Conditions: Hodgkin Lymphoma
Keywords: Relapsed Refractory Atezolizumab 17-191
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 3
Healthy volunteers: no

Brief summary:
This is a study with the purpose of studying the safety and efficacy of the study drug Atezolizumab in patients with relapsed or refractory Hodgkin lymphoma (HL). Atezolizumab could shrink cancer but it could also cause side effects. This study will also test any good and bad effects the study drug. Other aims include studying biomarkers that will help researchers understand how the drug works.

Detailed description:

Arms:
arm 1: Treatment will be Atezolizumab administered at 1200 mg IV every 3 weeks. A cycle is defined as 3 weeks of therapy. Therapy will continue until disease progression, intolerable toxicities or death for a maximum duration of treatment of 36 cycles.

Interventions: intervention 1: Atezolizumab
Intervention descriptions: intervention 1: All patients will receive atezolizumab 1200 mg via IV infusion on D1 of each 21-day cycle.

Protocol document:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
Page 1 of 72
 
 
  
 
 
 
 
A PH ASE II STUDY OF ATEZOLIZUMAB IN RELAPSED OR REFRACTORY HODGKIN 
LYMPHOMA 
PROTOCOL FACE PAGE FOR 
MS K THE RA P E UT IC /D IA GN OS T IC P RO T OC OL 
 
 
Principal Investigator/Department: 
Anas Younes, MD 
Medicine 
Co-Principal 
Investigator(s)/Department: 
Alison Moskowitz, MD 
Medicine 
Investigator(s)/Department: 
Connie Batlevi, MD, PhD 
John F. Gerecitano, MD, PhD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Anita Kumar, MD 
Matthew Matasar, MD 
Craig Moskowitz, MD 
Ariela Noy, MD 
Colette Owens, MD 
Maria L. Palomba, MD 
Carol Portlock, MD 
David Straus, MD 
Andrew Zelenetz, MD, PhD 
Andrew Intlekofer, MD, PhD 
Pamela Drullinsky, MD 
Oscar Lahoud, MD 
Heiko Schoder, MD 
Ravinder Grewal, MD 
Jeffrey Girshman, MD 
Lynn Brody, MD 
Ahmet Dogan, MD, PhD 
Ai Ni, PhD 
Susan McCall, NP 
Karen Louw, NP 
Georgia Rose, NP 
Tara Duggan, NP 
Emily Panzner, NP 
Devin Callan, R N 
Megan Leary, RN 
Helen Hancock, NP 
Jason Carter, PA 
Nadia Kralovic, PA 
Teresa Scardino, PA 
Jillian Solomon, PA 
Medicine 
Medicine 
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Radiology 
Radiology 
Interventional Radiology 
Pathology 
Epidemiology and 
Biostatistics 
Nursing 
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Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
Page 2 of 72
 
 
 
 
 
Ashley Bilger, PA 
Mila Gorsky, MD 
Audrey Hamilton, MD 
Neha Korde, MD 
Louise Ligresti, MD 
Regina Byrne, ANP 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD, PhD 
Hani Hassoun, MD 
Michelle Wisniewski, PA 
Wanqing Iris Zhi, M.D., Ph.D 
Avni Desai, MD 
Sham Mailankody, MD 
Jahan Aghalar, MD 
Jason Konner, MD 
Azadeh Namakydoust, MD 
Marina Shcherba, DO 
Virginia Klimek, MD 
Medicine 
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Consenting Professional(s)/Department: Connie Batlevi, MD, PhD. 
John F. Gerecitano, MD, PhD 
Anas Younes, MD 
Alison Moskowitz, MD 
Paul Hamlin, MD 
Steven Horwitz, MD 
Anita Kumar, MD 
Matthew Matasar, MD 
Craig Moskowitz, MD 
Ariela Noy, MD 
Colette Owens, MD 
Maria L. Palomba, MD 
Carol Portlock, MD 
David Straus, MD 
Andrew Zelenetz, MD, PhD 
Pamela Drullinsky, MD 
Oscar Lahoud, MD 
Mila Gorsky, MD 
Audrey Hamilton, MD 
Neha Korde, MD 
Louise Ligresti, MD 
Arlyn Apollo, MD 
Zoe Goldberg, MD 
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Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
Page 3 of 72
 
 
 
 
 
Kenneth Ng, MD 
Tiffany Troso-Sandoval, MD 
Philip Caron, MD, PhD 
Hani Hassoun, MD 
Wanqing Iris Zhi, M.D., Ph.D 
Avni Desai, MD 
Sham Mailankody, MD 
Jahan Aghalar, MD 
Jason Konner, MD 
Azadeh Namakydoust, MD 
Marina Shcherba, DO 
Virginia Klimek, MD 
Medicine 
Medicine 
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Ple ase Note: A Conse nting Professional must have completed the mandatory Human 
Subje cts Education and Ce rtification Program. 
 
 
 
OneMSK Sites 
Manhattan 
Westchester 
Basking Ridge 
Commack 
Monmouth 
Rockville Centre 
 
 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
4 
 
 
 
 
 
Table of Contents 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................... 5 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS ................................................................. 6 
 
Primary Objectives ......................................................................................................... 6 
 
Secondary Objectives ..................................................................................................... 6 
 
3.0 
BACKGROUND AND RATIONALE ...................................................................... 6 
 
3.1 Hodgkin Lymphoma .................................................................................................. 6 
 
3.2 Immunotherapeutic strategies in HL and a role for the PD-1/PD-L1 axis ................ 7 
 
3.3.................................................................................................................................... 8 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION.............................................. 9 
 
4.1   Design ..................................................................................................................... 9 
 
4.2   Intervention ........................................................................................................... 10 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................ 10 
 
5.1.3 Concomitant and Excluded Therapies................................................................. 12 
 
5.1.3.1 Concomitant Therapy........................................................................................ 12 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................ 16 
 
6.1   Subject Inclusion Criteria ...................................................................................... 16 
 
6.2   Subject Exclusion Criteria..................................................................................... 18 
 
7.0 
RECRUITMENT PLAN ......................................................................................... 20 
 
8.0 
PRETREATMENT EVALU ATION........................................................................ 21 
 
9.0 
TREATMENT/INTERVENTION  PLAN................................................................. 21 
 
9.5 
Use in Pregnancy................................................................................................. 24 
 
9.6 
Use in Nursing Women ........................................................................................ 25 
 
10.0 
EVALU ATION DURING TREATMENT/INTERVENTION ................................... 25 
 
10.5 
Correlative Studies .......................................................................................... 27 
 
Treatment Discontinuation Vis it .................................................................................... 30 
 
11.0 
TOXICITIES/SIDE EFFECTS............................................................................... 31 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ...... 40 
 
13.0 
CRITERIA FOR REMOVAL FROM STUDY........................................................ 43 
 
14.0 
BIOSTATISTICS................................................................................................... 43 
 
14.1 Outcomes Measures ......................................................................................... 45 
 
Primary Efficacy Outcome Measure .............................................................................. 45 
 
Secondary Efficacy Outcome Measures ......................................................................... 45 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
5 
 
 
 
 
 
Safety Outcome Measures............................................................................................. 45 
 
15.0 
RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES................................................................................................................. 45 
 
15.1 
Research Participant Registration .................................................................... 46 
 
15.2 
Randomization .................................................................................................. 46 
 
16.0 
DAT A M AN AGEMENT ISSUES .......................................................................... 46 
 
16.1 
Retention of Records ........................................................................................... 47 
 
16.2 
Study Medication Accountability.......................................................................... 47 
 
16.1 
Quality Assurance............................................................................................. 48 
 
16.2 
Data and Safety Monitoring .............................................................................. 48 
 
17.0 
PROTECTION OF HUMAN SUBJECTS ............................................................. 49 
 
17.1 
Privacy............................................................................................................... 49 
 
17.2 
Serious Adverse Event (SAE) Reporting .......................................................... 50 
 
Methods and Timing for Assessing and Recording Safety Variables.................................... 51 
 
Adverse Event Reporting Period.................................................................................... 51 
 
Assessment of Adverse Events ...................................................................................... 51 
 
Specif ic Instructions for Recording Adverse Events........................................................ 52 
 
17.2.1 ......................................................................................................................... 56 
 
IND Annual Reports ..................................................................................................... 58 
 
18.0 
INFORMED CONSENT PROCEDURES ............................................................. 58 
 
19.0 
REFERENCES...................................................................................................... 58 
 
20.0 
APPENDICES....................................................................................................... 66 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Title . A PHASE II S TUDY OF ATEZOLIZUMAB IN RELAPSED OR 
REF RACTORY HO DGKIN LYMP HOMA 
 
Obje ctive s: The main objectives is to determine the 12 month progression- free survival 
of atezolizumab in relapsed/refractory HL patients who are anti-PD-1 previously treated 
and relapsed/refractory (R/R) HL patients who are anti-PD-1 treatment naïve. 
 
Patie nt Population: Patients with relapsed or refractory Hodgkin’s lymphoma who had 
previous P D-1 therapy (cohort 1) and R/R HL patients who are anti-PD-1 treatment naïve 
(cohort 2). 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
6 
 
 
 
 
 
Study De sign: This is a protocol comprised of a single institution phase II study in HL 
evaluating the efficacy of atezolizumab. 
 
Tre atme nt Plan: Following enrollment, patients will be assigned to receive therapy with 
Atezolizumab (1200mg) given intravenously every 3 weeks according to the dosing 
schedule described in the protocol. Patients will accrue in a two stage design and 
monitored for safety of Atezolizumab, complete response rate, progression free survival 
and correlative biomarkers. 
 
Time to Comple tion: A maximum of 57 patients will be treated with atezolizumab. The 
study will enroll 25 patients in cohort 1 and 32 patients in cohort 2. To reach this goal, we 
anticipate enrolling 2 patients per month in cohort 1 and 3 patients per month in cohort 2. 
 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Obje ctives 
Determine the 12 month progression-free survival of atezolizumab in relapsed/refractory 
HL patients who are anti-PD-1 previously treated (cohort 1) and relapsed/refractory HL 
patients who are anti-P D-1 treatment naïve (cohort 2). 
 
Se condary Obje ctives 
1.   Determine the disease control rate, overall response rate, complete response rate, 
duration of response of atezolizumab , and progression free survival of 
atezolizumab  in relapsed/refractory HL patients who are anti-P D-1 previously 
treated (cohort 1) and in relapsed/refractory HL patients who are treatment naïve 
(cohort 2). 
2.   To determine whether pre-treatment tumor expression of MHC-I, MHC-II, PD- 
L1, or P D-L2, the effector to regulatory T cell ratio at baseline or in response to 
therapy, changes in expression of T-cell extrinsic apoptosis-related markers FasL 
and TRAIL, or PI3K activation on HRS cells at baseline or in response to therapy 
predicts treatment response. 
3.   To determine the safety and toxicity of atezolizumab in patients with relapsed and 
refractory Hodgkin lymphoma. 
 
 
 
3.0 
BACKGROUND AND RATIONALE 
 
3.1 Hodgkin Lymphoma 
 
Classical Hodgkin lymphoma (HL) is an aggressive B-cell lymphoma with an 
annual incidence of fewer than ten thousand cases per year [8].  It is primarily a 
disease of younger individuals with the majority of patients diagnosed between 
the age of 15 and 30.  HL is a curable disease in all untreated patients with 
chemotherapy and/or radiation.  However, up to one third of patients relapse 
following standard therapy [9-11].  For these patients, the standard of care is 
salvage chemotherapy followed by autologous stem cell transplantation; however, 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
7 
 
 
 
 
 
this carries a high risk of treatment-related morbidity and some risk of transplant- 
associated mortality.  Additionally, this strategy is curat ive only in about one half 
of patients who relapse [12, 13 ].  The majority of patients with disease that persist 
or recurs after salvage autologous stem cell transplantation ultimately succumb to 
their disease; the only curative option in this setting is allogeneic transplantation 
which is associated with high rates of transplant associated morbidity and 
mortality and is only able to achieve long-term remissions in a fraction of patients 
[14, 15]. 
 
3.2 Immunotherapeutic strateg ies in HL and a role for the PD-1/PD-L1 
axis 
 
One exciting prospect for therapeutic intervention in HL is via targeting of the co- 
stimulatory receptor P rogrammed Cell Death-1 (PD-1; CD279), a cell surface 
signaling molecule that delivers inhibitory signals that regulate the balance 
between T cell activation and tolerance by interacting with its ligands, P D-L1 
(CD274; B7-H1) and P D-L2 (B7-DC/CD273). P D-1 is a 55 kD type I 
transmembrane protein that is a member of the CD28 family of T-cell 
costimulatory receptors, which also includes CTLA-4, ICOS, and BTLA [34]. 
PD-1 is primarily expressed on activated T cells, B cells, and myeloid cells [35] 
and is upregulated on many tumor- infiltrating lymphocytes [36]. Binding of either 
PD-1 ligand to P D-1 suppresses T-cell activation in both murine and human 
systems [40]. In response to ligand binding, P D-1 recruits the tyrosine 
phosphatases S HP-1 and S HP-2 to the ITSM motif within its cytoplasmic tail, 
leading to the dephosphorylation of TC R-proximal signaling molecules required 
for T cell activation such as C D3ζ, PKCθ and ZAP-70 [41-43]. Expression of 
either P D-1 ligand is thought to occur in healthy individuals in response to 
chronic antigenic stimulation in order to limit T-cell mediated damage to end- 
organs; indeed, PD-1 mediated suppression of T cell responses was initially 
described in murine models of chronic viral infection, a phenomenon known as T- 
cell “exhaustion” [44]. 
 
Recently, malignant co-opting of this regulatory pathway has been described via 
constitutive expression of P D-1 ligands in HL. A recent integrative analysis 
reveals selective 9p24.1 amplification, which includes the PD-L1 and P D-L2 loci, 
increased P D-L1 expression, and further induction via JAK2 in nodular sclerosing 
HL [26, 48].  Even in patients without genetic amplifications of P D-L1 or P D-L2, 
physiologic upregulation of these ligands likely occurs downstream of JAK/STAT 
signaling, IFN
 production or, in EBV-associated cases of cHL, expression of the 
viral-associated protein LMP-1 [49, 50]. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
8 
 
 
 
 
 
These findings suggested that the P D-1/PD-L1 pathway plays a critical role in HL 
immune evasion and should be considered as an attractive target for therapeutic 
intervention. Indeed, blockade of PD-1 increases the sensitivity of T cells to 
foreign antigens and increases effector function and cytokine production of both 
CD4 and C D8 T cells in both models of both t umor and virally mediated chronic 
T cell exhaustion [44, 56, 57].  F urthermore, in lymphomas, P D-1 expressing 
tumor infiltrating lymphocytes have impaired cytokine responses to antigenic 
stimulation that can be reversed by blockade of PD-1, leading to an increase in 
IL-2 and IFN-g production, an upregulation in expression profiles suggestive of 
NK and cytotoxic T cell activity, and ultimately tumor rejection [54].  This 
correlative data provided a strong rationale for targeting PD-1/PD- L1 interaction 
in lymphoma. 
 
3.3 Clinical activity of anti-PD-1 the rapy 
 
In HL, anti-PD-1 therapy has resulted in impressive and durable remissions in 
patients with highly refractory disease.  Both pembrolizumab and nivolumab, 
monoclonal antibodies targeted at P D-1 on tumor-infiltrating T-cells, elicited 
overall response rate s of 60-70%, with many remissions lasting greater than one 
year.  Despite this encouraging activity, a number of outstanding issues remain 
with respect to blockade of the PD-1/P D-L1 axis.  Complete remission to both 
pembrolizumab and nivolumab remain rare (<20%) and the duration of response 
remains less than one year, with more than half of patients progressing at 12 
months. 
 
The optimal method for targeting the PD-1 pathway in HL remains unknown. 
Despite the high activity of anti-PD-1 therapy in HL, P D-1 expression within the 
HL microenvironment is often low to absent.9 On the contrary, P D-L1 is almost 
universally expressed on the RS cells of HL tumors, and the extent of PD- L1 
amplification in HL correlates with prognosis.  Direct targeting of P D-L1, rather 
than PD-1, may more profoundly promote anti-tumor immune responses in HL.  It 
may also more effectively silence any pro-survival signals transmitted to HL Reed 
Sternberg cells through P D-L1 ligation.  In this manner we hypothesize that 
targeting PD-L1 may be more effective than anti-PD-1 therapy in HL and 
potentially overcome resistance to anti-PD-1 therapy.  It should be noted that P D- 
L2 expression on RS cells has been described; it is possible that engagement of 
PD-L2 to PD-1 will counteract the impact of PD-L1 blockade and thus reduce 
efficacy of anti-P D-L1 therapy.  We will evaluate for this possibility b y assessing 
PD-L1, PD-L2, and P D-1 expression within patients’ tumor samples and 
correlating expression with response. 
 
Furthermore, the mechanism by which impairing the P D-L1/P D-1 interaction in 
HL promotes anti- tumor responses remains enigmatic.  In solid tumors, blocking 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
9 
 
 
 
 
 
this interaction results in enhanced C D8 T cell-dependent immune responses. 
However, HL is characterized by a very high prevalence of mutations in the beta- 
2-microglobulin gene, resulting in constitutive loss of major histone compatibility 
complex class-1 (MHC-1) expression on RS cells, which should eliminate any 
CD8 T-cell anti-tumor responses.  We will evaluate how anti-PD-L1 therapy 
affects anti-tumor responses in cHL through immunohistochemical, flow 
cytometry, and high-throughput T cell receptor sequencing studies performed on 
biopsies obtained prior to and on therapy and correlating with clinical response. 
 
Several anti-PD-L1 agents are in development and have demonstrated significant 
activity in melanoma, non-small cell lung cancer, renal cell carcinoma, and 
bladder cancer; but they have not been evaluated in HL. Atezolizumab, a 
humanized IgG1 anti-PD-L1 monoclonal antibody, has already demonstrated 
safety and efficacy in multiple tumor types. We propose a phase II study 
evaluating atezolizumab in both anti-P D-1 resistant and naïve patients with rel/ref 
HL. 
 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.1 
Design 
 
We will aim to enroll 2 cohorts of patients. Initially, we will open cohort 1, which 
will include patients with previous anti-PD-1 therapy.  Should cohort 1 not meet 
criteria for early stopping at the end of the first stage, we will open a second 
cohort which will include patients who never received anti-PD-1 therapy. 
Eligible patients will receive atezolizumab IV every 3 weeks.  Patient will 
undergo disease assessment with P ET/C T every 3 cycles for the first 12 cycles 
and subsequently every 4 cycles.  Treatment may continue for up to 2 years. 
 
POPULATION AND S AMP LE 
Patients aged 18 and older with rel/ref HL who have failed or been deemed 
ineligible for autologous stem cell transplant and who have received prior 
Brentuximab vendotin will be enrolled.  Patients must have measurable disease 
(according to RECIL Criteria) prior to enrolling on study. 
 
TRIAL SCHEMA 
 
Patients will receive treatment on study once every 3 weeks and response 
assessment with PET scans will be performed every 3 cycles for the first 12 
cycles and subsequently every 4 cycles.  Treatment may continue for up to 2 years. 
 
 
CLINICAL PRACTICE 
 
Patients will be seen and evaluated at MSK outpatient lymphoma clinics. 
Infusion of treatment will be performed as per MSK standard practice at MSK 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
10 
 
 
 
 
 
 
 
TREATMENT REGIMEN 
Atezolizumab 1200 mg IV every 3 weeks 
 
4.2 
Intervention 
 
Treatment will be Atezolizumab administered at 1200 mg IV every 3 weeks. A 
cycle is defined as 3 weeks of therapy.  Therapy will continue until disease 
progression, intolerable toxicities or death for a maximum duration of treatment 
of 36 cycles. 
 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.1 Background on Ate zolizumab 
 
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 C hinese 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 programmed death- ligand 1 (P D-L1) and inhibits its 
interaction with its receptor, programmed death-1 (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. 
 
5.1.1 Formulation 
 
The Atezolizumab drug product is provided in a single- use, 20-cc USP/P h. 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. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
11 
 
 
 
 
 
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 (21 [ 2] days).  Atezolizumab will be delivered in infusion bags 
with IV infusion lines that have product contacting surfaces of polyvinyl chloride 
(PVC) or polyolefin and 0.2 m in- line filters (filter membrane of 
polyethersulfone [P ES]).  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 ( 15) minutes.  If the 
first infusion is tolerated without infusion-associated AEs, the second infusion 
may be delivered over 30 ( 10) minutes.  If the 30- minute infusion is well 
tolerated, all subsequent infusions may be delivered over 30 ( 10) minutes.  For 
the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) should be determined within 60 minutes before, during 
(every 15 [ 5] minutes), and 30 ( 10) minutes after the infusion.  For 
subsequent infusions, vital signs will be collected within 60 minutes before and 
within 30 minutes after the 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 C ycles  2 at the discretion of the treating 
physician.  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. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
12 
 
 
 
 
 
• 
In the event that a patient experiences a moderate IRR (NCI CTC AE 
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 CTC AE 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. 
 
Guidelines for dosage modification, treatment interrup tion, or discontinuation and 
the management of specific adverse events are provided below sections. 
 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the screening 
evaluation and the treatment discontinuation visit. 
 
5.1.3 Concomitant and Excluded The rapies 
 
5.1.3.1 Concomitant Therapy 
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 S tates, equivalent medications may be substituted per local 
practice).  Serious infusion-associated events manifested by dyspnea, hypotension, 
wheezing, b ronchospasm, 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 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 ad ministered 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 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
13 
 
 
 
 
 
warfarin at a stable dose level), or other allowed maintenance therapy should 
continue their use.  Males and females of reproductive potential should use highly 
effective means of contraception. 
 
 
 
 
 
 
 
 
 
 
5.1.3.2 Excluded The rapy 
 
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: 
• 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, 
investigational agents, or herbal therapy. 
• 
After Cycle 1, certain forms of radiotherapy may be considered for pain 
palliation if patients are deriving benefit (e.g., treatment of known bony 
metastases); Atezolizumab administration may be suspended during 
radiotherapy. 
 
It is strongly recommended tha t: 
 
• 
Traditional herbal medicines not are administered because the ingredients of 
many herbal medicines are not fully studied and their use may result in 
unanticipated drug-drug interactions that may cause, or confound assessment 
of, toxicity. 
 
Patients are not allowed to receive immunostimulatory agents, including but not 
limited to IFN-, IFN-, or IL-2, during the entire study.  These agents, in 
combination with Atezolizumab, could potentially increase the risk for 
autoimmune conditions. 
 
Patients should a lso not be receiving immunosuppressive medications, including 
but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide. 
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 ATEZO LIZUMAB but may be 
administered at the discretion of the treating physician.  If feasible, alternatives to 
these agents should be considered. 
 
In addition, all patients (including those who discontinue the study early) should 
not receive other immunostimulatory agents for 10 weeks after the last dose of 
Atezolizumab 


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Approval date: 17-Jan-2018 
14 
 
 
 
 
 
5.2 Summar y 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 P hase I starting dose. 
Comprehensive pharmacology, PK, and toxicology evaluations were thus 
undertaken with ATEZO LIZUMAB. 
 
 
 
 
The safety, pharmacokinetics, and toxicokinetics of Atezolizumab were 
investigated in mice and cynomolgus monkeys to support intravenous (IV) 
administration and to aid in projecting the appropriate starting dose in humans. 
Given the similar binding of Atezolizumab for cynomolgus monkey and human 
PD-L1, the cynomolgus monkey was selected as the primary and relevant 
nonclinical model for understanding the safety, pharmacokinetics, and 
toxicokinetics of Atezolizumab. 
 
Overall, the nonclinical pharmacokinetics and toxicokinetics observed for 
Atezolizumab supported entry into clinical studies, including providing adequate 
safety factors for the proposed P hase 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. 
 
5.3 Clinical Experience with Ate zolizumab 
 
5.3.1 Ongoing Clinical Studies 
 
Current studies of Atezolizumab include one ongoing P hase Ia monotherapy study, 
three ongoing combination studies, five P hase II studies, and one Phase III study. 
Details of all ongoing studies can be found in the Atezolizumab Investigator’s 
Brochure. 
 
5.3.2 Clinical Safety 
 
The presented safety data for Atezolizumab have been derived mainly from the 
treatment of patients in P hase Ia Study PCD4989g.  As of 10 May 2014, 
Atezolizumab has been administered to approximately 775 patients with solid and 
hematologic malignancies.  No dose-limiting toxicities (DLTs) have been 
observed at any dose level, and no maximum tolerated dose (MTD) was 
established.  Fatigue was the most frequently reported adverse event (AE). 


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Approval date: 17-Jan-2018 
15 
 
 
 
 
 
Adv e rse Events 
The following safety data are from PCD4989g, in which Atezolizumab is being 
used as single-agent therapy in patients with locally advanced or metastatic solid 
tumors or hematologic malignancies.  In 412 treated patients, 97.1% reported an 
AE while on study.  O f these AEs, 48.8% were Grade 1 or 2 in maximum se verity 
on the basis of National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 4.0 (NCI CTCAE v4.0).  The most frequently observed 
AEs (occurring in  10% of treated patients ) included fatigue, nausea, decreased 
appetite, pyrexia, dyspnea, diarrhea, constipation, cough, headache, back pain, 
vomiting, anemia, arthralgia, rash, insomnia, asthenia, abdominal pain, chills, 
pruritus, and upper respiratory tract infection. 
 
Grade  3 AEs were reported by 199 of 412 patients (48.3%).  There were 51 
patients (12.4%) who reported Grade  3 AEs that were assessed as related to 
study drug by the investigators.  The most frequently reported related Grade  3 
AEs included fatigue (5 patients [1.2%]), increased ALT and increased AS T (each 
reported in 4 patients [1.0%]); and asthenia, autoimmune hepatitis, and hypoxia 
(each reported in 3 patients [0.7%]). 
 
Immune-Related Adverse Events 
Given the mechanism of action of Atezolizumab, events associated with 
inflammation and/or immune-mediated AEs have been closely monitored during 
the ATEZO LIZUMAB clinical program.  These include potential dermatologic, 
hepatic, endocrine, and respiratory events as well as events of hepatitis/elevated 
liver function tests (LF Ts) and influenza- like illness.  Expected adverse drug 
reactions associated with Atezolizumab include the following: 
hepatitis/transaminitis, hypothyroidism, infusion-related reactions (IRRs), 
pneumonitis, influenza-like illness, and dermatologic reactions.  Potential adverse 
drug reactions inc lude the following: anti-therapeutic antibodies (ATAs), colitis, 
endocrine disorders, hypersensitivity, neurologic disorders, and pericardial 
effusion. 
 
For furthe r de tails, see the Atezolizumab Inve stigator’s Brochure . 
 
5.3.3 Clinical Activ ity 
 
 
Efficacy in Urothelial Bladder Cancer Patie nts 
 
Recently, a single-arm, multicenter phase 2 trial of atezolizumab in locally 
advanced and metastatic urothelial carcinoma who have progressed on platinum- 
based chemotherapy showed a 15% overall response rate, with durable ongoing 
responses in 84% of patients initially responding to treatment at a median follow- 
up of 11.7 months (Rosenberg JE Lancet 2016).  Increased PD-L1 expression by 
IHC was associated in higher rates of response.  Based on these results, the FDA 
has approved atezolizumab for metastatic urothelial carcinoma that has 
progressed on platinum-based chemotherapy. 


Memorial Sloan Kettering Cancer Center
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Approval date: 17-Jan-2018 
16 
 
 
 
 
 
Efficacy in Non-Small Ce ll Lung Cancer Patie nts 
 
Atezolizumab was compared to docetaxel in patients with previously treated 
advanced or me tastatic non-small cell lung cancer in a multicenter, open-label 
phase 2 randomized controlled trial (POPLAR) ( Fehrenbacher Lancet 2016). 
Atezolizumab was found to improve overall survival (12.6 vs. 9.7 months) 
compared to docetaxel.  S imilar to what was seen in urothelial carcinoma, more 
favorable responses were seen in patients with high tumor expression of P D-L1 
as well as high baseline effector T-cell/interferon-gamma associated gene 
expression in pre-treatment samples. 
 
5.4 Clinical Pharmacokinetics and Immunogenicity 
 
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 (C L) 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 ATAs has been observed in patients in all dose cohorts and 
was associated with cha nges 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. 
 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
Describe the characteristics of the patient/subject population. 
 
6.1 
Subject Inclusion Criteria 
 
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  18 years. 
• 
Patient has histologically confirmed diagnosis of Hodgkin lymphoma 
• 
Patients must have received at least 2 prior regimens and have received or be 
deemed ineligible for autologous stem cell transplant, and must have received 
prior brentuximab vedotin. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
17 
 
 
 
 
 
• 
Patients who received prior anti-PD-1 therapy are eligible for cohort 1 only 
and patients who have not received prior anti-PD-1 therapy are eligible for 
cohort 2 only. 
 
• 
Patient has at least one measurable nodal lesion (≥ 2 cm) according to RECIL 
Criteria 
• 
Adequate hematologic and end organ function, defined by the following 
laboratory results obtained within 14 days prior to the first study treatment 
(Cycle 1, Day 1): 
o ANC  1500 cells/L 
o WBC counts  2500/L 
o Lymphocyte count  300/L 
o Hemoglobin  9.0 g/dL 
o Total bilirubin  1.5  upper limit of normal (ULN) with the following 
exception: 
▪ Patients with known Gilbert disease who have serum bilirubin 
level  3  ULN may be enrolled. 
o AST and ALT  3.0  ULN with the following exception: 
▪ Patients with liver involvement: AST and/or ALT  5  ULN 
o Alkaline phosphatase  2.5  ULN with the following exception: 
▪ Patients with documented liver involvement or bone metastases: 
alkaline phosphatase  5  ULN 
 
o Serum creatinine  1.5  ULN or creatinine clearance  50 mL/min on 
the basis of the Cockcroft-Gault glomerular filtration rate estimation: 
 
o (140 age ) (we ight in k g) (0.85 if fe ma le) 
72  (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 90 days after the last dose of Atezolizumab 
• 
Female subject of childbearing potential should have a negative serum 
pregnancy within 28 days prior to receiving the first dose of study medication. 


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Approval date: 17-Jan-2018 
18 
 
 
 
 
 
• Eastern Cooperative O ncology Group (ECOG) Performance S tatus of 0 or 1 
(see Appendix 3) 
 
 
6.2 
Subject Exclusion Criteria 
 
Patients who meet any of the following criteria will be excluded from study entry. 
No medical comorbidities are considered exclusions from study eligibility other 
than those listed below. 
 
Ge neral Exclusion Criteria: 
• 
Patients who have undergone prior allogeneic transplant are excluded only if 
they remain on any immunosuppression or have signs or symptoms of clinical 
graft- versus- host disease 
 
• 
Any approved anticancer therapy, including chemotherapy, hormonal therapy, 
or radiotherapy, within 3 weeks prior to initiation of study treatment. 
 
• 
Herbal therapy (including herbal therapy intended as anticancer therapy) < 1 
week prior to C ycle 1, Day 1 
 
• 
AEs from prior anticancer therapy that have not resolved to Grade  1 except 
for alopecia 
 
• 
Known clinically significant liver disease 
 
• 
Active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited 
liver disease 
 
• 
Pregnancy, lactation, or breastfeeding 
 
• 
Known hypersensitivity to C hinese hamster ovar y cell products or other 
recombinant human antibodies 
 
• 
Inability to comply with study and follow-up procedures 
• 
History or risk of autoimmune disease, including but not limited to systemic 
lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, 
vascular thrombosis associated with antiphospholipid syndrome, 
Wegener’s granulomatosis, Sjögren’s syndrome, Bell’s palsy, Guillain-Barré 
syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or 
glomerulonephritis 
 
• 
Patients with a history of autoimmune hypothyroidism AND without normal 
thyroid hormone levels on a stable dose of thyroid replacement hormone 
• 
Myocardial infarction or arterial thromboembolic events within 6 months 
prior to baseline or severe or unstable angina, New York Heart Association 
(NYHA) C lass III or IV disease, or a Q Tc interval > 470 msec. 
 
• 
History of Torsades de pointes, ventricular tachycardia, or ventricular 
fibrillation 
 
• 
Uncontrolled heart failure or hypertension or uncontrolled diabetes mellitus 


Memorial Sloan Kettering Cancer Center
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Approval date: 17-Jan-2018 
19 
 
 
 
 
 
• 
Patients with uncontrolled eczema, psoriasis, lichen simplex chronicus of 
vitiligo with dermatologic manifestations (patients without ophthalmologic 
involvement, rash covering <10% of the body surface area and requiring only 
low potency topical steroids, and without exacerbations requiring systemic 
therapy are eligible.) 
• 
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. 
• 
A history of radiation pneumonitis in the radiation field (fibrosis) is permitted 
provided that symptoms have resolved. 
• 
Any other diseases, metabolic dysfunction, physical examination finding, o r 
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 (PC R) is negative for HCV RNA. 
• 
Patients with active tuberculosis 
 
• Severe infections within 4 weeks prio r to C ycle 1, Day 1, including but not 
limited to hospitalization for complications of infection, bacteremia, or severe 
pneumonia 
• Signs or symptoms of infection within 2 weeks prior to C ycle 1, Day 1 
• Received oral or IV antibiotics within 2 weeks prior to C ycle 1, Day 1 for 
treatment of active infection (Patients receiving prophylactic antibiotics (e.g., 
for prevention of a urinary tract infection or chronic obstructive pulmonary 
disease) are eligible) 
 
• Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary 
tract infection or chronic obstructive pulmonary disease) are eligible. 
• 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 


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20 
 
 
 
 
 
• Administration of a live, attenuated vaccine within 4 weeks before C ycle 1, 
Day 1 or anticipation that such a live, attenuated vaccine will be required 
during the study 
 
• Malignancies other than the disease under study within 5 years prior to C ycle 
1, Day 1, with the exception of those with a negligible risk of metastasis or 
death and with expected curative 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  6, and prostate-specific antigen 
[PSA]  10 mg/mL, etc.) 
 
Medication-Related Exclusion Criteria: 
• 
Prior anti-PD-L1 therapies are excluded. 
 
o Patients who have received prior treatment with immunotherapy including 
anti-PD-1 antiCTLA-4 may be enrolled, provided that there was no 
history of severe immune-related adverse effects (NCI CTCAE Grade 3 
and 4) 
• Treatment with investigational agent within 4 weeks prior to Cycle 1, Day 1 
(or within five half- lives of the investigational product, whichever is longer ) 
• Treatment with systemic immunosuppressive medications (including but not 
limited to prednisone, cyclophosphamide, azathioprine, methotrexate, 
thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks 
prior to 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) may be 
enrolled. 
 
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 
 
 
7.0 
RECRUITMENT PLAN 
 
The study will be conducted at Memorial S loan Kettering Cancer Center. Patients will be 
treated by the lymphoma service at MSKCC. Every effort will be made to include women 
and minorities in this research study. Patients will be recruited by the treating team of 
physicians and medical professionals. The consenting attending physician will inform 
patients of their diagnosis, current treatment options, including standard treatment, and 
the risks, benefits, and exper imental nature of this treatment program. All patients will be 
required to sign a statement of informed consent that conforms to FDA and IRB 


Memorial Sloan Kettering Cancer Center
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Approval date: 17-Jan-2018 
21 
 
 
 
 
 
guidelines. Written consent will be obtained by individua l specified in section 18. 
Registration of patients is des cribed in section 15. 
 
8.0 
PRETREATMENT EVALUATION 
 
Prior to initiating treatment: 
 
• 
Histopathologic confirmation of HL; if unconfirmed, patients will be required to 
undergo biopsy of most accessible PET-avid lesion.  For patients who have 
undergone biopsy confirmation of relapse following their most recent therapy, tissue 
blocks and unstained slides will be obtained for confirmation and correlative studies. 
 
 
 
 
Within 4 weeks prior to initiating treatment: 
 
• 
Medical history and demographics 
• 
Complete history and physical exam (including weight, pulse, blood pressure, 
temperature, ECOG performance status) 
• 
Medication review 
• 
Blood work: CBC with differential, P T/INR, aP TT, electrolytes (Na, K, Cl, CO2), 
BUN, Cr, total bilirubin,  total protein, albumin,  AST,  ALT, alkaline phosphatase, 
magnesium, phosphorus, LDH, amylase, lipase 
• 
Thyroid function testing (TSH, free T3, and free T4) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
• 
Hepatitis B surface antigen and Hepatitis B core antibody 
• 
Hepatitis C antibody 
• 
Serum beta-HC G (for WOCBP only) to assess for pregnancy 
• 
PET scan 
• 
Separate C T chest/abdomen/pelvis and neck CT if clinically indicated (MRI will be 
used for those who are unable to undergo C T scans) 
 
 
9.0 
TREATMENT/INTERVENTION PLAN 
 
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, beginning on 
C1D1 and on D1 of each 3-week treatment cycle after all procedures and assessments 
have been completed. Atezolizumab will be delivered in infusion bags with IV infusion 
lines that have product contacting surfaces of polyvinyl chloride (PVC) or polyolefin and 
0.2 m in- line filters (filter membrane of polyethersulfone [P ES]). 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 ( 15) minutes.  If the first infusion is tolerated 


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Approval date: 17-Jan-2018 
22 
 
 
 
 
 
without infusion-associated AEs, the second infusion may be delivered over 30 ( 10) 
minutes.  If the 30- minute infusion is well tolerated, all subsequent infusions may be 
delivered over 30 ( 10) minutes.  For the first infusion, the patient’s vital signs (heart 
rate, respiratory rate, blood pressure, and temperature) should be determined within 
60 minutes before, during (ever y 15 [ 5] minutes), and 30 ( 10) minutes after the 
infusion.  For all subsequent infusions, vital signs will be collected within 60 minutes 
before and within 30 minutes after the infusion, but not during the infusion unless 
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. 
 
 
 
 
9.1 
Tre atme nt Sche ma 
 
All patients will receive atezolizumab 1200 mg via IV infusion on D1 of each 21 -day 
cycle. 
 
9.2 
Tre atme nt duration 
 
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, any of the other reasons for 
treatment discontinuation listed in Section 7.1, or a maximum treatment duration of 24 
months. 
 
After discontinuation of treatment, patients will comp lete an EO T visit within 7 days 
after the last study drug dose and Safety Follow-up visits within 30 days for those 
patients who have study drug related adverse events at the EOT visit. Patients who have 
not experienced PD are to be followed every 4 months until PD or they start alternate 
therapy for their lymphoma. 
 
9.3 Dose Adjustme nts 
 
There will be no dose reduction for Atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 84 days beyond the scheduled date of delayed infusion 
if study drug-related toxicity requiring dose suspension is experienced.  If Atezolizumab 
is held because of AEs for  84 days beyond the scheduled date of infusion, the patient 
will be discontinued from ATEZOLIZUMAB and will be followed for safety and 
effica cy. 
 
If a patient must be tapered off steroids used to treat AEs, Atezolizumab may be held for 
additional time beyond 84 days from the scheduled dose until steroids are discontinued or 


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23 
 
 
 
 
 
reduced to a prednisone dose (or dose equivalent) of  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 principal 
investigator 
 
9.4 Contrace ption 
Atezolizumab may have adverse effects on a fetus in utero.  F urthermore, it is not known 
if atezolizumab has transient adverse effects on the composition of sperm. 
 
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azospermia (whether due to having had a vasectomy or due to an underlying 
medical condition). 
 
Female subjects will be considered of non-reproductive potential if they are either: 
 
• 
Postmenopausal (defined as at least 12 months with no menses without an 
alternative medical cause; in women < 45 years of age a high follicle stimulating 
hormone (FS H) level in the postmenopausal range may be used to confirm a post- 
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence of 12 months of amenorrhea, a single FS H 
measurement is insufficient.). 
 
OR 
 
 
• 
Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
 
OR 
 
• 
Has a congenital or acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of study drug by complying with one of the following: 
 
• 
Practice abstinence† from heterosexual activity; 
OR 
• 
Use (or have their partner use) acceptable contraception during heterosexual 
activity. 
 
Acceptable methods of contraception are‡ : 


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24 
 
 
 
 
 
Single method (one of the following is acceptable): 
• 
Intrauterine device (IUD) 
• 
Vasectomy of a female subject’s male partner 
• 
Contraceptive rod implanted into the skin 
 
Combination method (requires use of two of the following): 
• 
Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
Cervical cap with spermicide (nulliparous women only) 
• 
Contraceptive sponge (nulliparous women only) 
• 
Male condom or female condom (cannot be used together) 
• 
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, 
or subcutaneous contraceptive injection 
 
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
 
If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region. 
 
Subjects should be informed that taking the study medication might involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study.  In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days 
prior to the initiation of study medication for oral contraception) throughout the study 
period up to 120 days after the last dose of trial therapy.  If there is any question that a 
subject of childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
 
9.5 
Use in Pre gnancy 
 
If a subject inadvertently becomes pregnant while on treatment with atezolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed 
or terminated.  The outcome of the pregnancy will be reported to Genentech without 
delay within 2 working days to Genentech if the outcome is a serious adverse experience 
(e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). 
 
The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the fetus or newborn to Genentech. 
If a 


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25 
 
 
 
 
 
male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to Genentech. 
 
9.6       Use in Nursing Wome n 
 
It is unknown whether atezolizumab is excreted in human milk.   Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast- feeding are not eligible for enrollment. 
 
 
 
 
 
 
 
 
 
 
 
10.0   EVALUATION DURING TREATMENT/INTERVENTION 
 
Evaluations during this period are per Table 7. 
 
Screeni ng C1D1 
C2D1 a nd D1 of 
a ddi ti onal cycl es 
EOT 
30 da y FU 
a fter l as t 
dos e 
Da y 
-28 
-14 
+/-3 da ys 
wi thi n 7 da ys 
foll owi ng drug 
dis conti nua ti on 
+/- 7 da ys 
Obta i n I nformed Cons ent 
X 
Demogra phy 
X 
Incl usi on/excl usi on cri teria 
X 
Medi cal His tory/ Dia gnosis / 
Trea tmen t hi s tory 
X 
Pri or/concomi ta nt medi ca tions 
X 
X 
X 
X 
Physi cal exa mi na ti on 
X 
X 
X 
X 
X 
ECOG a nd Vi tals (Wei ght, Bl ood 
press ure, Pul s e, Res p, Temp) 
X 
X 
X 
X 
He matol ogy: CBC wi th Di ff 
X 
X 
X 
X 
Chemi s try (BMP, TBi l i , AST, ALT, 
TP, Al b, AP, LDH, Ma g, Phos , 
a myl as e, li pas e) 
X 
X 
X 
X 
Serum Cytoki nes 
X 
X 
X 
Coa gul a ti on (a PTT a nd PT/INR) 
X 
Uri nal ysi s 
X 
X 
X 
X 
Serum/Uri ne beta -HCG for wo men 
of chil dbea ri ng a ge 
X 
As cli nicall y i ndi ca ted 
Hepa ti ti s B/C 
X 
As cli nicall y i ndi ca ted 
Thyroi d functi on tes ti ng (TSH, free 
T3, a nd free T4) 
X 
As cli nicall y i ndi ca ted 


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26 
 
 
 
 
 
Ra di ogra phic ass ess ment 
X 
After ev ery 3 cycl 
es until C12, a nd 
then ev ery 
4 cycl es 
therea fter 
X (i f not done 
wi thi n 4 weeks ) 
Fres h Tumor bi ops y 
X* 
X 
X 
Res ea rch bl ood tes ts 
X 
X (C2D1 onl y) 
X 
 
*Pre-treat ment fres h tumor biops y for patients without pathologic confirmat ion of re laps ed dis eas e prior to 
s tudy enrollment. 
  
 
Patients will be closely monitored for safety and tolerability throughout the study.  All 
assessments must be performed and documented for each patient. 
 
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and local laboratory test values are acceptable. 
 
If the timing of a protocol- mandated study visit coincides with a holiday and/or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible 
date, with subsequent visits rescheduled accordingly. 
 
10.1 
Laboratory Assessments 
 
Laboratory assessments will include the following: 
 
• 
Hematology (C BC, including RBC count, hemoglobin, hematocrit, WBC count with 
differential [neutrophils, eosinophils, lymphocytes, monocytes, basophils, and other 
cells], and platelet count) 
• 
Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, 
chloride, bicarbonate, calcium, phosphorus, total bilirubin, ALT, AS T, 
alkaline p hosphatase, LDH, total protein, and albumin) 
 
• 
Coagulation (aPTT and INR) 
• 
Pregnancy test (for women of childbearing potential) 
• 
Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
• 
Serum cytokine panel (IL-10, IL-6, IL-1B, TNF-a) 
• 
Thyroid function testing (TSH, free T3, and free T4), Epstein-Barr virus (EBV) 
serology (EBNA IgG), hepatitis B virus (HBV) serology (HBsAg, antibodies against 
HBsAg, hepatitis B core antigen), and HCV serology (anti-HCV) as clinically 
indicated 
 
o HBV DNA test is req u ired for patients w ho have known positive 
serology for anti- HBc 
 
o HCV RN A test is required for patients who have known positive serology 
for anti- HCV 


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• 
All patients will 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). Acceptable samples include core needle biopsies for 
deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcuta neous, or mucosal lesions. 
 
10.2 
Physical Examination 
 
A complete physical examination will be performed at screening and at the treatment 
discontinuation visit and should include the evaluation of head, eye, ear, nose, and throat 
and cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems. 
 
A limited physical examination will be performed at other visits to assess changes from 
baseline abnormalities and any new abnormalities and to evaluate patient-reported 
sympto ms.  New or worsened abnormalities should be recorded as AEs if appropriate. 
 
As part of tumor assessments, a physical examination should also include the evaluation 
of the presence and degree of enlarged lymph nodes, skin neoplasm, hepatomegaly, and 
spleno megaly. 
 
10.3 
Me dical History 
 
Medical history includes clinically significant diseases within the previous 5 years, 
smoking history, cancer history (including tumor characteristics such as hormone 
receptor status), prior cancer therapies and procedures, and all medications used by the 
patient within 7 days before the screening visit (including prescription, over-the-counter, 
and herbal/homeopathic remedies and therapies). 
 
10.4 
Vital Signs 
 
Vital signs will include measurements of heart rate, respiratory rate, systolic and diastolic 
blood pressures while the patient is in a seated position, and temperature. 
 
For the first infusion, the patient’s vital signs (heart rate, respiratory rate, blood pressure, 
and temperature) should be determined within 60 minutes before, during (every 
15 [ 5] minutes), and 30 ( 10) minutes after the infusion.  For subsequent infusions, 
vital signs will be collected within 60 minutes before and within 30 minutes after the 
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. 
 
10.5 
Corre lative Studie s 
 
 
Rationale for corre lative studies 


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We hypothesize that PD-L1 blockade with atezolizumab will promote sustained 
responses in Hodgkin lymphomas by promoting clonal T cell r esponses, and b) inhibiting 
pro-survival back-signaling through P D-L1. We propose a series of correlative analyses 
that will characterize changes in tumor- infiltrating T-cells and HL RS cells in response to 
treatment.  These will include assays performed on both primary tumor tissue obtained 
both prior to and on treatment and on peripheral blood obtained throughout the course of 
therapy: 
 
Acquisition of biospe cimens 
 
Biopsies 
 
All patients without pathologic confirmation of relapsed or refractory HL will undergo 
IR-guided core biopsy prior to initiation of treatment with Atezolizumab (denoted “pre- 
treatment biopsy” below).  All patients undergo repeat IR-guided core biopsy when 
technically feasible, and fine needle aspiration when core biopsy is deemed to be 
technically difficult, before cycle 2 of therapy (denoted “on-treatment biopsy” below). 
When technically feasible, a total of eight to ten (8-10) cores will be obtained with each 
biopsy for morphologic review and correlative studies (described below). Biopsies will 
be placed in RPMI-1640 media and sent either directly to the pathology department for 
flow cytometry and sorting (described below) or viably cryopreserved at -80°C in 90% 
fetal bovine serum (F BS) and 10% DMSO until needed. 
 
Perip hera l b lood 
 
All patients will have 5 additional tubes of blood drawn on C1D1, C2D1, and at the end 
of treatment. Serum will be frozen and peripheral blood mononuclear cells will be viably 
cryopreserved from all tubes. 
 
Proposed assa ys 
 
1.   Immuno histoc he mistry o f pre-tre atme nt pa tie nt b iopsies : Three (3) pre-treatment and 
on-treatment core biopsies will be fixed in formaldehyde and allocated for 
morphologic review and immunohistochemistry (IHC). Immunohistochemical 
staining will be performed with antibodies against MHC-I, MHC-II, PD-1, PD-L1, 
PD-L2, FoxP3, FasL, TRAIL, phospho-S6 (S235/236), and phosphor-Akt (S473). We 
will follow previously well-established protocols for IHC analysis of FFP E tissue 
(Vose et al JCO 2008, Iqbal et al Blood 2014). 
 
2.   Flo w c yto metry a na lysis a nd sorting o f p re a nd o n-trea tme nt patie nt b iopsie s : F ive (5) 
pre-treatment and on-treatment core biopsies will be placed in RPMI media and sent 
to the pathology department, where single cell suspensions will be generated. 
Clinical flow cytometry using 3-laser BD-FACSCANTO-10 instrument (Becton 
Dickinson Immunocytometry S ystems (BDIS)) and 9-10 color assays will be 


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performed with specific emphasis on markers likely to be affected by treatment with 
pembrolizumab, including: 
Basic T-ce ll subse ts: C D3+ T cells and 2 subsets: CD3+CD4+ and C D3+CD8+. 
Effector a nd me mory subse ts : defined by CD45RA, CD28, C D27, and CCR7 
Re gula tory T ce lls: defined by CD4, CD25, CD127, and CCR4. 
Activatio n/e xha ustio n: defined by expression of PD-1, LAG-3, TIM-3, and C TLA-4 
 
3.   TCR c lo na lity e va luatio n: F low-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 
(Promega).  C lonal TCR diversity will be assessed using the Adaptive ImmunoS EQ 
kit.  The resulting multip lexed PC R product will be sequenced on an Illumina MiSeq 
system and analyzed using the ImmunoS EQ analyzer. 
 
4.   RNA-seque nc ing o f HL RS ce lls: F low-cytometry-sorted RS cells will undergo low- 
input RNA extraction, cDNA synthesis, and RNA sequencing as previously described 
(Reichel et al Blood 2015). 
 
5.   Multip le xed serum c ytok ine a na lysis : Sera or plasma from patients will be collected 
at C1D1, C2D1, and at the end of and stored at -20oC.  Circulating levels of six 
cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5 or IL-10) and chemokines (CXC L8/IL-8, 
CCL5/RANTES, CXC L9/MIG, CCL2/MCP-1, and CXC L10/IP-10) will be assessed 
via a cytometric bead array kit from BD biosciences as per the manufacturer’s 
instruction. Briefly, bead populations with distinct fluorescence intensities are coated 
with capture antibodies specific for the above cytokines and chemokines. Two -color 
cytometric analysis will be carried out using flow cytometry. Data will be obtained 
and analyzed by CBA software. Data are analyzed in dot-plot F L-2 vs. F L-3; the six 
FL-3 particles with different fluorescent intensities are distributed along the axis.  A 
single set of diluted standards is used to generate a standard curve for each analyte 
(standard ranging from 0 to 5000 pg/ml). The concentration of the cytokine 
calibrators is expressed vs. median fluorescence intensity (F L-2) (MFI) in the 
standard curves. 
 
Clinical Corre lation: Data obtained above will be correlated to clinical outcomes 
including best response and progression- free survival, to determine whether any of the 
correlative data serves as a predictive or prognostic biomarker for patients treated with 
atezolizumab. 
 
The above studies may provide biologically relevant parameters, both for determining 
patients who are more likely to respond to therapy as well as to monitor correlatives of 
antitumor immunity, particularly in the peripheral blood, where they may serve as a 
useful monitoring tool.  Correlative studies of patients treated with checkpoint inhibitors 


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have demonstrated evidence of on-target efficacy in peripheral blood mononuclear cells, 
but whether this correlates with duration or efficacy of therapy is unknown. 
Understanding the biology of the tumor microenvironment both pre-/post-treatment will 
be critical for evaluating the role that these immunomodulatory drugs plan in inducing an 
effective antitumor immune response.  Examination of biopsies both pre- and post 
treatment will be critical to exploring this area, as this is thought to be the primary site 
where restoration of antitumor immune responses occurs.  Thus, evaluation of the tumor 
microenvironment via the approaches described above will be critical to determine the 
mechanism by which antitumor immunity is restored in response to therapy and to 
develop rational biomarkers for selecting appropr iate patients and monitoring responses 
on treatment. 
 
 
 
 
 
 
 
 
 
Prioritization of corre lative studies 
 
The correlative plan above designates allocation of ten (10) cores from pre-treatment and 
on-treatment biopsies.  S hould fewer samples be obtained, the priority for allocation of 
core biopsy samples will be as follows: 
 
Core 
Allocation 
1 
FFPE for IHC 
2 
Flow cytometry and sorting 
3 
Flow cytometry and sorting 
4 
FFPE for IHC 
5 
Flow cytometry and sorting 
6 
Snap frozen 
7 
FFPE for IHC 
8 
Flow cytometry and sorting 
9 
Snap frozen 
10 
FFPE for IHC 
 
Tre atme nt 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. 


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11.0 
TOXICITIES/SIDE EFFECTS 
 
11.1 Ge neral Plan to Manage Safety Concerns. 
 
Measures will be taken to ensure the safety of patients participating in this trial, including 
the use of stringent inclusion and exclusion criteria (see Section 6.1 and Section 6.2) and 
close monitoring (as indicated below) See Section 16.2 for complete details regarding 
safety reporting for this study. 
 
Eligibility Crite ria 
Eligibility criteria were selected to guard the safety of patients in this trial.  Results from 
the nonclinical toxicology studies with Atezolizumab, as well as the nonclinical/clinica l 
data from other PD-L1/PD-1 inhibitors, were taken into account (see Section 5.2) 
 
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 v4.0.  Patients will b e 
assessed for safety (including laboratory values) according to the schedule in Section 10. 
Patients will be followed for safety for 30 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 Section 9 and 10 for the list and timing of study assessments).  All serious adve rse 
events (S AEs) and protocol-defined events of special interest (see Section 17.2) will be 
reported in an expedited fashion. In addition, the investigators will review and evaluate 
observed AEs on a regular basis. 
 
Patients who have an ongoing study treat ment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. 
 
11.2 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, any of the other reasons fo r 
treatment discontinuation listed in Section 7.1, or a maximum treatment duration of 24 
months. 
 
There will be no dose reduction for Atezolizumab in this study.  Patients may temporarily 
suspend study treatment for up to 84 days beyond the scheduled date of delayed infusion 


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if study drug-related toxicity requiring dose suspension is experienced.  If Atezolizumab 
is held because of AEs for  84 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 17.2. 
 
If a patient must be tapered off steroids used to treat AEs, Atezolizumab may be held for 
additional time beyond 84 days from the scheduled dose until steroids are discontinued or 
reduced to a prednisone dose (or dose equivalent) of  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 investigator. 
 
Any toxicity 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 AEs observed with immunomodulatory agents have been mild and 
self- limiting, such events should be recognized early and treated promptly to avoid 
potential major complications.  Discontinuation of Atezolizumab may not have an 
immediate therapeutic effect, and there is no available antidote for Atezolizumab. 
In severe cases, immune-related toxicities may be acutely managed with topical 
corticosteroids, systemic corticosteroids, mycophenolate, or TNF inhibitors. 
 
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. 
 
Management of hepatitis/transaminitis, colitis, rash, and hypothyroidism are presented in 
this section as they have been observed with Atezolizumab and are potentially immune 
related. 
 
Gastrointe stinal Toxicity 
Immune- mediated colitis has been associated with the administration of Atezolizumab. 
Patients should be advised to inform the investigator if any diarrhea occ urs, even if it is 
mild. 
 
If the event is of significant duration or magnitude, or is associated with signs of systemic 
inflammation or acute phase reactants (e.g., increased C RP or platelet count or bandemia), 
it is recommended that sigmoidoscopy (or colonoscopy, if appropriate) with colonic 
biopsy with three to five specimens for standard paraffin block be performed.  If possible, 
one or two biopsy specimens should be snap frozen and stored. 
 
Treatment may be restarted following the resolution of colitis.  In addition, if the patient 
is being managed with corticosteroids, treatment should not be restarted until the steroids 


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have been tapered down to a prednisone dose  10 mg/day.  Patients who resume 
treatment should be monitored closely for signs of renewed diarrhea.  Table 1 provides a 
summary of dose modification guidelines for gastrointestinal toxicities. 


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Table 1 
Dose Modification Guidelines for Gastrointestinal Toxicity 
 
Toxicity 
Description  
Management 
Diarrhea 
Grade 2 (46 stools per 
day over baseline)  5 days 
 
 
 
 
 
 
Grade 2 (46 stools per 
day over baseline)  5 days 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abdominal pain 
 
Blood or mucus in stool 
 
OR 
 
Grade  3 ( 7 stools/day 
over baseline) with 
peritoneal signs, ileus, or 
fever 
 
 
 
 
 
 
 
 
 
 
 
 
NSAID  nonsteroidal anti-inflammatory drug. 
Hold Atezolizumab and 
discontinue NSAIDS (or 
other medications known to 
exacerbate colitis). 
Investigate for etiology. 
Restart Atezolizumab once 
at baseline stool frequency. 
Hold ATEZOLIZUMAB and 
discontinue NSAIDS (or 
other medications known to 
exacerbate colitis) while 
etiology is being 
investigated.  Consider 
referral to a 
gastroenterologist. 
Administer anti-diarrheal 
agent (e.g., Imodium). 
Consider oral budesonide, 
mesalamine, or 10 mg oral 
prednisone equivalent per 
day. 
Restart Atezolizumab once 
at baseline stool frequency. 
 
Hold ATEZOLIZUMAB and 
discontinue NSAIDS (or 
other medications known to 
exacerbate colitis). 
Rule out bowel perforation. 
Consider administering 
prednisone 60 mg/day or 
equivalent. 
Taper steroids over 1 
month.  Restart 
ATEZOLIZUMAB if diarrhea 
is resolved and systemic 
steroid dose is  10 mg oral 
prednisone equivalent per 
day. 
Permanently discontinue 
Atezolizumab for 
life-threatening, 
immune-related diarrhea or 
colitis. 


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He patotoxicity 
Immune- mediated hepatitis has been associated with the administration of Atezolizumab. 
 
While in this study, patients presenting with right upper-quadrant abdominal pain and/or 
unexplained nausea or vomiting should have LFTs performed immediately, and LF Ts 
should be reviewed before administration of the next dose of study drug. 
 
If LF Ts increase, neoplastic, concurrent medications, 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 of increased 
LFTs.  Anti-nuclear antibody, peri- nuclear anti- neutrophil cytoplasmic antibody, anti- 
liver kidney microsomal, and anti-smooth muscle antibody tests should be performed if 
an autoimmune etiology is considered. 
 
Patients with LF T abnormalities should be managed according to the guidelines in 
Table 2. 
 
Table 2 
Dose Modification Guidelines for He patotoxicity 
 
Toxicity 
Description 
Management 
LFT abnormalities AST/ALT ( ULN to 
3  ULN) with total 
bilirubin  2  ULN 
Continue with the standard monitoring 
plan (i.e., LFTs every 3 weeks before 
dosing). 
AST/ALT ( 3  ULN to 
 10  ULN) with total 
bilirubin  2  ULN 
Continue Atezolizumab. Monitor 
LFTs at least weekly. Consider 
referral to a hepatologist. 
AST/ALT  10  ULN 
Hold Atezolizumab. 
Consider administering IV steroids for 
2448 hours (prednisone 60 mg/day 
equivalent) followed by an oral 
prednisone (or equivalent) taper over 
24 weeks.  If LFT results do not 
decrease within 48 hours after initiation 
of systemic steroids, addition of an 
alternative immunosuppressive agent 
(e.g., mycophenolate or TNF 
antagonist) to the corticosteroid 
regimen may be considered.  Monitor 
LFTs every 4872 hours until 
decreasing and then follow weekly. 
Restart Atezolizumab if AST/ALT 
 3  ULN with bilirubin  2  ULN and 
steroid dose is  10 mg oral prednisone 
equivalent per day. 
Permanently discontinue Atezolizumab 
for life-threatening, immune-related 
hepatic events. 


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Table 2 
Dose Modification Guidelines for He patotoxicity (cont.) 
 
Toxicity 
Description  
Management 
LFT abnormalities 
(cont.) 
AST/ALT  3  ULN with 
bilirubin  2  ULN 
Hold Atezolizumab. 
Consult a hepatologist. 
Consider administering IV steroids for 
2448 hours (prednisone 60 mg/day 
equivalent) followed by oral taper over 
1 month.  If LFTs results do not 
decrease within 48 hours after initiation 
of systemic steroids, addition of an 
alternative immunosuppressive agent 
(e.g., mycophenolate or TNF 
antagonist) to the corticosteroid 
regimen may be considered.  Monitor 
LFTs every 4872 hours until 
decreasing and then follow weekly. 
Restart Atezolizumab if AST/ALT 
 3  ULN with bilirubin  2  ULN and 
steroid dose is  10 mg oral prednisone 
equivalent per day. 
 
IV  intravenous; LFT  liver function test; TNF  tumor necrosis factor alpha; 
ULN  upper limit of normal. 
 
De rmatologic Toxicity 
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 performed unless contraindicated.  Low-grade rash and pruritus AEs have been 
treated with symptomatic therapy (e.g., antihistamines).  Topical or parenteral 
corticosteroids may be required for more severe symptoms. 
 
Dermatologic toxicity and rash should be managed according to the guidelines in Table 3. 


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Table 3 
Dose Modification Guidelines for De rmatologic Toxicity 
 
Toxicity 
Description  
Management 
 
Dermatologic toxicity/rash 
(e.g., maculopapular or 
purpura) 
Grade 1:  Mild 
 10% BSA 
 
 
 
 
 
 
Grade 2:  Moderate 
10%30% BSA 
 
 
 
 
 
 
Grade 3: Severe 
 30% BSA 
 
Continue ATEZOLIZUMAB 
symptomatic therapy with 
antihistamine PRN. 
Consider topical steroids 
and/or other symptomatic 
therapy (e.g., 
antihistamines). 
Continue ATEZOLIZUMAB. 
Consider dermatologist 
referral. 
Administer topical steroids. 
Consider higher potency 
topical steroid if rash is 
unresolved. 
 
Hold ATEZOLIZUMAB. 
Consult dermatologist. 
Administer oral prednisone 
10 mg or equivalent.  If the 
rash is unresolved after 
4872 hours, administer 
oral prednisone 60 mg or 
equivalent. 
Restart ATEZOLIZUMAB if 
rash is resolved and 
systemic dose is  10 mg 
oral prednisone equivalent 
per day. 
Permanently discontinue 
ATEZOLIZUMAB for 
life-threatening, 
immune-related 
dermatologic toxicity. 
BSA  body surface area; PRN  as needed. 
 
Endocrine Toxicity 
Hypothyroidism has been associated with the administration of ATEZOLIZUMAB. 
 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status 
changes, or constipation should be investigated for the presence of thyroid, pituitary, or 
adrenal endocrinopathies, as well as for hyponatremia or hyperkalemia.  An 
endocrinologist should be consulted if an endocrinopathy is suspected. 
Thyroid-stimulating hormone (TSH) and free T4 levels should be obtained to determine 
whether thyroid abnormalities are present.  TS H, prolactin, and a morning cortisol level 
will help to differentiate primary adrenal insufficiency from primary pituitary 
insufficiency. 


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Hypothyroidism sho uld be managed according to the guidelines in Table 4. 
 
Table 4 
Dose Modification Guidelines for Endocrine Toxicity 
 
Toxicity 
Description  
Management 
 
Hypothyroidism  
TSH elevated, 
asymptomatic 
 
Continue ATEZOLIZUMAB. 
Start thyroid-replacement 
hormone. 
Monitor TSH weekly. 
TSH elevated, symptomatic  Hold ATEZOLIZUMAB. 
Consider referral to an 
endocrinologist. 
Restart ATEZOLIZUMAB 
when symptoms are 
controlled by thyroid 
replacement and TSH 
levels are decreasing. 
TSH  thyroid-stimulating hormone. 
 
Pulmonary Toxicity 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of ATEZOLIZUMAB and have primarily been 
observed in patients with underlying NSCLC. 
 
Mild-to- moderate events of pneumonitis have been reported with ATEZO LIZUMAB. 
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 (COPD), or pulmonary 
hypertension and the following should be performed: 
• 
Measurement of oxygen saturation (i.e., arterial blood gas) 
• 
High-resolution C T scan of the chest 
• 
Bronchoscopy with bronchoalveolar lavage and biopsy 
• 
Pulmonary function tests (with diffusion capacity of the lung for carbon 
monoxide [DLCO]) 
 
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. 
 
Pulmonary toxicity should be managed according to the guidelines in Table 5. 


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Table 5 
Dose Modification Guidelines for Pulmonary Toxicity 
 
Toxicity 
Description  
Management 
 
Pulmonary toxicity                   GGO or non-infectious 
infiltrate in absence of 
hypoxia, or dyspnea 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypoxia or dyspnea in 
presence of GGO or 
infiltrate without alternative 
etiology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GGO  ground glass opacities. 
 
Pote ntial Pancre atic Toxicity 
Hold treatment with 
ATEZOLIZUMAB. 
Re-evaluate after 1 week. 
If no worsening in 
GGO/infiltrates and patient 
still asymptomatic, resume 
treatment with 
ATEZOLIZUMAB. 
If GGO/infiltrates worsen 
and patient is still 
asymptomatic, continue to 
hold ATEZOLIZUMAB and 
refer for bronchoscopy. 
Consider starting low-dose 
oral prednisone 10 mg or 
equivalent. 
Re-evaluate after 1 week. 
Resume ATEZOLIZUMAB if 
GGO/infiltrates improving. 
Hold ATEZOLIZUMAB. 
Consult a pulmonologist. 
Investigate for other 
etiologies and consider 
bronchoscopy.  If 
bronchoscopy is consistent 
with immune-related 
etiology, start 60 mg 
prednisone equivalent per 
day followed by taper over 
2 weeks. 
Restart ATEZOLIZUMAB if 
symptomatically improved, 
infiltrates are resolved, and 
steroid use is  10 mg 
prednisone equivalent per 
day. 
Permanently discontinue 
ATEZOLIZUMAB for 
life-threatening, 
immune-related pulmonary 
events. 
Symptoms of abdominal pain associated with elevations of amylase and lipase, 
suggestive of pancreatitis, have been associated with administration of other 
immunomodulatory agents.  The differential diagnosis of acute abdominal pain should 


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include pancreatitis.  Appropriate workup should include an evaluation for obstruction, as 
well as serum amylase and lipase tests. 
 
Pote ntial Eye Toxicity 
An ophthalmologist should evaluate visual complaints.  Uveitis or episcleritis may be 
treated with topical corticostero id eye drops.  ATEZO LIZUMAB should be permanently 
discontinued for immune- mediated ocular disease that is unresponsive to local 
immunosuppressive therapy. 
 
Ocular toxicity should be managed according to the guidelines in Table 6. 
 
Table 6 
Dose Modification Guidelines for Eye Toxicity 
 
Toxicity 
Description 
Management 
Eye toxicity (autoimmune 
uveitis, iritis, or episcleritis) 
Symptomatic 
Hold ATEZOLIZUMAB. 
Consult ophthalmologist and 
start topical corticosteroid 
eye drops. 
ATEZOLIZUMAB may be 
restarted following 
resolution of the events. 
Permanently discontinue 
ATEZOLIZUMAB for 
immune-mediated ocular 
disease that is unresponsive 
to local immunosuppressive 
therapy. 
 
 
12.0 
CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
12.1 Tumor and Response Ev aluation 
 
Response and progression of disease will be evaluated in this study using the RECIL 
criteria23. Clinical evaluation and tumor assessments will be performed periodically, as is 
indicated in Table 7, based on physical examination, radiological evaluation and core 
bone marrow biopsy (in patients with pre-existing bone marrow involvement). C linical 
suspicion of disease progression at any time will require a physical examination and 
radiological confirmation to be performed promptly, rather than waiting for the next 
scheduled tumor assessment. In case of an unscheduled or delayed tumor assessment for 
any reason, subsequent tumor assessments must be performed according to the originally 
planned schedule from baseline. Patients who withdraw due to toxicity will be considered 
study failures at the time of withdrawal; patients withdrawing before first response 
assessment will be considered primary treatment failures. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
41 
 
 
 
 
 
Measurability of le sion for objective re sponse 
 
• 
Measurable disease: lesions that can be accurately measured in two dimensions by 
CT, MRI, plain x-ray of other conventional technique and have a greatest 
transverse diameter of 1.5 cm or greater. 
• 
Non-measurable disease: All other lesions including uni dimensional lesions, 
lesions too small to be considered measurable, pleural or pericardial effusions, 
ascites, bone disease, leptomeningeal disease, lymphangitis, pulmonitis, 
abdominal masses not confirmed by C T, or disease documented only by indirect 
evidence (e.g. lab values). 
• 
Patients may receive palliative radiotherapy to an isolated site of disease 
progression so long as they are deemed by their treating physician to be 
continuing to derive clinical benefit from ATEZO LIZUMAB.  However, for 
purposes of response assessment this will be considered progression of disease. 
 
Assessment of tumor burden in lymphoma clinical trials can use the sum of longest 
diameters (SLD). In patients with disseminated disease, a maximum of three target 
lesions should be selected and used to estimate tumor response. Target lesions should be 
selected from those with the largest size that can be reproducibly measured and 
preferably representing multiple sites and/organs. In most cases, lymph nodes can be 
considered target lesions if the lymph node longest diameter measures ≥15 mm. S imilar 
to RECIS T 1.1, a lymph node measuring between 10 and 14 mm is considered abnormal 
but should not be selected as a target lesion. Lymph nodes measuring <10mm in diameter 
are considered normal. In certain anatomical sites (inguinal, axillary, and portocaval), 
normal lymph nodes may exist in a narrow, elongated form, and such nodes should not be 
selected as target lesions if alternatives are available. Extranodal lesions are selected as 
target lesions if they have soft tissue component, based on their size, and the ease of 
reproducibility of repeated measurements, with a minimum measurement of the longest 
diameter of ≥ 15 mm. All other lesions should be identified as nontarget lesions and 
should be recorded at baseline, without the need to measure them. Nontarget lesions 
should be followed and reported as present, absent, or clear progression. 
 
 
Obje ctive disease re sponse assessment 
 
Objective status is to be recorded at each evaluation according to the RECIL Criteria 
[31]. 
 
EVALU ATION, STAGING, AND RESPONSE ASSESSM ENT FOR HODGKIN AND 
NON-HODGKIN LYMPHOM A: THE RECIL CRITERIA[31] 
 
 
 
Table 7. RECIL 2017: Criteria for RECIL Re sponse Asse ssment of Lymphoma 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
42 
 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
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43 
 
 
 
 
 
 
 
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: 
• 
Disease progression 
• 
Ineligibility (at the pretreatment evaluation) of the patient as defined in the 
inclusion/ exclusion criteria 
• 
Treatment will be discontinued at the request of the patient, refusal of therapy, 
non-compliance, or upon the development of an interc urrent significant medical 
illness. 
• 
Significant protocol violation 
• 
Unacceptable toxicity 
• 
Decision by the investigator that termination is in the patient’s best medical 
interest. 
• 
Loss to follow- up 
• 
Development of active HBV infection, hepatitis, or HIV infe ction 
• 
Pregnancy or a positive pregnancy test 
• 
Death of the patient 
 
In addition to the general study treatment withdrawal criteria, the following study specific 
criteria will also require premature study treatment discontinuation: 
 
• 
Use of prohibited medication 
• 
Start of any other anti- neoplastic therapy 
 
 
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 and they will be considered study failures at that point.  Patients who 
withdraw prior to first response assessment will be considered treatment failures. 
 
 
See Section 8 for assessments that are to be performed for patients who prematurely 
withdraw from the study during the treatment period. 
 
14.0 
BIOSTATISTICS 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
44 
 
 
 
 
 
This is a phase II study in which we are aiming to evaluate for evidence of activity of 
anti-PD-L1 therapy in rel/ref HL.  The primary endpoint for both cohorts is 12 month 
progression-free survival (PFS). For patients previously treated with anti-PD-1 therapy, 
based on historical data showing a 12- mo nth PFS of 9% [Vardhana, unpublished], a 12m 
PFS rate of 10% is considered undesirable and 30% considered desirable. With a S imon 
two-stage minimax design with type-I error of 0.05 and power of 0.8, 15 patients will be 
enrolled at the first stage. If less than 2 patients are alive and progression-free by 12 
months, the trial will stop and the therapy will be considered not efficacious. If >=2 
patients are alive and progression- free by 12 months, then additional 10 patients will be 
enrolled in the second sta ge to make the total sample size 25. If less than 6 of the 25 
patients are alive and progression- free by 12 months, the therapy will be considered not 
promising. If >=6 of the 25 patients are alive and progression-free by 12 months, the 
therapy will be considered promising for the anti-PD-1 refractory patients. 
 
For patients never treated with anti-PD-1 therapy before, based on historical data 
showing a median PFS of 10 months and a 12- month PFS of 46% [116, 117], a 12m PFS 
rate of 40% is considered undesirable and 62% considered desirable. With a S imon two- 
stage minimax design with type-I error of 0.05 and power of 0.8, 20 patients will be 
enrolled at the first stage. If less than 9 patients are alive and progression-free by 12 
months, the trial will stop and the therapy will be considered not efficacious. If >=9 
patients are alive and progression- free by 12 months, then additional 12 patients will be 
enrolled in the second stage to make the total sample size 32. If less than 18 of the 32 
patients are alive a nd progression- free by 12 months, the therapy will be considered not 
promising. If >=18 of the 32 patients are alive and progression-free by 12 months, the 
therapy will be considered promising for the anti-PD-1 native patients. 
 
As mentioned in Section 4.1, we will first open cohort 1 with patients previously treated 
with anti-PD-1 therapy. S hould cohort 1 not meet criteria for early stopping at the end of 
the first stage, we will open a second cohort which will include patients who never 
received anti-PD-1 therapy. 
 
In both cohorts, the recruitment will continue at the end of the first stage without halting. 
There is a probability that more patients than necessary will be enrolled when the therapy 
is not efficacious. However, if there are an excess of early progressio ns, the first stage 
stopping rule will catch them. Moreover, the two-stage design is nevertheless better than 
a single stage design, which requires the same sample size, and efficacy criterion yet 
recruits the full cohort regardless of the interim outcome. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
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45 
 
 
 
 
 
14.1 Outcomes Measures 
 
 
Primary Efficacy Outcome Me asure 
 
The primary endpoint of this study is 12 month PFS in both cohorts. The primary 
endpoint will be computed as proportions along with exact 95% confidence intervals. 
Patients withdrawn from the study for reason of pregnancy will be replaced and not be 
evaluated for the primary endpoint; however, patients withdrawn for all other reasons 
will be considered as progression so long as they have received any study treatment. 
 
Se condary Efficacy Outcome Me as ure s 
 
Secondary endpoints include determination of the overall response rate (defined as CR or 
PR as best overall response), disease control rate (defined as CR or P R as best response 
or SD for 2 or more assessments), complete response rate, progression free survival, and 
duration of response (defined for those who respond as time from documented objective 
response (C R or P R) until progression) of atezolizumab in relapsed/refractory HL 
patients who are anti-P D-1 previously treated (cohort 1) and in relapsed/refractory HL 
patients who are treatment naïve (cohort 2 ).  Patients will undergo disease assessment 
with P ET/C T every 3 cycles of for the first 12 cycles and subsequently every 4 cycles 
until treatment intolerance, disease progression, or 2 years of treatment.  PFS and 
duration of response will be computed by Kaplan Meier method. 
 
Exploratory goals are to determine whether pre-treatment tumor expression of MHC-I, 
MHC-II, PD-L1, or P D-L2, the effector to regulatory T cell ratio at baseline and change 
in ratio in response to therapy, changes in expression of T-cell extrinsic apoptosis-related 
markers FasL and TRAIL in response to therapy, or PI3K activation on HRS cells at 
baseline or change in PI3K activation in response to therapy predicts treatment response 
in terms of PFS and overall response rate. With the exception of pre-treatment MHC-I 
and MHC-II, which will be treated as categorical variables, all other correlative measures 
will be treated as continuous variables.  Wilcoxon rank sum tests will be used for 
correlation between the continuous variables and overall response rate. F isher’s exact will 
be used for correlation between categorical variables and overa ll response rate. Cox’s 
proportional hazards model will be used for correlation with PFS. Other measurements 
from the proposed assays will be summarized by descriptive statistics. 
 
Safe ty Outcome Measures 
 
Toxicity will be graded using CTCAE (version 4) guidelines and will be compared to 
toxicity observed with anti-PD-1 in HL. 
 
15.0 
 RESEARCH PARTICIPANT REGISTRATION AND RANDOMIZATION 
PROCEDURES 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
46 
 
 
 
 
 
15.1 
Re search Participant Re gistration 
 
 
 
 
 
 
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 C hecklist. 
 
The individual signing the Eligibility C hecklist is confirming whether or not the 
participant is eligible to enroll in the study. Study staff are responsible for 
ensuring that all institutional requirements nec essary to enroll a participant to the 
study have been completed. See related C linical Research Policy and Procedure 
#401 (Protocol Participant Registration). 
 
15.2 
Randomization 
 
No randomization will occur on this study. 
 
16.0 
DAT A M AN AGEMENT ISSUES 
 
This clinical research study will be monitored both internally by the PI and externally by 
the MSKCC IRB.  In terms of internal review, the PI will continuously monitor and 
tabulate AEs.  Appropriate reporting to the MSKCC IRB will be made.  The PI of this 
study will also continuously monitor the conduct, data, and safety of this study to ensure 
that: 
 
• 
Interim analyses occur as scheduled, 
 
• 
Stopping rules for toxicity and/or response are met, 
 
• 
Risk/benefit ratio is not altered to the detriment of the subjects, 
 
• 
Appropriate internal monitoring of AEs and outcomes is done, 
 
• 
Over-accrual does not occur, 
 
• 
Under-accrual is addressed with appropriate amendments or actions, and 
 
• 
Data are being appropriately collected in a reasonably timely manner. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
47 
 
 
 
 
 
Routine monitoring will be carried out via a periodic team conference among 
investigators during which toxicity data, including all SAEs, will be reviewed and other 
issues relevant to the study such as interim assessment of accrual, outcome, and 
compliance with study guidelines, will be discussed.  Monitoring will be carried out on 
an ongoing basis.  The severity, relatedness, and whether or not the event is expected will 
be reviewed. 
 
A Research S tudy Assistant (RS A) will be assigned to the study. The responsibilities of 
the RS A include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate 
the activities of the protocol study team. 
 
The data collected for this study will be entered into a secure database. Source 
documentation will be available to support the computerized patient record. 
 
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 P I.  All source documents will be 
available for inspection by the FDA and the MSKCC IRB. 
 
16.1 
Re te ntion of Re cords 
 
FDA regulations (21 CF R §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 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. 
 
16.2 
Study Me dication 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. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
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48 
 
 
 
 
 
Accurate records of all study dr ug 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 C linical Material 
form as directed by Genentech. 
 
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. Accrual 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. 
 
Random-sample data quality and protocol compliance audits will be conducted by 
the study team, at a minimum of two times per year, more frequently if indicated. 
 
16.2 
Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) P lans at Memorial S loan-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 ://ca ncertria ls. nc i. nih. go v/resea rc hers/dsm/inde x. html. 
 
The DS M P lans at MSKCC were established and are monitored by the O ffice of 
Clinical Research. The MSKCC Data and Safety Monitoring P lans can be found 
on the MSKCC Intranet at: 
https://o ne. mskcc.o rg/sites/p ub /c linrese arc h/Doc ume nts/MSKCC%20Data %20a n 
d%20Sa fety%20Mo nitoring%20P la ns.pd f/ 
 
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 (DS MB) 
for P hase III clinical trials, report to the Center’s Research Council and 
Institutional Review Board. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
49 
 
 
 
 
 
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.) Will be addressed and the monitoring procedures will be 
established at the time of protocol activation. 
 
17.0 
PROTECTION OF HUMAN SUBJECTS 
 
Potential risks to human subjects include drug related toxicity; pain and discomfort 
associated with therapy; treatment side effects; phlebotomy; and possible psychologic 
discomfort from the stresses associated with obtaining imaging studies (e.g., CT scan, 
PET scan). 
 
If an adverse medical event occurs, the patient will first contact the primary oncologist or 
the principal investigator. At nights and weekends, there is an oncology physician on call 
at all times. Patients may either call or come directly to the Urgent Care Center at 
Memorial Hospital (or to their local emergency room) to be seen. 
 
Costs to the patient (third party insurer) will include the cost of blood tests and diagnostic 
studies, office visits, and those admissions which may be required as a consequence of 
treatment-related complications. 
 
All serious adverse events incurred while a patient is on study will be reported to the IRB 
at Memorial Hospital and Genentech. All serious adverse experiences and relevant 
laboratory findings will be reported to the principle investigator immediately. An adverse 
experience is considered serious if death occurs, the condition is life threatening, 
hospitalization is required, or there is permanent disability or incapacity. All information 
regard ing serious adverse experiences must be recorded on the form provided. Patients 
suffering serious adverse reactions must be carefully followed and all follow-up 
information also recorded. 
 
All life threatening and lethal known, unknown, or suspected reactions (toxicities) must 
be reported to the principle investigator. An S AE report will be submitted to the IRB 
within 5 days. Any death, regardless of cause, must be reported to the principle 
investigator by telephone or fax and in writing. It is the treating physician’s responsibility 
to investigate and report the date and cause of death of any patient entered on this trial. 
 
17.1 
Priv acy 
 
MSK’s Privacy O ffice 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 P rivacy Board (IRB/PB). 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
50 
 
 
 
 
 
17.2 
Se rious Adverse Event (SAE) Re porting 
 
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 subject 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 signs consent.  SAE 
reporting is required for 30-days after the participant’s last investigational 
treatment or intervention. Any events that occur after the 30-day period and that 
are at least possibly related to protocol treatment must be reported. 
 
If an SAE requires submission to the IRB office per IRB SOP RR-408 ‘Reporting 
of Serious Adverse Events’, the SAE report must be sent to the IRB within 5 
calendar days of the event. The IRB requires a Clinical Research Database 
(CRDB) SAE report be submitted electronically to the SAE Office as follows: 
 
For IND/IDE trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to 
saemskind@mskcc.org. 
 
For all other trials: Reports that include a Grade 5 SAE should be sent to 
saegrade5@mskcc.org.  All other reports should be sent to sae@mskcc.org. 
 
The report should contain the following information: 
Fields populated from CRDB: 
• 
Subject’s initials 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number and title 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
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51 
 
 
 
 
 
Data needing to be entered: 
 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
The grade of the event 
• 
Relationship of the adverse event to the treatment (drug, device, or 
intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following 
o A explanation of how the AE was handled 
o A description of the subject’s condition 
o Indication if the subject 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 
 
The PI’s signature and the date it was signed are required on the completed 
report. 
 
 
 
Additional S AE re porting Guidelines 
 
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. F ood 
and Drug Administration (F DA), appropriate Institutional Review Boards (IRBs), 
and Genentech, Inc., in accordance with CFR 312.32 (Investigational New Drug 
[IND] Safety Reports). 
 
Ad verse Eve nt Repo rting Perio d 
The study period during which all AEs and S AEs must be reported begins after 
informed consent is obtained and initiation of study treatment and ends 30 days 
following the last administration of study treatment or study 
discontinuation/termination, whichever is earlier.  After this period, invest igators 
should only report S AEs that are attributed to prior study treatment. 
 
Assessme nt o f Ad verse Eve nts 
All AEs and S AEs, 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. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
52 
 
 
 
 
 
To ensure consistency of AE and S AE causality assessments, investigators should 
apply the following general guideline: 
 
Ye s 
There is a plausible temporal relationship between the onset of the AE and 
administration of ATEZOLIZUMAB, 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 ATEZOLIZUMAB; and/or the AE 
abates or resolves upon discontinuation of ATEZOLIZUM AB or dose reduction 
and, if applicable, reappears upon re-challenge. 
 
No 
Evidence exists that the AE has an etiology other than ATEZO LIZUMAB (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. 
 
Spec ific Instructio ns fo r Re cord ing Ad verse Eve nts 
Investigators should use correct medical terminology/concepts when reporting 
AEs or SAEs.  Avoid colloquialisms and abbreviations. 
 
Dia gnosis versus S igns a nd S ympto ms 
If known at the time of reporting, a diagnosis should be reported rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather 
than jaundice, asterixis, and elevated transaminases).  However, if a constellation 
of signs and/or symptoms cannot be medically characterized as a single diagnosis 
or syndrome at the time of reporting, it is acceptable to report the information that 
is currently available.  If a diagnosis is subsequently established, it should be 
reported as follow- up information. 
 
Deaths 
All deaths that occur during the protocol-specified AE reporting period, 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 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
53 
 
 
 
 
 
unknown and cannot be ascertained at the time of reporting, report “Unexplained 
Death.”  Deaths that occur during the protocol-specified adverse event reporting 
period that are attributed by the investigator solely to progression of disease 
should be recorded only in the study CRF. 
 
Pre-existing Med ica l Cond itio ns 
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 S AE 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”). 
 
Hosp ita lizatio ns fo r Med ica l or S urgica l Proced ures 
Any AE that results in hospitalization or prolonged hospitalization should be 
documented and reported as an S AE.  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 S AE.  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. 
 
Pregna nc ies in Fe ma le Patie nts 
Female patients of childbearing potential will be instructed to immediately inform 
the investigator if they become pregnant during the study or within 90 days after 
the last dose of study drug.  A Pregnancy Report C RF 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 C RF.  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 S AEs 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. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
54 
 
 
 
 
 
A C linical Trial P regnancy 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 "P rotocol Administrative and Contact Information 
& List of Investigators" ). 
 
Abortio ns 
Any spontaneous abortion 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). 
 
Conge nita l Ano ma lie s/Birth De fec ts 
Any congenital anomaly/birth defect in a child bor n to a female patient or female 
partner of a male patient exposed to study drug should be classified as an S AE, 
recorded on the Adverse Event C RF, and reported to Genentech Drug Safety 
immediately (i.e., no more than 24 hours after learning of the event). 
 
Post-Stud y Ad verse Eve nts 
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 conceived 
offspring of a female patient who participated in the study, this should be reported 
as an S AE. 
 
Safe ty Reco nc ilia tio n 
The investigator agrees to conduct reconciliation for the product.  Genentech and 
the investigator will agree to the reconciliation periodicity and format, but agree 
at minimum to exchange monthly line listings of cases received by the other party. 
If discrepancies are identified, the investigator 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. 
 
Ad verse Eve nts o f Spec ia l Inte rest 
Adverse events of special interest (AESIs) are defined as a potential safety 
problem, identified as a result of safety monitoring of the IMP. 
 
The following AEs are considered of special interest and must be reported to the 
Genentech Drug Safety expedit iously, irrespective of regulatory seriousness 
criteria: 
• 
Pneumonitis 
• 
Hypoxia or dyspnea, Grade  3 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, or adrenal insufficiency 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
55 
 
 
 
 
 
• 
Vasculitis 
• 
Hepatitis 
• 
Transaminitis: Grade  2 (AS T or ALT  3  ULN and bilirubin  2  ULN) 
or AS T/ALT  10  ULN 
• 
Systemic lupus erythematosus 
 
• 
Guillain-Barré syndrome 
• 
Myasthenia gravis 
• 
Meningoencephalitis 
• 
Nephritis 
• 
Pericardial effusion 
 
• 
Skin reactions:  vitiligo, pemphigoid 
• 
Events suggestive of hypersensitivity, cytokine release, influenza- like illness, 
systemic inflammatory response syndrome, systemic inflammatory activation, 
or infusion-reaction syndromes 
• 
Colitis 
 
Ad verse Eve nt Repo rting 
Investigators must report all S AEs to Genentech within the timelines described 
below.  The completed MedWatch/case report should be faxed immediately upon 
completion to Genentech Drug Safety at: 
(650) 225-4682 
OR 
 
(650) 225-5288 
 
Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available. 
 
SAE reports, whether related or unrelated to ATEZOLIZUMAB, will be 
transmitted to Genentech within 24 hours of the Awareness Date. 
 
AES Is will be transmitted to Genentech within 15 calendar days of the Awareness 
Date. 
 
Additional reporting requirements to Genentech include the following: 
 
• 
Any reports of pregnancy following the start of administration with the 
ATEZOLIZUMAB and within the follow-up period (for female patients 
within one year after the last dose of ATEZO LIZUMAB or the partner of a 
male patient within three months of completing therapy) will be transmitted to 
Genentech within 24 hours of the Awareness Date. 


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IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
56 
 
 
 
 
 
• 
All non-serious ATEZOLIZUMAB AEs originating from the study will be 
forwarded Genentech quarterly. 
Note: Investigators should also report events to their IRB as required. 
MedWatc h 3500 A Repo rting Guide lines 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (item 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 relatio nship of the AE to each investigational 
product and suspect medication 
 
Follow-Up Informatio n 
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., date of birth, initial, patient number), protocol 
description and number, if assigned, brief AE 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.) 
 
Occasionally Genentech may contact the reporter for additional information, 
clarification, or current status of the patient for whom and AE was reported.  For 
questions regarding SAE reporting, you may contact the Genentech Drug Safety 
representative noted above or the Medical Science Liaison assigned to the study. 
Relevant follow-up information should be submitted to Genentech Drug Safety as 
soon as it becomes available and/or upon request. 
 
MedWatch 3500A (Mandatory Reporting) form is available at 
http ://www. fda. go v/Abo utFDA/ReportsMa nua lsForms/Forms/de fa ult. htm 
  
 
17.2.1  Additional Re porting Re quirements for IND 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
57 
 
 
 
 
 
For sponsor IND studies, some additional reporting requirements for the F DA 
apply in accordance with the guidance set forth in 21 CFR § 600.80. 
 
Events meeting the following criteria need to be submitted to the F DA as 
expedited IND Safety Reports according to the following guidance and timelines: 
 
7 Cale nda r Da y Te lep ho ne or Fa x Report 
The investigator is required to notify the FDA of any fatal or life-threatening AE 
that is unexpected and assessed by the investigator to be possibly related to the 
use of ATEZOLIZUMAB.  An unexpected AE is one that is not already described 
in the ATEZOLIZUMAB Investigator’s Brochure.  S uch reports are to be 
telephoned or faxed to the F DA and Genentech within 7 calendar days of first 
learning of the event. 
 
15 Cale nda r Da y Writte n Report 
The Investigator is also required to notify the F DA 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 ATEZO LIZUMAB.  An 
unexpected AE is one that is not already described in the ATEZOLIZUMAB 
Investigator’s Brochure. 
 
Written IND Safety reports should include an Analysis of S imilar Events in 
accordance with regulation 21 CF R § 312.32.  All safety reports previously filed 
by the investigator with the IN D 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, 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). 
 
Contact Information for IND Safe ty Re ports 
FDA fax numbe r for IND safe ty re ports: 
 
Fax: (800) F DA-0178 
 
All writte n IND safe ty re ports submitted to the FDA by the inve stigator must 
also be faxe d to the following: 
 
Ge ne ntech D rug Safe ty Fax : (650) 225 4682 or (650) 225 5288 
Site ’s IRB: 
Janelle Walkley 
 
205 East 64th Street, Lower Concourse 173, New York, NY 10065 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
58 
 
 
 
 
 
T 646.449.1338 
 
wa lk le yj@ mskcc.org 
 
For que stions re lated to safe ty re porting, ple ase contact Ge nentech Drug 
Safe ty: 
Tel: (888) 835-2555 
 
Fax: (650) 225-4682 or (650) 225-5288 
 
IND Annua l Repo rts 
Copies of all IND annual reports submitted to the FDA by the 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 inclusion in the study. Participants will also be informed t hat 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/P B-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: 
 
1.   The nature and objectives, potential risks and benefits of the intended study. 
2.   The length of study and the likely follow-up required. 
3.   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.) 
4.   The name of the investigator(s) responsible for the protocol. 
5.   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 particip ant 
must receive a copy of the signed informed consent form. 
 
 
19.0 
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Approval date: 17-Jan-2018 
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Approval date: 17-Jan-2018 
66 
 
 
 
 
 
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20.0 
APPENDICES 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
67 
 
 
 
 
 
Appe ndix 1 
Calculation of Cre atinine Cle arance Using the Cockcroft-Gault 
Formula 
 
 
 
 
Creatinine C leara nce (me n) (140-Age) Lea n Bod y We ight [k ilo gra ms] 
Serum Creatinine (mg/dL)  72 
 
 
Creatinine C leara nce (wo me n) 0.85 (140-Age ) Lea n Bod y We ight [k ilo gra ms] 
Serum Creatinine (mg/dL)  72 
 
 
Reference: 
 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted 
serum creatinine (editorial). Nephron 1992;62:249. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
68 
 
 
 
 
 
Appe ndix 2 
Curre nt National Cance r Institute Common Te rminology Crite ria for Adve rse 
Eve nts (NCI CTCAE) 
 
 
 
Please use the following link to the NCI CTCAE website: 
 
http ://c tep.ca nce r. go v/pro toco lDe ve lop me nt/e lectro nic_app lica tio ns/c tc. htm 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
69 
 
 
 
 
 
Appe ndix 3 Easte rn Cooperative Oncology Group (ECOG) Performance Status Scale 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able t o 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities; up and about  50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair  50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
70 
 
 
 
 
 
 
 
EQUIPM ENT NEEDED 
 
• 
Tourniquet 
• 
Oxygen 
Appe ndix 4 Anaphylaxis Pre cautions 
 
• 
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, the following procedures 
should be performed: 
 
1. 
Stop the study drug infusion. 
2. 
Apply 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. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
71 
 
 
 
 
 
Appe ndix 5 Safe ty Re porting 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 Safe ty Re porting questions, contact Ge nentech Safe ty: (888) 835-2555 
 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET. 


Memorial Sloan Kettering Cancer Center
IRB Number: 17-191 A(2) 
Approval date: 17-Jan-2018 
72 
 
 
 
 
 
Appe ndix 6 FDA Me dWatch 3500 For m 
 
A copy of this form can be found in the link below 
 
http://www.fda.gov/downloads/About FDA/ReportsManualsForms/Forms/UCM349464.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
.