Conditions: Lymphoma
Keywords: Advanced Stage Follicular Lymphoma Relapsed Refractory Atezolizumab Dose Local Radiotherapy (2 x 2Gy) 17-360
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the safety and effects of atezolizumab with low dose radiation on people with relapsed or refractory follicular lymphoma, In this study, the patient will get either atezolizumab with low dose radiation or, atezolizumab alone. To be better, the atezolizumab and low dose radiation should increase life by 1 year or more compared to the usual approach.

Detailed description:

Arms:
arm 1: All patients will receive open-label atezolizumab 1200mg IV on day 1 of a 21-day cycle for a planned total of 17 cycles of therapy (1 year). arm 2: All patients will receive open-label atezolizumab 1200mg IV on day 1 of a 21-day cycle for a planned total of 17 cycles of therapy (1 year). 4Gy will be administered in 2 fractions to a single nodal site amenable to radiation as identified by the radiation oncologist on day 2 and day 3 of Cycle 1 (over the two days following to the first dose of atezolizumab ).

Interventions: intervention 1: atezolizumab intervention 2: Low- Dose, Local Radiotherapy
Intervention descriptions: intervention 1: 1200mg IV on day 1 of a 21-day cycle for a planned total of 17 cycles of therapy (1 year). intervention 2: 4Gy will be administered in 2 fractions to a single nodal site amenable to radiation as identified by the radiation oncologist on day 2 and day 3 of Cycle 1 (over the two days following to the first dose of atezolizumab ).

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  1 of 115
 
 
 
 
 
 
TWO-ARM PARALLEL PHASE 2 CLINICAL TRIAL OF ATEZOLIZUMAB 
WITH/WITHOUT LOW DOSE, LOCAL RADIOTHERAPY (2 X 2GY) IN PATIENTS WITH 
RELAPSED/REFRACTORY ADVANCED STAGE FOLLICULAR LYMPHOMA 
PROTOCOL FACE PAGE FOR 
MSK THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator/Department: M. Lia Palomba, MD 
Medicine/Lymphoma 
Co-Principal 
Investigator(s)/Department: 
Andrew Zelenetz, MD, PhD 
Joachim Yahalom, MD 
Medicine/Lymphoma 
Radiation Oncology 
Investigator(s)/Department: 
Batlevi, Connie, MD, PhD 
Hamlin, Paul, MD 
Horwitz, Steven, MD 
Joffe, Erel, MD 
Kumar, Anita, MD 
Matasar, Matthew, MD 
Moskowitz, Alison, MD 
Noy, Ariela, MD 
Straus, David, MD 
Younes, Anas, MD 
Rodriguez-Rivera, Ildefonso, MD 
Von Keudell, Gottfried, MD 
Gorsky, Mila, MD 
Hamilton, Audrey, MD 
Korde, Neha, MD 
Ligresti, Louise, MD 
Owens, Colette, MD 
Danila, Daniel, MD 
Mauro, Michael, MD 
Gu, Ping, MD 
Mauro, Michael, MD 
Preeshagul, Isabel, MD 
Wang, Rui, MD 
Aghalar, Jahan, MD 
Desai, Avni, MD 
Lahoud, Oscar, MD 
Mailankody, Sham, MBBS 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Regional Networks 
Medicine/Regional Networks 
Medicine/Regional Networks 
MedicineRegional Networks 
MedicineRegional Networks 
Medicine/Genitourinary Onc 
Medicine/Leukemia 
Medicine/Genitourinary Onc 
Medicine/Leukemia 
Medicine/Thoracic Onc 
Medicine 
Medicine/Genitourinary Onc 
Medicine/Gastrointestinal Onc 
Medicine/Marrow Transplant 
Medicine/Cellular Therapeutics 
Center (CTC) 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  2 of 115
 
 
 
 
 
Korde, Neha, MD 
Klimek, Virginia, MD 
Konner, Jason, MD 
 
 
 
Namakydoust, Azadeh, MD 
Shcherba, Marina, DO 
 
Apollo, Arlyn, MD 
Goldberg, Zoe, MD 
Ng, Kenneth, MD 
Troso-Sandoval, Tiffany, MD 
Caron, Philip, MD, PhD 
Hassoun, Hani, MD 
Momtaz, Parisa, MD 
 
 
 
Bilger, Ashley, PA 
Davey, Theresa, PA 
Duggan, Tara, NP 
Hancock, Helen, NP 
Rose, Georgia, NP 
Schreiber, Jillian, PA 
Ames, Ashley, NP 
Devin, Callan, RN 
Carter, Jason, PA 
Depaola, Nadia, PA 
McCall, Susan, NP 
Schreiber, Jillian, PA 
Palumbo, Teresa, PA 
 
Dogan, Ahmet, MD, PhD 
Getrajdman, George, MD 
 
Girshman, Jeffrey, MD 
Peled, Jonathan, MD 
Grewal, Ravinder, MD 
 
Byrne, Regina, NP 
Matthews, Leslie, NP 
O'Connor, Katherine, NP 
Wisniewski, Michelle, PA 
Pierre, Amy, NP 
Arnell, Geri, RN 
Cogswell, Janet, RN 
Heinz, Nicole, RN 
Kelly, Irene, RN 
Medicine/Regional Networks 
Medicine/Leukemia 
Medicine/Gynecologic Medical 
Oncology Service 
 
Medicine 
Regional Networks 
 
Med/Regional Networks 
Med/Regional Networks 
Med/Regional Networks 
Med/Regional Networks 
Med/Regional Networks 
Med/Regional Networks 
Medicine/Melanoma and 
Immunotherapeutics Service 
 
Medicine/Lymphoma 
Medicine/Lymphoma 
Nursing 
Nursing 
Nursing 
Medicine/Lymphoma 
Nursing 
Nursing 
Medicine/Lymphoma 
Medicine/Lymphoma 
Nursing 
Medicine/Lymphoma 
Medicine/Lymphoma 
 
Pathology Dept & Molecular Div 
Radiology/Interventional 
Radiology Serv 
Radiology 
Graduate Medical Education 
Radiology 
 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 
Nursing 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  3 of 115
 
 
 
 
Kennedy, Maureen, RN 
Langish, Raylene, RN 
Mar-Chaim, Sherie, RN 
Pierre, Amy, NP 
Nursing 
Nursing 
Nursing 
Nursing 
Consenting 
Professional(s)/Department: 
Aghalar, Jahan, MD 
Apollo, Arlyn, MD 
Batlevi, Connie, MD, PhD 
Caron, Philip, MD, PhD 
Desai, Avni, MD 
Goldberg, Zoe, MD 
Gorsky, Mila, MD 
Gu, Ping, MD 
Hamilton, Audrey, MD 
Hamlin, Paul, MD 
Hassoun, Hani, MD 
Horwitz, Steven, MD 
Joffe, Erel, MD 
Klimek, Virginia, MD 
Konner, Jason, MD 
Kriplani, Anuja, MD 
Kumar, Anita, MD 
Lahoud, Oscar, MD 
Ligresti, Louise, MD 
Mailankody, Sham, MBBS 
Matasar, Matthew, MD 
Moskowitz, Alison, MD 
Namakydoust, Azadeh, MD 
Ng, Kenneth, MD 
Noy, Ariela, MD 
Owens, Colette, MD 
Palomba, M. Lia, MD 
Shcherba, Marina, DO 
Straus, David, MD 
Troso-Sandoval, Tiffany, MD 
Younes, Anas, MD 
Zelenetz, Andrew, MD, PhD 
Danila, Daniel, MD 
Gu, Ping, MD 
Kriplani, Anuja, MD 
Mauro, Michael, MD 
Momtaz, Parisa, MD 
Preeshagul, Isabel, DO 
Rodriguez-Revira, Ildefonso, MD 
Von Keudell, Gottfried, MD 
Medicine/Genitourinary Onc 
Med/Regional Networks 
Medicine/Lymphoma 
Med/Regional Networks 
Medicine/Gastrointestinal Onc 
Med/Regional Networks 
Med/Regional Networks 
Medicine/Genitourinary Onc 
Med/Regional Networks 
Medicine/Lymphoma 
Med/Regional Networks 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Leukemia 
Medicine/Gynecologic Medical 
Oncology Service 
Graduate Medical Education 
Medicine/Lymphoma 
Medicine/Marrow Transplant 
Regional Networks 
Medicine/Cellular Therapeutics 
Center (CTC) 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine 
Med/Regional Networks 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Lymphoma 
Regional Networks 
Medicine/Lymphoma 
Med/Regional Networks 
Medicine/Lymphoma 
Medicine/Lymphoma 
Medicine/Genitourinary Onc 
Medicine/Gastrointestinal Onc 
Medicine Medicine/Leukemia 
Medicine/Melanoma and 
Immunotherapeutics Service 
Medicine/Thoracic Onc 
Medicine/Lymphoma 
Medicine/Lymphoma 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  4 of 115
 
 
 
 
Wang, Rui, MD 
Medicine 
 
 
Please Note: A Consenting Professional must have completed the mandatory Human 
Subjects Education and Certification Program. 
 
OneMSK Sites 
Manhattan 
Basking Ridge 
Westchester 
Nassau 
Commack 
Monmouth 
Bergen 
 
 
 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  5 of 115 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ......................................................................... 9 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................................ 10 
 
2.1 Primary Objectives................................................................................................................. 10 
 
2.2 Secondary Objectives ............................................................................................................ 11 
 
3.0 
BACKGROUND AND RATIONALE ..................................................................................... 11 
 
3.1 Natural History and Current Management of Follicular Lymphoma ........................................ 11 
 
3.2 Radiotherapy Background...................................................................................................... 12 
 
3.3.1 Summary of Nonclinical Experience ................................................................................ 14 
 
3.3.2 Clinical Experience with Atezolizumab............................................................................. 15 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.............................................................. 18 
 
4.1 
Design............................................................................................................................... 18 
 
4.1.1 Rationale for Patient Population ...................................................................................... 18 
 
4.1.2 Rationale for Atezolizumab Starting Dose and Schedule ................................................. 18 
 
4.1.3 Rationale for Radiotherapy Dose and Schedule .............................................................. 19 
 
4.1.4 Rationale for Potential Treatment Beyond Progression ................................................... 19 
 
4.2 
Intervention ....................................................................................................................... 20 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................................. 20 
 
5.1 Study Drug:  ATEZOLIZUMAB............................................................................................... 20 
 
5.1.1 Formulation ..................................................................................................................... 20 
 
5.1.2 Dosage Administration, and Storage ............................................................................... 20 
 
5.2 Low- Dose, Local Radiotherapy ............................................................................................ 21 
 
5.2.1 Simulation ....................................................................................................................... 21 
 
5.2.2 Treatment Planning ......................................................................................................... 21 
 
5.2.3 Treatment Delivery (LINAC- based)................................................................................. 23 
 
5.2.4 Study Medication Accountability ...................................................................................... 23 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................................. 23 
 
6.1 
Subject Inclusion Criteria................................................................................................... 23 
 
6.2 
Subject Exclusion Criteria ................................................................................................. 25 
 
General Exclusion Criteria: .......................................................................................................... 25 
 
7.0 
RECRUITMENT PLAN ......................................................................................................... 28 
 
8.0 
PRETREATMENT EVALUATION ........................................................................................ 28 
 
9.0 
TREATMENT/INTERVENTION PLAN.................................................................................. 29 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  6 of 115 
 
 
 
9.1 Atezolizumab administration .................................................................................................. 29 
 
9.2 Concomitant and Excluded Therapies.................................................................................... 29 
 
9.2.1 Concomitant Therapy ...................................................................................................... 29 
 
9.2.2 Excluded Therapy ........................................................................................................... 30 
 
9.3 Guidelines for Dosage Modification and Treatment Interruption or Discontinuation ................ 30 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION ..................................................... 31 
 
10.1 Study Assessments ............................................................................................................. 31 
 
10.1 Laboratory/ Pathology Assessments ................................................................................ 31 
 
10.2 Treatment Discontinuation Visit............................................................................................ 32 
 
10.3 Follow-Up Assessments....................................................................................................... 32 
 
10.4 Post-Treatment Evaluations ................................................................................................. 32 
 
10.5 Survival and Subsequent Anticancer Therapy...................................................................... 33 
 
10.6 End of Study ........................................................................................................................ 33 
 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................................... 33 
 
11.1 Definition of Adverse Event .................................................................................................. 33 
 
11.1.1 Adverse Events ............................................................................................................. 34 
 
11.1.2 Assessment of Adverse Events ..................................................................................... 35 
 
11.1.4 Post- Study Adverse Events .......................................................................................... 36 
 
11.1.5 Specific Instructions for Recording Adverse Events....................................................... 37 
 
11.2 Risks Associated with Atezolizumab .................................................................................... 41 
 
11.2.1. Management of Specific Safety Concerns with ATEZOLIZUMAB ................................. 41 
 
11.2.2 Management of Patients Who Experience Atezolizumab Specific Adverse Events ........ 41 
 
11.2.3 Management of Systemic Immune Activation ................................................................ 42 
 
11.2.4 Infusion Related Reactions ............................................................................................ 43 
 
11.2.5 Safety Reconciliation ..................................................................................................... 44 
 
11.3 Diagnosis Versus Signs and Symptoms............................................................................... 44 
 
11.4 Deaths ................................................................................................................................. 44 
 
11.5 Pre- existing Medical Conditions .......................................................................................... 45 
 
11.6 Hospitalizations for Medical or Surgical Procedures............................................................. 45 
 
11.6.1 Pregnancies in Female Patients .................................................................................... 45 
 
11.6.2 Pregnancies in Female Partners of Male Patients ......................................................... 46 
 
11.6.3 Abortions ....................................................................................................................... 46 
 
11.6.4 Congenital Anomalies/ Birth Defects ............................................................................. 46 


Page  7 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
11.7 Serious Adverse Events....................................................................................................... 46 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ......................... 47 
 
12.1 Tumor and Response Evaluation ......................................................................................... 47 
 
12.1.1 Outcome Measures ....................................................................................................... 48 
 
12.1.2 Primary Efficacy Outcome Measure .............................................................................. 48 
 
12.1.3 Secondary Efficacy Outcome Measure .......................................................................... 48 
 
12.1.4 Safety Outcome Measure .............................................................................................. 48 
 
12.2 Correlative Studies............................................................................................................... 48 
 
12.2.1 Assessment of T- Cell Receptor Diversity/ Clonality ...................................................... 48 
 
12.2.2 Assessment of Biomarkers Related to PD-L1, Tumor Biology, and Immune Cell Biology 
................................................................................................................................................. 48 
 
12.2.3 Cytokine/ Chemokine Levels ......................................................................................... 50 
 
13.0 CRITERIA FOR REMOVAL FROM STUDY ......................................................................... 50 
 
13.1 Patient Discontinuation ........................................................................................................ 50 
 
13.2 Study Treatment Discontinuation ......................................................................................... 50 
 
13.3 Study and Site Discontinuation ............................................................................................ 51 
 
14.0 BIOSTATISTICS .................................................................................................................. 52 
 
14.2 Planned Efficacy Evaluations ............................................................................................... 52 
 
14.3 Primary Efficacy Variables ................................................................................................... 53 
 
14.4 Secondary Efficacy Variables............................................................................................... 53 
 
14.5 Method of Analysis............................................................................................................... 53 
 
14.6 Method of Analysis for Correlative Endpoints....................................................................... 53 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES ... 54 
 
15.1 Research Participant Registration ..................................................................................... 54 
 
15.2 Randomization .................................................................................................................. 54 
 
16.0 DATA MANAGEMENT ISSUES ........................................................................................... 54 
 
16.1 Quality Assurance ............................................................................................................. 54 
 
16.1.1 Data Entry and Database .............................................................................................. 54 
 
16.2 Data and Safety Monitoring ............................................................................................... 55 
 
16.2.1 Monitoring ..................................................................................................................... 56 
 
16.2.2 Assessment of Safety .................................................................................................... 56 
 
16.2.3 Management of Specific Safety Concerns with Atezolizumab ........................................ 56 
 
16.3 Retention of Records ........................................................................................................... 56 


Page  8 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
16.4 Study Close- Out.................................................................................................................. 57 
 
17.0 PROTECTION OF HUMAN SUBJECTS .............................................................................. 57 
 
17.1 Privacy .............................................................................................................................. 57 
 
17.2 Serious Adverse Event (SAE) Reporting ........................................................................... 57 
 
17.2.1 Methods and Timing for Assessing and Recording Safety Variables .......................... 58 
 
18.0 INFORMED CONSENT PROCEDURES .............................................................................. 60 
 
19.0 REFERENCES ..................................................................................................................... 61 
 
20.0 APPENDICES ...................................................................................................................... 64 


Page  9 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a two-arm, parallel, open-label, phase II clinical trial designed to assess the efficacy and 
safety of atezolizumab alone and of atezolizumab in combination with low-dose local radiotherapy in 
patients with relapsed or refractory follicular lymphoma. 
 
Fifty patients will be enrolled at an estimated accrual rate of 3 patients per month, and will be 
randomly assigned to receive atezolizumab alone or atezolizumab and local, low-dose radiotherapy. 
 
See Figure 1 for Study Schema. 


Page  10 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Figure 1: Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.1 Primary Objectives 
 
To determine the objective response rate of either atezolizumab alone or atezolizumab with 
low-dose, localized radiotherapy (2 x 2 Gy, on Day 2 & 3) to single site of disease in patients 
with relapsed/refractory advanced stage follicular lymphoma requiring therapy (as measured 
in the non-irradiated sites of disease). 


Page  11 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
2.2 Secondary Objectives 
 
To determine the progression-free survival and overall survival of atezolizumab alone and of 
atezolizumab with low-dose, localradiotherapy (2 x 2 Gy, on day 2 & 3) in patients with 
relapsed/refractory advanced stage follicular lymphoma requiring therapy 
 
 
To assess the safety of atezolizumab alone or atezolizumab with low-dose, localized 
radiotherapy in patients with relapsed/refractory advanced stage FL grade I-IIIA. 
 
2.3 Exploratory Objectives 
 
 
To determine if clinical responses to atezolizumab are associated with preexisting tumor 
antigen restricted effector T cells or the development of a more clonal T-cell receptor (TCR) 
repertoire, and we will determine what impact the addition of concurrent local, low-dose 
radiotherapy has on TCR diversity and clinical responses. 
 
Using immunohistochemistry, multiplex immunofluorescence, and fresh tissue 
immunophenotyping with pre-treatment and on-treatment tissue samples and peripheral 
blood, aim to assess biomarkers related to PD-L1 and/or immune cell biology and tumor 
biology that might contribute to our understanding of the mechanism of response to PD-L1 
therapy and of the abscopal effect of radiation therapy in follicular lymphoma. 
 
Perform a preliminary assessment of the prognostic value of minimal residual disease 
(MRD). 
 
 
To determine what impact treatment with atezolizumab and the addition of concurrent local, 
low-dose radiotherapy has on peripheral blood cytokine/chemokine levels. 
  
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Natural History and Current Management of Follicular Lymphoma 
Follicular lymphoma is the most common subtype of indolent non-Hodgkin lymphoma in the Western 
hemisphere and is associated with follicle center B cells that typically contain the translocation 
t(14:18), which leads to overexpression of the intracellular anti-apoptotic protein Bcl-2. 
 
The clinical course of follicular lymphoma is characterized by remission and relapse 
(Gallagher et al. 1986). Early-stage indolent follicular lymphoma may be effectively treated with 
radiation therapy, but patients with advanced disease are not usually cured with conventional 
treatment. 
 
The disease initially responds to radiation, single-agent rituximab, and/or combination 
immunochemotherapy, but patients eventually suffer multiple relapses distinguished by increasing 
refractoriness and decreasing duration of objective response in subsequent lines of therapy. 
Patients ultimately die from recurrent disease, infection, or treatment-related toxicity. A previous 
phase II trial evaluated the combination of an anti-programmed death-1 receptor (PD-1) antibody, 
pidilizumab, in combination with rituximab in patients with relapsed follicular lymphoma (Westin et al. 
2013).  Patients received intravenous (IV) pidilizumab 3 mg/kg every 4 weeks for 4 infusions and 
rituximab 375 mg/m2 IV weekly for 4 weeks starting 17 days after the first infusion of pidilizumab. 


Page  12 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Patients with stable disease or better after 4 infusions of pidilizumab received up to 8 additional 
infusions every 4 weeks for a total of 12 doses. The combination of pidilizumab and rituximab was 
well tolerated, with no autoimmune or treatment-related adverse events (AEs) of Grade 3 or 4. The 
most common Grade 1 AEs were anemia (14 patients) and fatigue (13 patients), and the most 
common Grade 2 AE was respiratory infection (5 patients). Of the 29 patients evaluable for activity, 
19 (66%) achieved an objective response: CRs were noted in 15 (52%) patients and partial 
responses (PRs) in 4 (14%). 
 
In a multicenter phase I study of PD-1 blockade with nivolumab in relapsed/refractory hematologic 
malignancies, an ORR of 40% was observed (including 1/10 CR and 3/10 PR) among patients with 
follicular lymphoma (Lesokhin et al. 2015). 
 
In a multicenter phase 1b study of atezolizumab combined with obinutuzumab in patients with 
DLBCL or FL, there was preliminary evidence that the combination was well tolerated, and an ORR 
of 21.4% (3/14) and CRR of 14.2% (2/14) was observed at the first response assessment (after 
cycle 4) among patients with relapsed/refractory FL, with 6 additional patients with FL had stable 
disease (Palomba et al. 2016). 
 
These data demonstrate that PD-L1 blockade with ATEZOLIZUMAB might safely and effectively 
induce clinical responses in patients with follicular lymphoma. 
 
3.2 Radiotherapy Background 
Radiotherapy is an established treatment modality in the management of patients with non-Hodgkin 
lymphoma. Indolent non-Hodgkin lymphoma (e.g. FL, MZL, CLL/SLL) and mantle cell lymphoma 
(MCL) are exquisitely radiosensitive. Nonetheless, radiation doses ranging from 36 to 45 Gy were 
historically used for the treatment of these histologies based on outdated dose-response studies with 
questionable methodologies. 
 
A randomized study from the United Kingdom [Lowry et al, 2011] compared the historical standard 
radiation dose of 40-45 Gy to 24 Gy in 361 subjects with indolent non-Hodgkin lymphoma, mostly 
comprised of early stage FL and MZL. At a median follow-up of 5.6 years, there was no demonstrated 
loss of efficacy associated with reduced radiotherapy doses of 24 Gy. No differences were observed 
in the rates of objective response or within radiation field progression, and there was no difference in 
progression-free survival and overall survival. 24 Gy is therefore the recommended dose for most 
patients with early stage follicular lymphoma. 
 
In follicular lymphoma, responses have been described using doses at low as 0.75 Gy. Based on case 
reports of patients achieving durable local disease control following 4 Gy in 2 fractions, as well as a 
number of small case series confirming that 4 Gy in 2 fractions is an effective dose in follicular 
lymphoma, a phase III randomized non-inferiority trial from the UK [Hoskin et al, 2014] compared low- 
dose radiotherapy (4 Gy in 2 fractions) and conventional dose radiotherapy (24 Gy in 12 fractions) in 
patients with follicular lymphoma or marginal zone lymphoma having local radiotherapy for definitive 
or palliative local control. The primary endpoint was time to local disease progression. A total of 614 
sites in 548 patients with FL (and some with MZL) were prospectively randomized to receive either 
low-dose radiotherapy (4 Gy in 2 fractions) or conventional dose radiotherapy (24 Gy in 12 fractions). 


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Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
The intent of radiotherapy was palliative and definitive in 60% and 40% of subjects, respectively. 
Conventional dose radiotherapy with 24 Gy was superior. However, low-dose radiotherapy (4Gy in 2 
fractions) was associated with minimal toxicity and achieved high rates of local tumor control (44.3% 
CR, 29.8% PR).  Therefore low-dose radiotherapy (4 Gy in 2 fractions) is considered an appropriate 
approach when the goal of radiotherapy is palliative. 
 
In patients treated with an intratumoral TLR9 agonist, induction of circulating tumor reactive cytotoxic 
T lymphocytes (CTLs) and responses at distant sites was only observed with concurrent low-dose, 
local radiotherapy with 4Gy in 2 fractions [Brody et al, 2010]. This dose and fractionation is therefore 
sufficient to induce both local disease control and a systemic immune response in patients with 
follicular lymphoma. 
 
Follicular lymphoma (FL) is an indolent but incurable disease with a variable course, and most 
patients with relapsed/refractory FL ultimately die of their disease. There is a significant need for 
alternative therapeutic strategies in FL, and one therapeutic target is the inhibitory receptor PD-1. 
PD-1-triggered T-cell suppression is critical to modulate T-cell response to antigens, but results in 
pathologic immune tolerance in the tumor microenvironment (TME). A recent phase I study of 
nivolumab in relapsed/refractory lymphoid malignancies demonstrated that PD-1/PD-L1 blockade is 
active in FL, with a 40% overall response rate [Lesokhin et al, 2014]. The experience with 
atezolizumab in FL is encouraging, although with short follow up (See Section 1.2.2.3). 
 
T-cell infiltrates and their spatial distribution within the TME are important predictors of outcomes in 
FL [Dave et al, 2004; Ame-Thomas et al, 2012; Ame-Thomas et al, 2014; Ansell et al, 2013; De 
Jong et al, 2011]. Gene expression profiling of FL has shown that immune response signatures of 
non-malignant cells in the TME are the strongest predictor of outcomes [Dave et al, 2004]. Tumor- 
infiltrating lymphocytes (TILs) in the FL microenvironment upregulate PD-1 and show diminished 
responses to antigens and cytokines in a manner that can be reversed by treatment with a PD-1 
blocking antibody [Myklebust et al, 2013]. While FL cells do not generally express PD-L1 and PD-L2, 
PD-L1 is expressed on infiltrating macrophages, which co-localize with PD-1+ tumor-infiltrating T 
cells. 
 
PD-L1/PD-1 blockade therapy interrupts adaptive immune tolerance of cancer tissues through 
activation of tumor reactive CTLs, and it has recently been shown that clinical response to PD-1 
blockade therapy in melanoma is associated with the presence of clonal expansion of preexisting 
tumor antigen-restricted CTLs within the TME [Tumeh et al, 2014]. The mechanisms of clinical 
response to PD-1/PD-L1 blockade in FL are not fully understood. 
 
There is a need for novel combination strategies to augment the activity of PD-1/PD-L1 blockade in 
FL. In addition to its direct cytotoxic effects, radiotherapy (RT) initiates immunogenic cell death of 
tumor cells via multiple mechanisms. RT leads to the release of tumor antigen into the TME, 
translocation of calreticulin to the tumor cell membrane, and release of endogenous adjuvants (e.g. 
HMGB1, uric acid, heat shock proteins), which in turn lead to the recruitment of dendritic cells, cross 
presentation of tumor antigens by dendritic cells, and cross priming of tumor CTLs [Vatner et al, 
2014]. 


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Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
The combination of RT and either PD-1 or PD-L1 blockade is synergistic in mouse models of 
colorectal cancer, melanoma, and breast cancer, with improved tumor control and survival, and 
induction of a durable tumor-specific response and resistance against tumor re-challenge [Dovedi et 
al, 2014]. Because concurrent RT and PD-1/PD-L1 blockade resulted in synergistic effect on survival 
whereas sequential therapy did not (RT administered 5 or 7 days prior to PD-1/PD-L1 blockade) 
[Dovedi et al, 2014], investigators testing the combination of RT and immune checkpoint blockade 
should limit the time interval between RT and the initiation of immune checkpoint blockade. The 
addition of local RT to CTLA4 blockade increased the density and diversity of tumor antigen 
restricted CTLs in a breast cancer mouse model [Pilones et al, 2015]. 
  
Low-dose local radiotherapy (RT) with 4Gy in 2 fractions induces durable local disease control 
without significant toxicity [Hoskin et al, 2014], and has been shown to induce an abscopal effect in 
patients with FL, with patients treated with the intratumoral TLR9 agonist CpG inducing circulating 
tumor reactive CTLs and achieving responses at distant sites only with concomitant low-dose 
irradiation [Brody et al, 2010]. This dose and fractionation of RT is therefore safe and sufficient to 
induce a systemic immune response in patients with relapsed/refractory, advanced stage FL. 
 
We therefore hypothesize that a radiotherapy-induced systemic immune response can augment 
atezolizumab activity in patients with advanced stage FL. 
 
3.3 Background of Atezolizumab 
Atezolizumab (ATEZOLIZUMAB) is a human immunoglobulin (Ig) G1 monoclonal antibody consisting 
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 prevents Fc-
effector function at expected concentrations in humans.  ATEZOLIZUMAB targets human 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. 
 
ATEZOLIZUMAB is being investigated as a potential therapy against solid tumors and hematologic 
malignancies in humans. 
 
3.3.1 Summary of Nonclinical Experience 
The nonclinical strategy of the ATEZOLIZUMAB program was to demonstrate in vitro and in vivo 
activity, to determine in vivo pharmacokinetic (PK) behavior, to demonstrate an acceptable safety 
profile, and to identify a Phase I starting dose. Comprehensive pharmacology, PK, and toxicology 
evaluations were thus undertaken 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 


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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 down-modulating the PD-L1/PD-1 pathway and supported entry into 
clinical trials in patients. 
 
Refer to the ATEZOLIZUMAB Investigator’s Brochure for details on the nonclinical studies. 
 
3.3.2 Clinical Experience with Atezolizumab 
 
3.3.2.1 Ongoing Clinical Studies 
Current studies of ATEZOLIZUMAB include one ongoing Phase Ia monotherapy study, three 
ongoing combination studies, five Phase II studies, and one Phase III study.  Details of all ongoing 
studies can be found in the ATEZOLIZUMAB Investigator’s Brochure. 
 
Phase Ib Study BO29563 
A phase 1b study of PD-L1 blockade with atezolizumab in combination with the anti-CD20 
monoclonal antibody obinutuzumab in patients with relapsed/refractory follicular lymphoma and 
diffuse large B-cell lymphoma is ongoing. This combination appears well-tolerated, and significant 
clinical activity has been observed among patients with relapsed/refractory follicular lymphoma, with 
an ORR of 21.4% (3/14) and CRR of 14.2% (2/14) and 6 additional patients with stable disease at 
the first response assessment after cycle 4 (Palomba et al. 2016). 
 
3.3.2.2 Clinical Safety 
Study PCD4989g, in which atezolizumab is being used as a single agent in patients with locally 
advanced or metastatic solid tumors or hematologic malignancies, provides the majority of data (with 
558 safety-evaluable patients as of the data extraction date of 11 May 2015) for the safety profile of 
atezolizumab as monotherapy. 
 
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities (DLTs), and no clear 
dose-related trends in the incidence of adverse events have been determined. 
 
The safety profile of atezolizumab as a single agent is observed to be consistent across different 
indications.  The most common cancer types for these patients include NSCLC, urothelial bladder 
cancer, melanoma, and renal cell carcinoma.  Safety data for NSCLC are also derived from Studies 
GO28625 (FIR) and GO28753 (POPLAR). 
 
 
 
Adverse Events 
 
Of the 558 patients with available safety data, 520 (93.2%) experienced at least one adverse event, 
including 376 patients (67.4%) who experienced one treatment-related adverse event.  Commonly 


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reported events (reported in  10% of all patients) included fatigue, decreased appetite, nausea, 
pyrexia, constipation, and cough (see Table 1). 
 
Table 1 
Study PCD4989g:  Adverse Events with Frequency  10% of Patients 
for All Grades 
 
Preferred Term 
All Grades 
n (%) 
All Grades 
Related 
n (%) 
Grade 3 4 
n (%) 
Grade 3 4 
Related 
n (%) 
Any adverse event 
520 (93.2) 
376 (67.4) 
239 (42.8) 
66 (11.8) 
Fatigue 
192 (34.4) 
115 (20.6) 
13 (2.3) 
6 (1.1) 
Decreased Appetite 
142 (25.4) 
62 (11.1) 
4 (0.7) 
0 (0.0) 
Nausea 
136 (24.4) 
65 (11.6) 
5 (0.9) 
2 (0.4) 
Pyrexia 
117 (21.0) 
63 (11.3) 
2 (0.4) 
0 (0.0) 
Constipation 
116 (20.8) 
8 (1.4) 
2 (0.4) 
0 (0.0) 
Cough 
113 (20.3) 
11 (2.0) 
1 (0.2) 
1 (0.2) 
Dyspnea 
112 (20.1) 
18 (3.2) 
18 (3.2) 
4 (0.7) 
Diarrhea 
110 (19.7) 
53 (9.5) 
2 (0.4) 
1 (0.2) 
Anemia 
104 (18.6) 
26 (4.7) 
23 (4.1) 
5 (0.9) 
Vomiting 
96 (17.2) 
28 (5.0) 
3 (0.5) 
2 (0.4) 
Asthenia 
88 (15.8) 
53 (9.5) 
8 (1.4) 
4 (0.7) 
Back Pain 
85 (15.2) 
9 (1.6) 
8 (1.4) 
1 (0.2) 
Headache 
83 (14.9) 
32 (5.7) 
2 (0.4) 
1 (0.2) 
Arthralgia 
79 (14.2) 
35 (6.3) 
2 (0.4) 
0 (0.0) 
Pruritus 
75 (13.4) 
55 (9.9) 
0 (0.0) 
0 (0.0) 
Rash 
73 (13.1) 
53 (9.5) 
0 (0.0) 
0 (0.0) 
Abdominal Pain 
63 (11.3) 
12 (2.2) 
8 (1.4) 
0 (0.0) 
Insomnia 
62 (11.1) 
7 (1.3) 
1 (0.2) 
0 (0.0) 
Peripheral edema 
59 (10.6) 
7 (1.3) 
 
 
Chills 
57 (10.2) 
31 (5.6) 
0 (0.0) 
0 (0.0) 
Note: ‘  ‘ refers to missing Common Terminology Criteria grade. 
 
Grade 3 4 adverse events (on the basis of National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 4 (NCI CTCAE v4) were reported in 239 patients (42.8%), of which 66 
(11.8%) were considered related. Grade 3 and Grade 4 adverse events considered treatment 
related by the investigator included dyspnea, pneumonitis, increased ALT, increased AST, increased 
gamma-glutamyl transferase (GGT), lymphocyte count decreased, cardiac tamponade, asthenia, 
autoimmune hepatitis, pneumonia, influenza, and hypoxia. 
 
Refer to the Atezolizumab Investigator’s Brochure for details on adverse events observed in patients 
treated with atezolizumab monotherapy or in combination with other agents. 


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Immune-Mediated Adverse Events 
 
Given the mechanism of action of atezolizumab, events associated with inflammation and/or 
immune-mediated adverse events have been closely monitored during the atezolizumab clinical 
program. These include potential dermatologic, hepatic, endocrine, gastrointestinal, and respiratory 
events. 
 
Refer to the Atezolizumab Investigator’s Brochure for details on immune-mediated adverse events 
that were observed in patients treated with atezolizumab.  Guidelines for the management of 
immune-mediated adverse events are described in the Atezolizumab Investigator’s Brochure. 
 
For additional information, refer to the Atezolizumab Investigator’s Brochure. 
 
3.3.2.3 Atezolizumab Clinical Activity 
As of the data cutoff of 1 January 2014, efficacy analyses were performed on 386 efficacy evaluable 
patients who were defined as those patients, with measurable disease at baseline, treated by 1 July 
2013 in Study PCD4989g (to ensure that each patient had a minimum of 6 months follow-up). 
Patients with multiple tumor types were included in the study, with the largest cohorts consisting of 
patients with NSCLC, RCC, and bladder cancer. Objective responses with ATEZOLIZUMAB 
monotherapy were observed in a broad range of malignancies, including NSCLC, RCC, melanoma, 
bladder cancer, colorectal cancer, head and neck cancer, gastric cancer, breast cancer and 
sarcoma.  Altogether, there were 47 patients with responses with a median duration of response of 
75.7 weeks (range:  11.7 to 85.9 weeks, where “  ” denotes censored value). The majority of 
these responses have been durable, with 72.3% (34/47) of responses ongoing as of the clinical 
cutoff date. 
 
Analyses of tumor-infiltrating immune cells for PD-L1 expression on baseline tumor tissue have been 
performed for Study PCD4989g.  Preliminary results from Study PCD4989g suggest that PD-L1 
expression in tumor-infiltrating immune cells is likely to be associated with response to 
ATEZOLIZUMAB. 
 
Efficacy in Hematologic Malignancies 
Eleven patients with hematologic malignancies have been treated with the anti PD-L1 antibody 
atezolizumab in the Phase Ia Study PCD4989g. This includes patients with refractory/late-line 
multiple myeloma (n  4), FL (n  3), cutaneous T-cell lymphoma (n  2), DLBCL (n  1), and Hodgkin’s 
lymphoma (n  1).  Best responses of PR were observed in the 2 patients with cutaneous T-cell 
lymphoma, while best response of stable disease was observed in patients with FL (n  3), Hodgkin’s 
lymphoma (n  1), and multiple myeloma (n  2). 
 
Additional patients have been treated with atezolizumab in the phase 1b study BO29563. This 
includes patients with relapsed/refractory follicular lymphoma and diffuse large B-cell lymphoma. 
Significant clinical activity has been observed among patients with follicular lymphoma,   with an 
ORR of 21.4% (3/14) and CRR of 14.2% (2/14), plus 6 additional patients with stable disease 


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following cycle 4 (Palomba et al. 2016). For further details, see the ATEZOLIZUMAB Investigator’s 
Brochure. 
 
3.3.2.4 Clinical Pharmacokinetics 
On the basis of available preliminary PK data (0.03 20 mg/kg), ATEZOLIZUMAB appeared to show 
linear pharmacokinetics at doses  1 mg/kg.  For the 1-mg/kg and 20-mg/kg dose groups, the mean 
clearance (CL) and the mean volume at steady state (Vss) had a range of 3.20 4.43 mL/kg and 
48.1 64.1 mL/kg, respectively, which is consistent with the expected profile of an IgG1 antibody in 
humans. 
 
The development of anti-therapeutic antibodies has been observed in patients in all dose cohorts 
and was associated with changes in pharmacokinetics for some patients in the lower dose cohorts 
(0.3, 1, and 3 mg/kg). The development of detectable ATAs has not had a significant impact on 
pharmacokinetics for doses from 10 20 mg/kg. Patients dosed at the 10-, 15-, and 20-mg/kg dose 
levels have maintained the expected target trough levels of drug despite the detection of ATAs. To 
date, no clear relationship between detection of ATAs and AEs or IRRs has been observed. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
4.1.1 Rationale for Patient Population 
This study is designed to obtain safety and efficacy data for atezolizumab and for atezolizumab plus 
low-dose, local radiotherapy in patients with relapsed/refractory follicular lymphoma. Enrollment will 
be offered to patients with relapsed/refractory follicular lymphoma who fulfill stringent eligibility 
criteria. This indication was selected in part because of preliminary evidence of activity of PD-1/PD- 
L1 antibodies in patients with follicular lymphoma. Patients will be randomly assigned to receive 
atezolizumab alone or atezolizumab plus low-dose, local radiotherapy (see Section 15). This study 
will allow an assessment of the activity of single-agent atezolizumab and of atezolizumab in 
combination with low-dose, local radiotherapy in patients with follicular lymphoma. 
 
4.1.2 Rationale for Atezolizumab Starting Dose and Schedule 
The dose of atezolizumab will be 1200 mg IV on Day 1 (+/-2 days) of each 21-day cycle. 
 
The atezolizumab dose is informed by available clinical activity, safety, PK, and immunogenicity 
data. Anti-tumor activity has been observed across doses from 1 mg/kg to 20 mg/kg administered 
q3w.  The MTD of atezolizumab was not reached and no DLTs have been observed at any dose in 
Study PCD4989g.  Available preliminary PK data (0.03 20 mg/kg) from Study PCD4989g suggest 
that for doses  1 mg/kg q3w, overall, atezolizumab exhibits pharmacokinetics that are both linear 
and consistent with typical IgG1 antibodies.  Detectable ATAs were observed in patients at all dose 
levels but were only associated with changes in pharmacokinetics for patients in the lower dose 
cohorts (0.3, 1, and 3 mg/kg).  It is unclear from currently available data in these lower dose cohorts 
if administration of higher doses to patients with both detectable ATAs and reduced exposure would 
restore exposure to expected levels.  No clear relationship between the development of measurable 


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ATAs and safety or efficacy has been observed.  Available data suggest that development of 
detectable ATAs does not appear to have a significant impact on pharmacokinetics in most patients 
at doses of 10 to 20 mg/kg administered q3w.  Correspondingly, patients dosed at the 10-, 15-, and 
20-mg/kg q3w dose levels have maintained target trough levels of drug despite the detection of 
ATAs. 
 
Currently available PK and ATA data suggest that the 15-mg/kg atezolizumab q3w regimen 
(equivalent to the 1200-mg q3w fixed dose) for Phase II and Phase III studies would be sufficient to 
both maintain Ctrough  6 g/mL and further safeguard against both interpatient variability and the 
potential effect of ATAs that could lead to subtherapeutic levels of atezolizumab relative to the 
10-mg/kg atezolizumab q3w regimen (or fixed-dose equivalent).  From inspection of available 
observed Ctrough data, moving further to the 20-mg/kg atezolizumab q3w regimen does not appear to 
be warranted to maintain targeted Ctrough levels relative to the proposed 15-mg/kg atezolizumab q3w 
level. 
 
Simulations (Bai et al. 2012) do not suggest any clinically meaningful differences in exposure 
following fixed dose or dose adjusted for weight. A fixed dose of 1200 mg q3w was selected 
(equivalent to a body weight based dose of 15 mg/kg q3w) on the basis of this analysis. 
 
4.1.3 Rationale for Radiotherapy Dose and Schedule 
In the FORT Trial, a phase III randomized non-inferiority trial comparing low-dose radiotherapy (4 Gy 
in 2 fractions) and conventional dose radiotherapy (24 Gy in 12 fractions) in patients with follicular 
lymphoma or marginal zone lymphoma having local radiotherapy for definitive or palliative local 
control, low-dose radiotherapy (4Gy in 2 fractions) was associated with minimal toxicity and high 
rates of local tumor control (44.3% CR, 29.8% PR).4 In patients treated with an intratumoral TLR9 
agonist, induction of circulating tumor reactive CTLs and responses at distant sites was only 
observed with concurrent low-dose, local radiotherapy with 4Gy in 2 fractions.5 This dose and 
fractionation is therefore safe and sufficient to induce both local disease control and a systemic 
immune response in patients with follicular lymphoma. 
 
4.1.4 Rationale for Potential Treatment Beyond Progression 
Cancer immunotherapy may result in early apparent radiographic progression 
(pseudoprogression/tumor immune infiltration), including the appearance of new lesions followed by 
delayed response (Wolchok et al. 2009).  Additionally, responding tumors may appear to increase in 
size because of the influx of immune cells (Hoos et al. 2010; Pennock et al. 2012).  Unconventional 
response patterns have been described in patients treated with anti-CTLA-4 (Wolchok et al. 2009) 
and have been observed in the preliminary experience with atezolizumab in Study PCD4989g. This 
has led to the use of Modified RECIST criteria to account for potential pseudoprogression in clinical 
trials of MPLD3280A.  Patients with CLL and NHL treated with the Bruton tyrosine kinase inhibitor 
ibrutinib or the PI3K inhibitor idelalisib have demonstrated reduction in adenopathy and clinical 
responses accompanied by transient lymphocytosis (Davis and Letai 2012; de Rooij et al. 2012; 
Fiorcari et al. 2013). Tumor flare in patients with lymphoma and CLL has been described in patients 
treated with lenalidomide (Eve and Rule 2010; Chanan-Khan et al. 2011). This clinical response has 
been studied in vitro and is believed to be due to inhibition of B-cell receptor signaling and integrin 


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α4β1 adhesion of malignant cells to fibronectin and VCAM-1.  Current response criteria for 
lymphoma do not take into account such lymphocytosis, which is a phenomenon somewhat similar 
to the pseudoprogression described above in solid tumor patients. The potential for false-positive 
results on PET scans are also observed for patients with lymphoma. 
 
4.2 
Intervention 
 
All patients will receive open-label atezolizumab 1200mg IV on day 1 (+/- 2 days) of a 21-day cycle 
for 1 year, for a planned total of up to 17 cycles of therapy. For patients assigned to receive 
atezolizumab and low-dose radiotherapy, 4Gy will be administered in 2 fractions to a single nodal 
site amenable to radiation as identified by the radiation oncologist on day 2 and day 3 of Cycle 1. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Study Drug:  ATEZOLIZUMAB 
Once marketing authorization is received commercial ATEZOLIZUMAB will be used and will not be 
provided by Genentech for “on-label” studies. For studies done before marketing authorization 
and/or "out of label", ATEZOLIZUMAB will be provided free of charge by Genentech but switched to 
commercial drug once marketing authorization is received.  Genentech will replace any 
ATEZOLIZUMAB drug that is not reimbursed. For studies done “out of label,” ATEZOLIZUMAB will 
be provided free of charge by Genentech. The Principal Investigator of the study will ensure 
maintenance of complete and accurate records of the receipt, dispensation, and disposal or return of 
all study drug in accordance with 21 Code of Federal Regulations (CFR), Part 312.57 and 312.62, 
and Genentech requirements. 
 
5.1.1 Formulation 
The ATEZOLIZUMAB drug product is provided in a single-use, 20-cc 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 left in a vial.  Vial contents should not be frozen 
or shaken and should be protected from direct sunlight. 
 
For further details, see the ATEZOLIZUMAB Investigator’s Brochure. 
 
5.1.2 Dosage Administration, and Storage 
The dose level of ATEZOLIZUMAB to be tested in this study is 1200 mg (equivalent to an average 
body weight based dose of 15 mg/kg) administered by IV infusion every 3 weeks (every 21 [ 2] 
days) for a total of 17 cycles.  ATEZOLIZUMAB will be delivered in infusion bags with IV infusion 


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lines that have product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 0.2 Pm in- 
line filters (filter membrane of polyethersulfone [PES]).  No incompatibilities have been observed 
between ATEZOLIZUMAB and PVC or polyolefin infusion materials (bags or infusion lines). 
 
Administration of ATEZOLIZUMAB will be performed in a setting with emergency medical facilities 
and staff who are trained to monitor for and respond to medical emergencies. 
 
The initial dose of ATEZOLIZUMAB will be delivered over 60 (r 15) minutes.  If the first infusion is 
tolerated without infusion-associated AEs, the second infusion may be delivered over 30 (r 10) 
minutes.  If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 
30 (r 10) minutes. Vital signs should be collected within 60 minutes prior to each infusion and at the 
end of each infusion. Vital signs should be collected during the infusion only if clinically indicated. 
Patients 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 may be 
administered for Cycles t 2 at the discretion of the treating physician. 
 
Guidelines for dosage modification, treatment interruption, or discontinuation and the management 
of specific adverse events are provided in Section 9.2 and Section 11.2.1, respectively. 
 
5.2 Low- Dose, Local Radiotherapy 
 
5.2.1 Simulation 
 
Simulation techniques may vary based on the location of the site that needs to be treated. 
PET or CT simulation will be done as per radiation oncologist discretion. 
 
 
Simulation should be done prior to radiation treatment start. 
 
 
Typically, patients will be positioned in an immobilization device, which may vary depending 
on the site that needs to be treated. An Alpha Cradle, Aquaplast mold, facemask, or 
equivalent immobilization devices may be used. Alternatively, simulation can be done without 
the use of any immobilization at the discretion of the treating radiation oncologist. 
 
 
IV and oral contrast may be used for simulation, unless the patient has an allergy that cannot 
be adequately pre-medicated. 
 
Motion management, including but not limited to deep inspiration breath hold and 4D scans, can be 
used at the discretion of the treating radiation oncologist. 
 
5.2.2 Treatment Planning 
 
When available, an FDG-PET scan is preferred for treatment planning purposes and will be 
acquired on a flat tabletop when possible with the same immobilization devices used for the 
treatment planning CT simulation. MRI scans may also be acquired when deemed necessary 
by the treating radiation oncologist. 


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A 3D conventional radiotherapy (3D CRT) or intensity-modulated radiation treatment (IMRT) 
plan will be developed using Eclipse TM. Institutional standards for radiation quality 
assurance and radiation delivery will be used. 
 
 
Either photons or electrons can be used at the discretion of the treating radiation oncologist. 
 
 
The concept of ISRT (involved-site radiotherapy) as discussed in more detail in the ILROG 
guidelines will be used [4]. 
 
 
Modern RT planning in lymphoma incorporates the current concepts of volume determination 
as outlined in the ICRU Report 83 [5] based on defining a gross tumor volume (GTV) and 
clinical target volume (CTV) which is expanded to create a planning target volume (PTV). 
The PTV is then used to define dose coverage. This approach allows direct comparison with 
the diagnostic imaging, increasing the accuracy with which lymph node localization is 
defined. 
 
 
The gross tumor volume (GTV) will be identified on the treatment planning CT and PET-CT 
or MRI when used. The attending radiation oncologist after reviewing the diagnostic CT, and 
other available imaging modalities when available will define the final GTV. 
 
 
CTV encompasses in principle the original GTV with a 1-2cm margin, even if extended 
beyond the involved tissue or organ. Yet, normal structures such as lungs, kidneys, muscles 
that were clearly uninvolved, though previously displaced by the GTV, should be excluded 
from the CTV based on clinical judgment. In outlining the CTV the following points should be 
considered 
 
o Quality and accuracy of imaging ͒
 
o Concerns of changes in volume since imaging ͒
 
o Spread patterns of the disease ͒
 
o Potential sub-clinical involvement ͒
 
o Adjacent organs constraints ͒
 
 
If motion management techniques are used, at sites where respiratory motion is involved an 
ITV (internal target volume) will be defined. ITV is defined in the ICRU Report 62 as the CTV 
plus a margin taking into account uncertainties in size, shape, and position of the CTV within 
the patient. The ITV is mostly relevant when the target is moving, most commonly in the 
chest and upper abdomen with respiratory movements. 
 
 
PTV is the volume that takes into account the CTV (and ITV, when relevant) and also 
accounts for set-up uncertainties in patient positioning and alignment of the beams during 


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treatment planning and through all treatment sessions. Typically, the expansion from CTV (or 
ITV when used) is 0.5cm. 
 
 
The clinician and / or treatment planner adds the PTV and applies margins that depend on 
estimated set up variations that are a function of immobilization device, body site, and 
internal organ motion and patient cooperation. In general, margins for uncertainties, which 
are based on probability levels, should be added quadratically in order to avoid overly large 
margins based on the most extreme and least likely situations. 
 
 
The Organs at Risk (OAR) are critical normal structures that can manifest adverse effects 
from radiation, usually dependent on the radiation dose and thus can influence treatment 
planning or the prescribed dose. They should be outlined on the simulation study. The 
planner should calculate dose 
 
 
Volume Histograms (DVH) and the plan should be evaluated by the clinician in consideration 
of this information. 
 
o Institutional dose-constraints guidelines will be met. 
  
 
5.2.3 Treatment Delivery (LINAC- based) 
 
All patients will receive a total of 400cGy delivered in two fractions, one fraction per day, on days 
2 and 3 of cycle 1. 
 
 
Initial positioning will be based on the initial simulation parameters and will be based on KV 
imaging with shifts to bony anatomy as appropriate. 
 
 
Active monitoring of treatment delivery accuracy will be accomplished using KV imaging 
immediately before all treatment fields. 
 
5.2.4 Study Medication Accountability 
If study drug will be provided by Genentech, the recipient will acknowledge receipt of the drug by 
returning the INDRR-1 form indicating shipment content and condition.  Damaged supplies will be 
replaced. 
 
Accurate records of all study drug dispensed from and returned to the study site should be recorded 
by using the institution’s drug inventory log or the National Cancer Institute drug accountability log. 
 
All partially used or empty containers should be disposed of at the study site according to 
institutional standard operating procedure.  Return unopened, expired, or unused study drug with the 
Inventory of Returned Clinical Material form as directed by Genentech. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.1 
Subject Inclusion Criteria 


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Patients must meet the following criteria for study entry: 
 
 
Signed Informed Consent Form (ICF) 
 
 
Ability and willingness to comply with the requirements of the study protocol. 
 
 
Age t 18 years 
 
 
Relapsed or refractory follicular lymphoma grade 1, 2, or 3A 
 
o Relapsed disease is defined as having relapsed after greater than 6 months of 
prior treatment for follicular lymphoma 
 
o Refractory disease is defined as failure to achieve a complete response or 
relapsed within 6 months of treatment for follicular lymphoma 
 
 
Pretreatment biopsy for fresh tumor tissue collection is required 
 
o If patient has recently undergone a biopsy and has not received any intercurrent 
anti-lymphoma therapy, archival tissue can be used 
 
 
Stage III/IV disease 
 
o Stage II disease is also eligible if disease is not encompassible within a single 
radiation field, as determined by the radiation oncologist. 
 
 
At least one prior treatment for follicular lymphoma (no restriction to number or type of prior 
therapies) 
 
o Patients treated for transformed diffuse large B cell lymphoma (DLBCL) who have 
retrograde transformation are eligible provided they have received at least one 
prior treatment for the follicular lymphoma 
 
Site of disease amenable to low-dose, local radiotherapy (2 x 2Gy), as recommended by the 
radiation oncologist. 
 
At least one bi-dimensionally measurable  lesion ! 1.5 cm in its longest diameter by CT scan or 
magnetic resonance imaging as defined by the Lugano Classification 
 
Adequate hematologic and end organ function: 
 
o ANC t 1500 cells/PL 
 
▪ 
If there is documented bone marrow involvement of follicular lymphoma, 
ANC must be t 1000 cells/PL 
 
o Platelet count t 75,000/PL 
 
▪ 
If there is documented bone marrow involvement of follicular lymphoma, 
platelet count must be t 50,000/PL 
 
o Hemoglobin t 9.0 g/dL 
 
▪ 
If there is documented bone marrow involvement of follicular lymphoma, 
hemoglobin must be t 8.0 g/dL 
 
o Total bilirubin d 1.5 u upper limit of normal (ULN) 
 
▪ 
Patients with known Gilbert disease who have serum bilirubin 
level d 3 u ULN may be enrolled. 


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o AST and ALT d 3.0 u ULN 
▪ 
Patients with liver involvement:  AST and/or ALT d 5 u ULN 
 
o Alkaline phosphatase d 3 u ULN 
 
▪ 
Patients with documented liver involvement or bone metastases: 
alkaline phosphatase d 5 u ULN 
 
o Serum creatinine d 1.5 u ULN or creatinine clearance t 30 mL/min on the basis 
of the Cockcroft-Gault glomerular filtration rate estimation: 
 
▪ 
(140   age) u (weight in kg) u (0.85 if female) 
72 u (serum creatinine in mg/dL) 
 
 
For female patients of childbearing potential and male patients with partners of childbearing 
potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception 
(i.e., one that results in a low failure rate [ 1% per year] when used consistently and correctly) 
and to continue its use for 5 months after the last dose of ATEZOLIZUMAB. Women must 
refrain from donating eggs during this same period. 
 
o A woman is considered to be of childbearing potential if she is postmenarcheal, 
has not reached a postmenopausal state (t 12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another 
cause as determined by the investigator (e.g., Müllerian agenesis). The definition 
of childbearing potential may be adapted for alignment with local guidelines or 
regulations. 
o  Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit 
ovulation, hormone-releasing intrauterine devices, and copper intrauterine 
devices. 
 
o 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. If required per local 
guidelines or regulations, locally recognized acceptable methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 
 
 
Willingness to undergo on-treatment biopsies unless not clinically feasible while on treatment 
 
 
 
6.2 
Subject Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry. 
 
General Exclusion Criteria: 
 
Follicular lymphoma grade 3B 


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Concurrent aggressive non-Hodgkin lymphoma (eg, diffuse large B cell lymphoma [DLBCL]) 
 
 
Any anticancer therapy, including chemotherapy, hormonal therapy, investigational therapy, 
or radiotherapy, within 3 weeks, or 5 half lifes, whichever is shortest, prior to initiation of study 
treatment.  However, the following are allowed: 
 
o Hormone-replacement therapy or oral contraceptives 
 
o Herbal therapy, provided it is discontinued at least 1 week  prior to Cycle 1, Day 1 
 
o Palliative radiotherapy for bone metastases, provided most recent fraction not given 
within  2 weeks  of Cycle 1, Day 1 and most recent fraction was not administered to 
planned area of radiation while on study. 
 
AEs from prior anticancer therapy that have not resolved to Grade d 1, with exception of alopecia 
or skin/nail hyperpigmentation. 
 
Bisphosphonate therapy for symptomatic hypercalcemia within 2 weeks of cycle 1, day 1 
 
o Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) 
is allowed.  Denosumab should not be used while on therapy (see section 9.2.2) 
 
 
Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; 
cirrhosis; fatty liver; and inherited liver disease 
 
 
Active central nervous system (CNS) involvement of lymphoma. 
 
o Patients with a history of CNS involvement of lymphoma are eligible, provided they 
received treatment greater than 30 days prior to cycle 1 day 1 and there is no evidence of 
involvement on most recent assessment. 
 
Pregnant or breastfeeding, or intention of becoming pregnant during study treatment or within 5 
month after the final dose of study treatment. 
 
o Women of childbearing potential must have a negative serum pregnancy test result within 
30 days prior to initiation of study treatment. 
 
 
Known hypersensitivity to Chinese hamster ovary cell products, other recombinant human 
antibodies, or to any component of the atezolizumab formulation. 
 
Inability to comply with study and follow-up procedures 
 
 
Active or history of autoimmune disease, including but not limited to myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel 
disease, vascular thrombosis associated with antiphospholipid syndrome, 
Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple 
sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis 
 
o Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
 
o Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be 
eligible. 
 
o Patients with inactive inflammatory bowel disease, not currently receiving therapy, 
may be eligible. 


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o Patients with eczema, psoriasis, lichen simplex chronicus or vitiligo with dermatologic 
manifestations only (e.g., patients with psoriatic arthritis would be excluded) are 
permitted provided that they meet the following conditions: 
 
▪ 
Rash must cover less than 10% of body surface area (BSA) 
 
▪ 
Disease is well controlled at baseline and only requiring low potency 
topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%) 
 
▪ 
No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral 
steroids) 
 
History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing 
pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of 
active pneumonitis on screening chest computed tomography (CT) scan 
 
o History of radiation pneumonitis is permitted provided patient is asymptomatic and did 
not require systemic or inhaled corticosteroids for treatment of symptomatic radiation 
pneumonitis. 
 
Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory 
finding giving reasonable suspicion of a disease or condition that contraindicates the use of an 
investigational drug or that may affect the interpretation of the results or render the patient at 
high risk from treatment complications 
 
History of HIV infection or active hepatitis B (chronic or acute) or hepatitis C infection 
 
o Patients with past or resolved hepatitis B infection (defined as having a negative 
hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis 
B core antigen] antibody test) are eligible. 
 
o Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction (PCR) is negative for HCV RNA. 
 
 
Active tuberculosis 
 
 
Severe infections within 4 weeks prior to Cycle 1, Day 1, including but not limited 
to hospitalization for complications of infection, bacteremia, or severe pneumonia 
 
Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a 
major surgical procedure during the course of the study 
 
Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1, within 5 
months after the final dose, or anticipation that such a live, attenuated vaccine will be required 
during the study 
 
o Influenza vaccination should be given during influenza season only 
(approximately October to March).  Patients must not receive live, attenuated 
influenza vaccine (e.g., FluMist£) within 4 weeks prior to Cycle 1, Day 1 or at any time 
during the study. 
 
Malignancies other than the disease under study within 3 years prior to Cycle 1, Day 1, with 
the exception of those with a negligible risk of metastasis or death and with expected curative 


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outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin 
cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in 
situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care 
management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason 
score d 6, and prostate-specific antigen [PSA] d 10 mg/mL, etc.) 
 
Medication Related Exclusion Criteria 
 
 
Prior treatment with anti PD-1, or anti PD-L1 therapeutic antibody or pathway-targeting agents. 
Patients who have received prior treatment with anti CTLA-4 may be enrolled, provided the 
following reqirements are met: 
o Minimum of 12 weeks from the first dose of anti CTLA-4 and ! 6 weeks from the last 
dose 
 
o No history of severe immune-related adverse effects from anti CTLA-4 (NCI CTCAE 
Grade 3 and 4) 
 
 
Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN]-D 
or interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to 
Cycle 1, Day 1 
 
Treatment with systemic immunosuppressive medications (including but not limited to 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis 
factor [anti-TNF] agents) within 1 week prior to Cycle 1, Day 1 
 
o Patients who have received acute, low-dose, systemic immunosuppressant 
medications (e.g., a one-time dose of dexamethasone for nausea or prednisone for 
intravenous contrast allergy) may be enrolled. 
 
o Palliative systemic steroids for palliation of disease are allowed but must be 
discontinued at least 7 days prior to cycle 1, day 1 
 
o The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
 
 
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins 
 
Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation 
 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s treatment team, the 
protocol investigator, or research team. If the investigator is a member of the treatment team s/he 
will screen their patient’s medical records for suitable research study participants and discuss the 
study and their potential for enrolling in the research study. Furthermore, eligible patients from the 
lymphoma services will be identified by investigators at the time of medical disciplinary rounds or in 
clinic at Memorial Sloan Kettering Cancer Center. 
 
8.0 
PRETREATMENT EVALUATION 


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Pretreatment evaluations will be performed according to study flowchart in Appendix 1. 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
9.1 Atezolizumab administration 
Atezolizumab will be administered on an every 21-day (+/-2 days) dosing schedule. Atezolizumab 
will be initiated at 1200mg IV for a planned total of 17 cycles of therapy.  Dose modification or 
treatment interruption/discontinuation may occur as described in section 9.2. 
 
For patients assigned to receive atezolizumab and low-dose radiotherapy, 4Gy will be administered 
in 2 fractions, on days 2 and 3 of cycle 1, to a single nodal site amenable to radiation as identified by 
the radiation oncologist (see section 5.2). 
 
9.2 Concomitant and Excluded Therapies 
 
9.2.1 Concomitant Therapy 
Concomitant therapy includes any prescription medications or over-the-counter preparations used 
by a patient between the 14 days preceding the screening evaluation and the treatment 
discontinuation visit. 
 
Patients who experience infusion-associated symptoms may be treated symptomatically with 
acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor antagonist, 
as per standard practice (for sites outside the United States, equivalent medications may be 
substituted per local practice).  Serious infusion-associated events manifested by dyspnea, 
hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory 
distress should be managed with supportive therapies as clinically indicated (e.g., supplemental 
oxygen and 2-adrenergic agonists. 
 
Systemic corticosteroids and Con TNF inhibitors may attenuate potential beneficial immunologic 
effects of treatment with ATEZOLIZUMAB but may be administered at the discretion of the treating 
physician.  If feasible, alternatives to corticosteroids should be considered.  Premedication may be 
administered for Cycles  2 at the discretion of the treating physician.  The use of inhaled 
corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension 
or adrenocortical insufficiency is allowed.  Megastrol administered as appetite stimulant is 
acceptable while the patient is enrolled in the study. 
 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or therapeutic 
anticoagulation therapy (such as low-molecular-weight heparin or warfarin at a stable dose level), or 
other allowed maintenance therapy (see Section 6.2) should continue their use.  Males and females 
of reproductive potential should use highly effective means of contraception. 


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9.2.2 Excluded Therapy 
 
Any concomitant therapy intended for the treatment of cancer, whether health authority approved or 
experimental, is prohibited. This includes but is not limited to the following: 
 
G-CSF solely to maintain the ANC and not associated with the treatment of a documented or 
suspected infection in the setting of febrile neutropenia 
 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational agents, or 
herbal therapy 
 
Traditional herbal medicines should not be administered because the ingredients of many 
herbal medicines are not fully studied and their use may result in unanticipated drug-drug 
interactions (DDIs) that may cause or confound assessment of toxicity. 
 
The following therapies are excluded while patients are receiving atezolizumab and for 10 weeks 
after the last dose of atezolizumab: 
 
Patients who are receiving a RANKL inhibitor (denosumab) prior to enrollment must be willing 
and eligible to receive a bisphosphonate instead; denosumab could potentially alter the activity 
and the safety of atezolizumab. 
 
Patients are not allowed to receive immunostimulatory agents, including but not limited to IFN-α, 
IFN-γ, or IL-2. These agents, in combination with atezolizumab, could potentially increase the 
risk for autoimmune conditions. 
 
Patients should not receive other immunostimulatory agents for 10 weeks after the last dose of 
atezolizumab. 
 
Patients should not receive immunosuppressive medications, including but not limited to 
cyclophosphamide, azathioprine, and methotrexate. These agents could potentially alter the 
activity and the safety of atezolizumab.  Systemic corticosteroids and anti TNF agents may 
attenuate potential beneficial immunologic effects of treatment with atezolizumab but may be 
administered at the discretion of the treating physician.  If feasible, alternatives to these agents 
should be considered. 
 
Patients must not receive live, attenuated influenza vaccine (e.g., FluMist£) within 4 weeks prior 
to Cycle 1, Day 1 or at any time during the study.  Inactivated vaccines are allowed. 
In addition, the investigator should contact the Medical Monitor if questions arise regarding 
medications not listed above. 
 
9.3 Guidelines for Dosage Modification and Treatment Interruption or Discontinuation 
ATEZOLIZUMAB treatment will be given as long as the patient continues to experience clinical 
benefit in the opinion of the investigator until the earlier of unacceptable toxicity, symptomatic 
deterioration attributed to disease progression, or any of the other reasons for treatment 
discontinuation listed in Section 13.1. 
 
There will be no dose reduction for ATEZOLIZUMAB in this study.  Patients may temporarily 
suspend study treatment for up to 42 days beyond the scheduled date of delayed infusion if study 
drug-related toxicity requiring dose suspension is experienced.  If ATEZOLIZUMAB is held because 


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of AEs for ! 42 days beyond the scheduled date of infusion, the patient will be discontinued from 
ATEZOLIZUMAB and will be followed for safety and efficacy as specified in Section 10.2 and 10.3. 
 
If a patient must be tapered off steroids used to treat AEs, ATEZOLIZUMAB may be held for 
additional time beyond 42days from the scheduled dose until steroids are discontinued or reduced to 
a prednisone dose (or dose equivalent) of d 10 mg/day.  The acceptable length of interruption will be 
at the discretion of the investigator. 
 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be allowed. 
The acceptable length of interruption will be at the discretion of the Principal Investigator. 
 
Any toxicities associated or possibly associated with ATEZOLIZUMAB treatment should be 
managed according to standard medical practice. Additional tests, such as autoimmune serology or 
biopsies, may be used to determine a possible immunogenic etiology.  Although most irAEs 
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 there is no available antidote 
for ATEZOLIZUMAB.  In severe cases, immune-related toxicities may be acutely managed with 
topical corticosteroids, systemic corticosteroids, or other immunosuppressive agents. 
 
Patients should be assessed clinically (including review of laboratory values) for toxicity prior to, 
during, and after each infusion.  If unmanageable toxicity due to ATEZOLIZUMAB occurs at any time 
during the study, treatment with ATEZOLIZUMAB should be discontinued. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 Study Assessments 
The flowchart of scheduled study assessments is provided in Appendix 1. 
 
Patients will be closely monitored for safety and tolerability throughout the study.  All assessments 
must be performed and documented for each patient. 
 
10.1 Laboratory/ Pathology Assessments 
Samples for hematology, serum chemistries, coagulation, urinalysis, and the pregnancy test will be 
analyzed at the study site’s local laboratory.  Analysis of biomarkers on tumor and blood samples 
will be performed on site. Refer to section 12.2 and Appendix 9 for correlative studies workflow. 
 
 
The following assessments will be performed at Memorial Sloan-Kettering Cancer Center: 
 
 
Baseline tumor biopsy 
 
o All patients will undergo a baseline tumor biopsy sample collection within 30 
days of registration. 
 
▪ 
If the patient has recently undergone a biopsy and has not received 
any intercurrent anti-lymphoma therapy, archival tissue can be used 


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o Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes 
or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or 
mucosal lesions. 
 
o Every intention should be made to collect the pre treatment biopsy from the same site 
that will be radiated. The on protocol biopsy should be in the same location unless 
clinically unfeasible or not in the interest of the patient’s safety. 
 
On-treatment tumor biopsy 
 
o All patients will undergo an on-treatment tumor biopsy sample collection, if clinically 
feasible, during Cycle 2 (as per study flowchart in Appendix 1). 
 
o Acceptable samples include fine needle aspirations or core needle biopsies for deep 
tumor tissue or lymph nodes or excisional, incisional, punch, or forceps biopsies for 
cutaneous, subcutaneous, or mucosal lesions. Core needle biopsies are preferred. 
 
o The tissue will be used for correlative investigations. 
 
Tumor biopsy at the time of initial radiographic progression (This tumor biopsy is  optional based 
on whether it is feasible to obtain enough tissue at the site and therefore, ‘clinically 
indicated/feasible’, and not optional for the patient to choose whether or not they want one for 
the study) 
 
o Patients may undergo a tumor biopsy sample collection, if clinically feasible, at the first 
evidence of early radiographic disease progression (i.e., not preceded by meaningful 
tumor regression). Biopsy at time of initial radiographic progression is recommended but 
not mandatory. 
 
o Acceptable samples include fine needle aspirations or core needle biopsies for deep 
tumor tissue or lymph nodes or excisional, incisional, punch, or forceps biopsies for 
cutaneous, subcutaneous, or mucosal lesions. 
 
o If CT-guided is necessary for the investigational on-treatment biopsy, the average tissue 
radiation dose resulting from CT-guided biopsy procedures is 4.56 mGy. 
 
 
10.2 Treatment Discontinuation Visit 
Patients who discontinue from treatment will be asked to return to the clinic no more than 30 days 
after the last treatment for a treatment discontinuation visit.  The visit at which a response 
assessment shows progressive disease may be used as the treatment discontinuation visit. 
 
10.3 Follow-Up Assessments 
Patients who discontinue early from treatment or who complete the study treatment period will be 
followed as outlined below. If disease progression is clinically suspected, this should be 
confirmed by radiological examination as soon as possible.  For patients who are being 
treated beyond progression, see Appendix 4 for the frequency of imaging assessments to 
monitor response. 
 
10.4 Post-Treatment Evaluations 
Patients who discontinue study treatment for reasons other than PD (e.g., toxicity) should continue 
to undergo the full tumor assessment 6 8 weeks after study treatment is discontinued and 


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every six months thereafter until the patient dies, experiences PD, withdraws consent, or until the 
study closes, whichever occurs first.  Patients who start a new anticancer therapy in the absence of 
PD should continue to be followed for progression according to the protocol schedule unless 
consent is withdrawn, the patient dies, or the study closes, whichever occurs first. 
 
For patients who experience PD or who discontinue the study treatment due to an AE or SAE, full 
tumor assessment should be obtained within 30 days after the last dose of study treatment or before 
another anticancer therapy is initiated.  Additional required tests for these patients are outlined in 
Appendix 1. 
 
Patients that drop out prior to evaluation due to PD, AE, SAE will be assessed for survival and 
toxicity every 3 months until the start of new anti-lymphoma therapy. 
 
Female patients of reproductive potential who are not surgically sterile must practice adequate birth 
control for a minimum of twelve months post-treatment; male patients who are not surgically sterile 
must practice adequate birth control for a minimum of three months post-treatment. 
 
10.5 Survival and Subsequent Anticancer Therapy 
Survival follow-up information will be collected via telephone calls, patient medical records, and/or 
clinic visits approximately every 3 months until death, loss to follow-up, or study termination by the 
funding source of Principal Investigator.  All patients who have discontinued treatment without 
disease progression will undergo all follow-up exams noted in Appendix 1 during follow-up.  All other 
patients will be followed for survival and new anticancer therapy information only, unless the patient 
requests to be withdrawn from follow-up (this request must be documented in the source documents 
and signed by the investigator). If the patient withdraws from study treatment but not from follow-up, 
the study staff may use a public information source (e.g., county records) to obtain information about 
survival status only. 
 
10.6 End of Study 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date 
at which the last data point required for statistical analysis (i.e., efficacy analysis) or safety follow-up 
is received from the last patient, whichever occurs later.  LPLV is expected to occur 2 years after the 
last patient is enrolled. 
 
11.0 TOXICITIES/SIDE EFFECTS 
 
11.1 Definition of Adverse Event 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the 
use of an investigational medicinal product (IMP) or other protocol-imposed intervention, regardless 
of attribution. 


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This includes the following: 
 
 
AEs not previously observed in the patient that emerge during the protocol-specified AE 
reporting period, including signs or symptoms that were not present prior to the AE reporting 
period 
 
Complications that occur as a result of protocol-mandated interventions (e.g., invasive 
procedures such as cardiac catheterizations) 
 
If applicable, AEs that occur prior to assignment of study treatment associated with medication 
washout, no treatment run-in, or other protocol-mandated intervention 
 
Pre-existing medical conditions (other than the condition being studied) judged by the 
investigator to have worsened in severity or frequency or changed in character during the 
protocol-specified AE reporting period. 
 
 
An adverse event is considered serious if it: 
 
 
Results in death 
 
Is life-threatening 
 
Results in inpatient hospitalization of over 24 hours or prolongation of existing hospitalization 
 
Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
Results in a congenital anomaly/birth defect 
 
Is an Important Medical Event (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
  
 
Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
 
11.1.1 Adverse Events 
All AEs (including SAEs and protocol-defined events of special interest [see Section 6.2]), 
regardless of attribution, will be recorded until 30 days after the last dose of study treatment, until 
study discontinuation/termination, or until initiation of subsequent anticancer therapy, whichever 
occurs first.  After this period, investigators should report only those AEs (including 
pregnancy-related AEs) considered related to prior study treatment.  Ongoing AEs considered 
related to study treatment will be followed until one of the following conditions is met:  the event has 
resolved to baseline grade, the event is assessed by the investigator as stable, new anticancer 
treatment is initiated, the patient is lost to follow-up, the patient withdraws consent, or it has been 
determined that study treatment or participation is not the cause of the AE. 
 
See the Schedule of Assessments provided in Appendix 1for specified follow-up assessments. 


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11.1.2 Assessment of Adverse Events 
All AEs and SAEs, whether volunteered by the patient, discovered by study personnel during 
questioning, or detected through physical examination, laboratory test, or other means, will be 
reported appropriately. Each reported AE or SAE will be described by its duration (i.e., start and end 
dates), regulatory seriousness criteria if applicable, suspected relationship to the study drug (see 
following guidance), and actions taken. 
 
To ensure consistency of AE and SAE causality assessments, investigators should apply the 
following general guideline: 
Yes 
 
There is a plausible temporal relationship between the onset of the AE and administration of 
MDPL3280A, and the AE cannot be readily explained by the patient’s clinical state, intercurrent 
illness, or concomitant therapies; and/or the AE follows a known pattern of response to 
MDPL3280A; and/or the AE abates or resolves upon discontinuation of MDPL3280A or dose 
reduction and, if applicable, reappears upon re-challenge. 
 
No 
 
Evidence exists that the AE has an etiology other than MDPL3280A (e.g., pre-existing medical 
condition, underlying disease, intercurrent illness, or concomitant medication); and/or the AE 
has no plausible temporal relationship to ATEZOLIZUMAB administration (e.g., cancer 
diagnosed 2 days after first dose of study drug). 
 
Expected AEs are those AEs that are listed or characterized in the Package Insert (PI) or current 
Investigator’s Brochure. 
 
Unexpected AEs are those not listed in the PI or current Investigator’s Brochure or not identified. 
This includes AEs for which the specificity or severity is not consistent with the description in the PI 
or Investigator’s Brochure.  For example, under this definition, hepatic necrosis would be 
unexpected if the PI or Investigator’s Brochure only referred to elevated hepatic enzymes or 
hepatitis. 
 
11.1.3 Adverse Events of Special Interest 
 
Adverse events of special interest (AESIs) are defined as a potential safety problem, identified as a 
result of safety monitoring of the IMP. AESIs are a subset of Events to Monitor (EtMs) of scientific 
and medical concern specific to the product, for which ongoing monitoring and rapid communication 
by the Investigator to the Sponsor is required. Such an event might require further investigation in 
order to characterize and understand it. Depending on the nature of the event, rapid communication 
by the trial Sponsor to other parties (e.g., Regulatory Authorities) may also be warranted. 
 
The following AEs are considered of special interest and must be reported to the Genentech Drug 
Safety expeditiously (see Section 17.2 for reporting instructions), irrespective of regulatory 
seriousness criteria: 


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Adverse events of special interest for this study include the following: 
 
 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in combination 
with either an elevated bilirubin or clinical jaundice, as defined by Hy’s law: 
 
Treatment-emergent ALT or AST > 3xULN in combination with total bilirubin > 2xULN 
 
Treatment-emergent ALT or AST > 3xULN in combination with clinical jaundice 
o Data related to a suspected transmission of an infectious agent by the study drug 
(STIAMP), as defined below: 
▪ 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product. This term applies only 
when a contamination of the study drug is suspected 
 
 
Pneumonitis 
 
 
Colitis 
 
 
Endocrinopathies:  Diabetes mellitus, pancreatitis, adrenal insufficiency, hyperthyroidism, and 
hypophysitis 
 
 
Hepatitis, including AST or ALT > 10xULN 
 
 
Systemic lupus erythematsus (SLE) 
 
 
Guillain-Barré syndrome 
 
 
Myasthenia gravis or myasthenic syndrome 
 
 
Meningoencephalitis 
 
 
Nephritis 
 
 
Myositis 
 
 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
 
Myopathies, including rhabdomyolysis 
 
Grade >/=2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
Vasculitis 
 
Autoimmune hemolytic anemia 
 
Severe cutaneous reactions (e.g. Stevens-Johnson Syndrome, dermatitis bullous, toxic 
epidermal necrolysis) 
 
Events suggestive of hypersensitivity, cytokine release, influenza like illness, systemic inflammatory 
response syndrome, SIA(systemic immune activation) or infusion reaction syndromes 
 
11.1.4 Post- Study Adverse Events 
The investigator should expeditiously report any SAE occurring after a patient has completed or 
discontinued study participation if attributed to prior ATEZOLIZUMAB exposure.  If the investigator 
should become aware of the development of cancer or a congenital anomaly in a subsequently 


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conceived offspring of a female patient who participated in the study, this should be reported as an 
SAE. adequately to Genentech Drug Safety during the follow-up period. 
 
11.1.5 Specific Instructions for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs.  Avoid 
colloquialisms and abbreviations. For more information, refer to Section 17.2. 
 
Eliciting Adverse Events 
 
A consistent methodology for eliciting AEs at all subject evaluation time points should be adopted. 
Examples of non-directive questions include: 
 
 
“How have you felt since your last clinical visit?” 
 
 
“Have you had any new or changed health problems since you were last here?” 
 
 
 
 
Specific Instructions for Recording Adverse Events 
 
Investigators should use correct medical terminology/concepts when reporting AEs or SAEs. Avoid 
colloquialisms and abbreviations. (See Section 11.3-11.7) 
 
 
 
 
Exchange OF SINGLE CASE REPORTS 
 
Memorial Sloan Kettering (MSK) will be responsible for collecting all protocol-defined Adverse 
Events (AEs) and Special Situation Reports (including pregnancy reports) originating from the Study 
for the Product. 
 
Investigators must report all Adverse Events/Serious Adverse events (SAEs), AEs of Special 
Interest (AESIs)  and Special Situation Reports (including pregnancy reports) adequately to 
Genentech within the timelines described below. The completed MedWatch or CIOMS I form or 
Genentech approved reporting forms should be faxed immediately upon completion to Genentech 
Drug Safety at: 
 
Fax: 650-238-6067 
 
Email:  usds_aereporting-d@gene.com 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available and/or upon request. 
 
MEDWATCH 3500A REPORTING GUIDELINES 


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In addition to completing appropriate patient demographic and suspect medication information, the 
report should include the following information within the Event Description (section 5) of the 
MedWatch 3500A form: 
 
 
Protocol description (and number, if assigned) 
 
 
Description of event, severity, treatment, and outcome if known 
 
 
Supportive laboratory results and diagnostics 
 
 
Investigator’s assessment of the relationship of the adverse event to each investigational product 
and suspect medication 
 
Follow-Up Information 
 
Additional information may be added to a previously submitted report by any of the following 
methods: 
 
 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
 
 
Adding supplemental summary information and submitting it as follow-up with the original 
MedWatch 3500A form 
 
 
Summarizing new information and faxing it with a cover letter including patient identifiers (i.e. 
D.O.B. initial, patient number), protocol description and number, if assigned, brief adverse event 
description, and notation that additional or follow-up information is being submitted (The patient 
identifiers are important so that the new information is added to the correct initial report) 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsFo rms/Forms/UCM048334.pdf 
 
 
 
 
Reporting to Regulatory Authorities, Ethics Committees and Investigators 
 
MSK, as the Sponsor of the Study, will be responsible for the expedited reporting of safety reports 
originating from the Study to the Regulatory Authorities (FDA) where it has filed a clinical trial 
approval, in compliance with local regulations. 
 
Sponsor will be responsible for the distribution of safety information to its own investigators, where 
relevant 
 
Additional Reporting Requirements for IND Holders (if applicable): 


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For Investigator-Initiated IND Studies, some additional reporting requirements for the FDA apply in 
accordance with the guidance set forth in 21 CFR §600.80. 
 
Events meeting the following criteria need to be submitted to the Food and Drug Administration 
(FDA) as expedited IND Safety Reports according to the following guidance and timelines: 
 
 
 
 
7 Calendar Day Telephone or Fax Report: 
 
The Investigator is required to notify the FDA of any fatal or life-threatening adverse event that is 
unexpected and assessed by the Investigator to be possibly related to the use of atezolizumab. An 
unexpected adverse event is one that is not already described in the atezolizumab Investigator 
Brochure. Such reports are to be telephoned or faxed to the FDA and Genentech/Roche within 7 
calendar days of first learning of the event. 
 
 
 
 
15 Calendar Day Written Report 
 
The Investigator is also required to notify the FDA and all participating investigators, in a written IND 
Safety Report, of any serious, unexpected AE that is considered reasonably or possibly related to 
the use of atezolizumab. An unexpected adverse event is one that is not already described in the 
atezolizumab investigator brochure. 
 
Written IND Safety reports should include an Analysis of Similar Events in accordance with 
regulation 21 CFR 
 
§ 312.32. All safety reports previously filed by the investigator with the IND concerning similar events 
should be analyzed and the significance of the new report in light of the previous, similar reports 
commented on. 
 
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, 
Genentech/Roche, and all participating investigators within 15 calendar days of first learning of the 
event. The FDA prefers these reports on a MedWatch 3500 form, but alternative formats are 
acceptable (e.g., summary letter). 
 
 
 
 
FDA fax number for IND Safety Reports: 
Fax: 1 (800) FDA 0178 
All written IND Safety Reports submitted to the FDA by the Investigator must also be faxed to 
Genentech/Roche Drug Safety: 


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Fax: (650) 225-4682 or (650) 225-4630 
 
 
 
 
And Sponsor will be responsible for the distribution of safety information to Site IRB 
 
Tel: (212) 639-7592 
 
Fax: (212) 888-0940 
 
 
 
 
For questions related to safety reporting, please contact Genentech/Roche Drug Safety: 
Tel: (888) 835-2555 
Fax: (650) 225-4682 or (650) 225-4630 
 
 
 
 
AGGREGATE REPORTS 
IND ANNUAL REPORTS 
All IND annual reports submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech 
 
Copies of such reports should be emailed to Genentech at: Genentech Drug Safety CTV mail box: 
ctvist_drugsafety@gene.com 
 
Sponsor  will forward a copy of the Final Study Report to Genentech/Roche upon completion of the 
Study. 
 
QUERIES 
 
Queries related to the Study will be answered by Sponsor. However, responses to all  safety 
queries from regulatory authorities or for publications will be discussed and coordinated between 
the Parties. The Parties agree that Genentech/Roche shall have the final say and control over safety 
queries relating to the Product. Sponsor agrees that it shall not answer such queries from regulatory 
authorities and other sources relating to the Product independently but shall redirect such queries to 
Genentech/Roche. 
 
Both Parties will use all reasonable effort to ensure that deadlines for responses to urgent requests 
for information or review of data are met. The Parties will clearly indicate on the request the reason 
for urgency and the date by which a response is required. 


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SAFETY CRISIS MANAGEMENT 
 
In case of a safety crisis, e.g., where safety issues have a potential impact on the indication(s), on 
the conduct of the Study, may lead to labeling changes or regulatory actions that limit or restrict the 
way in which the Product is used, or where there is media involvement, the Party where the crisis 
originates will contact the other Party as soon as possible. 
 
The Parties agree that Genentech/Roche shall have the final say and control over safety crisis 
management issues relating to the Product. Sponsor agrees that it shall not answer such queries 
from media and other sources relating to the Product but shall redirect such queries to 
Genentech/Roche 
 
11.2 Risks Associated with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase 
the risk of immune-related AEs, specifically the induction or enhancement of autoimmune conditions. 
AEs with potentially immune-related causes, including rash, hypothyroidism, hepatitis/transaminitis, 
colitis, myositis, and myasthenia gravis, have been observed in Study PCD4989g.  Although most 
immune-related AEs observed with immunomodulatory agents have been mild and self-limiting, 
such events should be recognized early and treated promptly to avoid potential major complications 
(Di Giacomo et al. 2010). 
 
A more detailed safety profile of ATEZOLIZUMAB is provided in the ATEZOLIZUMAB Investigator’s 
Brochure. 
 
11.2.1. Management of Specific Safety Concerns with ATEZOLIZUMAB 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase 
the risk of immune-mediated adverse events, specifically the induction or enhancement of 
autoimmune conditions or systemic immune activation .  Adverse events with potentially 
immune-related causes, including rash, hypothyroidism, hepatitis or elevated transaminase, colitis, 
myositis, and myasthenia gravis have been observed in Study PCD4989g. 
 
For further details regarding clinical safety and a more comprehensive list of observed adverse 
events with atezolizumab, see the Atezolizumab Investigator’s Brochure. 
 
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 (Di Giacomo et al., 2010).  Suggested workup and management 
guidelines for suspected immune-mediated adverse events are provided in Section 6 (Guidance for 
the Investigator) of the Atezolizumab Investigator’s Brochure. 
 
11.2.2 Management of Patients Who Experience Atezolizumab Specific Adverse Events 
Guidelines for management of specific adverse events listed below are outlined in the Atezolizumab 
Investigator’s Brochure. 
 
Gastrointestinal toxicity 


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Hepatotoxicity 
 
 
Dermatologic toxicity 
 
 
Endocrine toxicity 
 
 
Pulmonary toxicity 
 
 
Potential pancreatic toxicity 
 
 
Potential ocular toxicity 
 
 
Neurologic toxicity 
 
 
Immune-related nephritis 
 
 
Immune-related myositis 
 
11.2.3 Management of Systemic Immune Activation 
Systemic immune activation (SIA) is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, SIA is considered a potential risk when 
given in combination with other immunomodulating agents.  SIA should be included in the differential 
diagnosis for patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the following: 
 
CBC with peripheral smear 
 
 
PT, PTT, fibrinogen, and D-dimer 
 
 
Ferritin 
 
 
Triglycerides 
 
 
AST, ALT, and total bilirubin 
 
 
LDH 
 
 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If SIA is still suspected after the initial evaluation, contact the Medical Monitor for additional 
recommendations. 
 
Diagnostic criteria and recommended management of SIA is described in the table below (Table 2). 
 
Table 2. Diagnostic Criteria and Management for Systemic Immune Activation 


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11.2.4 Infusion Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and are judged 
to be related to study drug infusion should be captured as a diagnosis (e.g., infusion related 
reaction) on the Adverse Event eCRF. If possible, avoid ambiguous terms such as "systemic 
reaction."  If a patient experiences both a local and systemic reaction to the same dose of study 
drug, each reaction should be recorded separately on the Adverse Event eCRF. 
 
The management of IRRs will be according to severity as follows: 
 
 
In the event that a patient experiences a mild (NCI CTCAE Grade 1) IRR, the infusion rate 
should be reduced to half the rate being given at the time of event onset. Once the event has 
resolved, the investigator should wait for 30 minutes while delivering the infusion at the reduced 
rate.  If tolerated, the infusion rate may then be increased to the original rate. 
 
In the event that a patient experiences a moderate IRR (NCI CTCAE Grade 2) or flushing, 
fever, or throat pain, the infusion should be immediately interrupted and the patient should 
receive aggressive symptomatic treatment. The infusion should be restarted only after the 
symptoms have adequately resolved to baseline grade. The infusion rate at restart should be 
half of the infusion rate that was in progress at the time of the onset of the IRR. 
 
For severe or life-threatening IRRs (NCI CTCAE Grade 3 or 4), the infusion should be stopped 
immediately, and aggressive resuscitation and supportive measures should be initiated. 
Patients experiencing severe or life-threatening IRRs will not receive further infusion and will be 
further managed as clinically indicated until the event resolves. 


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For anaphylaxis precautions, see Appendix 7. 
 
 
 
 
11.2.5 Safety Reconciliation 
MSK agrees to conduct the Case Transmission verification to ensure that all single case reports 
have been adequately received by Genentech via MSK emailing Genentech a quarterly line-listing 
documenting single case reports sent by MSK to Genentech in the preceding time period. 
 
The periodic line-listing will be exchanged within seven (7) calendar days of the end of the agreed 
time period. Confirmation of receipt should be received within the time period mutually agreed upon. 
 
If discrepancies are identified, MSK and Genentech will cooperate in resolving the discrepancies. 
The responsible individuals for each party shall handle the matter on a case-by-case basis until 
satisfactory resolution. The sponsor shall receive reconciliation guidance documents within the 
‘Activation Package’. 
 
Following Case Transmission Verification, single case reports which have not been received by 
Genentech shall be forwarded by MSK to Genentech within five (5) calendar days from request by 
Genentech. 
 
At the end of the study, a final cumulative Case Transmission Verification report will be sent to 
Genentech 
 
 
 
 
11.3 Diagnosis Versus Signs and Symptoms 
For adverse events other than infusion-related reactions, 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 report based on the single 
diagnosis, with a starting date that corresponds to the starting date of the first symptom of the 
eventual diagnosis. 
 
11.4 Deaths 
All deaths that occur during the protocol-specified AE reporting period (see Section 17.2), regardless 
of attribution, will be reported to the appropriate parties. When recording a death, the event or 
condition that caused or contributed to the fatal outcome should be reported as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, report 
“Unexplained Death.”  Deaths that occur during the protocol-specified adverse event reporting 


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period (see Section 17.2) that are attributed by the investigator solely to progression of disease 
should be recorded only in the study {e}CRF. 
 
11.5 Pre- existing Medical Conditions 
A pre-existing medical condition is one that is present at the start of the study.  Such conditions 
should be reported as medical and surgical history.  A pre-existing medical condition should be re- 
assessed throughout the trial and reported as an AE or SAE only if the frequency, severity, or 
character of the condition worsens during the study. When reporting such events, it is important to 
convey the concept that the pre-existing condition has changed by including applicable descriptors 
(e.g., “more frequent headaches”). 
 
11.6 Hospitalizations for Medical or Surgical Procedures 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE. If a patient is hospitalized to undergo a medical or surgical procedure as a 
result of an AE, the event responsible for the procedure, not the procedure itself, should be reported 
as the SAE.  For example, if a patient is hospitalized to undergo coronary bypass surgery, record the 
heart condition that necessitated the bypass as the SAE. 
 
Hospitalizations for the following reasons do not require reporting: 
 
 
Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for 
pre-existing conditions, 
 
Hospitalization or prolonged hospitalization required to allow efficacy measurement for the 
study, or 
Hospitalization or prolonged hospitalization for scheduled therapy of the target disease of the 
study. 
 
11.6.1 Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the investigator if 
they become pregnant during the study or within 5 Months after the last dose of study drug.  A 
Pregnancy Report CRF should be completed by the investigator immediately (i.e., no more than 
24 hours after learning of the pregnancy) and submitted via fax.  A pregnancy report will 
automatically be generated and sent to Genentech Drug Safety.  Pregnancy should not be recorded 
on the Adverse Event CRF. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as serious, 
and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in a child born 
to a female subject exposed to the study drug should be reported as an SAE The investigator 
should discontinue study drug and counsel the patient, discussing the risks of the pregnancy and the 
possible effects on the fetus.  Monitoring of the patient should continue until conclusion of the 
pregnancy.  Any SAEs associated with the pregnancy (e.g., an event in the fetus, an event in the 
mother during or after the pregnancy, or a congenital anomaly/birth defect in the child) should be 
reported on the Adverse Event CRF. 


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A Clinical Trial Pregnancy Reporting Form and fax cover sheet should be completed and faxed to 
Genentech Drug Safety or its designee immediately (i.e., no more than 24 hours after learning of the 
pregnancy), using the fax numbers provided to investigators (see "Protocol Administrative and 
Contact Information & List of Investigators" ) 
 
11.6.2 Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the ICF to immediately inform the investigator if their partner 
becomes pregnant during the study. 
 
ATEZOLIZUMAB Male patients who received study treatment should not attempt to father a child 
until end of study.  A Pregnancy Report CRF should be completed by the investigator immediately 
(i.e., no more than 24 hours after learning of the pregnancy) and faxed to Genentech Drug Safety. 
 
11.6.3 Abortions 
Any spontaneous abortion should be classified as an SAE (as the Principal Investigator considers 
spontaneous abortions to be medically significant events), recorded on the Adverse Event CRF, and 
reported to Genentech Drug Safety immediately (i.e., no more than 24 hours after learning of the 
event; see Section 17.2). 
 
11.6.4 Congenital Anomalies/ Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient or female partner of a male 
patient exposed to study drug should be classified as an SAE, recorded on the Adverse Event CRF, 
and reported to Genentech Drug Safety immediately (i.e., no more than 24 hours after learning of 
the event; see Section 17.2). 
 
11.7 Serious Adverse Events 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
 
Death 
 
A life-threatening adverse event 
 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
 
A congenital anomaly/birth defect 
 
Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
The adverse event severity grading scale for the NCI CTCAE v5.0 will be used for assessing 
adverse event severity. Below Table should be used for assessing severity for adverse events that 
are not specifically listed in the NCI CTCAE. 


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Adverse Event Severity Grading Scale for Events Not Specifically Listed in 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 
age̻appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life̻threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or limiting 
self̻care activities of daily living b,c 
4 
Life-threatening consequences or urgent intervention indicated 
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 (v5.0), w hich 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 w ho are not bedridden. 
 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
 
d. 
Grade 4 and 5 events must be reported as serious adverse events 
  
 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 Tumor and Response Evaluation 
Any evaluable or measurable disease must be documented at screening and reassessed at each 
subsequent tumor evaluation. Irradiated sites of disease, previously irradiated lesions, or lesions that 
are intended to be used to collect tissue samples for biopsy should not be counted as target lesions. 
Response will be assessed by the investigator per the Lugano Classification (Cheson et al, 2014; 
see Appendix 4) at tumor assessment timepoints (see Appendix 5). 
 
 
Site of disease deemed amenable to low-dose, local radiotherapy (2 x 2Gy) should not be 
counted as target lesions. 


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
Previously irradiated lesions should not be counted as target lesions.
 
 
 
 
Lesions that are intended to be used to collect tissue samples for biopsy should not be counted 
as target lesions. 
 
Bone lesions should not be counted as target lesions. 
 
 
 
12.1.1 Outcome Measures 
Response will be assessed by the investigator using the Lugano Classification (see Appendix 4). 
 
12.1.2 Primary Efficacy Outcome Measure 
Objective response rate of atezolizumab alone and of atezolizumab with low-dose, local 
radiotherapy (objective response defined as CR or PR; as measured in non-irradiated sites of 
disease). 
 
12.1.3 Secondary Efficacy Outcome Measure 
Progression-free survival and overall survival of atezolizumab alone and of atezolizumab with low- 
dose, local radiotherapy (as measured in non-irradiated sites of disease). 
 
12.1.4 Safety Outcome Measure 
Nature, frequency, severity, and timing of adverse events. 
 
12.2 Correlative Studies 
 
12.2.1 Assessment of T- Cell Receptor Diversity/ Clonality 
We will determine if clinical responses to atezolizumab are associated with preexisting tumor antigen 
restricted effector T cells or the development of a more clonal T-cell receptor (TCR) repertoire, and 
we will determine what impact the addition of concurrent local, low-dose radiotherapy has on TCR 
diversity and clinical responses. 
 
TCR clonality evaluation:  Flow-cytometry-sorted CD4+ and CD8+ T cells from both pre and on- 
treatment biopsies and peripheral blood mononuclear cells will be separated and DNA will be 
promptly extracted using a low-input DNA extraction kit (Qiagen).  Clonal TCR diversity will be 
assessed using the Adaptive ImmunoSEQ kit. The resulting multiplexed PCR product will be 
sequenced on an Illumina MiSeq system and analyzed using the ImmunoSEQ analyzer. (Appendix 
9) 
 
12.2.2 Assessment of Biomarkers Related to PD-L1, Tumor Biology, and Immune Cell Biology 
Using immunohistochemistry, multiplex immunofluorescence, and fresh tissue immunophenotyping, 
we will assess biomarkers related to PD-L1 and/or immune cell biology and tumor biology that might 
contribute to our understanding of the mechanism of response to PD-L1 therapy and of the abscopal 
effect of radiation therapy in follicular lymphoma. 
 
Immunohistochemistry of pre-treatment patient biopsies: Three to four (3-4) core biopsies will 
be fixed in formalin and allocated to the Molecular Cytology Core Facility for morphologic review and 


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immunohistochemistry (IHC). Immunohistochemical staining will be performed with antibodies 
against CD3, CD4, CD8, CD68, FoxP3, TBET, GATA3, B2M, MHC-I, MHC-II, PD-1, PD-L1, and PD- 
L2. We will follow previously well-established protocols for IHC analysis of FFPE tissue. (Appendix 
9) 
 
Flow cytometry analysis and sorting of pre and on-treatment patient biopsies Four (4) core 
biopsies will be placed in RPMI media and sent to Pathology. They will then be delivered to the Cell 
Marker Lab, where single cell suspensions will be generated.  Clinical flow cytometry using 3-laser 
BD-FACSCANTO-10 instrument (Becton Dickinson Immunocytometry Systems (BDIS)) and 9- 
10  color assays (Appendix 9) will be performed with specific emphasis on markers likely to be 
affected by treatment with atezolizumab, including: 
 
Basic T-cell subsets: CD3+ T cells and 2 subsets: CD3+CD4+ and CD3+CD8+. 
 
Effector and memory subsets: defined by CD45RA, CD28, CD27, and CCR7 
 
Regulatory T cells: defined by CD4, CD25, CD127, and CCR4. 
 
Activation/exhaustion: defined by expression of PD-1, LAG-3, TIM-3, and CTLA-4 
 
 
Preferred order of core biopsies to be obtained, media, and destination of sample: 
 
Core 
Media 
Destination 
1 
Formalin 
Pathology 
2 
RPMI 
Pathology 
3 
Formalin 
Pathology 
4 
RPMI 
Pathology 
5 
Formalin 
Pathology 
6 
RPMI 
Pathology 
7 
RPMI 
Pathology 
8 
Flash Frozen 
CSP 
9 
Flash Frozen 
CSP 
10 
Formalin 
Pathology 
 
 
 
Peripheral blood: 
 
All patients will have four (4) additional tubes of blood drawn during screening and on treatment as 
per Appendix 1. 
 
 
Two (2) Green Top tubes are to be drawn and sent to the HOTB lab for PBMC Storage. 
 
 
One (1) Red Top Tube is to be drawn and sent to the HOTB lab for serum cytokines assay. 
 
 
One (1) Purple top tube will be ordered for SOC clinical flow cytometry. The remainder of this 
tube is to be delivered to the Cell Marker lab for subsequent testing. 


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Refer to Appendix 9 for more information regarding workflow for bloods collections and delivery. 
Serum will be frozen and peripheral blood mononuclear cells will be viably cryopreserved for flow 
cytometric analysis of T cells subsets (as above). Peripheral blood samples will be stored in 
Zuckerman 2013 (HOTB). (Appendix 9) 
 
Should inadequate number of core biopsy samples be obtained, the priority for allocation of core 
biopsy samples will be as follows: (1) IHC, (2) TCR clonality evaluation, (3) Flow cytometry analysis. 
(Appendix 9) 
 
12.2.3 Cytokine/ Chemokine Levels 
To understand the prevalence of circulating cytokines/chemokines and the impact they may have on 
the clinical activity and/or safety of atezolizumab treatment, a panel of cytokines and chemokines 
may be investigated by ELISA or other protein assay methods. Levels of soluble PD-L1 in peripheral 
blood may also be assessed. One SST tube will be drawn during screening and on treatment as per 
Appendix 1, and will be sent to Zuckerman 1419 for processing and storage. (Appendix 9) 
 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
13.1 Patient Discontinuation 
Patients have the right to voluntarily withdraw from the study at any time for any reason. In addition, 
the investigator has the right to withdraw a patient from the study at any time. Reasons for 
withdrawal from the study may include, but are not limited to, the following: 
 
Patient withdrawal of consent at any time 
 
 
Any medical condition that the investigator determines may jeopardize the patient’s safety if he 
or she continues in the study 
 
 
Investigator determines it is in the best interest of the patient 
 
 
Patient non-compliance 
 
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 Case Report 
Form (CRF).  However, patients will not be followed for any reason after consent has been 
withdrawn.  Patients who withdraw from the study will not be replaced if they received any protocol 
treatment. 
 
 
See Sections10.3, 10.4, and 10.5 for assessments that are to be performed for patients who 
prematurely withdraw from the study during the treatment period. 
 
13.2 Study Treatment Discontinuation 
Patients must discontinue study treatment if they experience any of the following: 
 
 
Pregnancy 
 
 
Immune related adverse event that requires atezolizumab to be withheld for >42 days 
 
 
Disease progression 


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In case of CT findings suggestive of pseudoprogression in patients with persistent clinical benefit 
investigator should contact the principal investigator to discuss further patient management. 
Because of the present potential for tumor flares immunotherapies, which result in early apparent 
radiographic progression (pseudoprogression/tumor immune infiltration), including the appearance 
of new lesions followed by delayed response (Wolchok et al. 2009), patients whose CT scans meet 
criteria for disease progression may continue to receive study treatment at the discretion of the 
principal investigator (1) if a moderate increase is seen in 1 lesion only or (2) if at least two the 
following criteria are met: 
 
 
Absence of symptoms and signs, including worsening of laboratory values (e.g. increased LDH) 
that indicate unequivocal disease progression. 
 
 
No declining ECOG performance status 
 
 
Absence of tumor progression to critical anatomical sites (e.g. leptomeningeal disease) cannot 
be management protocol-allowed medical interventions 
 
 
The primary reason for study treatment discontinuation should be documented on the appropriate 
CRF. 
 
Patients with radiographic evidence of progression/ residual metabolically active disease who 
continue to receive study treatment will require the following: 
 
• 
CT scan repeated 4-8 weeks later after documenting pseudoprogression 
• 
If the CT scan shows persistent or further progression a tumor biopsy will be completed. 
Patients who discontinue study treatment prematurely will not be replaced. 
13.3 Study and Site Discontinuation 
The Principal Investigator or Genentech 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 AEs in this or other studies indicates a potential health hazard to 
patients. 
 
Patient enrollment is unsatisfactory. 
 
Genentech will notify the investigator if Genentech decides to discontinue the study. 
 
The Principal Investigator 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 (GCP) 


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No study activity (i.e., all patients have completed and all obligations have been fulfilled) 
 
 
14.0 
BIOSTATISTICS 
 
14.1 Determination of Sample Size 
 
To accomplish our primary objectives we will use a randomized parallel 2-arm 1-stage design. All 
patients will be randomly assigned to one of the two treatment arms, and each arm will be monitored 
and analyzed separately. For both arms, a 43% or higher response rate is considered promising, 
whereas a 20% or lower is considered not promising. 
 
Novel therapies [e.g. bortezomib or lenalidomide] have single agent ORR of ~20% in 
relapsed/refractory FL [Goy 2005, Witzig 2009, Di Bella 2010] and are highly active in combination 
[e.g. when combined with the anti-CD20 monoclonal antibody rituximab]. These data suggest that 
excluding an ORR <20% while targeting an ORR >43% would be a conservative approach to 
evaluation of atezolizumab treatment effect as a single agent or in combination with low dose local 
radiotherapy in this population of patients with relapsed/refractory FL. To this end for each arm, a 
total of 25 patients will be accrued (once one arm reaches the enrollment goal of 25, randomization 
will stop and all the future patients will be automatically assigned to the other arm). 
 
If 8 or fewer patients in either treatment arm respond, that treatment will be considered not 
promising. If 9 or more patients respond in either treatment arm, then that arm will be declared 
promising and worthy of further investigation. 
 
This 1-stage design has type 1 and 2 error rates at 0.05 and 0.2, respectively. Given this design we 
may stop either arm early if we have observed 17 or more non-responders. If both arms are 
declared desirable by demonstrating 9 or more responses in their 25-patient cohorts, we will use the 
pick-the-winner approach as a general principle where the choice of which arm will be suitable for 
further study will be based on the absolute number of responses. If the treatment arm with a higher 
number of responses is also associated with more toxicity, then the investigators will weigh both the 
absolute number of responses and toxicity in selecting which arm is suitable for further study. If the 
difference in the true response rates of the treatment arms is 10% (i.e. 43% vs 53%) then the 
chance that the regimen with the higher response rate will be picked is over 70%. If the difference in 
the true response rates of the treatment arms is 15% (i.e. 43% vs 58%) then the chance that the 
regimen with the higher response rate will be picked is over 80%. 
 
14.2 Planned Efficacy Evaluations 
Patients will have their response classified according to the Lugano Classification as outlined in 
Appendix 4. Patients who have received at least one cycle of therapy and the planned radiation 
therapy (if randomized to receive radiotherapy) will be considered evaluable for response. Patients 
will be monitored periodically for the primary and secondary measurements (see Appendix 4 and 
Appendix 5 for protocol requirements regarding required imaging modalities and reporting 
requirements). 


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14.3 Primary Efficacy Variables 
Objective response is defined as a CR or PR, as determined by investigator assessment using the 
Lugano Classification on Treatment Response Assessment Timepoints (Appendix 4).  Patients not 
meeting these criteria, including patients without any post-baseline tumor assessment, will be 
considered nonresponders in the analysis of objective response. 
 
14.4 Secondary Efficacy Variables 
PFS is defined as the time from the first day of study treatment to PD or death, whichever occurs 
first.  If a patient is alive and has not experienced PD, PFS will be independently censored at the day 
of the last tumor assessment.  Patients with no post-baseline tumor assessments will be included in 
the PFS analysis but censored at the start of treatment. 
 
OS is defined as the time from the first day of study treatment to death from any cause.  For OS, 
patients without a date of death will be independently censored on the date a patient was last known 
to be alive. 
 
Incidence of toxicity and adverse events will be summarized by frequencies and percentages for 
each of the two cohorts. 
 
Patients with early withdrawal from the study will be considered as independently censored 
according to previous paragraphs. However, the censoring may be related to the disease status and 
therefore not independent. Therefore, sensitivity analyses will be conducted where these patients 
will be counted as events. 
 
14.5 Method of Analysis 
The best overall response is the best response recorded from the start of treatment until 
progression/recurrence (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started), and is the best overall response rate at any response 
assessment timepoint (see Appendix 5). Objective response rates will be described for patients 
assigned to each treatment arm as long with exact 95% confidence intervals. 
 
Progression-free survival, and overall survival will be calculated from the start of treatment by using 
the Kaplan-Meier method along with 95% confidence intervals. Patients’ withdrawals from 
interventions for reasons other than progression or death will be treated as independent censoring, 
and sensitivity analyses will be conducted as described in 14.4 
 
14.6 Method of Analysis for Correlative Endpoints 
Objective response rates, progression-free survival, and overall survival will be estimated for patients 
with preexisting tumor antigen restricted tumor infiltrating lymphocytes (TILs) and patients without 
preexisting tumor antigen restricted (TILs), and for patients who demonstrate a 2-fold expansion of T 
cell receptor (TCR) clonality and patients who do not demonstrate a 2-fold expansion of TCR 
clonality, and groups will be compared using Fisher’s exact tests (ORR) and logrank tests (PFS and 
OS). Similar comparison will be performed to associate other biomarkers described in 2.3 


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with the outcomes. To assess the impact of treatment on peripheral blood cytokine/chemokine 
levels, Wilcoxon signed rank test will be used to test the intra-patient changes in these factors. 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.1 
Research Participant Registration 
 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. During 
the registration process registering individuals will be required to complete a protocol specific 
Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether or not the 
participant is eligible to enroll in the study. Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been completed. See 
related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
 
15.2 
Randomization 
 
After eligibility is established and immediately after consent is obtained, patients will be registered 
and randomized. Patients will be randomized using the Clinical Research Database (CRDB). 
Randomization will be accomplished by the method of random permuted block.  At the time of 
registration, patients will be randomized to either receive radiation (GROUP 1) or to not receive 
radiation (GROUP 2). 
 
16.0 
DATA MANAGEMENT ISSUES 
 
16.1 
Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accural rates and extent and accuracy of evaluations and follow- up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. The study coordinator and investigators are 
responsible for ensuring that the eligibility checklist is completed in a legible and timely manner for 
every patient enrolled in the study, and that data are recorded on the appropriate forms and in a 
timely manner.  Any errors on source data should be lined through, but not obliterated, with the 
correction inserted, initialed, and dated by the study coordinator or PI.  All source documents will be 
available for inspection by the FDA and the Memorial Sloan Kettering Cancer Center IRB. 
 
16.1.1 Data Entry and Database 
The data will be collected and entered into electronic Case Report Forms (eCRFs) using the internet 
based system Medidata Rave. 
 
Required Medidata Forms 
Baseline 
Visit 
SAE 
Off Study 
Screening Forms 
X 
 


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Visit Forms 
X 
X 
Concomitant 
Medications Form 
X 
 
X 
X 
X 
Adverse Event Forms 
X 
X 
X 
Treatment Forms 
X 
X 
Laboratory Forms 
X 
X 
X 
X 
Response Forms 
X 
X 
Hospitalization Forms 
 
X 
MSK SAE Report Form 
 
X 
Off Study Forms 
 
X 
 
 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. The plans address the new policies 
set forth by the NCI in the document entitled “Policy of the National Cancer Institute for Data and 
Safety Monitoring of Clinical Trials” which can be found at 
http://www.cancer.gov/clinicaltrials/conducting/dsm- guidelines. The DSM Plans at MSK were 
established and are monitored by the Office of Clinical Research. The MSK Data and Safety 
Monitoring Plans can be found on the MSK Intranet at: 
http://inside2/clinresearch/Documents/MSKCC%20Data%20and%20Safety%20Mon 
itoring%20Plans.pdf 
 
There are several different mechanisms by which clinical trials are monitored for data, safety and 
quality. There are institutional processes in place for quality assurance (e.g., protocol monitoring, 
compliance and data verification audits, therapeutic response, and staff education on clinical 
research QA) and departmental procedures for quality control, plus there are two institutional 
committees that are responsible for monitoring the activities of our clinical trials programs. The 
committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II clinical trials, and 
the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, report to the Center’s 
Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for its level of 
risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in-house 
sponsored, industrial sponsored, NCI cooperative group, etc.) W ill be addressed and the monitoring 
procedures will be established at the time of protocol activation. 


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16.2.1 Monitoring 
Safety will be evaluated in this study through the monitoring of all serious and non-serious AEs, 
defined and graded according to NCI CTCAE v5.0.  Patients will be assessed for safety (including 
laboratory values) according to the schedule in Appendix 1 patients will be followed for safety for 90 
days following the last dose of study treatment or until receipt of another anticancer therapy, 
whichever comes first. 
 
General safety assessments will include serial interval histories, physical examinations, and specific 
laboratory studies, including serum chemistries and blood counts (see Appendix 1 for the list and 
timing of study assessments).  All serious adverse events (SAEs) and protocol-defined events of 
special interest (see Section 17.2) will be reported in an expedited fashion (see Section 17.2). In 
addition, the investigators will review and evaluate observed AEs on a regular basis. 
 
Patients who have an ongoing study treatment related AE upon study completion or at 
discontinuation from the study will be followed until the event has resolved to baseline grade, the 
event is assessed by the investigator as stable, new anticancer treatment is initiated, the patient is 
lost to follow-up, the patient withdraws consent, or until it has been determined that study treatment 
or participation is not the cause of the AE. 
 
16.2.2 Assessment of Safety 
Safety assessments will consist of monitoring and reporting AEs and SAEs that are considered 
related to ATEZOLIZUMAB, all events of death, and any study-specific issue of concern. 
 
16.2.3 Management of Specific Safety Concerns with Atezolizumab 
The PD-L1/PD-1 pathway is involved in peripheral tolerance; therefore, such therapy may increase 
the risk of immune-mediated adverse events, specifically the induction or enhancement of 
autoimmune conditions or systemic immune activation.  Adverse events with potentially 
immune-related causes, including rash, hypothyroidism, hepatitis or elevated transaminase, colitis, 
myositis, and myasthenia gravis have been observed in Study PCD4989g. 
 
For further details regarding clinical safety and a more comprehensive list of observed adverse 
events with atezolizumab, see the Atezolizumab Investigator’s Brochure. 
 
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 (Di Giacomo et al., 2010).  Suggested workup and management 
guidelines for suspected immune-mediated adverse events are provided in Section 6 (Guidance for 
the Investigator) of the Atezolizumab Investigator’s Brochure. 
 
16.3 Retention of Records 
FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 of the 
guideline) require that records and documents pertaining to the conduct of clinical trials and the 
distribution of investigational drug, patient records, consent forms, laboratory test results, and 
medication inventory records, must be retained for 2 years after the last marketing application 


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approval in an ICH region or after at least 2 years have elapsed since formal discontinuation of 
clinical development of the investigational product.  All state and local laws for retention of records 
also apply. 
 
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must comply 
with the record retention requirements set forth in the FDA IND regulations and the relevant national 
and local health authorities, whichever is longer. 
 
16.4 Study Close- Out 
Any study report submitted to the FDA by the Principal Investigator should be copied to Genentech. 
This includes all IND annual reports and the Clinical Study Report (final study report).  Additionally, 
any literature articles that are a result of the study should be sent to Genentech.  Copies of such 
reports should be mailed to the assigned Clinical Operations contact for the study: 
 
ATEZOLIZUMAB Protocols 
Email:  anti-pdl-1-mpd3280a-gsur@gene.com 
 
 
And to Genentech Drug Safety CTV oversight mail box at: ctvist_drugsafety@gene.com 
 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
17.1 
Privacy 
 
MSK’s Privacy Office may allow the use and disclosure of protected health information pursuant to a 
completed and signed Research Authorization form. The use and disclosure of protected health 
information will be limited to the individuals described in the Research Authorization form. A 
Research Authorization form must be completed by the Principal Investigator and approved by the 
IRB and Privacy Board (IRB/PB). 
 
17.1.1 Confidentiality 
 
Patient medical information obtained by this study is confidential and may be disclosed to third 
parties only as permitted by the ICF (or separate authorization to use and disclose personal health 
information) signed by the patient or 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 
FDA and other regulatory agencies, national and local health authorities, Genentech representatives 
and collaborators, and the IRB/Ethics Committee (EC) for each study site, if appropriate. 
 
17.2 
Serious Adverse Event (SAE) Reporting 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 


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Death 
 
A life-threatening adverse event 
 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions 
 
Results in a congenital anomaly/birth defect 
 
Is an Important Medical Event (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may 
jeopardize the patient or participant and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30-days after the participant’s last investigational 
treatment/intervention. Any event that occur after the 30-day period that is unexpected and at least 
possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and is 
related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB 
SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 
calendar days of the event. All other SAEs must be submitted within 30 calendar days of the event. 
 
The report should contain the following information: 
 
 
The date the adverse event occurred 
 
The adverse event 
 
The grade of the event 
 
Relationship of the adverse event to the treatment(s) 
 
If the AE was expected 
 
Detailed text that includes the following 
o An explanation of how the AE was handled 
o A description of the participant’s condition 
o Indication if the participant remains on the study 
 
If an amendment will need to be made to the protocol and/or consent form 
 
If the SAE is an Unanticipated Problem 
  
 
17.2.1 
Methods and Timing for Assessing and Recording Safety Variables 
 
The investigator is responsible for ensuring that all AEs and SAEs that are observed or reported 
during the study are collected and reported to the U.S. Food and Drug Administration (FDA), 


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appropriate Institutional Review Boards (IRBs), and Genentech, Inc., in accordance with CFR 
312.32 (Investigational New Drug [IND] Safety Reports). 
  
 
 
17.2.3 Adverse Event Reporting to Genentech 
 
 
Serious adverse events (SAEs), AEs of Special Interest (AESIs), pregnancy reports (including 
pregnancy occurring in the partner of a male study subject), and other Special Situation Reports 
where the patient has been exposed to the Genentech Product, will be sent on a MedWatch form or 
CIOMS I form or on Genentech approved reporting forms to Genentech Drug Safety. Transmission 
of these reports (initial and follow-up) will be either electronically or by fax and within the timelines 
specified below: 
 
Fax: 650-238-6067 
Email: usds_aereporting-d@gene.com 
 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as soon as it 
becomes available. 
 
 
 
SADRs 
Serious AE reports that are related to the Product shall be transmitted to Genentech within fifteen (15) 
calendar days of the awareness date. 
 
Other SAEs 
 
Serious AE reports that are unrelated to the Product shall be transmitted to Genentech within thirty 
(30) calendar days of the awareness date. 
 
AESIs 
 
AESIs shall be forwarded to Genentech within fifteen (15) calendar days of the awareness date. 
 
 
 
Special Situation Reports 
 
Pregnancy reports 
 
While such reports are not serious AEs or Adverse Drug Reactions (ADRs) per se, as defined 
herein, any reports of pregnancy (including pregnancy occurring in the partner of a male study 
subject), where the fetus may have been exposed to the Product, shall be transmitted to Genentech 
within thirty (30) calendar days of the awareness date. Pregnancies will be followed up until the 
outcome of the pregnancy is known, whenever possible, based upon due diligence taken to obtain 
the follow-up information. 


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Pregnancies in Female Partners of Male Patients 
 
Male patients will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 30 days after the last dose 
of study drug.  A Clinical Trial Pregnancy Reporting Form should be completed and submitted to 
Genentech within thirty (30) calendar days of the awareness date. 
 
 
 
Other Special Situation Reports 
 
In addition to all SAEs, pregnancy reports and AESIs, the following other Special Situations Reports 
should be collected even in the absence of an Adverse Event and transmitted to Genentech within 
thirty (30) calendar days: 
 
 
Data related to the Product usage during breastfeeding 
 
 
Data related to overdose, abuse, misuse or medication error (including potentially exposed or 
intercepted medication errors) 
 
 
Drug interaction 
 
 
Use of a Medicinal Product in a Pediatric and Elderly population (in addition, reasonable 
attempts should be made to obtain and submit the age or age group of the patient, in order to be 
able to identify potential safety signals specific to a particular population) 
 
Occasionally Genentech may contact the reporter for additional information, clarification, or current 
status of the patient for whom an adverse event was reported.It is understood and agreed that the 
Sponsor will perform adequate due diligence with regard to obtaining follow-up information on 
incomplete AE, Special Situations and pregnancy reports. 
 
 
Note:  Investigators should also report events to their IRB as required. 
 
IND Annual Reports 
 
Copies of all IND annual reports submitted to the FDA by the Principal Investigator should be sent to 
Genentech Drug Safety via fax: 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
 
 
18.0 
INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full details 
of the protocol and study procedures as well as the risks involved to participants prior to their 


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inclusion in the study. Participants will also be informed that they are free to withdraw from the study 
at any time. All participants must sign an IRB/PB-approved consent form indicating their consent to 
participate. This consent form meets the requirements of the Code of Federal Regulations and the 
Institutional Review Board/Privacy Board of this Center. The consent form will include the following: 
 
 
The nature and objectives, potential risks and benefits of the intended study. 
 
 
The length of study and the likely follow-up required. 
 
 
Alternatives to the proposed study. (This will include available standard and investigational 
therapies. In addition, patients will be offered an option of supportive care for therapeutic 
studies.) 
 
 
The name of the investigator(s) responsible for the protocol. 
 
 
The right of the participant to accept or refuse study interventions/interactions and to withdraw 
from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information.  In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization component 
of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed informed consent form.The consent indicates that individualized de 
identified information collected for the purposes of this study may be shared with other qualified 
researchers. Only researchers who have received approval from MSK will be allowed to access this 
information which will not include protected health information, such as the participant’s name, 
except for dates. It is also stated in the Research Authorization that their research data may be 
shared with other qualified researchers. 
 
 
19.0 
REFERENCES 
 
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Relapsed or Refractory Lymphoid Malignancies. In: ASH Annual Meeting. Vol San Francisco; 2014. 
 
2. Myklebust JH, Irish JM, Brody J, et al. High PD-1 expression and suppressed cytokine signaling 
distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood. 
2013;121(8):1367-1376. doi:10.1182/blood-2012-04-421826. 
 
3. Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive 
immune resistance. Nature. 2014;515(7528):568-571. doi:10.1038/nature13954. 


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4. Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with 
indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol. 
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5. Brody JD, Ai WZ, Czerwinski DK, et al. In situ vaccination with a TLR9 agonist induces systemic 
lymphoma regression: a phase I/II study. J Clin Oncol. 2010;28(28):4324-4332. 
doi:10.1200/JCO.2010.28.9793. 
 
6. Dave SS, Wright G, Tan B, et al. Prediction of survival in follicular lymphoma based on molecular 
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7. Ame-Thomas P, Le Priol J, Yssel H, et al. Characterization of intratumoral follicular helper T cells 
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8. Ame-Thomas P, Tarte K. The yin and the yang of follicular lymphoma cell niches: role of 
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9. Ansell SM. Malignant B cells at the helm in follicular lymphoma. J Clin Oncol. 2013;31(21):2641- 
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10. De Jong D, Fest T. The microenvironment in follicular lymphoma. Best Pr Res Clin Haematol. 
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11. Vatner RE, Cooper BT, Vanpouille-Box C, Demaria S, Formenti SC. Combinations of 
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12. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired Resistance to Fractionated 
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13. Pilones KA. Unique changes in the TCR repertoire of tumor-infiltrating lymphocytes underlie the 
synergy of radiotherapy with CTLA-4 blockade . In: AACR Annual Meeting. Vol Philadelphia; 2015. 
 
14. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy 
induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin 
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15. Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin 
lymphoma: a randomised phase III trial. Radiother Oncol. 2011;100(1):86-92. 
 
16. Palomba ML, Till, BG, Park, SI, et al. A phase Ib study evaluating the safety and clinical activity of 
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17. Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in 
relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:667-675. 
 
18. Witzig TE, Wiernik PH, Moore T, et al. Lenalidomide oral monotherapy produces durable 
responses in relapsed or refractory indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27:5404- 
5409. 
 
19. Di Bella N, Taetle R, Kolibaba K, et al. Results of a phase 2 study of bortezomib in patients with 
relapsed or refractory indolent lymphoma. Blood. 2010;115:475-480. 
 
20. Vose, J., et al., International peripheral T-cell and natural killer/T-cell lymphoma study: pathology 
findings and clinical outcomes. J Clin Oncol, 2008. 26(25): p. 4124-30. 
 
21. Iqbal, J., et al., Gene expression signatures delineate biological and prognostic subgroups in 
peripheral T-cell lymphoma. Blood, 2014. 123(19): p. 2915-23. 
 
22. Hejblum G, Lambotte O, Galicier L, et al. A web-based Delphi study for eliciting helpful criteria in 
the positive diagnosis of hemophagocytic syndrome in adult patients. PLoS ONE 2014;9(4):e94024. 
doi: 10.1371/journal.pone.0094024. 
 
23. Henter JI, Horne A, Aricó M, et al. HLH-2004: diagnostic and therapeutic guidelines for 
hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 2007;48:124 31. 


Page  64 of 115 
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IRB Number: 17-360 A(4) 
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20.0 
APPENDICES 
 
20.1. Appendix 1- Study Flowchart 
 
20.2. Appendix 2- Calculation of Creatinine Clearance Using the Cockcroft- Gault Formula 
 
20.3. Appendix 3- Current National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) 
 
20.4. Appendix 4- The Lugano Classification 
 
20.5. Appendix 5- Imaging and Reporting Requirements for Tumor Response Assessments 
 
20.6. Appendix 6- Anaphylaxis Precautions 
 
20.7. Appendix 7- Safety Reporting Fax Cover Sheet 
 
20.8. Appendix 8- Management of Toxicities Associated with Atezolizumab 
 
20.9. Appendix 9- Work Flow for Correlative Studies 


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20.1 Appendix 1 
 
Flowsheet 
 
Screening 
Cycle 1 
Low-dose 
radiotherapy 
Cycle 2 
Treatment 
Visits 
Treatment 
Visits 
Follow 
Up Visits 
Off Treatment 
Visit 
within 30 
days of 
C1D1 
unless 
otherwise 
specified 
Day 1 
Cycle 1, Day 2 
and 3 
Day 1 
(+/- 2 
days) 
Day 
14-20 
Cycle 3, 4, 6, 
7, 8, 10, 11, 
12, 14, 15, 
16: Day 1 
(+/- 2 days) 
Cycle 5, 9, 13, 
17: Day 1 (+/- 
2 days) 
Every 6 
Months 
(+/- 14 
days) 
Informed 
consent L 
X 
Medical history 
and 
demographics 
X 
Physical 
examination, 
including vital 
signsa , height , 
weight, and 
performance 
status 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 


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Page  66 of 115 
 
 
Bone marrow 
biopsy & 
aspirate 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
CBC w/ 
differential b 
X 
j 
j 
j 
j 
X 
X 
Chemistry panel 
c 
X 
j 
j 
j 
j 
X 
X 
TSHi 
X 
Xj 
Xj 
Xj 
Xj 
X 
X 
Creatinine 
phosphokinase 
X 
j 
j 
j 
j 
X 
X 
PTT and PT/INR 
X 
Urinalysis 
X 
Infectious 
disease testingk 
X 
Pregnancy test 
(urine or blood) n 
X n 
Tumor 
Assessment 
e 
em 
e 
e 
Tumor biopsy 
Xf 
Xf 
Xf 
Research blood 
samples 
g 
g 
g 
g 
g 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 


Memorial Sloan Kettering Cancer Center
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Page  67 of 115 
 
 
 
Radiation 
oncology 
consultation 
X 
Low- dose 
radiotherapyh 
Xh 
Electrocardiogra 
m 
X 
X 
a   Heart rate, systolic and diastolic blood pressure while the patient is in a seated position, and temperature. 
 
b   Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count (neutrophils, bands, eosinophils, 
lymphocytes, monocytes, basophils, other cells). 
 
c   Sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, calcium, total and direct bilirubin, total protein, albumin, ALT, AST, 
alkaline phosphatase, amylase, lipase, LDH, uric acid, magnesium, phosphorus. 
 
d   Bone marrow biopsy and aspirate is required within 60 days of C1D1, provided no treatment has been administered in the interim.  For 
patients with involvement of follicular lymphoma at baseline, repeat testing is required only to confirm CR or as clinically indicated. 
 
e   Imaging and reporting requirements for tumor assessment is described in Appendix 5. Patients will require a PET scan with diagnostic 
quality CT CAP (with intravenous and oral contrast, unless contraindicated) at study screening, Cycle 5, and EOT.  A baseline PET with 
diagnostic CT CAP scan is required within 45 days of C1D1.  For patients who have had a PET scan performed within 45 days of C1D1, 
a simulation scan (PET, CT, or MRI) will only be done if the patient is randomized to Arm 2 (RT arm).  For patients who have not had a 
PET scan within 45 days of C1D1, baseline PET imaging will be a PET-simulation scan. 
 
f     Tumor biopsy is required in all patients within 45 days of C1D1. Tumor FNA or core biopsy is required in all patients at Cycle 2 Days 14- 
20 (core biopsy is preferred). Tumor biopsy is recommended at time of progression on study.  Tumor biopsy should be outside the field 
of radiation to allow for an accurate assessment of systemic changes to the tumor microenvironment following local irradiation. 
Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions 
 
g   Research blood samples will be collected for correlative investigations as outlined in Section 12.2 of the protocol. Additional information 
about the workflow for correlatives can be found in Appendix 9. 
 
h   Only if randomized to low- dose radiotherapy arm 
 
i   T3 and T4 should be tested only if TSH is abnormal. 


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j   Labs can be done within 5 days of day 1 of each cycle. 
 
k   Infectious disease testing includes: Epstein-Barr virus (EBV) serology (EBNA IgG), Hepatitis B virus (HBV) serology (HBsAg, antibodies 
against HBsAg, hepatitis B core antigen), HCV serology (anti-HCV), and HIV 1 & 2 antibodies. HBV DNA test is required for patients 
who have positive serology for anti-HBc.  HCV RNA test is required for patients who have positive serology for anti-HCV. 
 
L   Within 45 Days of  C1D1 
 
m On treatment imaging window must be +/- 14 days of Cycle X Day 1 target date. 
 
n For women of childbearing potential 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
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Page  69 of 115 
 
 
 
22.2 Appendix 2 
Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula 
 
 
 
 
Creatinine Clearance (men)  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
 
 
  
 
 
Reference: 
Creatinine Clearance (women)  0.85  (140-Age)  Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL)  72 
 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted serum 
creatinine (editorial). Nephron 1992;62:249. 
 
 
 
 
22.3 Appendix 3 
Current National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) 
 
 
Please use the following link to the NCI CTCAE website: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 


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22.4 Appendix 4 
 
The Lugano Classification 
Selection of Target Lesions1 
 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
 
1.  Clearly measurable in two diameters (longest diameter [LDi] and shortest diameter)at 
baseline 
All nodal lesions must measure: 
1.5 cm in LDi regardless of short axis measurement. 
 
2.  All measurable extranodal lesions should have an LDi 1.0cm. All other lesions (including 
nodal, extranodal, and assessable disease) should be followed as non-target lesions. 
3.  If possible, the lesions should be from disparate regions of the body. 
4.  Should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved 
 
Selection of Nontarget Lesions2 
 
Nontarget lesions will be qualitatively assessed at each subsequent time point. All of the sites of 
disease present at baseline and not classified as target lesions will be classified as nontarget 
lesions, including any measurable lesions that were not chosen as target lesions. Examples of 
nontarget lesions include: 
 
1. All bone lesions, irrespective of the modality used to assess them 
2.  Lymphangitis of the skin or lung 
3.  Cystic lesions 
 
Splenomegaly and hepatomegaly (all lymphomas) 
 
The recommendation is to use a cutoff for splenomegaly of more than 13 cm. Similar to splenic 
involvement, diffusely increased or focal uptake, with or without focal or disseminated nodules, 
supports liver involvement. 
 
4. Irradiated lesions 
5.  Measurable lesions beyond the maximum number of six 
6.  Groups of lesions that are small and numerous 
7.  Pleural/pericardial effusions and/or ascites 
8.  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. 
 
 
 
1 Target Lesions are reported on the cCRF “Indicator Lesion” form. 
 
2 Nontarget Lesions are reported on the eCRF “Non-Indicator Lesion” form. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  71 of 115 
 
 
 
 
 
 
Existing effusions/ascites: Effusions, ascites, or other fluid collections will be followed as 
nontarget lesions. At each time point, 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. 
 
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 duringCycle 10, 
between Days 15 and 21. Assessment by PET should follow the criteria described by Cheson et 
al. 2014, which is presented in the table below (the Lugano Classification). 


Ul 
 
 
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cp 
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Response and Site 
PET-CT-Based Response 
CT-Basod Response 
Complete Response 
Comploto motabotiC responso 
 
Lymph nodes  and extralymphallc sites 
Scorn 1, 2,or 3 • with or without a residual 
Complete radiologic response  (all of the lotloWing): 
mass on SPS • 
• 
Target nodes/nodal masses must regress to 
Itis recognized that in Waldeyer's ring  or 
,;1.5 em in LDi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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extranodal s1tes with high physiologic uptake • 
No extralymphatic sites of disease 
or with activa1ion within spleen or marrow 
(e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake may 
be greater than normal mediastinum and/or 
llwr. In this circumstance, complete 
metabolic response may be inferredIf uptake 
at sites oflntllal ln\Oivement Is no greater 
than surrounding normaltissue aw n If the 
tissue has h gh physiologic uptake. 
Nonmeasured lesion 
Not applicable  
Absent 
 
Organ enlargement 
Not applicable  
Regress to normal 
 
New lesions 
None  
None 
 
Bone ma rrow  
No evidence of FDG-a\A d disease in marrow 
Normal by morphology; if 
indeterminate, IHC-nogalive 
 
PartialRosponso 
Part al motabot1c response  
Part al romlsslon (all or tho following): 
• 
2:50% decreaseIn SPD of up to 6 target 
measurable nodes and extranodal sites 
• 
When a lesion Is too small to measue on CT. 
assign 5 mm •5 mm as the default value 
• 
When no longer visible,0•0 mm 
• 
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nonnal; use actual measurement br cak;ulation 
  
 
 
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Response and Site 
PET-CT-Based Response 
CT-Based Response 
Lymph nodes and e<tralymphatic sites 
Score 4 or s•wtih raducod uptak e compared 
,.;th baseil ne and residual mass(es) of any 
size 
At interim, these findings suggest responding 
disease 
At end of treatment, these findingsIndicate 
roslduel   disease 
Nonmeasuredlesions 
Not applicable 
AbsenVnormal. regressed.but noincrase 
Organ enlargement  
Not applicable  
Spleen must have regressed bY >50% inlength 
beyond nonnal 
New lesions 
None  
None 
Bone rna rrCYtN 
Residual uptake higher than uptake in normal    Not applicable 
marrow but reduced compared with baseline 
(diffuse uptake compatible with reactive 
changes trom chem otherapy allowed).  If 
thole are persistent focalchanges in the 
matrow in tho context of a nodalre.sponse, 
consideration should be given to further 
evaluation 'hith MRI or biopsy or an Interval 
scan 
No Response or Stable Disease  
No metabolic res ponse  
Stable disease 
Target ncdcs/ncdal masses,cxtranodal 
Score 4 or 5 with no significant change in  
<50% decrease from bascfinc in SPD  of up to 
lesions 
FOG uptake from baseline at interim or end  
6 dominant, measurable nodes and extranodal sites; 
of treatment  
no criteria for progressive disease are met 
Nonmeasumd lesions 
Not applicable  
No increase consistent with progression 
Organ enlargement  
Not applicable 
No incr ease consistent \vith progression 
New lesions  
None  
None 
Bone marrow 
No change from baseline  
Not appllcable 
cp 
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and Site  
PET-CT-Based 
Progmssiu Diaaa 
Pr<:>gnas!liw metabolic dis-e 
reuiw disease requ11"1!S 
loliowinc PPD progl'li'llllion: 
 
lndhAdu!ll 
 
nooeslnodal masses 
 
Sc<lll!l 4 or 5 with lUi  incmae in  
of 
bas >line 
 
E:.tranodallesiorrs 
 
N!ilw FDG·a\lid 10ci c< Mis!Bnt with'""'""'""'"' 
alinterim or end..of.treatm >nlassessment 
An indi11idual nodelk!sion mu!lt be abnonnal with; 
• 
LOI >1.5 em and 
• 
Increase  
;,;50% fronn PPD nedir and 
• 
An increase in LOI or SDi f10m nadir 
• 
0.5 em lbr lmloM ,;2 em 
• 
1.0 em lbr lmloM >2 em 
• 
In tne settioo ot 
1he sphmk: 
>50% ot lhe extent of 
Increase  
baseline  
a 15om 
sp i!l!l'l m uslioo ease to    16  
If no 
splen<)ml!gl!ly, must inc ease bv alleasl2 em 
hm bas!l4iIll! 
• 
New or recurrent  spl• oom 
 
 
 
 
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Nonmeasured iesiorrs 
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New  Lesions 
New FDG·e\lid  fi:lci c< Mistent wilh iYnlph,orrJa 
rather than another alilliOSIY 
lnlaJnmallion). If uncE>IIaln nega1rding !!llotogy 
of new 
hi"""" 
be coooidered 
 
 
 
 
 
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New or recurrent  FDG-a11id  fi:lci 
New or clear  
of pre,existirlg 
oonmeasured  lesiOns 
• 
of 
resolved lesiorrs 
• A new node > 1,5 em in any axis 
• A new axtrenodalsite >1 .o em in any 
i! 
1.0 em in any 
its pl"l!Sence must be 
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• 
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5PS   S.point scale; CT  computed tomography; FOG   luorodeoxyglucose;Gt   gastrointestinal;IHC:mmunohistochemistry; LDi.longest 
transverse di ameter or a lesion;MRI   magnetic resonance imag,ng; PET   poSitron emission tomography: PPO   cross product of lhe LDi and 
perpendicular diameter: SOl shortest  axis perpendicular to the LOI; SPO-sum of the product or the perpendicular diameters br multiplelesions. 
• A score of 3 1n many patientsindicates a good prognosis Wlth standard treatment,especially ilat the lime of an 1nterim scan.    ver ,in 
trials on\Oivlng PET where de-escalallon Is lnl<lsllgated, it may be pn;fetable to consider a score of 3 as inadequate response (to avoid 
undertreatment).  Measured dominant lesions: up to six of the largest dominant nodes,nodal masses, and extranodalleslons selected to be 
cleay measurable in two diameters.  Nodes should prelerably be from disparate regions of the body and should include,where applicable, 
mediastinaland retrope  toneal areas.  Non-nodal leslonslnclude those In solid orga11s (e.g., llwr, spleen, kidneys, lungs).Gl lnvolvement, 
cut.aooous lesions. or those noted on palpallon.  Nonmoasurod lesions: any disease not solocted as measured, dominant d1sease  and truly 
assessable disease should be consdi ered not measured.  These sitesInclude any nodes. nodal masses. and extranodalsites not selected as 
dominant or measurable or that do not meet the requirements br measureblllty but are sllll considered abnonnal,as wellas truly assessable 
disease, whichIs any site of suspected disease that  would be difficult to bllow quantitatively with measurement, including pleuraleffusions, 
asc1tes, bone lesions, leptomeningeal disease,  abdominaJ masses, and other lesions that cannot be confirmed and followed by imaging.  In 
effusions,ascites,bone lesions,leptomeningealdisease, abdominalmasses, and other lesions that cannot be confinned and followed by 
1maging.  In Waldeye(s ring or in extranodal sites (e.g., Gl tract,ln.er, bone marrow), FOG uptake may be greater than1n the mediastinum with 
complete metabolic response, but should be no higher than surrounding nonnal physiologic uptake (e.g., v.;th marrow acti o tion as a result 
of chemolherapy or myeloid growth factors). 
•       PET SPS: 1, no uptake above background; 2, uptake smediastinum: 3. uptake > mediastinum but Sliver; 4, uptake 
moderately >liver;5,uptake markedly higher than liver and/or newlesions; X, new  areas of uptake unlikely to be real ted 
to lymphoma. 
 
 
 
 
 
 
 
 
 
 
 
 
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IRB Number: 17-360 A(4) 
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22.5 Appendix 5 
Imaging and Reporting Requirements for Tumor Response Assessments 
 
Imaging and Reporting Requirements for Tumor Response Assessments 
 
Timepo int 
Imaging Modality 
Reporting Requirement 
Screening (within six weeks of 
C1D1) 
PET-CT (must include diagnostic 
quality CT scan) 
NA 
On Treatment Response 
Assessment C5D1 
PET-CT (must include diagnostic 
quality CT scan) 
PET-CT criteria and CT 
critera 
On Treatment Response 
Assessments (C9D1, C13D1, +/- 
14 days) 
CT only 
CT criteria 
End of Treatment (4-6 weeks 
after C16) 
PET-CT (must include diagnostic 
quality CT scan) 
PET-CT criteria and CT 
critera 
Follow-up (every 6 months, +/- 4 
weeks) 
CT only 
CT criteria 
 
 
C =cycle; D = day; CT = computed tomography; NA = not applicable; PET-CT = positron emission 
tomography-computed tomography. 
 
All response criteria (PET-CT and CT) are based on the 2014 Lugano Classification (see Appendix 4). 
 
If the response assessment is discordant between the PET-CT and CT-based response, a follow-up scan in 
2-3 weeks (prior to the next cycle of therapy) is recommended to determine response (see the study schema 
[Figure 1]). 
 
For patients who are being treated beyond progression, CT scans (PET is optional) should be preformed 
every 3 months as long as treatment is ongoing and 4-6 weeks after the last dose of atezolizumab. 
Thereafter, patients will undergo CT scans every 6 months. 


Page  77 of 115 
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22.6 Appendix 6 
 
 
Anaphylaxis Precautions 
 
 
Equipment Needed 
 
 
Tourniquet 
 
Oxygen 
 
Epinephrine for subcutaneous, intravenous and/or endotracheal use in accordance 
with standard practice 
 
Antihistamines 
 
Corticosteroids 
 
Intravenous infusion solutions, tubing, catheters, and tape 
 
Procedures 
 
In the event of a suspected anaphylactic reaction during study drug infusion, th following 
procedures should be performed: 
 
1.  Stop the study drug infusion. 
2.  Aplly a tourniquet proximal to the injection site to slow systemic absorption of study 
drug. Do not obstruct arterial Flow in the limb. 
3.  Maintain an adequate airway. 
4.  Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
5.  Continue to observe the patient and document observation. 


Page  78 of 115 
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22. 7 Appendix 7 
 
 
Safety Reporting Fax Cover Sheet 
 
 
 
GENENTECH SUPPORTED RESEARCH 
 
AE/SAE FAX No:  (650) 225-4682 
 
Alternate Fax No:  (650) 225-5288 
 
Page 1 of   
 
 
Genentech Study Number 
Principal Investigator 
Site Name 
Reporter name 
Reporter Telephone # 
Reporter Fax # 
Initial Report Date 
  
/  
/  
 
dd / mmm / yyyy 
Follow-up Report Date 
  
/  
/  
 
dd / mmm / yyyy 
Patient Initials 
(Please enter a dash if the patient 
has no middle name) 
  
-   
-  
 
 
 
 
SAE or Safety Reporting questions, contact Genentech Safety:  (888) 835-2555 
 
PLEASE PLACE FDA MEDWATCH 3500 Form or SAFETY REPORT BEHIND THIS COVER 
SHEET. 


Page  79 of 115 
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22. 8 Appendix 8 
 
Management Of Toxicities Associated With Atezolizumab 
 
To date, the following adverse events are identified risks associated with atezolizumab: dermatologic 
reactions, hepatitis, hypothyroidism, pneumonitis, influenza-like illness, and IRRs. Potential risks 
associated with atezolizumab include colitis, endocrine disorders, hypersensitivity, neurologic 
disorders, pericardial effusions, eye toxicity, and development of anti-therapeutic antibodies. 
Detailed information is provided below for the following risks: GI toxicity, hepatotoxicity, dermatologic 
toxicity, hypothyroidism, pulmonary toxicity, influenza-like illness, systemic immune activation (SIA), 
pancreatic toxicity, pericardial effusions, eye toxicity, and IRRs. 
 
Gastrointestinal Toxicity 
 
Immune-related colitis has been associated with the administration of atezolizumab and is an 
identified risk for atezolizumab. 
 
Patients should be advised to inform the investigator if any event of diarrhea occurs, even if it is 
mild. Suspected colitis should be further evaluated, and infectious or alternative etiologies should be 
ruled out. 
 
If the event is of significant duration (>5 days) or is associated with signs of systemic inflammation or 
acute phase reactants (e.g., increased C-reactive protein or platelet count or bandemia), it is 
recommended to do the following: 
 
 
Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with three to five 
specimens for standard paraffin block to check for inflammation and lymphocytic infiltrates to 
confirm diagnosis of colitis. If possible, one or two biopsy specimens should be snap frozen 
and stored. 
 
 
Perform laboratory tests to rule out alternative etiology (i.e., WBCs and stool calprotectin). 
 
 
 
Hepatotoxicity 
 
Immune-related hepatitis has been associated with the administration of atezolizumab. Hepatitis is 
an identified risk for atezolizumab. 
 
Eligible patients must have adequate liver function, as manifested by measurements of total bilirubin 
and hepatic transaminases, and liver function will be monitored throughout study treatment. 
 
 
 
Patients presenting with right upper-quadrant abdominal pain and/or unexplained nausea or 
vomiting should have hepatic enzyme tests performed immediately, and results should be reviewed 
before administration of the next dose of study treatment. 


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If hepatic enzymes become elevated, neoplastic, concurrent medication, viral hepatitis, and toxic 
etiologies should be considered and addressed, as appropriate. Imaging of the liver, gall bladder, 
and biliary tree should be performed to rule out neoplastic or other causes for the hepatic enzyme 
elevations. Anti  nuclear antibody, perinuclear anti  neutrophil cytoplasmic antibody, anti  liver 
kidney microsome antibodies, and anti  smooth muscle antibody tests should be performed if an 
autoimmune etiology is considered. 
 
Dermatologic Toxicity 
 
 
Treatment-emergent rash has been associated with atezolizumab. The majority of the cases of rash 
were mild in severity and self-limited, with or without pruritus. Dermatologic reactions are an 
identified risk for atezolizumab. A dermatologist should evaluate persistent and/or severe rash or 
pruritus. A biopsy should be considered unless contraindicated. 
 
Hypothyroidism 
 
Hypothyroidism has been associated with the administration of atezolizumab and is an identified risk 
for atezolizumab. Patients with unexplained symptoms such as fatigue, myalgia, impotence, mental 
status change, or constipation should be investigated for the presence of thyroid, pituitary, or 
adrenal endocrinopathy, as well as for hyponatremia or hyperkalemia. An endocrinologist should be 
consulted if an endocrinopathy is suspected. TSH and free T4 levels should be evaluated to 
determine whether thyroid abnormalities are present. TSH, prolactin, and morning cortisol levels will 
help to differentiate primary adrenal insufficiency from primary pituitary insufficiency. 
 
 
Pulmonary Toxicity 
  
Dyspnea, cough, fatigue, hypoxia, and pulmonary infiltrates have been associated with the 
administration of atezolizumab and have primarily been observed in patients with underlying 
NSCLC. Pneumonitis is an identified risk for atezolizumab. Mild to moderate events of pneumonitis 
have been reported with atezolizumab. All pulmonary events should be thoroughly evaluated for 
other commonly reported etiologies, such as pneumonia/infection, lymphangitic carcinomatosis, 
pulmonary embolism, heart failure, chronic obstructive pulmonary disease, or pulmonary 
hypertension, as outlined below: 
 
 
Measurement of oxygen saturation (i.e., arterial blood gas) 
 
High-resolution CT scan of the chest 
 
Bronchoscopy with bronchoalveolar lavage and biopsy 
 
Pulmonary function tests (including diffusion capacity of the lung carbon monoxide) 
 
Pulmonary function testing with a pulmonary embolism protocol 
 
Patients will be assessed for pulmonary signs and symptoms throughout the study. Patients will also 
have CT scans of the chest at every tumor assessment. 
 
Influenza-Like Illness 


Page  81 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Influenza-like illness has been reported in patients receiving atezolizumab as a single agent and in 
combination with vemurafenib, bevacizumab, or platinum doublet therapy. Symptoms have included 
fever, fatigue, asthenia, chills, myalgia, arthralgia, and headache. Symptoms have occurred alone or 
concurrently. Influenza-like illness has been observed primarily 1-2 weeks after the first treatment 
cycle. The events have been mild to moderate in severity. 
 
Systemic Immune Activation 
  
SIA is a rare condition characterized by an excessive immune response. Given the mechanism of 
action of atezolizumab, SIA is considered a potential risk. SIA should be included in the differential 
diagnosis for patients who develop a sepsis-like syndrome after administration of atezolizumab. 
Initial workup should include serum ferritin, CBC, liver function tests, serum triglycerides, and a 
coagulation profile. In the event of suspected SIA, the Medical Monitor should be contacted for 
additional recommendations. Treatment with agents such as tocilizumab, as well as corticosteroids, 
should be considered in the event of SIA. 
 
 
Potential Pancreatic Toxicity 
 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of other immunomodulatory agents. 
 
The differential diagnosis of acute abdominal pain should include pancreatitis. Appropriate 
assessments should include an evaluation for obstruction, as well as serum amylase and lipase 
tests. If immune-related pancreatic toxicity is suspected, IgG4 levels and auto-antibodies (anti- 
plasminogen-binding protein peptide antibodies, peripheral anti-neutrophil cytoplasmic antibodies, 
anti-mitochondrial antibody, anti-lactoferin antibody, anti-carbonic anhydrase II, anti-smooth muscle 
antibody, and anti-nuclear antibody) should be evaluated. 
 
Pericardial Effusions 
  
Pericardial involvement with associated effusions is common in patients with NSCLC and has the 
theoretical potential to be exacerbated by inflammation associated with anti-tumor immunity 
following PD-L1 blockade. 
 
Patients presenting with dyspnea, chest pain, or unexplained tachycardia should be evaluated for 
the presence of a pericardial effusion. Patients with preexisting pericardial effusion should be 
followed closely for pericardial fluid volume measurements and impact on cardiac function. When 
intervention is required for pericardial effusions, appropriate assessments include evaluations of 
cytology, LDH, glucose, cholesterol, and cell count. For patients with a pericardial effusion causing 
end-diastolic right ventricular collapse, treatment may be restarted following the placement of a 
pericardial window, demonstration of hemodynamic stability, and resolution of right ventricular 
dysfunction. 
 
Potential Eye Toxicity 


Page  82 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
An ophthalmologist should evaluate visual complaints by examination. Uveitis or episcleritis may be 
treated with topical corticosteroid eye drops. Patients in the study are encouraged to maintain eye 
hydration, generally through the use of moisturizing eye drops. Atezolizumab should be permanently 
discontinued for immune-mediated ocular disease that is unresponsive to local immunosuppressive 
therapy. 
 
 
Infusion-Related Reactions 
 
 
With single-agent atezolizumab, IRR symptoms during the infusion have included fever, chills, 
dyspnea, and flushing/hypotension. They may occur within 30 minutes to 24 hours after infusion, are 
generally mild and manageable, and wane with subsequent infusions. The most common symptoms 
reported within 24 hours of the first cycle were pyrexia, fatigue, nausea, hypertension, headache, 
and diarrhea. IRRs have been reported during Cycles 1 and 2. 
 
 


Page  83 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
E \ent 
Action To Be Taken 
AST, ALT, or bilirubin increase 
Grade3 (or10 x ULN for 
patients with liver involvement) . 
Withhold study treatment and monitor liver enzymes at least e\ery 7 days. 
Investigate etiolo gy  Consutl with a hepatologist if immune etiolo gy is suspected. 
. 
Corti costeroid treatment may be required for immune-related hepatitis 
lfthere is improvement to Grade 5, 1, resume atezolizumab at full dose. 
Note: If hepatitis is treated with corticosteroids, atezolizumab should not be resumed until the corticosteroids 
. 
have been tapere d to 5, 10 mg/day of predni so ne or equivalent 
Perma ne ntl y discontinue study treatment for life-threatening liver toxicity 
Amylase or li[pase increa se: 
Grade3 
. 
Investigate etiolo gy  Consutl with a gastro e nterologist if immune etiology is suspected 
Corti co steroid treatment may be required for immune-related pancre atitis 
lfthere is improvement to Grade 5, 1 and patient is asymptomatic, resume atezolizumab at full dose and 
resume lenalidomide at current dose. 
Note: If pancreatitis is treated with corticosteroids, atezolizumab should not be resum ed until the 
corticosteroi d s have been tapered to 5, 10 mg/day of prednisone or equivalent. 
Ocul ar toxicity Grade2 
(autoimmune uveitis, iritis,or 
episcl eritis} 
. Investigate etiolo gy  Consutl with an ophthalm ol o gi st 
•. 
lfthere is improvement to Grade 5, 1, resume atezolizum a b at full dose. 
For immune- rel ated toxicity attributa bl e to atezolizumab, start topicalcorticosteroi d eye drops 
 
Guidelines for Management of Toxicities (cont.) 
 
 
 
 
 
 
 
 
 
 
 
. Withhold study treatment. 
 
 
 
 
 
 
. Withhold study treatment. 
 
 
 
 
CT=computed tomogra phy; FL=folllcular lymphoma; G-CSF =granulocyte colony-sti m ula ti ng factor, IRR=mfus1on-related react1on; LMWH= 
low- molecular-weight hepari n; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse E\ents; NHL = non- 
Hodgkin's lymphoma; NSAID=nonsteroidal anti-inflam m atory drug; TLS=tumor lysis syndro m e; TSH=thyroid-stim ul atin g hormone; ULN= 
upper limit normaL • Dose modifica ti ons apply only to e\ents that are considered to be related to lenalidomide. 
b  Accordi ng to Cairo - Bi sh op classi fi c ation system 
c  Graded according to NCI CTCAE Versi o n 3.0. 


Page  84 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
E .ent 
Action To Be Taken 
Diarrhea 
Grade 4 
. 
Pennanently discontinue study treatment 
Corticosteroid treatment is suggested for colitis manifested as Grade 4 diarrhea. 
Grade 2 or 3 
. 
Withhold study treatment. 
Investigat e etiology  Consutl with a gastroenterologist if immune etiology is suspected 
. 
Corticosteroid treatment may be required for colitis manifested as Grade 3 diarrhea. 
If diarrhea improves to Grade ::; 1, resume obinutuzumab at full dose. 
If immune-related diarrhea improves to Grade ::;   and any colitis has cleared as confinned by sigmoidoscopy 
1 
(or colonoscopy, if appropriate) with colonic biopsy, resume atezolizumab at full dose. 
Note: If colitis is treated w ith corticosteroids, atezolizumab should not be resumed until the corticosteroids 
have been tapered to::; 10 mg/day  off prednisone or equivalent 
Pneumopathy, non-infectious 
(i e ,dyspnea, hypoxia, 
pulmonary infiltrates) 
. 
Investigat e etiology  Consutl with a pulmonologist. 
If symptoms have resolved and CT lung findings are clear, resume atezolizumab at full dose. 
Tumor flare 
reaction 
Grade 3-4 c 
. 
Administer corticosteroids, NSAIDs, and/or narcotic analgesics at in.estigator's discretion. 
lfthere is improvement to Grade::; 1, resume atezolizumab at full dose. 
Grade 1-2 c . 
Continue study treatment 
Administer corticosteroids, NSAIDs, and/or narcotic analgesics at in.estigator's discretion. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. Withhold study treatment. 
 
. Withhold study treatment. 
 
 
 
 
 
CT=computed tomography; FL=folllcular lymphoma; G-CSF =granulocyte colony-st1mulat1n g factor, IRR=mfus1on-related react1on; LMWH= 
low- molecular-weight heparin; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse E .ents; NHL = non- 
Hodgkin's lymphoma; NSAID=nonsteroidal anti-inflammatory drug; TLS=tumor lysis syndrome; TSH=thyroid-stimulating hormone; ULN= 
upper limit normal. • Dose modifications apply only to e .ents that are consi dered to be related to lenalidomide. 
b   According to cairo-Bishop classification system 
c   Graded according to NCI CTCAE Version 3.0. 


Page  85 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
22. 9 Appendix 9 
Correlative Studies Work Flow 
 
 
Pre-treatment, on-treatment and relapsed biopsies will undergo the same analysis/processing and 
storage, to be performed at three designated MSKCC sites (Pathology Core, Diagnostic Molecular 
Pathology [DMP] and Hematologic Oncology Tissue Bank [HOTB]) 
 
INTERVENTIONAL RADIOLOGY 
 
3-4 Cores: Formalin (all in one container) going to Pathology for: 
 
- 
Diagnostic IHC 
- 
Research IHC panel (see antibody panel below) 
- 
DNA and RNA extraction for Lymphotrack test (to be given to DMP lab) 
- 
Nanostring Immune Panel (to be given to DMP lab) 
- 
4 Cores: RPMI (all in one container) going to Pathology for: 
 
- 
Diagnostic flow 
- 
Research multiparameter flow cytometry (see antibody panel below) 
 
2 Cores*: Snap frozen at HOTB and stored 
 
PHELOBOTOMY 
 
1 Purple Top Tube going to Pathology for clinical and research flow 
 
2 Green Top Tubes going to HOTB for PBMC storage 
 
1 Red Top Tube for HOTB for serum cytokines assay 
 
 
*The snap frozen samples are optional and should only be taken if they can be safely obtained 
without any additional risk to the patient. 


Page  86 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
IHC panel 
1.  CD3 
2.  CD4 
3.  CD8 
4.  MHC-I 
5.  MHC-II 
6.  Beta2 microglobulin 
7.  PD1 
8.  PDL1 
9.  PDL2 
10. CD68 
11. FoxP3 
12. Tbet 
13. GATA3 
 
Flow Cytometry Multiparameteric panel BD X50 machine 
1.  CD3 
2.  CD4 
3.  CD8 
4.  CD28 
5.  CD127 
6.  CD25 
7.  CD122 
8.  CD132 
9.  CD95 
10. CD69 
11. CD62L 
12. CD45RO 
13. LAG3 
14. TIM3 
15. PD1 
16. CD56 
17. CD16 
18. CD10 
19. CD19 
20. CD20 
21. CD27 
22. CD38 
23. CD138 
24. IgM 
25. IgG 


Page  87 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Appendix 1 
Risks Associated with Atezolizumab and Guidelines for Management of 
Adverse Events Associated with Atezolizumab 
 
Toxicities associated or possibly associated with atezolizumab treatment should be managed 
according to standard medical practice.  Additional tests, such as autoimmune serology or biopsies, 
should be used to evaluate for a possible immunogenic etiology. 
 
Although most immune-related 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-related toxicities may require acute management with topical 
corticosteroids, systemic corticosteroids, or other immunosuppressive agents. 
 
The investigator should consider the benefit risk balance a given patient may be experiencing prior 
to further administration of atezolizumab.  In patients who have met the criteria for permanent 
discontinuation, resumption of atezolizumab may be considered if the patient is deriving benefit and 
has fully recovered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an appropriate 
delegate) and the Medical Monitor. 
 
DOSE MODIFICATIONS 
 
There will be no dose modifications for atezolizumab in this study. 
 
TREATMENT INTERRUPTION 
 
Atezolizumab treatment may be temporarily suspended in patients experiencing toxicity considered 
to be related to study treatment. If corticosteroids are initiated for treatment of the toxicity, they must 
be tapered over 1 month to the equivalent of  10 mg/day oral prednisone before atezolizumab can 
be resumed. If atezolizumab is withheld for  12 weeks after event onset, the patient will be 
discontinued from atezolizumab.  However, atezolizumab may be withheld for  12 weeks to allow 
for patients to taper off corticosteroids prior to resuming treatment.  Atezolizumab can be resumed 
after being withheld for  12 weeks if the Medical Monitor agrees that the patient is likely to derive 
clinical benefit.  Atezolizumab treatment may be suspended for reasons other than toxicity (e.g., 
surgical procedures) with Medical Monitor approval.  The investigator and the Medical Monitor will 
determine the acceptable length of treatment interruption. 
 
MANAGEMENT GUIDELINES 
PULMONARY EVENTS 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated with 
the administration of atezolizumab.  Patients will be assessed for pulmonary signs and symptoms 
throughout the study and will have computed tomography (CT) scans of the chest performed at 
every tumor assessment. 


Page  88 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
EEE vvveeentt 
Maanaaageee m
mm eenntt 
PPuullm
mmoonnaaryryeevevnetn, t, 
G
Graaddee11 
     CCoonnttininuueeaatetezozloizliuzmumabaabnadnmdomnitoonrictolorscelloys. ely. 
     RRe-eevvaaluluaateteononsesreiarliaiml iamgainggi.ng. 
     CCoonnssidideerrppaatietinetnrterfeeerfrearlratol tpoulpmuolm
naorynaspryecsipaeliscti.alist. 
PPuullm
mmoonnaaryryeevevnetn, t, 
G
Graaddee22 
     W
Witthhhhooldldaatetezozloizliuzmum
abafborfourp utop1to2 w12eewkseeakftseraeftveernet voensnet to. anset. a 
     RReefeerrppaatiteiennt tttotopuplmulomnoanryarayndanindfeicntfieoucstioduisseadsiseesapseecisaplisetcsiaaanisdtscoannsdider 
cboronnscihdoesrcborpoynocrhBoAsLco. py or BAL. 
     IInnitiiaatteetrtereaatmtmenetnwt iwthitchocrtoicrotisctoesroteidrsoiedqsuievqauleinvtatloen1t t2om1g /2kgm/dga/ykgor/dalay oral 
preeddnnisisoonnee. . 
     IIff eeevveennttreressoolvlevsestotoGrGadraed1eo1r boerttbeer,ttreers,urmeseuamteezoalitzeuzmolaizbu. bmab. b 
     IIff eeevveennttddooeessnontorterseoslvoelvteo GtoraGdrea1deor1boerttebrewttheirlewwhiitlhehwolidthinhgoaldteinzgolizumab, 
apetermzoalnizeunmtlyadbi,scpoenrtminauneeantetlzyodlizisucmoanbtinaunde caotentzaocltizMuemdaicbalaMnodncitooor.tcact 
    MFoerdreiccaulrrMenotneitvoern. tcs, treat as a Grade 3 or 4 event. 
Pulmonary event, 
   For recurrentievents, treat as a Grade 3 or 4 event. cal Monitor. c 
Permanently dscontinueatezolizumaband contact Medi 
PGuralm
deo3naorry4event, 
Grade 3 or 4 
    PBreornmchaonsecnotplyy doirsBcoAnLtiiisnureecoamtemzoelnizduem
d.ab and contact Medical Monitor. c 
    BInritoiantcehtroesactmopeyntowr iBthAcLoritsicroescteormoim
dseenqdueivda.lent to 1 2 mg/kg/day oral 
   Ipnreitdiantiesotnreea. tment with corticosteroids equivalent to 1 2 mg/kg/day oral 
    pIfreevdennitsdoonees. not improve within 48 hours after initiating corticosteroids, 
   Icfoenvseidnetr daodedisngnoatnim
impmrounvoeswupitphriens4si8vehaoguersnta. fter initiating 
    cIfoervtiecnotsrteesroolivdess, tcooGnrsaiddder1aodrdbinetgtear,ntaim
pemr cuonrotiscousptperrreoisdssivoeveargte1ntm. onth. 
BAL   bronchoscopic    If event resolves to Grade 1 or better, taper corticosteroids over 
alveolar lavage. 
t 1 month. 
 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies such 
as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart failure, 
chronic obstructive pulmonary disease, or pulmonary hypertension.  Management guidelines for 
pulmonary events are provided in 
 
Table 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) to allow 
BAfLor cobrtrioconsctheorosidcsop(iifcinaitlivaeteodla) rtolabveargeed.uced to the equivalent of d 10 mg/day oral prednisone. The 
a Aactecezpotlaizbulemleanbgm
thaoyf tbhee w
exithenhdeeldd fpoerriaodloonfgtiemrepmeruiosdt boef atigmreeed(i.uep.,o!n b1y2tw
heeeinkvsesatfigteartoervaenndt the 
oMnesdeicta) ltoMoanlliotowr. for corticosteroids (if initiated) to be reduced to the equivalent of 
b   dIf c1o0rtm
icogs/dtearoyidosrahlapvreebdeneisnoinnnieti.ateTdh,ethaecycmeputsat bbleee tlaepnegrtehd oofvtehret e1xmteonndthedtoptheerioedquoivfatliemnet omf dus1t0 
bmeg/adgaryeoerdal uppreodnnbisyontheebeinfovreesatitgeaztoolirzuamndabthceanMbeedriceasul mMeodn.itor. 
cb IRf ecsourmticpotisotneorof iadtsezhoalivzeumbaebenmainyitbiaetecodn, sthideeyrem
d uinstpabteietnatspewrheod aorveedretriv1inmg obenntheftiot atnhdehave fully 
ereqcuoivvearleedntfrooomf dth1e0im
mm mg/udnaey-roelraatlepd reevdennits.oPnaetibeentfsorceanatbeezoreli-zcuhmallaebngceadnwbiteh raeteszuomlizeudm. ab only 
c R
afetesruampppprtoiovnal ohfaastbeezeonlizduomcuambemntaeyd bbbye bcootnhsthideeirnevdesintigpaatotire(notrsawn haopparroeprdiaetreivdinelgegbaeten)eafint danthde 
hMaevdeicaful lMlyorneitcoor.vered from the immune-related event.  Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
Table 1 
Management Guidelines for Pulmonary Events, Including Pneumonitis 
 
HEPATIC EVENTS 
 
Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 


Page  89 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
EEEvvveeentt 
Maanaaageee m
mm eenntt 
HHeeppaatticiceevveennt,t, 
G
Graaddee11 
     CC oonnttininuueeaatetezozloizliuzmum
aba. b. 
     M
MoonniittoorrLLFFTTssunutniltvilavluaelusersesroelsveoltvoewtoithwinitnhoinrmnaolrlm
imaitlsliomr ittos or 
tboasbealisneelivnaeluveasl.ues. 
HHeeppaatticiceevveennt,t, 
G
Graaddee22 
AAllll eeeveeennntsss::: 
     MM oonniittoorrLLFFTTssmm
oroerefrefqreuqeunetlyntulyntuil nretitlurrentutornbatoseblianesevlainluees. 
Evevnatluseosf.! 5 days’ duration: 
EveWnittthshoofld!at5ezdoaliyzsu’mdaubrafotirounp: to 12 weeks after event onset. a 
    W
Inititiahtheotlrdeaatmteeznotliwzuitm
h caobrtficoorsuteprotoids12eqwueiveaklesnat fttoer event 
o1n2semt.ga/kg/day oral prednisone. 
     IIfneitviaetnet rtreesaotlvmeesntot wGirtahdceo1rtoicrobsetteteror,idresseumqueivaateleznotliztoumab. b 
    1Ife2vemntgd/koge/sdnaoyt orerasol lpvreetdonGisroandeee 1 or better while withholding 
   Iafteeezvoelinzturmeasbo,lvpeesrmtoanGenratldyedi1scoorntbineutteera,terezosluizmume ab and 
acotenztaoclitzMuemdaicba.l bMonitor. c 
LFT   liver function 
a   Atezolizumab m 
testsIf. event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
ay beatweizthohliezludmfoar ba alonndgecropnetaricotdMofetdimicea(l i.Me.o, n!i1to2r.wceeks after 
 
hepatic transaminases, and liver function will be monitored throughout study treatment. 
Management guidelines for hepatic events are provided in 
 
Table 2. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
have liver function tests (LFTs) performed immediately and reviewed before administration of the 
next dose of study drug. 
 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
 
Table 2         Management Guidelines for Hepatic Events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
LFoTf d 1l0ivmerg/fduanyctoioranl pteresdtsn.isone. The acceptable length of the extended period of 
a Atimteezmoluizsut m
beabagmreaeyd buepownitbhyhtehledinfovresatilgoantogrear npdetrhioedMoefdticmael M(io.en.it,o!r. 12 weeks 
b   aIffcteorrrtiecvoestnetroooinds httta) vteo baelleonwinfoitiracteodr,titchoesytemruosidt sbe(iftaipneitriaedteodv)etrotb1emreodntuhcteodthtoe the 
eequuiivvaalelennt toof fd d101m0 gm/dga/ydaoyraol rparel dpnreisdonnnesobnefeo.reTahteee zaoclizcuemptaabbcleanlebnegrthesoufmthede. 
c    eRxetseunmdpetdionpeorfioatdezooflitzim
umeamb umsat ybbeeacgorneseidddeurepdonin bpyattiehnetsinwvheostaigreatdoerriavnindg tbheenefit 
M
aneddhicaavleMfuollnyirtoecr.overed from the immune-related event. Patients can be 
b Irfe-ccohratilcleonsgteedrowiditsh haatevzeolbizeuemnabinoitnialyteadft,etrhaepypm
rouvaslt hbaes tbaepeenreddocouvmeer ntte1d m
byobnoththto 
tthhee ienvqeusivtiagaletonrt (oofr dan10apmprgo/pdraiayteodraellepgraetden) iasnodntehebeMfoedreicaaalteMzoonliiitzour.mab can be 
resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients 
can be re-challenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 


Page  90 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
a   Atezolizumab ma e 
f 
, 
 
Table 2 
Management Guidelines for Hepatic Events (cont.) 
 
 
EEvveennt t 
ManMaagnemageenm
t ent 
HDepiaartircheeevaeonrt, 
Gcraodlietis3, oGr r4ade 1 
   PCeormntainnueentlaytedizsocloiznutinmuaeba.tezolizum ab and contact Medical 
 MInointiiatoter.  sc ymptomatic treatment. 
   CEonndsoidsecroppaytieisntrerecfoem
rraml teongdaesdtroifinstyem
stipntaolmspsepciearlsisitsftofror ! 7 days. 
  eMvaolnuiatotior nclaonsdellliyv.er biopsy to establish etiology of hepatic 
injury. 
Diarrhea or 
colitis, Grade 2 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Initiate treatment with corticosteroids equivalent to 
  1In 2itimatge/ksgy/m
dapytooom
raal ptircedtrneisaotm
nee.nt. 
   IPf eavteiennt tdroeefsernroatl itmopGroIvsepweicthiainlis4t8ishoreucrsoamftmereinnnidtieadtin. g 
  cFoortricroescteurroreidnst, ecovnesnitdseroar dedviengntasnthimamt puenrossiuspt pre5ssdivaeysa,giennittti.ate 
    Itfreeeaetnmt erenstowlvieths ctoorGtircaodsete1roooridbseteteqru, itvaapleernctotrotic1os2tem
rogid/skgo/vdeary oral 
tp1remdonnistho.ne. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
LFT   liver function tests. 
    If event does not resolve to Grade 1 or better while withholding 
y b awteitzhohleizldumforaab,lopnegremr apneeriondtlyo dtiismceon(it.ein.u!e1a2tewzeoelkizsuamftaerb and 
event onset) to allow cfoornctoarctitcM
osetedriociadlsM(ifoinnniiitttioart.ecd) to be reduced to the equivalent 
of d 10 mg/day oral prednisone. The acceptable length of the extended period of 
Dtiiamrerhmeuasot rbe agreed W
upiothnhboyldthaeteinzvoelsiztiugamtoarbafnodr tuhpe tMoe1d2icawl eMeoknsitaorf.ter event onset. a 
b coIflcitoisr,ticGorsatedreoi3ds haveRbeefeeenr pinaittiiaetnetd,tothGeyI mspuesct ibaelistat pfoerrreedvoavluear ttio1nmaonndthctoontfhirematory 
equivalent of d 10 mgb/dioaypsoyra. l prednisone before atezolizumab can be resumed. 
c    Resumption of atezolIiznuitmiaateb mtreaaytbmeecnotnwsiidtherceodritnicpoasttieeenrotsidwsheoqaurievadleernivtintog b1e n2efit 
and have fully recovem
regd/fkrgom/dathyeIVimm
mm eunthey-rlpelraetdedniesvoelonnt.ePaantidenctosncvaenrtbeto 1 2 mg/kg/day 
re-challenged with ateozroallizpurmedanbiosnolnyeafoter reaqpupirvoavlaelnhtauspboenenimdporcouvmeemnetendt.by both 
the investigator (oranIfaepvperonpt rriaetseodlveelesgtaoteG) arandddeth1e oMrebdeictatel rM, orensituom
r. e atezolizumab. b 
   If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
GI   gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the 
equivalent of d 10 mg/day oral prednisone. The acceptable length of the 
extended period of time must be agreed upon by the investigator and the Medical 
Monitor. 
b If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving 
benefit and have fully recovered from the immune-related event.  Patients can be 
re-challenged with atezolizumab only after approval has been documented by 
both the investigator (or an appropriate delegate) and the Medical Monitor. 
GASTROINTESTINAL EVENTS 
 
Immune-related colitis has been associated with the administration of atezolizumab.  Management 
guidelines for diarrhea or colitis are provided in 
 
Table 3. 


Page  91 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
Event 
Management 
Diarrhea or 
colitis, Grade 1 
    Continue atezolizumab. 
    Initiate symptomatic treatment. 
    Endoscopy is recommended if symptoms persist for ! 7 days. 
    Monitor closely. 
Diarrhea or 
colitis, Grade 2 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Initiate symptomatic treatment. 
    Patient referral to GI specialist is recommended. 
    For recurrent events or events that persist ! 5 days, initiate treatment 
with corticosteroids equivalent to 1 2 mg/kg/day oral prednisone. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Diarrhea or 
colitis, Grade 3 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to GI specialist for evaluation and confirmatory biopsy. 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
 
All events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. 
For events 
of 
significant 
duration 
or 
magnitude 
or 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GI   gastrointestinal. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
d 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
associated with signs of systemic inflammation or acute-phase reactants (e.g., increased C-reactive 
protein, platelet count, or bandemia):  Perform sigmoidoscopy (or colonoscopy, if appropriate) with 
colonic biopsy, with three to five specimens for standard paraffin block to check for inflammation and 
lymphocytic infiltrates to confirm colitis diagnosis. 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) 


Page  92 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Table 3 
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) (cont.) 
 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
    Permanently discontinue atezolizumab and contact Medical Monitor. c 
    Refer patient to GI specialist for evaluation and confirmation biopsy. 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
    If event resolves to Grade 1 or better, taper corticosteroids over 
t 1 month. 
GI   gastrointestinal. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
d 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
 
 
 
ENDOCRINE EVENTS 
 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab.  Management guidelines for endocrine events 
are provided in Table 4. 
 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, constipation, 
or mental status changes should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. The patient should be referred to an endocrinologist if an endocrinopathy is 
suspected. Thyroid-stimulating hormone (TSH) and free triiodothyronine and thyroxine levels should 
be measured to determine whether thyroid abnormalities are present.  Pituitary hormone levels and 
function tests (e.g., TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, 
testosterone, prolactin, adrenocorticotropic hormone [ACTH] levels, and ACTH stimulation test) and 
magnetic resonance imaging (MRI) of the brain (with detailed pituitary sections) may help to 
differentiate primary pituitary insufficiency from primary adrenal insufficiency. 


Page  93 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Table 4 
Management Guidelines for Endocrine Events 
 
 
 
Event 
Management 
Asymptomatic 
hypothyroidism 
    Continue atezolizumab. 
    Initiate treatment with thyroid replacement hormone. 
    Monitor TSH weekly. 
Symptomatic 
hypothyroidism 
    Withhold atezolizumab. 
    Initiate treatment with thyroid replacement hormone. 
    Monitor TSH weekly. 
    Consider patient referral to endocrinologist. 
    Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Asymptomatic 
hyperthyroidism 
TSH t 0.1 mU/L and  0.5 mU/L: 
    Continue atezolizumab. 
    Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
    Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism 
    Withhold atezolizumab. 
    Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
    Consider patient referral to endocrinologist. 
    Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
    Permanently discontinue atezolizumab and contact Medical Monitor 
for life-threatening immune-related hyperthyroidism. c 
MRI   magnetic resonance imaging; TSH   thyroid-stimulating hormone. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of d 10 mg/day oral prednisone. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the equivalent of d 10 
mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 


Page  94 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Table 4 
Management Guidelines for Endocrine Events (cont.)
 
 
 
 
Event 
Management 
Symptomatic adrenal 
insufficiency, Grade 2 4 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to endocrinologist. 
    Perform appropriate imaging. 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better or patient is not stable 
on replacement therapy while withholding atezolizumab, permanently 
discontinue atezolizumab and contact Medical Monitor. c 
Hyperglycemia, Grade 1 
or 2 
    Continue atezolizumab. 
    Investigate for diabetes. If patient has Type 1 diabetes, treat as a 
Grade 3 event. If patient does not have Type 1 diabetes, treat as per 
institutional guidelines. 
    Monitor for glucose control. 
Hyperglycemia, Grade 3 
or 4 
    Withhold atezolizumab. 
    Initiate treatment with insulin. 
    Monitor for glucose control. 
    Resume atezolizumab when symptoms resolve and glucose levels 
are stable. 
MRI   magnetic resonance imaging; TSH   thyroid-stimulating hormone. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of d 10 mg/day oral prednisone. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the equivalent of d 10 
mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 


Page  95 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Table 4 Management Guidelines for Endocrine Events (cont.) 
 
Event 
Management 
Hypophysitis 
(pan-hypopituitarism), 
Grade 2 or 3 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to endocrinologist. 
    Perform brain MRI (pituitary protocol). 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    Initiate hormone replacement if clinically indicated. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
    For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), 
Grade 4 
    Permanently discontinue atezolizumab and contact Medical Monitor. c 
    Refer patient to endocrinologist. 
    Perform brain MRI (pituitary protocol). 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    Initiate hormone replacement if clinically indicated. 
MRI   magnetic resonance imaging; TSH   thyroid-stimulating hormone. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of d 10 mg/day oral prednisone. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the equivalent of d 10 
mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be re-challenged with atezolizumab only 
after approval has been documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 


Page  96 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
OCULAR EVENTS 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  Management 
guidelines for ocular events are provided in 
 
 
 
Table 5. 
 
 
 
 
 
Table 5 
Management Guidelines for Ocular Events 


Page  97 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
 
Event 
Management 
Ocular event, 
Grade 1 
    Continue atezolizumab. 
    Patient referral to ophthalmologist is strongly recommended. 
    Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
    If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Patient referral to ophthalmologist is strongly recommended. 
    Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Ocular event, 
Grade 3 or 4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
    Refer patient to ophthalmologist. 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day 
oral prednisone. 
    If event resolves to Grade 1 or better, taper corticosteroids over 
t 1 month. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
d 10 mg/day oral prednisone. The acceptable length of the extended period of time must 
be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Page  98 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
 
 
IMMUNE-RELATED MYOCARDITIS 
 
Immune-related myocarditis has been associated with the administration of atezolizumab.  Immune- 
related myocarditis should be suspected in any patient presenting with signs or symptoms 
suggestive of myocarditis, including, but not limited to, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope. Immune-related myocarditis needs to be distinguished 
from myocarditis resulting from infection (commonly viral, e.g., in a patient who reports a recent 
history of gastrointestinal illness), ischemic events, underlying arrhythmias, exacerbation of 
preexisting cardiac conditions, or progression of malignancy. 
 
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme 
assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per 
institutional guidelines. A cardiologist should be consulted.  An endomyocardial biopsy may be 
considered to enable a definitive diagnosis and appropriate treatment, if clinically indicated. 
 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 6. 


Page  99 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Table 6 
Management Guidelines for Immune-Related Myocarditis 
 
 
Event 
Management 
Immune-related 
myocarditis, Grade 2 
    Withhold atezolizumab for up to 12 weeks after event onset a and 
contact Medical Monitor. 
    Refer patient to cardiologist. 
    Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
    Consider treatment with corticosteroids equivalent to 1 2 mg/kg/day 
IV methylprednisolone and convert to 1 2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Immune-related 
myocarditis, Grade 3-4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
    Refer patient to cardiologist. 
    Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
    Initiate treatment with corticosteroids equivalent to 1 2 mg/kg/day IV 
methylprednisolone and convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
    If event resolves to Grade 1 or better, taper corticosteroids 
over t 1 month. 
ECMO   extracorporeal membrane oxygenation; VAD   ventricular assist device. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to the equivalent of d 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by the 
investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the equivalent of 
d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 
 
 
INFUSION-RELATED REACTIONS 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, patients 
who experience an infusion-related reaction (IRR) with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for subsequent 


Page  100 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
EEE vvveeentt 
Maanaaageee m
mm eenntt 
IIRRR
R,,GGrraaddee11 
     RR eedduucceeininfufusisoinonrartaetteo thoahlf athlfethraeterabteeinbgeginivgengiavtetnheatttimtheeotfime 
oevf eenvteonntsoent.set. 
     AAfftteerrtthheeeevveentnht ahsarsesreoslvoeldv,etdh,ethineveinstvigeasttoigr asthoorusldhowualidt fowrait for 
330 m
mmininuutetesswwhihleilededlievleivrienrginthgethinefuisnifounsaiotnthaetrtehdeucreeeduracteed. rate. 
     IIff tthheeininfufussioionnisistotloerleatreadteadt tahtethreedruecdeudcreatde rfaotre30fomr 3in0utm
esinauftteers 
asyftmerptsoymmsphtaovmesrehsaovlveedre, sthoelvienfdu,stihone riantfeusmioany braeteincmreaaysebde to 
itnhecroeraigsineadl troatteh.e original rate. 
IIRRR
R,,GGrraaddee22 
     II nntteerrruuppt taatetezozloizliuzmum
abaibnfiunsfiuosni.on. 
     AAddmmiinnisisteter raaggggrersessivseivseymsypmtopmtoam
ticattriecatrmeeantmt (eee.gt.,(eo.rga.l,oor rIaVl or 
IaVntaihnisttihamistinaem, ianneti,-paynrtei-tpicymreetdicicm
ateiodni,cgaltuioconc, ogrltuiccooidcso,rticoids, 
eepiinneepphhrirninee, ,brbornocnhcohdoildatiloartso, rosx,yogxeyng, eIVn,flIuVidfsl)u.ids). 
     AAfftteerrssyymmpptotomms shahvaevreesreolsvoeldvetodbtaosbealinsee,lirnees,urmeesuinmfuesiionnfuast ihoanlf 
athtehraaltfethbeeeinragtgeivbeeninagt tghievetimn eatotfheevetinmt eonosfeet.vent onset. 
     FForr ssuubbsseeqquuenetnitnifnufsuiosniosn, cso, ncsoidnesridaedrmaindim
strinaitsiotnraotifoonraolf oral 
preem
meeddicicaatitoionnww
ithithanatinhtisihtaismtainmesin, easn,tia-pnytrie-ptiycrse, taicnsd,/oarnadn/aolrgesics 
aandalmgeosniiitcosr aclnodsemlyofonritIoRrRcslo. sely for IRRs. 
IIRRR
R,,GGrraaddee33oro4r 
4 
     SStoooppininfufussioionn. . 
     AAddmmiinnisisteter raaggggrersessivseivseymsypmtopmtoam
ticattriecatrmeeantmt (eee.gt.,(eo.rga.l,oor rIaVl or 
IaVntaihnisttihamistinaem, ianneti,-paynrtei-tpicymreetdicicm
ateiodni,cgaltuioconc, ogrltuiccooidcso,rticoids, 
eepiinneepphhrirninee, ,brbornocnhcohdoildatiloartso, rosx,yogxeyng, eIVn,flIuVidfsl)u.ids). 
     PPeerrmmaanneenntltylydidsicsocnotnintuineuaeteaztoelizoulmizaubmaanbd acnodntaccotnMtaecdticMael dical 
M
Moonniittoorr..a a 
 
infusions.  Metamizole (dipyrone) is prohibited in treating atezolizumab-associated IRRs because of 
its potential for causing agranulocytosis. 
 
Guidelines for medical management of IRRs during Cycle 1 are provided in 
 
Table 7.  For subsequent cycles, IRRs should be managed according to institutional guidelines. 
 
Table 7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IIRRRR   infinusfuiosnio-rne-lareteladteredacretioanc.tion. 
a   RReessuummpptitoionnofoaf taetzeozliozluizmuambambam
y baey cboensciodnersei ddd inrepdatinienptastwiehnotsarwehdoeraivreingdebreinvienfgit 
banednehfaitveanfudllyharevceovfuelrleydrefrcoomvethree dimfmroumnet-hreeelaimtem
d uevneen-tr.elPaatetidenetsvecnant. bPeatients can 
bree-crhea-lclehnaglleednwgeithd awteitzhoalizteuzmoalibzuom
nlyabaftoenr laypapfrtoevraal phpasrobveaelnhdaoscbuemeenntdeodcbuymbeonthtethde 
binyvebsotitghatttohre(oinrvaensatipgpartooprr(iaotreadnelaepgaptreo)parniadtethdeeMleegdaicteal)Maonndittohre. Medical Monitor. 
Management Guidelines for Infusion-Related Reactions 


Page  101 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
PANCREATIC EVENTS 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab. The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should include 
an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  Management 
guidelines for pancreatic events, including pancreatitis, are provided in Table 8. 
 
Table 8 Management Guidelines for Pancreatic Events, Including Pancreatitis 
 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase ! 1.5 2.0 u ULN: 
    Continue atezolizumab. 
    Monitor amylase and lipase weekly. 
    For prolonged elevation (e.g., ! 3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
Asymptomatic with amylase and/or lipase ! 2.0 5.0 u ULN: 
    Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to GI specialist. 
    Monitor amylase and lipase every other day. 
    If no improvement, consider treatment with corticosteroids 
equivalent to 1 2 mg/kg/day oral prednisone. 
    If event resolves to Grade 1 or better, resume 
atezolizumab. b 
    If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
    For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c 
GI   gastrointestinal. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of d 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the equivalent 
of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Page  102 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Table 8 
Management Guidelines for Pancreatic Events, Including Pancreatitis (cont.) 
 
 
Event 
Management 
Immune-related pancreatitis, 
Grade 2 or 3 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to GI specialist. 
    Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
    If event resolves to Grade 1 or better, resume 
atezolizumab. b 
    If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab and contact Medical Monitor. c 
    For recurrent events, permanently discontinue atezolizumab 
and contact Medical Monitor. c 
Immune-related pancreatitis, 
Grade 4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
    Refer patient to GI specialist. 
    Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone and convert to 
1 2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
    If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
    If event resolves to Grade 1 or better, taper corticosteroids 
over t 1 month. 
GI   gastrointestinal. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of d 10 mg/day oral 
prednisone. The acceptable length of the extended period of time must be agreed upon by 
the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the equivalent 
of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event. Patients can be re-challenged with 
atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor. 


Page  103 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
DERMATOLOGIC EVENTS 
 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self limited, with or without pruritus.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated. 
Management guidelines for dermatologic events are provided in Table 9. 
 
Table 9 
Management Guidelines for Dermatologic Events 
 
Event 
Management 
Dermatologic 
event, Grade 1 
    Continue atezolizumab. 
    Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2 
    Continue atezolizumab. 
    Consider patient referral to dermatologist. 
    Initiate treatment with topical corticosteroids. 
    Consider treatment with higher-potency topical corticosteroids if 
event does not improve. 
Dermatologic 
event, Grade 3 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to dermatologist. 
    Initiate treatment with corticosteroids equivalent to 10 mg/day 
oral prednisone, increasing dose to 1 2 mg/kg/day if event does 
not improve within 48 72 hours. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
Dermatologic 
event, Grade 4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of d 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be re- 
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
 
 
 
NEUROLOGIC DISORDERS 
 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab.  Patients may present with signs and symptoms of sensory and/or motor neuropathy. 
Diagnostic workup is essential for an accurate characterization to differentiate between alternative 
etiologies. Management guidelines for neurologic disorders are provided in Table 10. 


Page  104 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Table 10  Management Guidelines for Neurologic Disorders 
 
Event 
Management 
Immune-related 
neuropathy, 
Grade 1 
    Continue atezolizumab. 
    Investigate etiology. 
Immune-related 
neuropathy, 
Grade 2 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Investigate etiology. 
    Initiate treatment as per institutional guidelines. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and contact 
Medical Monitor. c 
Immune-related 
neuropathy, 
Grade 3 or 4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
    Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
    Refer patient to neurologist. 
    Initiate treatment as per institutional guidelines. 
    Consider initiation of corticosteroids equivalent to 1 2 mg/kg/day 
oral or IV prednisone. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after event 
onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent of 
d 10 mg/day oral prednisone. The acceptable length of the extended period of time 
must be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be re- 
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
 
 
IMMUNE-RELATED MENINGOENCEPHALITIS 
 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient presenting 
with signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to, 
headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed 
level of consciousness. Encephalopathy from metabolic or electrolyte imbalances needs to be 
distinguished from potential meningoencephalitis resulting from infection (bacterial, viral, or fungal) 
or progression of malignancy, or secondary to a paraneoplastic process. 
 
All patients being considered for meningoencephalitis should be urgently evaluated with a CT scan 
and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed safe by 


Page  105 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
the treating physician, a lumbar puncture should be performed and a neurologist should be 
consulted. 
 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in 
 
Table 11. 
 
EEE vvveeentt 
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     PPeerrmmaanneenntltylydidsicsocnotnintuineuaeteaztoelizoulmizaubmaanbd acnodntaccotnMtaecdticMael Mdiocnailtor. a 
    M
Reofneritopar.tiaent to neurologist. 
    RIneitifaetreptraetaietmntetnot wniethurcoolrotigciosst.teroids equivalent to 1 2 mg/kg/day IV 
    Imneittihaytelprteredantismoelonntewainthd contttviceortsttoer1o i2dsmegq/kugi/vdaalyenotratol p1re d2nisone or 
m
eqgu/ikvagl/ednatyupIVonmimetphryolvpermedennn ts. olone and convert to 
    1Ife2vemntgd/koge/sdnaoyt oimraplropvreee wnitishoinn4e8ohroeuqrsuaivfatelreinntituiaptionng 
icmorptircoovsetemroeidnst., consider adding an immunosuppressive agent. 
     IIff eeevveennttredsooelvsensotot iGmrpardoev1e owritbheitnte4r,8tahpoeurrcsoartficteorstineritoiaidtsinogver 
cto1rmticoonsthte. roids, consider adding an immunosuppressive agent. 
a   Resumption of atezoli 
fully recovered from th
zumaIfbemveayntbreecsoonlvseidserteodGinrapdaetie1ntosrwbheottaerrr e, tdaepreivrincgobrteicnoesfit arrrnodidhsave 
e imomvuenret-re1lamteodnethv.ent Patients can be re-challengedwith
a Ratezouuulm
izupmtioanb ooonf laytaefzteorliazpupmroavbalmhaaas bbbeeeecnodnoscidumereendteidn bpyatbieotnhtsthwe hinoveasrteigdaetorriv(ionrgabnenefit 
aappdrohparviaetefudlelylergeacteo)vaenreddthferoMmedthicealimMmonuitnoer.-related event.  Patients can be re- 
challenged with atezolizumab only after approval has been documented by both the 
investigator (or an appropriate delegate) and the Medical Monitor. 
Table 11  Management Guidelines for Immune-Related Meningoencephalitis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RENAL EVENTS 
 
Immune-related nephritis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate renal function, and renal function, including serum creatinine, should 
be monitored throughout study treatment.  Patients with abnormal renal function should be 
evaluated and treated for other more common etiologies (including prerenal and postrenal causes, 


Page  106 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
Event 
Management 
Renal event, 
Grade 1 
    Continue atezolizumab. 
    Monitor kidney function, including creatinine, closely until 
values resolve to within normal limits or to baseline values. 
Renal event, 
Grade 2 
    Withhold atezolizumab for up to 12 weeks after event onset. a 
    Refer patient to renal specialist. 
    Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day oral prednisone. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
Renal event, 
Grade 3 or 4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. 
    Refer patient to renal specialist and consider renal biopsy. 
    Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day oral prednisone. 
    If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
    If event resolves to Grade 1 or better, taper corticosteroids over 
t 1 month. 
 
and concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer the patient to a 
renal specialist 
if clinically 
indicated.  A 
renal biopsy 
may be required 
to enable a 
definitive 
diagnosis and 
appropriate 
treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of d 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 
Management Guidelines for Renal Events 
Patients with 
signs and 
symptoms of 
nephritis, in the 
absence of an 
identified 
alternate 
etiology, should 
be treated 
according to the 
guidelines in 
Table 12. 
 
Table 12 


Page  107 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMMUNE-RELATED MYOSITIS 
 
Immune-related myositis has been associated with the administration of atezolizumab.  Myositis or 
inflammatory myopathies are a group of disorders sharing the common feature of inflammatory 
muscle injury; dermatomyositis and polymyositis are among the most common disorders.  Initial 
diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in dermatomyositis), 
biochemical (serum creatine kinase increase), and imaging (electromyography/MRI) features, and is 
confirmed with a muscle biopsy. 
 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in 


Page  108 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
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IIm
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myyoossititisis, ,Grade 1 
Grade 1 
     CC oonnttininuueeaatetezozloizliuzmum
aba. b. 
     RReefeerrppaatiteiennt tttotorhrehuemuamtoalotogliosgt oisrtnoerunroeluogroislot.gist. 
     II nnittiiaatteetrtereaatmtmenetnatsapsepr einrsitnitsutitountaiol ngaulidgeuliindeesl.ines. 
IIm
mm
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m
myyoossititisis, ,Grade 2 
Grade 2 
     W
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abafborfourp utop1to2 w12eewkseeakftseraeftveernet voensnet t a 
aonnndsectonataaacntdMceodnictaaalcMt M
oneitdoirc.al Monitor. 
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     II nnittiiaatteetrtereaatmtmenetnatsapsepr einrsitnitsutitountaiol ngaulidgeuliindeesl.ines. 
     CC oonnssidideerrtrtereatamtm
enetnwt iwthitchorctoicrotsicteorsotiedrsoeidqsuievqalueinvtatloent to 
11 22 mmgg/k/kgg/d/dayayIVIVmmetheythlpyrlepdrneidsonliosnoeloanned acnodnvceortntvoert to 
11 22 mmgg/k/kgg/d/dayayoroarlaplrepdrendisnoinseonoer eoqrueivqauleivnat luepnotnupon 
iim
mpprroovveemmeennt.t. 
     IIff cccoorrtticicoossteteroroidisdsaraerieniitniaittt eiadteadndanevdeenvt edonet sdonoetsimnoptroim
veprove 
wwiitthhiinn4488hhoourusrsafateftreinr iitniaitttiiinagtincgorcticoortsicteorsotidesro, cidosn,scidoenrsaiddddirng 
aan diminmguannosimupmpruensosisvuepapgreensts. ive agent. 
     IIff eeevveennttreressoolvlevsestotoGrGadraed1eo1r boerttbeer,ttreers,urmeseuamteezolizum ab. b 
    aIfteevzeonlitzduomesabn.otbresolve to Grade 1 or better while withholding 
    Iafteeezvoelinztudmoaebs, pneortmraenseonlvtley dtoiscGornatdineue1aoter zboelitzteumr wabhialend 
wcoitnhtahcotldMinedgicaatleMzolnizituom
r. cab, permanently discontinue 
a   Atezolizumabmay beawteitzhohleizldumforaab laonnndgecropnetraiocdt M
ofetidmicea(li.M
e.,o!ni1to2rw. eceks after 
 
 
 
 
 
 
Table 13 
 
 
 
 
 
 
Table 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Aevteeentoolinzsuemt)atbo amllaowy bfoer wcoitrhtichoesldtefroooidas (loif ningiteiartpede)ritoodboefretidmuece(di.eto., t!he1e2qwuievealkesnt 
aofff tde1r 0evmegn/dt aoynsoeratl) ptoreadnlloiswonfeo.r Tcohertiaccocsetpetraobidlesle(inf ginthitioaftethde) etoxtebnedreeddpuecreiodd toof the 
etimqueivmaulestnbt eofagdre1e0dmugpo/dnabyyothrael ipnrvedstnigisaotonrea.ndThtheeaMcecdeipctaal bMleonleitonrg. th of the 
b   eIfxctoerntidcoesdteproeirdiosdhaovfetimbeeenminuistitabteed,atghreeyemduuspt obne tbaypethreedinovvv eeersttig1amtoornathndto tthheee 
M
eqeudivicaalelnMt oofndit1o0r.mg/day oral prednisone before atezolizumab can be resumed. 
cb IRf ecsourmticpotisotneorof iadtsezhoalivzeumbaebenmainyitbiaetecdon, sthideeyrem
d uinstpabteietnatspewrheod aorveedretriv1inmg obenntheftiot 
tahned ehqavueivfaullelynrteocfovde1re0dmfrgom/dathyeoimraml purneed-rneilsaotendeebveefnotr. ePaatteieznotslizcuamn abbe can be 
rree-scuhm
alleedn.ged with atezolizumab only after approval has been documented by both 
c Rthe inuuuvmepsttiigoantoorf(oarteaznoalipzpurm
oparbiatme adyelbegeacteo)nasnidetrheedMinedpicaatileMnotsniwtohr.o are deriving 
benefit and have fully recovered from the immune-related event.  Patients 
can be re-challenged with atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the 
Medical Monitor. 
Management Guidelines for Immune-Related Myositis 


Page  109 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
Table 13 Management Guidelines for Immune-Related Myositis (cont.) 
 
 
Immune-related 
myositis, Grade 3 
    Withhold atezolizumab for up to 12 weeks after event onset a 
and contact Medical Monitor. 
    Refer patient to rheumatologist or neurologist. 
    Initiate treatment as per institutional guidelines. Respiratory 
support may be required in more severe cases. 
    Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
    If event resolves to Grade 1 or better, resume atezolizumab. b 
    If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab and 
contact Medical Monitor. c 
    For recurrent events, treat as a Grade 4 event. 
Immune-related 
myositis, Grade 4 
    Permanently discontinue atezolizumab and contact Medical 
Monitor. c 
    Refer patient to rheumatologist or neurologist. 
    Initiate treatment as per institutional guidelines. Respiratory 
support may be required in more severe cases. 
    Initiate treatment with corticosteroids equivalent to 
1 2 mg/kg/day IV methylprednisolone, or higher-dose bolus if 
patient is severely compromised (e.g., cardiac or respiratory 
symptoms, dysphagia, or weakness that severely limits 
mobility); convert to 1 2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
    If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
    If event resolves to Grade 1 or better, taper corticosteroids 
over t 1 month. 
a   Atezolizumab may be withheld for a longer period of time (i.e., ! 12 weeks after 
event onset) to allow for corticosteroids (if initiated) to be reduced to the equivalent 
of d 10 mg/day oral prednisone. The acceptable length of the extended period of 
time must be agreed upon by the investigator and the Medical Monitor. 
b   If corticosteroids have been initiated, they must be tapered over t 1 month to the 
equivalent of d 10 mg/day oral prednisone before atezolizumab can be resumed. 
c    Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event. Patients can be 
re-challenged with atezolizumab only after approval has been documented by both 
the investigator (or an appropriate delegate) and the Medical Monitor. 


Page  110 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
 
 
 
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 for atezolizumab. 
 
Recommendations regarding early identification and management of systemic immune activation 
are provided below.  In the event of suspected systemic immune activation, atezolizumab should be 
withheld and clinical specialists (e.g., rheumatology, clinical immunology, or solid organ or 
hematopoietic stem cell transplant specialists) and the Medical Monitor should be consulted for 
additional guidance. 
 
Early disease recognition is critical, and systemic immune activation should be suspected if, in the 
absence of an alternative etiology, the patient meets two or more of the following criteria: 
 
Hypotension that is refractory to aggressive IV fluid challenge 
 
o Vasopressor support may be required. 
 
Respiratory distress that requires aggressive supportive care 
 
o Supplemental oxygen and intubation may be required. 
 
Fever ! 38.5qC 
 
 
Acute renal or hepatic failure 
 
 
Bleeding from coagulopathy 
 
 
Any of the following unexplained laboratory abnormalities (change from baseline):  cytopenias (in 
two or more lineages), significant transaminitis, or coagulopathy 
 
For patients with suspected systemic immune activation, an initial evaluation should include the 
following: 
 
CBC with peripheral smear 
 
 
PT, PTT, fibrinogen, and D-dimer 
 
 
Ferritin 
 
 
Soluble interleukin 2 (IL-2) receptor (soluble CD25) 
 
 
Triglycerides 
 
 
AST, ALT, and direct bilirubin 
 
 
LDH 
 
 
Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
Laboratory tests with normal results should be repeated frequently in patients for whom a high 
clinical suspicion of systemic immune activation exists. 


Page  111 of 115 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
 
 
 
If neurologic abnormalities are present, consider cerebrospinal fluid analysis and/or an MRI of the 
brain. 
 
If cytopenias are present (Grade t 2 in two or more lineages) or ferritin is t 3000 ng/mL, the following 
evaluations should also be performed: 
 
Bone marrow biopsy and aspirate (assess for evidence of hemophagocytosis) 
 
 
Adenovirus, cytomegalovirus, Epstein-Barr virus, herpes-simplex virus, and human herpesvirus 
6, 7, and 8 evaluation (for reactivated or active disease) 
 
Diagnostic criteria and recommended management for systemic immune activation are provided in 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria 
in the positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 
2014). 
Grades are based on National Cancer Institute Common Terminology Criteria for A Page 112 of 115 
Events. 
These recommendations do not replace clinical judgment and are intended as suggested 
guidance. 
 
 
 
Table 14. The diagnostic criteria apply only when alternative etiologies have been excluded. 
 
 
 
Systemic Immune Activation Diagnostic Criteria 
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor Criteria 
   Fever t 38.5qC on more than one 
occasion 
   Ferritin t 3000 ng/mL 
   Cytopenias (Grade t 2 in two or more 
lineages) 
   Age-adjusted soluble interleukin-2 
receptor elevated by t 2 standard 
deviations 
   Severe (Grade t 3) or progressive 
dysfunction in two or more organs 
   Decreased fibrinogen 
   Splenomegaly 
   Hemophagocytosis in bone marrow, spleen, 
or lymph nodes 
   Elevated J-glutamyl transpeptidase (GGT) 
or liver function tests (AST, ALT, or direct 
bilirubin) 
   Elevated triglycerides 
   Elevated LDH 
   Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of 
Criteria 
Diagnosis 
Action to Be Taken 
t 4 major criteria Consistent 
with 
systemic 
immune 
activation 
 Permanently discontinue atezolizumab. 
 Consider treatment with an immunosuppressive agent 
(i.e., cytokine inhibitors) and IV corticosteroids 
(i.e., methylprednisolone 1 g once daily or equivalent, or 
dexamethasone t 10 mg/m2 once daily if neurologic 
abnormalities are present). 
 Contact the Medical Monitor for additional 
recommendations. 
 Consider HLH-2004 protocol (Henter et al. 2007) if there 
is no clinical improvement. 
3 major criteria 
OR 
2 major plus 
t 3 minor criteria 
Probable 
systemic 
immune 
activation 
 Depending on clinical severity, follow guidelines for 
“Consistent with systemic immune activation” or 
“Possible systemic immune activation” diagnosis. 
 Clinical specialists and the Medical Monitor may be 
contacted for recommendations. 
2 major plus 
d 2 minor criteria 
OR 
1 major plus 
t 4 minor criteria 
Possible 
systemic 
immune 
activation 
 Withhold atezolizumab. 
 Consider treatment with IV corticosteroids. 
 Clinical specialists and the Medical Monitor may be 
contacted for additional recommendations. 
 Follow guidelines for “Consistent with systemic immune 
activation” diagnosis if there is no clinical improvement or 
if clinical worsening occurs. 
 If clinical improvement occurs, atezolizumab may be 
resumed following a benefit-risk assessment by the 
Medical Monitor. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria 
in the positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 
2014). 
Grades are based on National Cancer Institute Common Terminology Criteria for A Page 112 of 115 
Events. 
These recommendations do not replace clinical judgment and are intended as suggested 
guidance. 
 
 
 
 
 
 
dverse 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria 
in the positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 
2014). 
Grades are based on National Cancer Institute Common Terminology Criteria for A Page 113 of 115 
Events. 
These recommendations do not replace clinical judgment and are intended as suggested 
guidance. 
 
 
 
An adverse event of systemic immune activation should be reported on the Adverse Event eCRF if it 
meets the criteria for "consistent with systemic immune activation" or "probable systemic immune 
activation" as outlined in 
 
Systemic Immune Activation Diagnostic Criteria 
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor Criteria 
   Fever t 38.5qC on more than one 
occasion 
   Ferritin t 3000 ng/mL 
   Cytopenias (Grade t 2 in two or more 
lineages) 
   Age-adjusted soluble interleukin-2 
receptor elevated by t 2 standard 
deviations 
   Severe (Grade t 3) or progressive 
dysfunction in two or more organs 
   Decreased fibrinogen 
   Splenomegaly 
   Hemophagocytosis in bone marrow, spleen, 
or lymph nodes 
   Elevated J-glutamyl transpeptidase (GGT) 
or liver function tests (AST, ALT, or direct 
bilirubin) 
   Elevated triglycerides 
   Elevated LDH 
   Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of 
Criteria 
Diagnosis 
Action to Be Taken 
t 4 major criteria Consistent 
with 
systemic 
immune 
activation 
 Permanently discontinue atezolizumab. 
 Consider treatment with an immunosuppressive agent 
(i.e., cytokine inhibitors) and IV corticosteroids 
(i.e., methylprednisolone 1 g once daily or equivalent, or 
dexamethasone t 10 mg/m2 once daily if neurologic 
abnormalities are present). 
 Contact the Medical Monitor for additional 
recommendations. 
 Consider HLH-2004 protocol (Henter et al. 2007) if there 
is no clinical improvement. 
3 major criteria 
OR 
2 major plus 
t 3 minor criteria 
Probable 
systemic 
immune 
activation 
 Depending on clinical severity, follow guidelines for 
“Consistent with systemic immune activation” or 
“Possible systemic immune activation” diagnosis. 
 Clinical specialists and the Medical Monitor may be 
contacted for recommendations. 
2 major plus 
d 2 minor criteria 
OR 
1 major plus 
t 4 minor criteria 
Possible 
systemic 
immune 
activation 
 Withhold atezolizumab. 
 Consider treatment with IV corticosteroids. 
 Clinical specialists and the Medical Monitor may be 
contacted for additional recommendations. 
 Follow guidelines for “Consistent with systemic immune 
activation” diagnosis if there is no clinical improvement or 
if clinical worsening occurs. 
 If clinical improvement occurs, atezolizumab may be 
resumed following a benefit-risk assessment by the 
Medical Monitor. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Notes:  Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria 
in the positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 
2014). 
Grades are based on National Cancer Institute Common Terminology Criteria for A Page 113 of 115 
Events. 
These recommendations do not replace clinical judgment and are intended as suggested 
guidance. 
 
 
 
 
 
 
dverse 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  114 of 115 
 
 
 
Table 14. 
 
 
 
 
Systemic Immune Activation Diagnostic Criteria 
(applicable only when alternative etiologies have been excluded) 
Major Criteria 
Minor Criteria 
    Fever t 38.5qC on more than one occasion 
    Ferritin t 3000 ng/mL 
    Cytopenias (Grade t 2 in two or more 
lineages) 
    Age-adjusted soluble interleukin-2 receptor 
elevated by t 2 standard deviations 
    Severe (Grade t 3) or progressive 
dysfunction in two or more organs 
    Decreased fibrinogen 
    Splenomegaly 
    Hemophagocytosis in bone marrow, spleen, or 
lymph nodes 
    Elevated J-glutamyl transpeptidase (GGT) or 
liver function tests (AST, ALT, or direct bilirubin) 
    Elevated triglycerides 
    Elevated LDH 
    Decreased natural killer cell activity 
Diagnosis and Management of Systemic Immune Activation 
Number of Criteria 
Diagnosis 
Action to Be Taken 
t 4 major criteria 
Consistent 
with systemic 
immune 
activation 
  Permanently discontinue atezolizumab. 
  Consider treatment with an immunosuppressive agent 
(i.e., cytokine inhibitors) and IV corticosteroids 
(i.e., methylprednisolone 1 g once daily or equivalent, or 
dexamethasone t 10 mg/m2 once daily if neurologic 
abnormalities are present). 
  Contact the Medical Monitor for additional recommendations. 
  Consider HLH-2004 protocol (Henter et al. 2007) if there is no 
clinical improvement. 
3 major criteria 
OR 
2 major plus 
t 3 minor criteria 
Probable 
systemic 
immune 
activation 
  Depending on clinical severity, follow guidelines for “Consistent 
with systemic immune activation” or “Possible systemic 
immune activation” diagnosis. 
  Clinical specialists and the Medical Monitor may be contacted 
for recommendations. 
2 major plus 
d 2 minor criteria 
OR 
1 major plus 
t 4 minor criteria 
Possible 
systemic 
immune 
activation 
  Withhold atezolizumab. 
  Consider treatment with IV corticosteroids. 
  Clinical specialists and the Medical Monitor may be contacted 
for additional recommendations. 
  Follow guidelines for “Consistent with systemic immune 
activation” diagnosis if there is no clinical improvement or if 
clinical worsening occurs. 
  If clinical improvement occurs, atezolizumab may be resumed 
following a benefit-risk assessment by the Medical Monitor. 
Notes: Criteria are adapted from a Delphi Survey of 26 experts who provided helpful criteria in the 
positive diagnosis of hemophagocytic syndrome in adult patients (Hejblum et al. 2014). 
Grades are based on National Cancer Institute Common Terminology Criteria for Adverse Events. 
These recommendations do not replace clinical judgment and are intended as suggested guidance. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-360 A(4) 
Approval date: 08-Jul-2019 
Page  115 of 115 
 
 
 
Table 14  Diagnostic Criteria and Recommended Management for Systemic Immune 
Activation