, 
≥ 50% increase in SPD of more than one node, or 
≥ 50% increase in longest diameter of previously 
identified node > 1 cm in short axis 
Lesions PET positive if FDG-avid lymphoma or PET 
positive prior to therapy 
50% increase from 
nadir in the SPD of 
any previous lesions 
New or recurrent 
involvement 
CR = complete response; CT = computed tomography; FDG = 18F-fluorodeoxyglucose; PD = progressive disease; PET = positron-emission 
tomography; PR = partial response; SPD = sum of the product of the diameters. 
Excerpted from:  Juweid ME, Stroobants S, Hoekstra OS, et al. Use of positron emission tomography for response assessment of lymphoma: 
consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol 2007;25:571−8. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
137/Protocol GO29664, Version 5 
Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors 
Conventional response criteria may not be adequate to characterize the anti-tumor 
activity of immunotherapeutic agents like atezolizumab, which can produce delayed 
responses that may be preceded by initial apparent radiological progression, including 
the appearance of new lesions.  Therefore, modified response criteria have been 
developed that account for the possible appearance of new lesions and allow 
radiological progression to be confirmed at a subsequent assessment. 
Modified Response Evaluation Criteria in Solid Tumors (RECIST) is derived from 
RECIST, Version 1.1 (v1.1) conventions1 and immune-related response criteria2 (irRC).  
When not otherwise specified, RECIST v1.1 conventions will apply. 
Modified RECIST and RECIST v1.1:  Summary of Changes 
 
RECIST v1.1 
Modified RECIST 
New lesions after baseline 
Define progression 
New measurable lesions are 
added into the total tumor burden 
and followed. 
Non-target lesions 
May contribute to the 
designation of overall 
progression 
Contribute only in the assessment 
of a complete response 
Radiographic progression 
First instance of ≥ 20% 
increase in the sum of 
diameters or unequivocal 
progression in non-target 
disease 
Determined only on the basis of 
measurable disease 
RECIST = Response Evaluation Criteria in Solid Tumors. 
 
A. DEFINITIONS OF MEASURABLE/NON-MEASURABLE LESIONS 
All measurable and non-measurable lesions should be assessed at Screening and at the 
protocol-specified tumor assessment timepoints.  Additional assessments may be 
performed, as clinically indicated for suspicion of progression.   
                                            
 
1 Eisenhauer et al. Eur J Cancer 2009;45: 228−47; Topalian et al. N Engl J Med 
2012;366:2443−54; and Wolchok et al., Clin Can Res 2009;15:7412−20. 
2 Wolchok et al. Clin Can Res 2009;15:7412−20; Nishino et al. J Immunother Can 2014;2:17; 
Nishino et al. Clin Can Res 2013;19:3936−43. 


Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
138/Protocol GO29664, Version 5 
A.1  
MEASURABLE LESIONS 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size 
as follows: 
• 
10 mm by computed tomography (CT) or magnetic resonance imaging (MRI) scan 
(CT/MRI scan slice thickness/interval no greater than 5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, 
a lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and follow-up, 
only the short axis will be measured and followed. 
A.2  
NON-MEASURABLE LESIONS 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with short axis ≥ 10 but < 15 mm), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
mass/abdominal organomegaly identified by physical examination that is not measurable 
by reproducible imaging techniques. 
A.3  
SPECIAL CONSIDERATIONS REGARDING LESION 
MEASURABILITY 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone Lesions 
Bone scan, positron emission tomography (PET) scan, or plain films are not considered 
adequate imaging techniques for measuring bone lesions.  However, these techniques 
can be used to confirm the presence or disappearance of bone lesions. 
Lytic bone lesions or mixed lytic–blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above. 
Blastic bone lesions are non-measurable. 


Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
139/Protocol GO29664, Version 5 
Cystic Lesions 
Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor 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 patient, these are preferred for selection as 
target lesions. 
Lesions with Prior Local Treatment 
Tumor lesions situated in a previously irradiated area or in an area subjected to other 
loco-regional therapy are usually not considered measurable unless there has been 
demonstrated progression in the lesion.  Study protocols should detail the conditions 
under which such lesions would be considered measurable. 
B. TUMOR RESPONSE EVALUATION 
B.1 DEFINITIONS OF TARGET/NON-TARGET LESIONS 
Target Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means that, for instances in which patients have only one 
or two organ sites involved, a maximum of two lesions (one site) and four lesions 
(two sites), respectively, will be recorded.  Other lesions (albeit measurable) in those 
organs will be recorded as non-measurable lesions (even if the size is > 10 mm by 
CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs, but in addition, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance, the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures 
that may be visible by imaging even if not involved by tumor.  As noted above, 


Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
140/Protocol GO29664, Version 5 
pathological nodes that are defined as measurable and may be identified as target 
lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short 
axis of these nodes will contribute to the baseline sum.  The short axis of the node is the  
diameter normally used by radiologists to judge if a node is involved by solid tumor.  
Nodal size is normally reported as two dimensions in the plane in which the image is 
obtained (for CT, this is almost always the axial plane; for MRI, the plane of acquisition 
may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  For 
example, an abdominal node that is reported as being 20 mm × 30 mm has a short axis 
of 20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm 
should be recorded as the node measurement.  All other pathological nodes (those with 
short axis ≥ 10 mm but < 15 mm) should be considered non-target lesions.  Nodes that 
have a short axis of < 10 mm are considered non-pathological and should not be 
recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions. 
Non-Target Lesions 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required. 
It is possible to record multiple non-target lesions involving the same organ as a single 
item on the eCRF (e.g., “multiple enlarged pelvic lymph nodes” or “multiple liver 
metastases”). 
After baseline, changes in non-target lesions will contribute only in the assessment 
of complete response (i.e., a complete response is attained only with the complete 
disappearance of all tumor lesions, including non-target lesions) and will not be used 
to assess progressive disease. 
New Lesions 
During the study, all new lesions identified and recorded after baseline must be 
assessed at all tumor assessment timepoints.  New lesions will also be evaluated for 
measurability with use of the same criteria applied to prospective target lesions at 
baseline per RECIST, (e.g., non−lymph node lesions must be ≥ 10mm; see note for new 
lymph node lesions below).  Up to a maximum of five new lesions total (and a maximum 
of two lesions per organ), all with measurements at all timepoints, can be included in the 


Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
141/Protocol GO29664, Version 5 
tumor response evaluation.  New lesion types that would not qualify as target lesions per 
RECIST cannot be included in the tumor response evaluation. 
New lesions that are not measurable at first appearance but meet measurability criteria 
at a subsequent timepoint will be measured from that point on and contribute to the sum 
of longest diameters (SLD), if the maximum number of 5 measurable new lesions being 
followed has not been reached.  
B.2 CALCULATION OF SUM OF THE DIAMETERS 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated as a measure of tumor burden. 
The sum of the diameters is calculated at baseline and at each tumor assessment for 
the purpose of classification of tumor responses. 
Sum of the Diameters at Baseline:  The sum of the diameters for all target lesions 
identified at baseline prior to treatment on Day 1. 
Sum of the Diameters at Tumor Assessment:  For every on-study tumor assessment 
collected per protocol or as clinically indicated the sum of the diameters at tumor 
assessment will be calculated using tumor imaging scans.  All target lesions selected at 
baseline and up to five new measurable lesions (with a maximum of two new lesions per 
organ) that have emerged after baseline will contribute to the sum of the diameters at 
tumor assessment.  Hence, each net percentage change in tumor burden per 
assessment with use of modified RECIST accounts for the size and growth kinetics of 
both old and new lesions as they appear. 
Note:  In the case of new lymph nodes, RECIST v1.1 criteria for measurability 
(equivalent to baseline target lesion selection) will be followed.  That is, if at first 
appearance the short axis of a new lymph node lesion ≥ 15 mm, it will be considered a 
measureable new lesion and will be tracked and included in the SLD.  Thereafter, the 
lymph node lesion will be measured at subsequent timepoints and measurements will be 
included in the SLD, even if the short axis diameter decreases to < 15 mm (or even 
< 10 mm).  However, if it subsequently decreases to < 10 mm, and all other lesions are 
no longer detectable (or have also decreased to a short axis diameter of < 10 mm if 
lymph nodes), then a response assessment of CR may be assigned. 
If at first appearance the short axis of a new lymph node is ≥ 10 mm and < 15 mm, the 
lymph node will not be considered measurable but will still be considered a new lesion.  
It will not be included in the SLD unless it subsequently becomes measurable (short axis 
diameter ≥ 15 mm). 


Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
142/Protocol GO29664, Version 5 
The appearance of new lymph nodes with diameter < 10 mm should not be considered 
pathological and not considered a new lesion. 
B.3 RESPONSE CRITERIA 
Timepoint Response 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
Complete Response (CR):  Disappearance of all target and non-target lesions.  Lymph 
nodes that shrink to < 10 mm short axis are considered normal. 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of all 
target and all new measurable lesions, taking as reference the baseline sum of 
diameters, in the absence of CR. 
Note: the appearance of new measurable lesions is factored into the overall tumor 
burden, but does not automatically qualify as progressive disease until the sum of the 
diameters increases by ≥ 20% when compared with the sum of the diameters at nadir. 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum of the diameters while 
on study. 
Progressive Disease (PD):  At least a 20% increase in the sum of diameters of all 
target and selected new measurable lesions, taking as reference the smallest sum on 
study (nadir SLD; this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. 
Impact of New Lesions on Modified RECIST 
New lesions alone do not qualify as progressive disease.  However, their contribution to 
total tumor burden is included in the sum of the diameters, which is used to determine 
the overall modified RECIST tumor response. 


Appendix 5  
Modified Response Evaluation Criteria in Solid Tumors (cont.) 
Atezolizumab—F. Hoffmann-La Roche Ltd 
143/Protocol GO29664, Version 5 
Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is 
considered not evaluable (NE) at that timepoint.  If only a subset of lesion 
measurements are made at an assessment, usually the case is also considered NE at 
that timepoint, unless a convincing argument can be made that the contribution of the 
individual missing lesion(s) would not change the assigned timepoint response.  This 
would only happen in the case of PD.  For example, if a patient had a baseline sum of 50 
mm with three measured lesions and at follow-up only two lesions were assessed but 
those gave a sum of 80 mm, the patient will be assigned PD status, regardless of the 
contribution of the missing lesion. 
Table 1  Modified RECIST Timepoint Response Definitions 
% Change in Sum of the Diameters a 
Non-Target Lesion 
Response 
Assessment 
Overall Modified RECIST 
Timepoint Response 
− 100% from baseline b 
CR 
CR 
− 100% from baseline b 
Non-CR or not all 
evaluated 
PR 
≤  − 30% from baseline 
Any 
PR 
>  − 30% to < + 20% 
Any 
SD 
Not all evaluated 
Any 
NE 
≥  + 20%from nadir SLD 
Any 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; 
RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; 
SLD = sum of the longest diameter. 
a Percent change in sum of the diameters (including measurable new lesions when 
present). 
b When lymph nodes are included as target lesions, the % change in the sum of the 
diameters may not be 100% even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm in order to meet 
the definition of CR. 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
144/Protocol GO29664, Version 5 
Appendix 6  
Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication 
Selected sections from the Response Evaluation Criteria in Solid Tumors (RECIST), 
Version 1.11 are presented below, with slight modifications and the addition of 
explanatory text as needed for clarity.2 
MEASURABILITY OF TUMOR AT BASELINE 
DEFINITIONS 
At baseline, tumor lesions/lymph nodes will be categorized measurable or 
non-measurable as follows. 
a. Measurable Tumor Lesions 
Tumor Lesions.  Tumor lesions must be accurately measured in at least one dimension 
(longest diameter in the plane of measurement is to be recorded) with a minimum size of: 
• 
10 mm by CT or MRI scan (CT/MRI scan slice thickness/interval no greater 
than 5 mm) 
• 
10-mm caliper measurement by clinical examination (lesions that cannot be 
accurately measured with calipers should be recorded as non-measurable) 
• 
20 mm by chest X-ray 
 
Malignant Lymph Nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, 
only the short axis will be measured and followed.  See also notes below on “Baseline 
Documentation of Target and Non-Target Lesions” for information on lymph node 
measurement. 
b. Non-Measurable Tumor Lesions 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or 
pathological lymph nodes with ≥ 10 to < 15 mm short axis), as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast 
disease, lymphangitic involvement of skin or lung, peritoneal spread, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques. 
                                            
 
1 Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
Revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228−47. 
2 For consistency within this document, the section numbers and cross-references to other 
sections within the article have been deleted and minor formatting changes have been made. 


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c. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require 
particular comment, as outlined below. 
Bone lesions: 
• 
Bone scan, positron emission tomography (PET) scan, or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, 
these techniques can be used to confirm the presence or disappearance of 
bone lesions. 
• 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such 
as CT or MRI can be considered measurable lesions if the soft tissue component 
meets the definition of measurability described above. 
• 
Blastic bone lesions are non-measurable. 
 
Cystic lesions: 
• 
Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
• 
Cystic lesions thought to represent cystic metastases can be considered 
measurable lesions if they meet the definition of measurability described above.  
However, if non-cystic lesions are present in the same patient, these are preferred 
for selection as target lesions. 
 
Lesions with prior local treatment: 
• 
Tumor lesions situated in a previously irradiated area or in an area subjected to 
other loco-regional therapy are usually not considered measurable unless there 
has been demonstrated progression in the lesion.  Study protocols should detail 
the conditions under which such lesions would be considered measurable. 
 
TARGET LESIONS:  SPECIFICATIONS BY METHODS OF MEASUREMENTS 
a. Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as close as possible to the 
treatment start and never more than 4 weeks before the beginning of the treatment. 


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b. Method of Assessment 
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during study.  
Imaging-based evaluation should always be the preferred option. 
Clinical Lesions.  Clinical lesions will be considered measurable only when they are 
superficial and ≥ 10 mm in diameter as assessed using calipers (e.g., skin nodules).  
For the case of skin lesions, documentation by color photography, including a ruler to 
estimate the size of the lesion is suggested. 
Chest X-Ray.  Chest CT is preferred over chest X-ray, particularly when progression is 
an important endpoint, since CT is more sensitive than X-ray, particularly in identifying 
new lesions.  However, lesions on chest X-ray may be considered measurable if they 
are clearly defined and surrounded by aerated lung. 
CT, MRI.  CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions 
on CT scan on the basis of the assumption that CT slice thickness is 5 mm or less.  
When CT scans have slice thickness greater than 5 mm, the minimum size for a 
measurable lesion should be twice the slice thickness.  MRI is also acceptable. 
If prior to enrollment it is known that a patient is unable to undergo CT scans with 
intravenous (IV) contrast because of allergy or renal insufficiency, the decision as to 
whether a non-contrast CT or MRI (without IV contrast) will be used to evaluate the 
patient at baseline and during the study should be guided by the tumor type under 
investigation and the anatomic location of the disease.  For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to 
whether non-contrast CT or MRI (enhanced or non-enhanced) will be performed should 
also be based on the tumor type and the anatomic location of the disease and should be 
optimized to allow for comparison with the prior studies if possible.  Each case should be 
discussed with the radiologist to determine if substitution of these other approaches is 
possible and, if not, the patient should be considered not evaluable from that point 
forward.  Care must be taken in measurement of target lesions on a different modality 
and interpretation of non-target disease or new lesions since the same lesion may 
appear to have a different size using a new modality. 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be 
used as a method of measurement. 


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Modified Excerpt from Original Publication (cont.) 
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Endoscopy, Laparoscopy, Tumor Markers, Cytology, Histology.  The utilization 
of these techniques for objective tumor evaluation cannot generally be advised. 
TUMOR RESPONSE EVALUATION 
ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the 
overall tumor burden at baseline and to use this as a comparator for subsequent 
measurements.  Measurable disease is defined by the presence of at least 
one measurable lesion, as detailed above. 
BASELINE DOCUMENTATION OF TARGET AND NON-TARGET LESIONS 
When more than one measurable lesion is present at baseline, all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative 
of all involved organs should be identified as target lesions and will be recorded and 
measured at baseline.  This means in instances where patients have only one or two 
organ sites involved, a maximum of two lesions (one site) and four lesions (two sites), 
respectively, will be recorded.  Other lesions (albeit measurable) in those organs will 
be recorded as non-measurable lesions (even if the size is > 10 mm by CT scan). 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and be representative of all involved organs but, additionally, should lend 
themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement, in which 
circumstance the next largest lesion that can be measured reproducibly should be 
selected. 
Lymph nodes merit special mention since they are normal anatomical structures that 
may be visible by imaging even if not involved by tumor.  As noted above, pathological 
nodes that are defined as measurable and may be identified as target lesions must meet 
the criterion of a short axis of ≥ 15 mm by CT scan.  Only the short axis of these nodes 
will contribute to the baseline sum.  The short axis of the node is the diameter normally 
used by radiologists to judge if a node is involved by solid tumor.  Nodal size is normally 
reported as two dimensions in the plane in which the image is obtained (for CT scan, this 
is almost always the axial plane; for MRI the plane of acquisition may be axial, sagittal, 
or coronal).  The smaller of these measures is the short axis.  For example, an 
abdominal node that is reported as being 20 mm × 30 mm has a short axis of 20 mm and 
qualifies as a malignant, measurable node.  In this example, 20 mm should be recorded 
as the node measurement.  All other pathological nodes (those with short axis ≥ 10 mm 


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but < 15 mm) should be considered non-target lesions.  Nodes that have a short axis 
< 10 mm are considered non-pathological and should not be recorded or followed. 
Lesions irradiated within 3 weeks prior to Cycle 1 Day 1 may not be counted as target 
lesions. 
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.  If lymph 
nodes are to be included in the sum, then, as noted above, only the short axis is added 
into the sum.  The baseline sum of diameters will be used as a reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease), including pathological lymph nodes, should be 
identified as non-target lesions and should also be recorded at baseline.  Measurements 
are not required and these lesions should be followed as “present,” “absent,” or in rare 
cases “unequivocal progression.” 
In addition, it is possible to record multiple non-target lesions involving the same organ 
as a single item on the eCRF (e.g., “multiple enlarged pelvic lymph nodes” or “multiple 
liver metastases”). 
RESPONSE CRITERIA 
a. Evaluation of Target Lesions 
This section provides the definitions of the criteria used to determine objective tumor 
response for target lesions. 
• 
Complete response (CR):  disappearance of all target lesions 
Any pathological lymph nodes (whether target or non-target) must have 
reduction in short axis to < 10 mm. 
• 
Partial response (PR):  at least a 30% decrease in the sum of diameters of target 
lesions, taking as reference the baseline sum of diameters 
• 
Progressive disease (PD):  at least a 20% increase in the sum of diameters 
of target lesions, taking as reference the smallest sum on study (nadir), 
including baseline 
In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
The appearance of one or more new lesions is also considered progression. 
• 
Stable disease (SD):  neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum on study 


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b. Special Notes on the Assessment of Target Lesions 
Lymph Nodes.  Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded (measured in the same anatomical plane as the 
baseline examination), even if the nodes regress to < 10 mm on study.  This means that 
when lymph nodes are included as target lesions, the sum of lesions may not be zero 
even if CR criteria are met since a normal lymph node is defined as having a short axis 
< 10 mm. 
Target Lesions That Become Too Small to Measure.  While on study, all lesions 
(nodal and non-nodal) recorded at baseline should have their actual measurements 
recorded at each subsequent evaluation, even when very small (e.g., 2 mm).  However, 
sometimes lesions or lymph nodes that are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an 
exact measure and may report them as being too small to measure.  When this occurs, it 
is important that a value be recorded on the eCRF as follows: 
• 
If it is the opinion of the radiologist that the lesion has likely disappeared, 
the measurement should be recorded as 0 mm. 
• 
If the lesion is believed to be present and is faintly seen but too small to measure, a 
default value of 5 mm should be assigned and BML (below measurable limit) 
should be ticked.  (Note:  It is less likely that this rule will be used for lymph nodes 
since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value 
of 5 mm should be assigned in this circumstance as well and BML should also be 
ticked.) 
 
To reiterate, however, if the radiologist is able to provide an actual measure, that should 
be recorded, even if it is below 5 mm, and, in that case, BML should not be ticked. 
Lesions That Split or Coalesce on Treatment.  When non-nodal lesions fragment, the 
longest diameters of the fragmented portions should be added together to calculate the 
target lesion sum.  Similarly, as lesions coalesce, a plane between them may be 
maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion.  If the lesions have truly coalesced such that they are no longer 
separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the coalesced lesion. 


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c. Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response 
for the group of non-target lesions.  Although some non-target lesions may actually be 
measurable, they need not be measured and, instead, should be assessed only 
qualitatively at the timepoints specified in the protocol. 
• 
CR:  disappearance of all non-target lesions and (if applicable) normalization of 
tumor marker level) 
All lymph nodes must be non-pathological in size (< 10 mm short axis). 
• 
Non-CR/Non-PD:  persistence of one or more non-target lesion(s) and/or 
(if applicable) maintenance of tumor marker level above the normal limits 
• 
PD:  unequivocal progression of existing non-target lesions 
The appearance of one or more new lesions is also considered progression. 
 
d. Special Notes on Assessment of Progression of Non-Target Disease 
When the Patient Also Has Measurable Disease.  In this setting, to achieve 
unequivocal progression on the basis of the non-target disease, there must be an overall 
level of substantial worsening in non-target disease in a magnitude that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased 
sufficiently to merit discontinuation of therapy.  A modest increase in the size of one or 
more non-target lesions is usually not sufficient to qualify for unequivocal progression 
status.  The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
When the Patient Has Only Non-Measurable Disease.  This circumstance arises in 
some Phase III trials when it is not a criterion of study entry to have measurable disease.  
The same general concepts apply here as noted above; however, in this instance, there 
is no measurable disease assessment to factor into the interpretation of an increase in 
non-measurable disease burden.  Because worsening in non-target disease cannot be 
easily quantified (by definition:  if all lesions are truly non-measurable), a useful test that 
can be applied when assessing patients for unequivocal progression is to consider if the 
increase in overall disease burden based on the change in non-measurable disease is 
comparable in magnitude to the increase that would be required to declare PD for 
measurable disease; that is, an increase in tumor burden representing an additional 
73% increase in volume (which is equivalent to a 20% increase in diameter in a 
measurable lesion).  Examples include an increase in a pleural effusion from “trace” to 
“large” or an increase in lymphangitic disease from localized to widespread or may be 
described in protocols as “sufficient to require a change in therapy.”  If unequivocal 


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Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
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progression is seen, the patient should be considered to have had overall PD at that 
point.  Although it would be ideal to have objective criteria to apply to non-measurable 
disease, the very nature of that disease makes it impossible to do so; therefore, the 
increase must be substantial. 
e. New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for 
the identification of new radiographic lesions; however, the finding of a new lesion 
should be unequivocal, that is, not attributable to differences in scanning technique, 
change in imaging modality, or findings thought to represent something other than tumor 
(for example, some “new” bone lesions may be simply healing or flare of preexisting 
lesions).  This is particularly important when the patient’s baseline lesions show PR or 
CR.  For example, necrosis of a liver lesion may be reported on a CT scan report as a 
“new” cystic lesion, which it is not. 
A lesion identified during the study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of 
the initial scan. 
EVALUATION OF RESPONSE 
a. Timepoint Response (Overall Response) 
It is assumed that at each protocol-specified timepoint, a response assessment occurs.  
Table 1 provides a summary of the overall response status calculation at each timepoint 
for patients who have measurable disease at baseline. 
When patients have non-measurable (therefore, non-target) disease only, Table 2 is to 
be used. 


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Modified Excerpt from Original Publication (cont.) 
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Table 1  Timepoint Response:  Patients with Target Lesions 
(with or without Non-Target Lesions) 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not 
all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or no 
PD 
Any 
PD 
Yes or no 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; 
PR = partial response; SD = stable disease. 
 
Table 2  Timepoint Response:  Patients with Non-Target 
Lesions Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD a 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or no 
PD 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease. 
a “Non-CR/non-PD” is preferred over “stable disease” for non-target 
disease since stable disease is increasingly used as an endpoint for 
assessment of efficacy in some studies; thus, assigning “stable disease” 
when no lesions can be measured is not advised. 
 
b. Missing Assessments and Not-Evaluable Designation 
When no imaging/measurement is done at all at a particular timepoint, the patient is not 
evaluable at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered not evaluable at that timepoint, unless a 


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Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
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convincing argument can be made that the contribution of the individual missing lesion(s) 
would not change the assigned timepoint response.  This would be most likely to happen  
in the case of PD.  For example, if a patient had a baseline sum of 50 mm with three 
measured lesions and, during the study, only two lesions were assessed, but those gave 
a sum of 80 mm; the patient will have achieved PD status, regardless of the contribution 
of the missing lesion. 
If one or more target lesions were not assessed either because the scan was not done 
or the scan could not be assessed because of poor image quality or obstructed view, the 
response for target lesions should be “unable to assess” since the patient is not 
evaluable.  Similarly, if one or more non-target lesions are not assessed, the response 
for non-target lesions should be “unable to assess” except where there is clear 
progression.  Overall response would be “unable to assess” if either the target response 
or the non-target response is “unable to assess,” except where this is clear evidence of 
progression as this equates with the case being not evaluable at that timepoint. 
 


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


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Response Evaluation Criteria in Solid Tumors:  
Modified Excerpt from Original Publication (cont.) 
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progression even after discontinuation of treatment.  Symptomatic deterioration is not a 
descriptor of an objective response; it is a reason for stopping study therapy.  The 
objective response status of such patients is to be determined by evaluation of target 
and non-target disease as shown in Tables 1−3. 
For equivocal findings of progression (e.g., very small and uncertain new lesions; cystic 
changes or necrosis in existing lesions), treatment may continue until the next scheduled 
assessment.  If at the next scheduled assessment progression is confirmed, the date of 
progression should be the earlier date when progression was suspected. 
If a patient undergoes an excisional biopsy or other appropriate approach (e.g., multiple 
passes with large core needle) of a new lesion or an existing solitary progressive lesion 
that following serial sectioning and pathological examination reveals no evidence of 
malignancy (e.g., inflammatory cells, fibrosis, etc.), then the new lesion or solitary 
progressive lesion will not constitute disease progression. 
In studies for which patients with advanced disease are eligible (i.e., primary disease still 
or partially present), the primary tumor should also be captured as a target or non target 
lesion, as appropriate.  This is to avoid an incorrect assessment of CR if the primary 
tumor is still present but not evaluated as a target or non-target lesion. 
 


 
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Appendix 7  
Immune-Related Response Criteria 
INTRODUCTION 
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors [RECIST] and World Health Organization [WHO]) 
may not be sufficient to characterize fully activity in the new era of target therapies 
and/or biologics.  In studies with cytokines, cancer vaccines, and monoclonal antibodies, 
complete response, partial response, or stable disease has been shown to occur after 
an increase in tumor burden as characterized by progressive disease by traditional 
response criteria.  Therefore, conventional response criteria may not adequately assess 
the activity of immunotherapeutic agents because progressive disease (by initial 
radiographic evaluation) does not necessarily reflect therapeutic failure.  Long-term 
effect on the target disease must also be captured.  The immune-related response 
criteria1 (irRC) are criteria that attempt to do that by enhancing characterization of new 
response patterns that have been observed with immunotherapeutic agents 
(i.e., ipilimumab).  (Note:  The irRC only index and measurable new lesions are taken 
into account.) 
GLOSSARY 
Term 
Definition 
SPD 
Sum of the products of the two largest perpendicular diameters 
Tumor burden 
SPDindex lesions + SPDnew, measurable lesions 
Nadir 
Minimally recorded tumor burden 
irCR 
Immune-related complete response 
irPR 
Immune-related partial response 
irSD 
Immune-related stable disease 
irPD 
Immune-related progressive disease 
irBOR 
Immune-related best overall response 
 
BASELINE ASSESSMENT USING irRC 
Step 1.  Identify the index lesions (five lesions per organ, up to ten visceral lesions and 
five cutaneous lesions). 
                                            
 
1 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in 
solid tumors: immune-related response criteria. Clin Can Res 2009;15:7412−20. 


 
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Appendix 7  
Immune-Related Response Criteria (cont.) 
Step 2.  Calculate the SPD of all of these index lesions: 
SPD = ∑
i
(Largest diameter of lesion i) × (Second largest diameter of lesion i). 
POST-BASELINE ASSESSMENTS USING irRC 
Step 1. Calculate the SPD of the index lesions. 
Step 2. Identify new, measurable lesions (≥ 5 × 5 mm; up to five new lesions per organ:  
five new cutaneous lesions and ten visceral lesions).   
Step 3. Calculate the SPD of the new, measurable lesions. 
Step 4. Calculate the tumor burden: 
 
 
Tumor burden =  SPDindex lesions + SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change 
in tumor burden relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall 
Response 
Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmed by a repeat, consecutive assessment ≥ 4 weeks from the date 
first documented 
irPR 
Decrease in tumor burden ≥ 50% relative to baseline confirmed by a consecutive 
assessment ≥ 4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require confirmation 
irPD 
Increase in tumor burden ≥ 25% relative to nadir confirmed by a consecutive 
assessment ≥ 4 weeks from the date first documented 
irCR = immune-related complete response; irPD = immune-related progressive disease;  
irPR = immune-related partial response; irSD = immune-related stable disease. 
 


 
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Appendix 7  
Immune-Related Response Criteria (cont.)  
DETERMINATION OF irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related progressive disease; irPR = immune-related partial response;  
irSD = immune-related stable disease. 
 


 
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Appendix 8  
Lansky Performance Status Scale 
Score 
Description 
100 
Fully active; normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with 
quieter activities 
50 
Gets dressed, but lies around much of the day; no active play; 
able to participate in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 


 
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Appendix 9  
Karnofsky Performance Status Scale 
Score 
Description 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity; minor signs or symptoms of disease 
80 
Normal activity with effort; some signs or symptoms of disease 
70 
Cares for self; unable to carry on normal activity or do active work 
60 
Requires occasional assistance, but is able to care for most of his/her needs 
50 
Requires considerable assistance and frequent medical care 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated; death not imminent 
20 
Very sick; hospitalization indicated; death not imminent 
10 
Moribund; fatal processes progressing rapidly 
 


 
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Appendix 10  
Recommended Anaphylaxis Management 
The following equipment is needed in the event of a suspected anaphylactic 
reaction during study drug infusion.  All equipment and medication must be in the 
appropriate sizes and doses for the pediatric patients being treated. 
• 
Appropriate monitors (electrocardiogram, blood pressure, pulse oximetry) 
• 
Oxygen and masks for oxygen delivery  
• 
Airway management devices per standard of care 
• 
Epinephrine for intravenous, intramuscular, and/or endotracheal administration 
in accordance with institutional guidelines 
• 
Antihistamines (oral/IV H1 and H2 antagonists) 
• 
Corticosteroids (IV) 
• 
Albuterol (Salbutamol or equivalent) for bronchospasm 
• 
Intravenous infusion solutions, tubing, catheters, and tape 
 
The following are the procedures to follow in the event of a suspected 
anaphylactic reaction during study drug infusion: 
• 
Stop the study drug infusion. 
• 
Call for additional assistance! 
• 
Maintain an adequate airway. 
• 
Provide oxygen. 
• 
Ensure IV access × 2 if possible. 
• 
Ensure that appropriate monitoring is in place, with continuous electrocardiogram 
and pulse oximetry monitoring, if possible. 
• 
Administer epinephrine (1:1000, 0.01 mg/kg intramuscularly [IM]) into lateral thigh, 
or via route and dose as directed by physician-in-charge).  May repeat every 5−15 
minutes. 
• 
Administer antihistamines and other medications as required by patient status and 
directed by the physician in charge. 
• 
Continue to observe the patient and document observations until the patient is 
transferred to higher-level care. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
162/Protocol GO29664, Version 5 
Appendix 11  
Response Assessment in Neuro-Oncology Criteria 
Response 
Criteria 
Complete 
response 
Requires all of the following: 
• Complete disappearance of all enhancing measurable and non-measurable 
disease sustained for at least 4 weeks 
• No new lesions  
• Stable or improved non-enhancing (T2/FLAIR) lesions 
• Patients must be off corticosteroids (or on physiological replacement doses 
only) 
• Clinical status is stable or improved 
Partial 
response 
Requires all of the following: 
• ≥ 50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks 
• No progression of non-measurable T1 enhancing disease 
• No new lesions 
• Stable or improved non-enhancing (T2/FLAIR) lesions on the same or lower 
dose of corticosteroids compared to baseline 
• Clinical status is stable or improved 
Note:  Patients with non-measurable disease only cannot have a partial 
response; the best response possible is stable disease 
Stable 
disease 
Requires all of the following: 
• Patient does not qualify for complete response, partial response, or 
progression 
• Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline  
• Clinical status is stable or improved 
Note:  In the event that the corticosteroid dose was increased for new symptoms 
and signs without confirmation of disease progression on neuroimaging, and 
subsequent follow-up imaging shows that this increase in corticosteroids was 
required because of disease progression, the last scan considered to show stable 
disease will be the scan obtained when the corticosteroid dose was equivalent to 
the baseline dose. 
FLAIR = fluid-attenuated inversion recovery. 
Note:  Adapted from Wen PY, Macdonald DR, Reardon DA, et al. Updated response 
assessment criteria for high-grade gliomas: response assessment in neuro-oncology working 
group. J Clin Oncol 2012;28:1963−72. 
 


 
Atezolizumab—F. Hoffmann-La Roche Ltd 
163/Protocol GO29664, Version 5 
Appendix 11  
Response Assessment in Neuro-Oncology Criteria (cont.)  
Response  
Criteria 
Progression 
Defined by any of the following: 
• ≥ 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions compared with the smallest tumor measurement obtained 
either at baseline (of no decrease) or best response, on a stable or increasing 
dose of corticosteroids 
• Significant increase in T2/FLAIR non-enhancing lesions while taking stable 
or increasing doses of steroids compared with baseline scan or best response 
after initiation of therapy, not caused by comorbid events (e.g., radiation 
therapy, demyelination, ischemic injury, seizures, postoperative changes, or 
other treatment effects) 
• Presence of any new lesions 
• Clear clinical deterioration not attributable to other causes apart from the 
tumor (e.g., seizures, medication adverse effects, complications of therapy, 
cerebrovascular events, infection, and so on) or decreases in corticosteroid 
dose 
• Failure to return for evaluation due to death or deteriorating condition 
• Clear progression of nonmeasurable disease 
FLAIR = fluid-attenuated inversion recovery. 
Note:  Adapted from Wen PY, Macdonald DR, Reardon DA, et al. Updated response 
assessment criteria for high-grade gliomas: response assessment in neuro-oncology working 
group. J Clin Oncol 2012;28:1963−72.