Clinical trial NCT03513952
Conditions: Advanced Bladder Urothelial Carcinoma Advanced Ureter Urothelial Carcinoma Metastatic Bladder Urothelial Carcinoma Metastatic Renal Pelvis Urothelial Carcinoma Metastatic Ureter Urothelial Carcinoma Metastatic Urethral Urothelial Carcinoma Metastatic Urothelial Carcinoma Recurrent Bladder Urothelial Carcinoma Recurrent Renal Pelvis Urothelial Carcinoma Recurrent Ureter Urothelial Carcinoma Recurrent Urethral Urothelial Carcinoma Stage III Bladder Cancer AJCC v8 Stage III Renal Pelvis Cancer AJCC v8 Stage III Ureter Cancer AJCC v8 Stage III Urethral Cancer AJCC v8 Stage IV Bladder Cancer AJCC v8 Stage IV Renal Pelvis Cancer AJCC v8 Stage IV Ureter Cancer AJCC v8 Stage IV Urethral Cancer AJCC v8 Stage IVA Bladder Cancer AJCC v8 Stage IVB Bladder Cancer AJCC v8 Unresectable Bladder Urothelial Carcinoma Unresectable Renal Pelvis Urothelial Carcinoma Unresectable Ureter Urothelial Carcinoma
Sponsor: National Cancer Institute (NCI)
Start date: 2019-06-05; Completion date: 2024-04-01
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well atezolizumab when given with glycosylated recombinant human interleukin-7 (CYT107) works in treating patients with urothelial carcinoma that has spread to nearby tissue or lymph nodes (locally advanced), cannot be removed by surgery (inoperable), or has spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. CYT107 is a biological product naturally made by the body that may stimulate the immune system to destroy tumor cells. Giving atezolizumab and CYT107 may work better in treating patients with locally advanced, inoperable, or metastatic urothelial carcinoma compared to atezolizumab alone.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the clinical efficacy of the investigational treatment combination.

SECONDARY OBJECTIVES:

I. To determine the clinical activity and toxicity of the investigational treatment combination.

II. The clinical benefit rate (CBR), progression-free survival (PFS), duration of response (DOR), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related response criteria (irRC), and overall survival (OS).

III. The CBR, PFS, DOR, and OS in all patients and patients stratified by PD-L1 expression levels in the tumor microenvironment.

IV. The safety and toxicity of addition of CYT107 to atezolizumab.

EXPLORATORY OBJECTIVES:

I. To determine the immune correlates of the clinical activity of the investigational treatment combination.

II. Explore the effect of the investigational treatment combination on the number and phenotype of tumor-specific T cells in the peripheral blood.

III. Investigate for evidence that the investigational treatment combination increases the exposure of bladder cancer-specific antigens (e.g., cancer/testis antigens or neoantigens).

IV. Investigate changes in tumor microenvironment that correlate with response or provide information on potential actionable causes for lack of clinical benefit.

V. Investigate the potential that administration of atezolizumab with CYT107 may perturb the pharmacokinetics and immunogenicity of CYT107.

OUTLINE:

SAFETY RUN-IN PHASE: Patients assigned to the experimental arm (atezolizumab + CYT107). If the treatment combination of the experimental arm demonstrates an acceptable safety profile in the Safety Run-In (one or fewer patient experiences a protocol-defined Dose Limiting-Toxicity), randomized enrollment into the trial will begin. The Run-in phase patients will be analyzed and reported separately both for safety and for efficacy.

Patients are randomized to 1 of 2 groups.

GROUP 1 (experimental arm): Patients receive CYT107 intramuscularly (IM) on days 1, 8, 15, and 22, and atezolizumab intravenously (IV) over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT) and/or magnetic resonance imaging (MRI) scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.

GROUP 2 (control arm): Patients receive atezolizumab IV over 60 minutes on cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study.

After completion of study treatment, patients are followed up at 30 days and then every 12 weeks for up to 2 years.

Arms: arm 1: Patients receive CYT107 IM on days 1, 8, 15, and 22, and atezolizumab IV over 60 minutes on day 8 of cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles with atezolizumab repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study. arm 2: Patients receive atezolizumab IV over 60 minutes on cycle 1. Following cycle 1, patients receive atezolizumab IV over 30-60 minutes on day 1. Cycles repeat every 21 days for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or MRI scans, and collection of blood and stool samples on study. Patients may also undergo tumor biopsy at screening and on study. arm 3: Patients assigned to the experimental arm (atezolizumab + CYT107). If the treatment combination of the experimental arm demonstrates an acceptable safety profile in the Safety Run-In (one or fewer patient experiences a protocol-defined Dose Limiting-Toxicity), randomized enrollment into the trial will begin. The Run-in phase patients will be analyzed and reported separately both for safety and for efficacy.
Interventions: intervention 1: Atezolizumab intervention 2: Biopsy intervention 3: Biospecimen Collection intervention 4: Computed Tomography intervention 5: Glycosylated Recombinant Human Interleukin-7 intervention 6: Laboratory Biomarker Analysis intervention 7: Magnetic Resonance Imaging intervention 8: Positron Emission Tomography and Computed Tomography Scan
Intervention descriptions: intervention 1: Given IV intervention 2: Undergo biopsy of tumor intervention 3: Undergo collection of blood and stool samples intervention 4: Undergo CT intervention 5: Given IM intervention 6: Correlative studies intervention 7: Undergo MRI intervention 8: Undergo PET/CT

Protocol documents:
Prot_SAP_000.pdf: 
i 
 
SUMMARY OF CHANGES 
Protocol 
 
Protocol #: CITN-14, A4_v1.0 
NCI Protocol #: CITN-14, A4_v1.0 
Protocol Version Date: October 12, 2022  
 
I. 
Changes requested by the Pharmaceutical Management Branch  
# 
Section 
Page 
Comments 
1. 
8 1.1 
77 
Revised the Atezolizumab drug information, as requested by the 
Pharmaceutical Management Branch on October 6, 2022.  
 
 
II. 
Changes initiated by the Protocol Principal Investigator and CITN Coordinating Center 
# 
Section 
Page 
Comments 
2. 
3.2.8 
25 
Clarified that oral prednisone > 10 mg/day or equivalent is prohibited.  
3. 
3.2.14 
27 
Revised criterion to align with current available literature and standard 
language used on other immunotherapy trials. As currently written, 
exclusion criterion 3.2.14 is too prescriptive and limits enrollment of 
patients with established stability for autoimmune disease. As 
appropriate, allowing enrollment of these patients following 
consultation with the Protocol PI and/or CITN Coordinating Center 
may help trial accrual.   
 
III. 
Administrative Changes 
# 
Section 
Page 
Comments 
4. 
All sections 
All pages Updated version and date throughout protocol 
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NCI Protocol #: CITN-14 
Version Date: October 12, 2022 
2 
Statistician: 
Study Coordinator: N/A 
Axio Research 
2601, 4th Avenue, Suite 200 
Seattle, WA 98121 
Phone: (206) 547-2829 
Responsible Research Nurse: N/A 
Responsible Data Manager: N/A 
NCI-Supplied Agent(s):  
Atezolizumab (MPDL3280A; NSC 783608)  
Recombinant Human IL-7 (CYT107; NSC 767713) 
Other Agent(s): 
N/A 
IND #:  
 
IND Sponsor: 
DCTD, NCI 
Protocol Type / Version # / Version Date: Amendment #4 / Version 1.0 / October 12, 2022 
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NCI Protocol #: CITN-14 
Version Date: October 12, 2022 
3 
CONTACT INFORMATION 
For regulatory 
requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
Cancer Trials Support Unit 
(CTSU) via the Regulatory 
Submission Portal. 
Regulatory Submission Portal: 
(Sign in at 
https://www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately by phone or 
email: 1-866-651-CTSU 
(2878), or 
CTSURegHelp@coccg.org to 
receive further instruction and 
support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-CTSU 
(2878) for regulatory 
assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which 
can be accessed at 
https://www.ctsu.org/OPEN SYSTEM/ 
or https://OPEN.ctsu.org. 
Contact the CTSU Help Desk with any 
OPEN-related questions by phone or 
email:1-888-823-5923 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please see 
the data submission section 
of the protocol for further 
instructions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS. 
For clinical questions (i.e., patient eligibility or treatment-related) 
Contact the CITN Central Operations and Statistical Center at citn@fredhutch.org or (514) 718-2858 
For nonclinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) Contact the CTSU Help Desk by phone or email: 
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com.  
All calls and correspondence will be triaged to the appropriate CTSU representative. 
The CTSU Website is located at https://www.ctsu.org. 
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NCI Protocol #: CITN-14 
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STUDY SUMMARY 
Abbreviated Title 
Urothelial Carcinoma Therapy with Atezolizumab plus CYT107 
Trial Phase 
Phase II 
Clinical Indication 
Locally advanced or metastatic urothelial carcinoma 
Trial Type 
Randomized, controlled trial with initial Safety Run-In phase 
Safety Run-In 
Enrollment of 6 patients to the Experimental arm. If acceptable safety 
profile, patient randomization will begin.  
Type of control 
Randomized trial with primary end point of objective response rate 
(ORR). Secondary endpoint of clinical benefit rate (CBR), 
progression-free survival (PFS), Duration of Response (DOR) and 
overall survival (OS) will compare the control arm to the experimental 
arm.  
Randomization arm 
1 – Experimental 
IL-7 (CYT107), 10 mcg/kg intramuscularly (IM) days 1, 8, 15 and 22 
of cycle 1 only (28-day cycle) + Atezolizumab, 1200 mg intravenously 
(IV) day 8 of cycle 1 (28-day cycle) and day 1 of subsequent cycles
(21-day cycle)
2 – Control 
Atezolizumab, 1200 mg intravenously (IV) day 1 of each cycle (21-
day cycle) 
Stratification Factor 
None 
Trial Blinding 
None 
Number of trial patients 
54 patients 
Estimated duration of trial 
Trial is expected to be completed over a period of 30 months. 
Duration of Participation 
Each patient will participate in the trial from the time the Informed 
Consent Form (ICF) is signed through final protocol-specified contact. 
The active study will end when the last patient reaches 2 years.  
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TABLE OF CONTENTS 
STUDY SUMMARY .................................................................................................................................... 4 
TABLE OF CONTENTS .............................................................................................................................. 5 
1. 
OBJECTIVES ....................................................................................................................................... 7 
1.1 
Primary Objectives ........................................................................................................................ 7 
1.2 
Secondary Objectives .................................................................................................................... 7 
1.3 
Exploratory Objectives ................................................................................................................. 7 
2. 
BACKGROUND .................................................................................................................................. 8 
2.1 
Study Disease(s) ............................................................................................................................ 8 
2.2 
CTEP IND Agent(s) ...................................................................................................................... 8 
2.3 
Other Agent(s): N/A ................................................................................................................... 15 
2.4 
Rationale ..................................................................................................................................... 15 
2.5 
Integrated Correlative Studies Background ................................................................................ 16 
2.6 
Exploratory/Ancillary Correlative Studies .................................................................................. 19 
2.7 
Special Studies ............................................................................................................................ 22 
3. 
PATIENT SELECTION ..................................................................................................................... 23 
3.1 
Eligibility Criteria ....................................................................................................................... 23 
3.2 
Exclusion Criteria ....................................................................................................................... 25 
3.3 
Inclusion of Women and Minorities ........................................................................................... 28 
4. 
REGISTRATION PROCEDURES .................................................................................................... 28 
4.1 
Investigator and Research Associate Registration with CTEP ................................................... 28 
4.2 
CTSU Registration Procedures ................................................................................................... 29 
4.3 
Delegation of Tasks Log (DTL) .................................................................................................. 31 
4.4 
Patient Enrollment ...................................................................................................................... 32 
4.5 
General Guidelines ...................................................................................................................... 33 
5. 
TREATMENT PLAN ......................................................................................................................... 33 
5.1 
Agent Administration .................................................................................................................. 34 
5.2 
Safety Run-in: Definition of Dose-Limiting Toxicity ................................................................. 37 
5.3 
General Concomitant Medication and Supportive Care Guidelines ........................................... 38 
5.4 
Duration of Therapy .................................................................................................................... 40 
5.5 
Study Treatment beyond Disease Progression ............................................................................ 41 
5.6 
Duration of Follow-Up................................................................................................................ 41 
5.7 
Patient Replacement .................................................................................................................... 42 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................................. 42 
6.1 
Atezolizumab (MPDL3280A)..................................................................................................... 42 
6.2 
Recombinant Human IL-7 (CYT107) ......................................................................................... 64 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................................. 66 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) .......................................... 66 
7.2 
Adverse Event Characteristics .................................................................................................... 72 
7.3 
Expedited Adverse Event Reporting ........................................................................................... 72 
7.4 
Routine Adverse Event Reporting .............................................................................................. 76 
7.5 
Pregnancy .................................................................................................................................... 76 
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7.6 
Secondary Malignancy ................................................................................................................ 76 
7.7 
Second Malignancy ..................................................................................................................... 76 
8. 
PHARMACEUTICAL INFORMATION ........................................................................................... 77 
8.1 
CTEP IND Agent(s) .................................................................................................................... 77 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ......................................................... 81 
9.1 
Integrated Correlative Studies ..................................................................................................... 82 
9.2 
Exploratory Correlative Studies .................................................................................................. 85 
9.3 
Special Studies ............................................................................................................................ 88 
10. STUDY CALENDAR ........................................................................................................................ 91 
11. MEASUREMENT OF EFFECT ........................................................................................................ 95 
11.1 
Antitumor Effect – Solid Tumors ........................................................................................... 95 
11.2 
Other Response Parameters: Immune-Related Response Criteria (irRC) ............................. 101 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS .......... 101 
12.1 
Study Oversight..................................................................................................................... 101 
12.2 
Data Submission/Reporting .................................................................................................. 101 
12.3 
CTEP Multicenter Guidelines ............................................................................................... 103 
12.4 
Collaborative Agreements Language .................................................................................... 103 
12.5 
Genomic Data Sharing Plan: N/A ......................................................................................... 105 
13. STATISTICAL CONSIDERATIONS ............................................................................................. 105 
13.1 
Responsibility for Analyses .................................................................................................. 105 
13.2 
Study Design/Objectives ....................................................................................................... 105 
13.3 
Sample Size/Accrual Rate ..................................................................................................... 106 
13.4 
Stratification Factors ............................................................................................................. 107 
13.5 
Analysis of Secondary Endpoints ......................................................................................... 107 
13.6 
Reporting and Exclusions ..................................................................................................... 108 
14. REFERENCES ................................................................................................................................. 110 
APPENDIX A PERFORMANCE STATUS CRITERIA ....................................................................... 113 
APPENDIX B CTEP MULTICENTER GUIDELINES ......................................................................... 114 
APPENDIX C IMMUNE-RELATED RESPONSE CRITERIA ............................................................ 116 
APPENDIX D DOSE ADJUSTMENT FOR OBESE PATIENT ........................................................... 118 
APPENDIX E MICROBIOME SAMPLE COLLECTION .................................................................... 120 
APPENDIX F ABBREVIATIONS LIST ............................................................................................... 121 
 
 
 
 
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1. 
OBJECTIVES 
The goals of this trial are to evaluate the safety and tolerability of the investigational treatment 
combination, and to determine whether the addition of CYT107 to atezolizumab improves the 
objective response rate achieved by atezolizumab alone in patients with advanced/non-resectable 
bladder cancer who have recurrent disease after platinum chemotherapy. 
1.1 
Primary Objectives 
To determine the clinical efficacy of the investigational treatment combination. 
The primary endpoint will be the Objective Response Rate (ORR), defined by Complete 
Response (CR) or Partial Response (PR) as measured by RECIST v1.1. 
1.2 
Secondary Objectives 
To determine the clinical activity and toxicity of the investigational treatment combination. 
 The clinical benefit rate (CBR), progression-free survival (PFS), duration of response 
(DOR), as measured by RECIST 1.1 and irRC, and overall survival (OS). 
 The CBR, PFS, DOR, and OS in all patients and patients stratified by PD-L1 expression 
levels in the tumor microenvironment. 
 The safety and toxicity of addition of CYT107 to atezolizumab. 
1.3 
Exploratory Objectives 
To determine the immune correlates of the clinical activity of the investigational treatment 
combination. 
The endpoints will include the evaluation of the effect of the investigational treatment 
combination on the tumor microenvironment, based upon baseline and post-baseline tumor 
biopsy comparisons of: 
• 
Number, distribution, and phenotype of tumor-infiltrating cells 
• 
PD-L1 expression 
• 
Expression of Interferon γ (IFNγ) and associated inflammatory gene expression in the 
tumor microenvironment 
Explore the effect of the investigational treatment combination on the number and phenotype of 
tumor-specific T cells in the peripheral blood. Investigate for evidence that the investigational 
treatment combination increases the exposure of bladder cancer-specific antigens (e.g., 
Cancer/Testis Antigens or neoantigens). Investigate changes in tumor microenvironment that 
correlate with response or provide information on potential actionable causes for lack of clinical 
benefit. Investigate the potential that administration of atezolizumab with CYT107 may perturb 
the pharmacokinetics and immunogenicity of CYT107.  
 
 
 
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NCI Protocol #: CITN-14 
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2. 
BACKGROUND 
2.1 
Study Disease(s) 
The proposed clinical trial is a phase II, open-label, multicenter, randomized study of the 
administration of Atezolizumab (MPDL3280A) monotherapy or in combination with 
Recombinant Human IL-7 (CYT107) in patients with advanced or metastatic urothelial 
carcinoma. 
Urothelial carcinoma is the fifth most common malignancy in the United States [Siegel 2014]. 
Advanced or metastatic urothelial carcinoma carries a grim prognosis and has limited treatment 
options [von der Maase 2000]. The immunogenicity of urothelial bladder cancer (UBC) was first 
demonstrated by the successful use of BCG for non-muscle invasive bladder cancer and 
carcinoma in situ [Kamat 2001]. More recently, antibodies blocking PD-1/PD-L1 signaling in 
endogenous T cells have induced dramatic and durable clinical responses in patients with 
metastatic urothelial carcinoma, further highlighting urothelial carcinoma as a compelling target 
for T-cell immunotherapy [Powles 2014; Plimack 2017] 
Early studies with impressive response rates and durable responses led to regulatory approval of 
5 different PD-1/PD-L1 antibodies. This includes atezolizumab, durvalumab, nivolumab, 
avelumab, and pembrolizumab. Survival outcomes have been assessed in randomized phase 3 
trials with atezolizumab and pembrolizumab. Pembrolizumab was successful in demonstrating 
improved overall survival outcomes over taxane or vinflunine chemotherapy in the post-
platinum–treated advanced or metastatic UBC setting [Bellmunt 2017]. Atezolizumab also 
demonstrated an overall survival benefit over taxane or vinflunine chemotherapy in the post-
platinum–treated advanced or metastatic UBC setting in the intention to treat analysis 
(presentation abstract). However, the primary study endpoint was based on an enrichment 
biomarker approach based on PD-L1 immunohistochemical staining, and that enrichment 
approach failed, as the biomarker was very clearly prognostic for improved outcomes in both 
arms, but not predictive for improved response to atezolizumab. 
We now attempt to demonstrate improved clinically meaningful outcomes with the addition of 
CYT107 to atezolizumab over atezolizumab alone for patients with advanced or metastatic 
urothelial carcinoma. 
2.2 
CTEP IND Agent(s) 
 Atezolizumab (MPDL3280A) 
Atezolizumab is a human immunoglobulin (Ig) G1 monoclonal antibody consisting of 2 
heavy chains (448 amino acids) and 2 light chains (214 amino acids) and is produced in 
Chinese hamster ovary cells [Investigators's Brochure]. 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 nonglycosylated antibody that has 
minimal binding to Fc receptors, thus eliminating detectable Fc-effector function and 
associated antibody-mediated clearance of activated effector T cells. Atezolizumab 
targets human programmed death-ligand 1 (PD-L1) and inhibits the interaction with its 
 
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NCI Protocol #: CITN-14 
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PD-L1 and its receptors, PD-1 and B7-1 (also known as CD80), both of which function 
as inhibitory receptors expressed on T cells. 
Atezolizumab shows antitumor activity in both nonclinical models and cancer patients 
and is being investigated as a potential therapy in a wide variety of malignancies. 
Atezolizumab is being studied as a single agent in the advanced cancer and adjuvant 
therapy settings, as well as in combination with chemotherapy, targeted therapy, and 
cancer immunotherapy. 
Atezolizumab was approved in the United States by the FDA in 2016 for the treatment of 
locally advanced or metastatic urothelial carcinoma and as well as metastatic non–small 
cell lung carcinoma. In March 2021, following the review of recent Atezolizumab 
bladder cancer studies and evaluation of other available treatment options, the indication 
for Atezolizumab in patients with urothelial carcinoma who have previously received 
platinum-based chemotherapy has been withdrawn in the United States, according to the 
drug’s developer, Roche. The decision to withdraw the agent for use in this patient 
population does not affect indications for Atezolizumab in other diseases including non-
small cell lung cancer, small cell lung cancer, metastatic triple-negative breast cancer, 
hepatocellular carcinoma and melanoma or as first-line treatment in cisplatin-ineligible 
patients with locally advanced and metastatic urothelial carcinoma.  
2.2.1.1 
Mechanism of Action 
PD-L1 expression is prevalent in many human tumors (e.g., lung, bladder, ovarian, 
melanoma, colon carcinoma), and its overexpression has been associated with poor 
prognosis in patients with several cancers [Thompson 2006; Hamanishi 2007; 
Okazaki 2007; Hino 2010]. PD-L1 binds to 2 known inhibitory receptors expressed 
on activated T cells (PD-1 and B7.1), and receptor expression is sustained in states of 
chronic stimulation such as chronic infection or cancer [Blank 2005; Keir 2008]. 
Ligation of PD-L1 with PD-1 or B7.1 inhibits T-cell proliferation, cytokine 
production, and cytolytic activity, leading to the functional inactivation or inhibition 
of T cells. Aberrant expression of PD-L1 on tumor cells has been reported to impede 
antitumor immunity, resulting in immune evasion [Blank 2007]. Therefore, 
interruption of the PD-L1/PD-1 and PD-L1/B7.1 pathway represents an attractive 
strategy to reinvigorate tumor-specific T-cell immunity. 
Blockade of PD-L1 or PD-1 with monoclonal antibodies has been reported to result in 
strong and often rapid antitumor effects in several mouse tumor models [Iwai 2002; 
Strome 2003]. These data suggest that tumor-specific T cells may be present in the 
tumor microenvironment in an inactive or inhibited state, and blockade of the PD-
L1/PD-1 pathway can reinvigorate tumor-specific T-cell responses. 
Collectively, these data establish the PD-L1/PD-1 pathway as a promising new 
therapeutic target in patients with advanced tumors. Immune-related adverse events 
(irAEs) reported from the 2 recent studies were consistent with the role of the PD-
L1/PD-1 pathway in regulating peripheral tolerance. 
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2.2.1.2 
Summary of Nonclinical Experience 
The safety, pharmacokinetics (PK), 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, PK, and toxicokinetics of atezolizumab. 
Overall, the nonclinical PK and toxicokinetics observed for atezolizumab supported 
entry into clinical studies, including providing adequate safety factors for the 
proposed phase 1 starting doses. The results of the toxicology program were 
consistent with the anticipated pharmacologic activity of down-modulating the PD-
L1/PD-1 pathway and supported entry into clinical trials in patients. 
Refer to the Atezolizumab Investigator’s Brochure for details on the nonclinical 
studies. 
2.2.1.3 
Summary of Clinical Experience 
A summary of clinical data from company-sponsored atezolizumab trials is presented 
below. Details of all ongoing studies can be found in the most recent Atezolizumab 
Investigator’s Brochure. 
2.2.1.3.1. 
Clinical PK and Immunogenicity 
On the basis of available preliminary PK data (0.03–20 mg/kg), atezolizumab 
shows linear PK at doses ≥1 mg/kg [Investigators's Brochure]. Based on an 
analysis of exposure, safety, and efficacy data, the following factors had no 
clinically relevant effect: age (21−89 years), body weight, gender, positive ATA 
status, albumin levels, tumor burden, region, or ethnicity, renal impairment, mild 
hepatic impairment, level of PD-L1 expression, or ECOG status. No formal PK 
drug-drug interaction studies have been conducted with atezolizumab, and the 
interaction potential is unknown. Further details can be found in the current 
Investigator’s Brochure. 
The development of antitherapeutic antibodies (ATAs) has been observed in 
patients in all dose cohorts and was associated with changes in PK for some 
patients in the lower dose cohorts (0.3, 1, and 3 mg/kg) [Investigators's Brochure]. 
Patients dosed at ≥10 mg/kg maintained Cmin values well above the target serum 
concentration of 6 mcg/mL despite the detection of ATAs. Accordingly, the 
development of detectable ATAs does not appear to have a clinically significant 
impact on PK for doses above 10 mg/kg. To date, no relationship between the 
development of measurable ATAs and safety or efficacy has been observed. 
2.2.1.3.2. 
Clinical Safety Summary 
As of May 10, 2016, atezolizumab has been administered (alone or in 
combination with other agents) to approximately 6053 patients with solid tumors 
and hematologic malignancies [Investigators's Brochure]. The first-in-human 
monotherapy study PCD4989g (in patients with locally advanced or metastatic 
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NCI Protocol #: CITN-14 
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solid tumors or hematologic malignancies) provides the majority of monotherapy 
safety data, with 629 safety-evaluable patients as of the data extraction date. 
Currently, no maximum tolerated dose (MTD), no dose-limiting toxicities 
(DLTs), and no clear dose-related trends in the incidence of AEs have been 
determined. 
Fatigue, decreased appetite, nausea, diarrhea, constipation, and cough were 
commonly reported AEs in single and combination therapy [Investigators's 
Brochure]. AE profiles are similar across tumor types studied, including non–
small cell lung cancer (NSCLC), renal cell carcinoma (RCC), triple-negative 
breast cancer (TNBC), and urothelial carcinoma, and are consistent with the 
mechanism of action of atezolizumab. The overall immune-mediated AEs 
reported were considered moderate in severity, and the majority of patients were 
able to continue on atezolizumab therapy. 
As of the data extraction date of December 15, 2015, there were 629 safety-
evaluable patients from the first-in-human phase 1a study PCD4989g 
[Investigators's Brochure]. The median age was 61 years. Of the 629 patients, 619 
patients (98.4%) reported at least one AE of any grade or attribution to 
atezolizumab, and 316 patients (50.2%) experienced at least one grade 3 or 4 AE 
of any attribution. A total of 444 patients (70.6%) reported at least one treatment-
related AE, and 86 patients (13.7%) experienced at least one treatment-related 
grade 3 or 4 AE. The most frequently observed AEs of any grade and attribution 
(occurring in ≥10% of treated patients) include fatigue, decreased appetite, 
nausea, pyrexia, constipation, cough, dyspnea, diarrhea, anemia, vomiting, 
asthenia, back pain, headache, arthralgia, pruritus, rash, abdominal pain, 
insomnia, peripheral edema, and dizziness. 
Serious AEs (SAEs) have been reported in 261 patients (41.5%) in study 
PCD4989g [Investigators's Brochure]. Reported SAEs were consistent with the 
underlying disease. Treatment-related SAEs (57 patients [9.1%]) included 
pyrexia, dyspnea, pneumonitis, malaise, fatigue, hypoxia, colitis, and bone pain. 
Pooled single-agent safety data from 1978 patients with UC, NSCLC, and other 
indications (including trial PCD4989g) indicate that the most frequent (>1% of 
patients) serious adverse drug reactions (regardless of grade) include dyspnea 
(3.0%), back pain (1.2%), and abdominal pain (1.1%). A list of AEs considered 
“expected” for atezolizumab is presented in Section 7.1.1.1. 
2.2.1.3.3. 
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 atezolizumab clinical program [Investigators's Brochure]. To date, immune-
related adverse events associated with atezolizumab include hepatitis, 
pneumonitis, colitis, pancreatitis, diabetes mellitus, hypothyroidism, 
hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, myasthenic 
syndrome/myasthenia gravis, nephritis, myocarditis, and meningoencephalitis. 
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For further details, see the most recent Atezolizumab Investigator’s Brochure. 
2.2.1.3.4. 
Clinical Efficacy Summary 
Patients with multiple tumor types were included in study PCD4989g, with the 
largest cohorts consisting of patients with NSCLC, RCC, and UC [Investigators's 
Brochure]. Objective responses with atezolizumab monotherapy were observed in 
a broad range of malignancies, including NSCLC, RCC, melanoma, UC, 
colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and 
sarcoma. Both the preliminary and more mature efficacy data available suggest 
that treatment with atezolizumab as a single agent or in combination with other 
therapeutic agents results in antitumor activity across a range of tumor types and 
hematologic malignancies (UC, NSCLC, RCC, TNBC, melanoma, CRC, and 
NHL) and across lines of therapy. Clinical benefit was observed in terms of 
objective responses, durability of responses, and overall survival. Improved 
efficacy of atezolizumab was observed in the unselected patient population, as 
well as in patients with higher PD-L1 expression on TCs or ICs (e.g., NSCLC) or 
on ICs only (e.g., mUC, RCC). 
 Recombinant Glycosylated Human Interleukin-7 (CYT107) 
A relatively nontoxic regimen of weekly IL-7 will substantially increase the total body 
complement of T cells of all phenotypes. The current trial will test whether addition of 
IL-7 to atezolizumab, using an IL-7 regimen known to increase the total body 
complement of T cells, will increase the frequency and depth of clinical responses to 
atezolizumab. 
2.2.2.1 
Mechanism of action 
IL-7 is a homeostatic growth factor for T cells that normally contributes to 
maintaining the normal number of peripheral blood T cells. IL-7 is the T-cell 
equivalent of erythropoietin and thymopoietin with multiple functions that could 
increase the efficacy of atezolizumab. IL-7–mediated signaling can induce 
proliferation in the absence of T-cell receptor signaling [Swainson 2007]. IL-7 signals 
through the IL-7 receptor (IL-7R) heterodimer composed of the common γ-chain 
(CD132) cytokine receptor and a unique IL-7Rα (CD127). During normal conditions, 
IL-7R expression is maintained on resting T cells [Mackall 2011] and endogenous IL-
7 is continuously available in secondary lymphoid organs as a result of stromal cell 
IL-7 production [Takada 2009]. 
2.2.2.2 
Summary of Nonclinical Experience 
Exogenous IL-7 induces expansion of most categories of T cells. In preclinical and 
clinical studies IL-7 has been shown to: 
1. Increase peripheral blood T cells by several fold with little toxicity [Levy 2009; 
Sportes 2010; Perales 2012; Tredan 2015; Sheikh 2016], 
2. Expand all categories of T cells including CD8, CD4 and memory T cells [Sportes 
2010], 
3. Increase the total body complement of T cells including increased size of lymph 
nodes, spleen, liver [Sportes 2008], 
 
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4. Increase T-cell receptor (TCR) diversity by preferentially stimulating the growth 
of TREC positive, naïve T cells [Sportes 2008]. Continuous signaling by IL-7 
induces antiapoptotic and costimulatory responses that are essential for the 
survival of naïve T cells. 
5. Maintain effector T-cell function, 
6. Increase the ratio of CD8+ T cells to Tregs, as IL-7Rα expression is relatively low 
on FOXP3+ Treg cells compared with nonregulatory T-cell subsets [Liu 2006; 
Seddiki 2006]. 
7. Increase tissue infiltration of T cells into gut mucosa (other tissues have not been 
examined) [Sereti 2012]. 
8. Reverse neutrophil lymphocyte ratios [unpublished data – CITN12-03 
(NCT01881867)] 
9. Augment vaccine-induced cell responses in murine models [Melchionda 2005] 
10. Augment immune-mediated control of both tumors and viruses [Mackall 2011]. 
After either T-cell activation, IL-7 signaling, or both, IL-7Rα is down-regulated on 
terminally differentiated, senescent T cells [Fry 2003], [Park 2004] but becomes 
reexpressed after several days and remains expressed during the later contraction 
phase. IL-7Rα is also selectively expressed on a small minority of effector T cells that 
are destined to enter the central memory T-cell pool, thus implicating IL-7 as a 
modulator of the effector to memory cell transition [Kaech 2003]. 
2.2.2.3 
Summary of Clinical Experience 
The CYT107 dose and regimen have been established in prior clinical trials. More 
than 380 patients have been exposed to CYT107. Weekly CYT107 × 3 or 4 at doses 
of 10 to 20 µg/kg can double the number of peripheral blood T cells (CITN Immune 
Monitoring Lab data). Both naïve and memory T cells are expanded by CYT107 with 
a peak of proliferation at day 7. Repeated doses of CYT107 induce expansion of 
CD4+ and CD8+ T cells subsets. Importantly, there is no significant difference 
between the 10 and 20 mcg/kg dose levels and biological effect on CD4+ and CD8+ 
T-cell number increases [Levy 2012], Figures 1A and 1B]. The increases last for 
weeks to months in some individuals [Levy 2009]. Extrapolating from the increase in 
size of lymph nodes, spleen, and liver with FDG-PET, the total body burden of T 
cells also increased correspondingly [Sportes 2008]. However, the 10 µg/kg dose 
level is tolerated better, with no reported serious unexpected serious adverse reactions 
(SUSARs) reported compared to 4 cases reported at the 20 µg/kg dose. Importantly, 
the 20 µg/kg dose level has been associated with autoimmune adverse events, include 
Henoch-Schonlein purpura, lichen planus and the emergence of neutralizing 
antibodies [CYT107 Investigator's Brochure]. 
Regimens of weekly IL-7 at the 10 µg/kg level demonstrate an acceptable safety 
profile with very few grade 3 or 4 adverse events. More than 380 patients have been 
exposed to CYT107, including 236 patients in 7 phase I/IIa dose escalation studies 
with CYT107 in oncology, hematopoietic stem cell transplantation (HSCT), human 
immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV) 
infected patients and 2 phase II studies in patients with HIV. CYT107 has been well 
tolerated [CYT107 Investigator's Brochure]. The most frequent adverse events are: 
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injection site reactions, lymphadenopathy, pyrexia, rash, and fatigue. A cumulative 
819 administrations of CYT107 triggered 555 injection site reactions AE, i.e., 70% of 
CYT107 administrations led to at least one injection site reaction. The worst grade 
reported was grade 2 in 159 of 819 administrations (19.4%). No grade 3 or 4 injection 
site reactions were reported. 
Among the 555 injection site reactions related to CYT107: 
– 113 (20.3%) were of grade <1 
– 283 (51.0%) were of grade 1 
– 159 (28.7%) were of grade 2 
– No grade 3 or 4 injection site reactions were reported. 
Of note, this scoring was performed with reference to the DAIDS 2.0 scale which is 
more severe than CTCAE scoring. 
One true anaphylactic reaction and 4 acute allergic reactions have been reported, 
strictly in studies with repeated cycles of CYT107. The immunogenicity frequency 
and the occurrence of NADA (neutralizing antibodies) are higher with the exposure to 
multiple cycles of CYT107. 
Two studies analyzed the pharmacokinetics of CYT107 in patients with HIV-1 with 
CD4 T-cell counts of 101-400 cells/µL and plasma HIV RNA <50 copies/mL while 
receiving highly active antiretroviral therapy (HAART) for ≥12 months. Three dose 
levels of CYT107 were tested sequentially: 10, 20 and 30μg/kg. Increasing doses 
induced a dose response increase in peripheral blood T cells. The increases were 
nonlinearity above 20µg/kg/week in the lymphopenic patients and above 
30/µg/kg/week for the non-lymphopenic patients. The nonlinearity was presumed to 
be to the administered IL-7 being cleared by binding to an increased number of T 
cells, i.e., a "Target Mediated Drug Disposition" [CYT107 Investigator's Brochure]. 
Up to June 2013, all preclinical and clinical studies were conducted by Cytheris S.A. 
In September 2013 all CYT107 related assets were transferred to RevImmune, the 
company now responsible for conducting CYT107 development. 
The CITN has one ongoing trial of CYT107 started with Cytheris and continued with 
RevImmune CITN is the IND sponsor. The trial is testing CYT107 in patients with 
metastatic castration-resistant prostate cancer after treatment with sipuleucel-T 
(PROVENGE®, Dendreon Corporation), a prostatic acid phosphatase vaccine. The 
goal is to determine whether treatment with CYT107 can substantially increase and 
prolong immune responses to prostatic acid phosphatase and thereby eventually 
provide a novel, nontoxic regimen to prolong the survival of patients with metastatic 
castration-resistant prostate cancer [CITN12-03 (ClinicalTrials.gov Identifier: 
NCT01881867)]. 
After therapy with standard sipuleucel-T, patients are randomly assigned to 
observation or administration of CYT107 10 μg/kg on days 0, 7, 14, and 21. The 
randomized trial has accrued 54 of 70 patients with half in the CYT107 arm. Results 
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to date have confirmed that CYT107 (1) increases peripheral blood CD8+ and CD4+ 
T cells, and (2) reverses the neutrophil to lymphocyte ratio. Of note, a high neutrophil 
to lymphocyte ratio is a poor prognostic sign in most, if not all, clinical cancer 
circumstances in which it’s been assessed [Templeton 2014] including bladder cancer 
[Bhindi 2016]. No DLT have been observed. 
2.3 
Other Agent(s): N/A 
2.4 
Rationale 
Very few preclinical studies have combined IL-7 with PD-1 or anti-PD-L1 checkpoint blockade. 
One murine study showed the therapeutic efficacy of concomitant blockade of CTLA-4 and PD-
1 relies on interdependence of IL-7 and IFN-γ signaling in T cells, predicting the exogenous IL-7 
will boost the therapeutic efficacy [Shi 2016]. Another study of murine sepsis showed that IL-7 
reverses immune suppression by increasing lymphocyte proliferation, expression of lymphocyte 
adhesion molecules, interferon-gamma production, and CD28 expression on splenic CD8+ T 
cells. Combined treatment with IL-7 and anti-PD-1 produced additive effects on CD28 
expression, lymphocyte proliferation, and splenic secretion of interferon-gamma [Shindo 2015]. 
Of note, CYT107 therapy is currently being tested in human sepsis [ClinicalTrials.gov Identifier: 
NCT02640807]. In a recent Science paper [Pauken 2016] using the mouse model of chronic 
lymphocytic choriomeningitis virus (LCMV) infection explored the combined effect of IL-7 and 
anti-PD-L1 on the development and functionality of exhausted T cells. They confirmed that 
treatment with IL-7 starting in the effector phase can prevent development of T-cell exhaustion. 
By 8 to 11 weeks after treatment, however, the anti-PD-L1 reinvigoration of T cells was lost, and 
the quantity, proliferation, effector function, and inhibitory receptor expression of LCMV-
specific CD8 T cells in the anti-PD-L1–treated mice were comparable to those in control-treated 
mice. Interestingly at this stage the combined treatment with IL-7 and anti-PD-L1, resulted in 
more antigen-specific CD8 T cells and improved coproduction of interferon-γ and tumor necrosis 
factor–α. 
Atezolizumab induces remarkable responses in a subset of patients, yet the percentage of 
complete responses in the “all comers” population was only 5.5% and the median OS for all 
patients was only 7.9 months [Package Insert 2017]. Various mechanisms of immune escape, 
including (1) the lack of strong, tumor-specific antigens or epitopes recognized by T cells, 
(2) impaired or suppressed antigen presentation machinery including downregulation of major 
histocompatibility complex on cancer cells, (3) impaired or suppressed cytotoxic T-cell 
activation, (4) poor infiltration of T cells into the tumor microenvironment, and (5) increased 
immunosuppressive cytokines and cells in the tumor microenvironment prevent a large 
proportion of cancer patients from driving clinical benefit from anti-PD1/PD-L1 therapies [Kim 
2016]. Thus, additional therapies to increase the frequency and depth of responses to 
atezolizumab are needed. 
Atezolizumab has induced phenomenal lifesaving responses in some patients with advanced 
urothelial carcinoma, presenting an incredible foundation for building more effective regimens. 
The current trial will determine whether, by increasing the total body complement of T cells and 
expanding the T-cell repertoire, the addition of CYT107 to atezolizumab will improve upon the 
clinical benefit provided by atezolizumab alone. 
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2.5 
Integrated Correlative Studies Background 
 Evaluation of peripheral CD4+ and CD8+ T-cell counts – Integrated Laboratory 
Correlative Study #1 
As described above, CYT107 has been shown to double the number of peripheral blood 
lymphocytes including T cells. Thus, CD4+ and CD8+ T-cell numbers are important 
biomarkers for the effect of CYT107 on the peripheral T-cell populations. To assess the 
overall pharmacodynamic effect of atezolizumab plus CYT107 and to determine whether 
CYT107 in combination with atezolizumab results in the same, or different level, of 
expansion of peripheral lymphocytes, T-cell counts (both CD4+ and CD8+) will be 
evaluated in CLIA certified laboratories locally at each site. CD4+ and CD8+ T-cell 
counts will be evaluated at baseline, during treatment, and at end of therapy. 
Hypothesis: The combination of atezolizumab with CYT107 will result in similar levels 
of peripheral blood T-cell expansion as with CYT107 alone. 
 
 Slide-Based Immune Phenotype Panel -- Multispectral IHC – Integrated Laboratory 
Correlative Study #2 
Because tumor-infiltrating immune cells are associated with clinical outcomes, infiltrates 
from pre-treatment tumor tissue and from biopsies taken during treatment will be 
assessed by IHC to determine extent and the nature of T-cell infiltration and of the 
overall immune milieu of the tumor microenvironment (TME). 
Paired baseline and post-baseline tumor biopsies will be evaluated using quantitative 
multicolor immunohistochemistry (IHC) with Perkin-Elmer’s Vectra IHC platform. This 
platform employs spectral deconvolution imaging to separate optical signals from each 
antibody together with state-of–the-art image analysis capabilities to facilitate robust 
quantitative slide-based immunophenotyping. Using the Vectra multispectral imaging 
platform (PerkinElmer), adjacent tumor sections will be stained and imaged with a series 
of 5-6 antibodies per section simultaneously to investigate the spatial relationship 
between key immunomodulatory cell types and molecules. The antibodies will include, 
but are not limited to, the following: pancytokeratin (AE1/AE3), CD8, CD4, PD-1, PD-
L1, CD68, CD163, FOXP3, arginase, and pan-MHC class I and class II. Data will be 
generated in the form of total positive cells, positive cells/mm2, percentage positive cells 
in a population, ratios of cells and molecules of interest (e.g., PD-L1:CD8 or 
FOXP3+CD4+:CD8). Additionally, tumors may also be assayed by IHC for a variety of 
other markers including CD80, IFN-gamma CD3, CD5, TIA-1, CD20, CD11b, CD137, 
CD45RO, CD301CD56 and CD16 (natural killer [NK] and NK T cells), CD79a (B cells), 
GITR, TIM-3, FOXP3, LAG3. Furthermore, quantitative analysis of tumor-infiltrating 
lymphocyte (TIL) distribution (i.e., stromal, and interface/invasive margin) will be 
performed. Anti-PD-L1 immunohistochemical staining will be performed at HistoGeneX 
(Naperville, IL) with the SP142 clone, in addition to the multispectral IHC (msIHC) to 
serve as both an independent test and control for the reproducibility of the msIHC assay. 
The study is intended to evaluate for changes in the immune profile of the tumor 
microenvironment. If sufficient archival tumor tissue collected before therapy is not 
 
 
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available, a baseline biopsy will be obtained before enrolling in the study as part of this 
protocol. 
IHC studies will be performed under the direction of Dr. 
 at the Fred 
Hutchinson Cancer Research Center (Fred Hutch) Experimental Histopathology 
Laboratory, Seattle, WA, or other agreed upon investigator. 
Hypothesis: The combination of atezolizumab with CYT107 will alter the TME (tumor 
microenvironment) towards a pro inflammatory phenotype. 
 
 Assessment of tumor biopsy by gene expression analysis -- Interferon γ (INFγ) Gene 
Expression Signature - NanoString® nCounter® Human Immunology V2 Panel and the 
nCounter® PanCancer Immune Profiling Panel – Integrated Laboratory Correlative 
Study #3 
To identify potential signatures correlating with tumor T-cell infiltration patterns and 
clinical response Tumor tissue will be tested for gene expression using NanoString® 
technology on unstained tissue formalin-fixed paraffin-embedded (FFPE) slide material. 
Specifically, slides will be analyzed using both a 770-gene panel (nCounter® PanCancer 
Immune Profiling Panel) which contains markers for 24 different immune cell types and 
populations, 30 common cancer antigens and genes that representing immune responses 
including checkpoint blockade genes as well as the NanoString® nCounter® Human 
Immunology V2 Panel which contain genes associated with the INFγ Gene Expression 
Signature. These gene expression profiles may provide an additional detailed phenotype 
to guide correlative investigation. 
NanoString®-based gene expression analysis, specifically for the IFN γ Signature, will be 
used to test the hypothesis that the investigational study treatment regimen, CYT107 plus 
atezolizumab, will promote a proinflammatory antitumor immune response. The IFNγ 
Signature, which is comprised of IDO1, CXCL10, CXCL9, HLA-DRA, STAT1 and 
IFNγ, has previously been shown to correlate with anti-PD1 response and nonresponse. 
RNA will be extracted from all paraffin-embedded tumor samples and analyzed using the 
NanoString® nCounter Immunology V2 Profiling Pane, which includes the 
aforementioned genes of the IFNγ Signature, as well as over 700 other genes associated 
with inflammation. The samples used will be taken from tissue sections adjacent to those 
stained for multispectral IHC to facilitate comparison between these analysis sets. 
Samples will consist of matched pre- and post-treatment FFPE biopsies. 
These analyses will be performed in coordination with NanoString® Technologies in 
Seattle, WA, and analyzed using qualified analytic tools at the immunopathology lab of 
the Fred Hutch. 
Hypotheses: The combination of Atezolizumab with CYT107 will alter the TME towards 
a pro inflammatory GEP phenotype, and distinct gene expression patterns will be 
identified that may correlate with clinical outcomes. 
 
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 T-Cell Receptor Repertoire Analysis -- TCR sequencing – Integrated Laboratory 
Correlative Study #4 
We will perform TCR sequencing where pretreatment and post-treatment biopsies are 
available. TCR repertoire analysis will be performed on RNA extracted from FFPE 
biopsies, and T cells isolated from PBMCs from the research blood collections 
throughout study participation. TCR repertoire analysis has been standardized and 
commercialized by Adaptive Biosciences. The TCR sequences will also specifically be 
queried for sequences already known to encode for TCRs reactive to shared antigens 
often expressed in urothelial transitional cell carcinoma (e.g., MAGE-A3, NY-ESO-1, 
LAGE-1, and PRAME). 
Samples will be analyzed at Adaptive Bioscience in Seattle, WA, or other agreed upon 
vendor or collaborator. 
Hypothesis: The combination of Atezolizumab with CYT107 will result in emergence 
and/or increased prevalence of specific TCR sequences reflecting the clonal expansion of 
antitumor T cells, and expansion of those specific T-cell clones in TILs (exhibited by 
higher TCR clonality) will be associated with improved response to therapy. 
 
 Tumor-Associated Neo-antigen discovery -- Whole Exome Sequencing and RNAseq and 
Antigen Prediction – Integrated Laboratory Correlative Study #5 
In order to investigate the role of T-cell–mediated immunity directed towards tumor-
specific mutant antigens, genomic sequencing and RNAseq of tumor cells from baseline 
tumor biopsy relative to non-tumor cells from whole blood (PBMC) will be performed to: 
i) identify tumor-associated neoantigens; and ii) identify the genomic variances that may 
contribute to response or disease progression and provide an understanding of molecular 
abnormalities. 
DNA and RNA will be extracted from baseline or archival FFPE tumor biopsies will be 
sequenced to identify overexpressed known “shared” tumor-associated antigens (TAAs) 
and nonsynonymous expressed mutations using available and standard-of-practice 
technologies. For example, a computational approach (BIMAS and SYFPEITHI 
algorithms) can be utilized to analyze and prioritize these mutation-derived “virtual” 
antigens in terms of their likelihood to bind to/be presented by MHC I alleles (HLA-A2, 
A3, A24). Potential antigens can be encoded in tandem minigene constructs with 
intervening P2A viral sequences to allow for equimolar expression of multiple “long” 
(~27 amino acids) peptides centered on the putative antigenic mutational sites. These 
neoantigenic libraries will be cloned into an appropriate expression vectors to allow for in 
vitro- transcription of neoantigen-encoding mRNA for use in ELISPOT assays to detect 
neoantigen immune responses. RNAseq will also identify whether common “shared” 
antigens are also expressed, including MAGE-A3, NY-ESO-1, LAGE-1, and PRAME. 
Common epitopes sequences from these shared antigens will also be transduced as above. 
Quantitation of mutation burden may also be important for urothelial carcinoma, where 
 
 
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immunogenicity and/or responses to PD-1/PD-L1 axis-directed therapies may be 
associated with a high mutation burden. 
These analyses will be performed using qualified analytes and analytic tools at the 
immunopathology lab at the Fred Hutch or at a vendor, to be determined. 
Hypothesis: Clinical outcomes will correlate with neoantigen and mutational burden. 
 
 Antitumor Immune T-cell Responses – ELISPOT – Integrated Laboratory Correlative 
Study #6 
If there are positive clinical responses, antigen-specific T-cell responses may be assessed 
by IFNγ enzyme-linked immunospot (ELISPOT) assay to provide information regarding 
the effect of the atezolizumab and CYT107 regimen on antigen-specific T-cell–functional 
antitumor responses. The ability of the investigational treatment to induce a tumor 
antigen-specific immune response will be assessed using ex vivo incubation of PBMC-
derived T cells with autologous PBMC either pulsed with peptide antigens or 
recombinant proteins representing known ongoing and nascent antitumor responses 
(PRAME, NY-ESO-1, MAGE-A3 and/or p53), or neoantigens described above. Memory 
viral responses (influenza A, CEF) will also be assessed as controls. We will quantitate 
the strength of the antigen-specific T-cell responses and compare baseline and post-
baseline T-cell responses for each putative antigen. The absolute change in ELISPOT 
responses for antigens will be compared between the SFC/million PBMC at baseline 
(before treatment initiation) and at designated time points post-treatment. 
Assays will be performed in the CITN Immune Monitory Laboratory (CIML) at the Fred 
Hutch under the direction of Dr. 
, or an agreed upon vendor or collaborator. 
Hypothesis: The combination of atezolizumab with CYT107 will result in increased T-
cell responses to known and/or neoantigens. 
 
2.6 
Exploratory/Ancillary Correlative Studies 
 Assessment of PD-L1 expression at Baseline and Post-treatment -- 
Immunohistochemistry (IHC) – Exploratory Laboratory Correlative Study #1 
PD-L1 has been identified as an important correlative biomarker for clinical response to 
anti-PD-L1 and anti-PD-1 therapies. In particular, given that the function of atezolizumab 
is to block binding of PD-1 to PD-L1, expression of PD-L1 will be quantitated by IHC in 
baseline formalin-fixed paraffin-embedded tumor specimens, and from biopsies obtained 
after treatment. This is an important part of the correlative studies to explore whether this 
marker which correlates with response in other circumstances also correlates with 
response in this protocol population. For baseline samples, formalin-fixed, paraffin-
embedded tissue block(s) from tumor obtained before treatment will be obtained by the 
clinical site either from archival samples obtained from the relevant pathology 
laboratories where they were processed and stored, or from baseline biopsy as part of this 
 
 
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protocol (core, punch, or excisional). Post-treatment, formalin-fixed paraffin-embedded 
tumor specimens will be obtained from biopsy at week 11 (core, punch, or excisional) as 
part of this protocol. 
PD-L1 expression will be tested by IHC at HistoGeneX (Naperville, IL)with the PD-L1 
SP142 clone assay, or at other agreed upon vendor. 
Hypothesis: PD-L1 expression at baseline will correlate with clinical responses to 
atezolizumab and atezolizumab in combination with CYT107. In addition, atezolizumab 
administration may alter PD-L1 expression to an unknown extent. 
 
 Evaluation of the effect of atezolizumab with and without CYT107 on circulating 
Lymphocyte and Monocyte numbers and Phenotype – Exploratory Laboratory 
Correlative Study #2 
We will assess the effects of the atezolizumab with and without CYT107 on the 
frequency and phenotypic character of PBMC subsets including dendritic cells (DCs), 
monocyte populations, T cells, NK cells, and B cells. The effect on these immune cell 
subtypes of checkpoint inhibitors, and other immune modulators is being investigated in 
other CITN trials and may provide important correlative information on the success or 
failure of combination immunotherapy. 
A 14-color whole blood immunophenotyping assay will quantify in one panel the 
absolute number and proportion of T cells (both CD8+ and CD4+), NK cells 
(CD56+CD3-), NKT cells (CD56+CD3+), B cells (CD19+/CD20+), monocytes 
(CD16+), neutrophils (CD15+), as well as both myeloid DCs (CD45+HLA-
DR+CD11c+CD123-) and plasmacytoid DCs (CD45+HLA-DR+CD11c-CD123+). In 
addition, myeloid-derived suppressor cells (MDSC) will be measured using antibodies to 
HLA-DR, CD11b, and CD33 in this same multiparameter flow cytometric assay. 
Multiparameter flow cytometry on whole blood with a 12-color panel may also be used in 
parallel to further define the phenotype of T cells and to identify activated T cells, T-cell 
subsets (including regulatory T cells). This validated panel includes the markers CD45, 
CD3, CD4, CD8, CD45RA, CD197 (CCR7), CD28, CD127, CD25, HLA-DR, CD279 
(PD-1), CD278. 
Assays will be performed under the direction of Dr. 
 in the CIML at the Fred 
Hutch. 
Hypothesis: The combination of atezolizumab with CYT107 will perturb circulating 
lymphocyte and monocyte numbers and phenotypes to a yet unknown extent. 
 
 Multiplex Cytokines -- Multiplex ELISA – Exploratory Laboratory Correlative Study #3 
Perturbations in cytokines, chemokines, and growth factors have been associated with 
cancers and changes in plasma cytokine concentrations of proinflammatory and 
immunosuppressive cytokines may correlate with clinical responses to therapy. 
Measureable changes in serum and plasma cytokines have been associated with 
checkpoint blockade therapies. Comparison of baseline plasma cytokines, chemokines 
 
 
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and growth factors to longitudinal measurements during therapy may improve our 
understanding of the immunologic effects of the combination of atezolizumab plus 
CYT107 on cancer. Furthermore, these assays will be used to explore whether reactive 
changes in cytokine levels correlates with toxicity and/or efficacy of atezolizumab and 
CYT107. Longitudinally collected plasma samples will be evaluated using commercial 
multiplex immunoassays that are quantified by immunochemiluminescence detection or 
other appropriate technology. 
Assays will be performed at the Fred Hutch Shared Resources, or at other agreed upon 
vendor. 
Hypothesis: The combination of atezolizumab with CYT107 will perturb cytokines, 
chemokines, and growth factors to a yet unknown extent. 
 
 Kynurenine and tryptophan (Kyn/Trp) ratios and plasma Arginine levels – Exploratory 
Laboratory Correlative Study #4 
Over expression of indoleamine 2,3-dioxygenase (IDO) is known to result in increases in 
the Kyn/Trp ratio in blood and within some tumor microenvironments. Increases in 
Kyn/Trp ratios result in the subsequent suppression of T-cell responses and is a major 
mechanism of immune control. IDO is expressed by some tumors, but probably more 
importantly, it is expressed by lymphocytes as a normal mechanism and important 
mechanism to dampen immune responses. Expression of IDO (with subsequent increased 
Kyn/Trp ratio) may be one likely mechanism of checkpoint blockade and other 
immunotherapy failures. Thus, we will measure Kyn/Trp ratios in plasma taken at 
baseline, during treatment, and at end of treatment in this protocol to analyze, in patients 
who have failed clinical response to Atezolizumab plus IL-7 treatment, failure may be 
associated with increased Kyn/Trp levels. 
In addition, another important mechanism of immune control and suppression is through 
the changing concentrations of arginine insofar as decreased levels of arginine in plasma 
(ie arginine depletion) is associated with decreases in CD4 and CD8 T-cell proliferation 
and Th1 functions. Arginine depletion can occur by the release by MDSCs of arginase 
which converts L-arginine to ornithine. This may be another mechanism of tumor evasion 
as myeloid suppressor cells with high arginase activity are found in tumors. Thus, we will 
also measure arginine levels in the same plasma samples taken at baseline, during 
treatment, and at end of treatment in this protocol to analyze, in patients who have failed 
clinical response to Atezolizumab plus IL-7 treatment, whether failure may be associated 
with increased arginine levels in plasma. 
All assays will be performed at an agreed upon collaborator or vendor to be determined. . 
Hypothesis: Failure to respond to atezolizumab plus CYT107 treatment may be 
associated with increased Kyn/Trp ratios and/or increased plasma arginine levels in some 
patients. 
 
 
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 Microbiome Analyses – Exploratory Laboratory Correlative Study #5 
Recent reports in preclinical mouse tumor models suggest that the gut microbiome has an 
effect on response to checkpoint blockade immunotherapy, and there is growing evidence 
that the intestinal microbiome may have major influences on antitumor immune 
responses. The microbiota has long been known to have profound effects on innate and 
adaptive immunity. However, the impact and importance of the gut microbiome in human 
cancer patients’ responses to immunotherapy has not yet been well-characterized and will 
be important to determine. To begin to understand the role of the microbiome in 
responses to immunotherapy in this protocol, we will collect microbiome samples from 
patients at baseline and perform taxonomic profiling via 16 S rRNA gene sequencing and 
metagenomic whole-genome shotgun (WGS) sequencing. Fecal samples will be collected 
and stored using standard, at home stool-collection procedures, and we will assess the 
landscape of the gut microbiome. Sequencing data will be analyzed and compared to 
clinical responses to determine whether response or nonresponse to atezolizumab plus 
CYT107 can be correlated with specific microbiota. 
Assays will be performed in collaboration with Dr. 
 at Fred Hutch or 
other agreed upon collaborator. 
Hypothesis: The gut microbiome profile will affect the clinical response to the 
combination of atezolizumab with CYT107 to a yet unknown extent. 
 
2.7 
Special Studies 
 Assessment of Immunogenicity and Pharmacokinetics  
The known and predicted activities of these two immunotherapeutic agents in enhancing 
immune responses may, in combination, influence pharmacokinetics and 
immunogenicity. In particular CYT107 is pharmacologically targeting lymphocytes and 
subject to a PK target mediated clearance (like many other blood growth factors). This is 
the case for G-CSF and other factors. We have validated methods to measure CYT107 
blood samples for PK analysis as well as to detect and measure the presence of binding 
and neutralizing antibodies. We will thus measure CYT107 blood levels before the first 
and fourth administrations of CYT107, and at specified intervals after administration of 
CYT107. This would enable detection of any potential significant interference of the 
concomitant immunotherapies on CYT107 PK. Similarly, we will measure anti-CYT107 
binding antibodies before any CYT107 administration and after the last CYT107 
administration. Any subject presenting with binding antibodies will be further tested for 
the presence of anti-CYT107 neutralizing antibodies. While the number of patients will 
be too small to draw definitive conclusions, this might lead to a potential interference in 
the combination therapy deserving a further exploration. 
 
 
 
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3. 
PATIENT SELECTION 
3.1 
Eligibility Criteria 
 Patients must have histologically or cytologically documented locally 
advanced/inoperable or metastatic UBC, including renal pelvis, ureters, urinary bladder, 
and urethra. 
Note: Mixed histology tumors allowed if predominant histology is urothelial carcinoma. 
Note: Small cell or neuroendocrine carcinoma is not allowed if predominant. 
 Patients must have recurrent disease after any prior platinum-based chemotherapy 
regimen.  
 Patients must have measurable disease per RECIST 1.1 assessed by computed 
tomography (CT) scan or MRI. See Section 11 for the evaluation of measurable disease. 
 Patients must be ≥18 years of age on day of signing informed consent document. 
Because no dosing or adverse event data are currently available on the use of 
atezolizumab in combination with CYT107 in patients <18 years of age, children are 
excluded from this study, but will be eligible for future pediatric trials. 
 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 Patients must have a life expectancy of greater or equal to 12 weeks 
 Patients must have normal organ and marrow function as defined below: 
– leukocytes 
≥2,500/mcL 
– absolute neutrophil count 
≥1,000/mcL 
– platelets 
≥100,000/mcL 
– hemoglobin 
≥8 g/dL 
– total bilirubin 
≤1.5 × institutional upper limit of normal (ULN) 
(however, patients with known Gilbert’s disease 
who have serum bilirubin level ≤3 × ULN may 
be enrolled) 
– AST(SGOT)/ALT(SGPT) 
≤3 × ULN (AST and/or ALT ≤5 × ULN for 
patients with liver involvement) 
– alkaline phosphatase  
≤2.5 × ULN (≤5 x ULN for patients with 
documented liver involvement or bone 
metastases) 
– creatinine clearance 
≥30 mL/min/1.73 m2 by Cockcroft-Gault: 
 
(140 − age) × (weight in kg) × (0.85 if female) 
72 × (serum creatinine in mg/dL) 
 
 
 
 
 
 
 
 
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At the discretion of the treating physician, a 24-
hour urine creatinine clearance could be obtained 
and utilized as the gold standard if creatinine 
clearance by Cockcroft-Gault is <30, and 
prevents patient enrollment on the trial. 
 
– INR and aPTT 
≤1.5 × ULN (This applies only to patients who 
do not receive therapeutic anticoagulation; 
patients receiving therapeutic anticoagulation, 
such as low-molecular-weight heparin or 
warfarin, should be on a stable dose.) 
 Patients must provide tissue from an archival tumor sample (obtained within 2 years from 
screening visit) or newly obtained core, punch, or excisional biopsy of a tumor lesion if 
deemed relatively safe and technically feasible. 
 Female patients of childbearing potential must have a negative urine or serum pregnancy 
test within 72 hours before receiving the first dose of study agent(s). If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
Administration of atezolizumab may have an adverse effect on pregnancy and poses a 
risk to the human fetus, including embryo-lethality. CYT107 has not been tested for 
reproductive toxicity yet and may expose to the same risk. Women of child-bearing 
potential and men must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) before study entry, for the duration of study participation, 
and for 5 months (150 days) after the last dose of study agent. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, 
she should inform her treating physician immediately. 
 Patients must have the ability to understand and the willingness to sign a written 
informed consent document. 
 Patients positive for HIV are allowed on study, but HIV-positive patients must have: 
a. A stable regimen of HAART 
b. No requirement for concurrent antibiotics or antifungal agents for the prevention 
of opportunistic infections 
c. A CD4 count above 250 cells/mcL and an undetectable HIV viral load on 
standard PCR-based tests 
 
 
 
 
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3.2 
Exclusion Criteria 
 Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
 Patients who have had chemotherapy or radiotherapy within 2 weeks (4 weeks for 
nitrosoureas or systemic mitomycin C) before the initiation of study treatment. 
 Patients who have received more than 2 systemic cytotoxic chemotherapy regimens for 
metastatic urothelial carcinoma. 
Note: Prior perioperative chemotherapy is allowed and is not counted as a line of therapy 
if patient relapsed ≥12 months later and received additional platinum-based 
chemotherapy for metastatic disease. 
 Patients who have not recovered from adverse events (other than alopecia) due to agents 
administered more than 4 weeks earlier (i.e., have residual toxicities >Grade 1). 
However, the following therapies are allowed: 
• 
Hormone-replacement therapy or oral contraceptives 
• 
Herbal therapy ≥1 week before initiation of study treatment (herbal therapy intended 
as anticancer therapy must be discontinued at least 1 week before initiation of study 
treatment) 
• 
Palliative radiotherapy for bone metastases >2 weeks before initiation of study 
treatment 
 Patients who have received prior treatment with anti-PD-1, or anti-PD-L1 therapeutic 
antibody, or pathway-targeting agents. 
• 
Patients who have received prior treatment with anti-CTLA-4 may be enrolled, 
provided the following requirements are met: 
– Minimum of 12 weeks from the first dose of anti-CTLA-4 and >6 weeks from 
the last dose 
– No history of severe immune-related adverse effects from anti-CTLA-4 (NCI 
CTCAE Grade 3 and 4) 
 Patients who have received treatment with any other investigational agent within 4 weeks 
before initiation of study treatment. 
 Patients who have received treatment with systemic immunostimulatory agents 
(including, but not limited to, interferon [IFN]-α or interleukin [IL]-2) within 6 weeks 
before initiation of study treatment. 
 Patients who have received treatment with systemic immunosuppressive medications 
(including, but not limited to, oral prednisone (>10 mg/day or equivalent), 
cyclophosphamide, azathioprine, methotrexate, thalidomide, and antitumor necrosis 
factor [anti-TNF] agents) within 2 weeks before initiation of study treatment. 
• 
Patients who have received acute, low dose, systemic immunosuppressant 
 
 
 
 
 
 
 
 
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medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled. 
• 
The use of inhaled corticosteroids, and mineralocorticoids (e.g., fludrocortisone) for 
patients with orthostatic hypotension or adrenocortical insufficiency is allowed. 
 Patients taking bisphosphonate therapy for symptomatic hypercalcemia. 
Note: Use of bisphosphonate therapy for other reasons (e.g., bone metastasis or 
osteoporosis) is allowed. 
 Patients with known primary central nervous system (CNS) malignancy or symptomatic 
CNS metastases are excluded, with the following exceptions: 
• 
Patients with asymptomatic untreated CNS disease may be enrolled, provided all of 
the following criteria are met: 
– Evaluable or measurable disease outside the CNS 
– No metastases to brain stem, midbrain, pons, medulla, cerebellum, or within 
10 mm of the optic apparatus (optic nerves and chiasm) 
– No history of intracranial hemorrhage or spinal cord hemorrhage 
– No ongoing requirement for dexamethasone for CNS disease; patients on a 
stable dose of anticonvulsants are permitted. 
– No neurosurgical resection or brain biopsy within 28 days before initiation of 
study treatment 
• 
Patients with asymptomatic treated CNS metastases may be enrolled, provided all the 
criteria listed above are met as well as the following: 
– Radiographic demonstration of improvement upon the completion of CNS 
directed therapy and no evidence of interim progression between the 
completion of CNS directed therapy and the screening radiographic study 
– No stereotactic radiation or whole-brain radiation within 28 days before 
initiation of study treatment 
– Screening CNS radiographic study ≥4 weeks from completion of radiotherapy 
and ≥2 weeks from discontinuation of corticosteroids 
Note: Patients with CNS metastases enrolled on trial must also have a brain MRI 
imaging at all standard radiologic evaluation timepoints (refer to Section 10) 
 Patients with known hypersensitivity to Chinese hamster ovary cell products or other 
recombinant human antibodies. 
 Patients who have a history of severe allergic, anaphylactic, or other hypersensitivity 
reactions to chimeric or humanized antibodies or fusion proteins 
 Patients with known clinically significant liver disease, including active viral, alcoholic, 
or other hepatitis; cirrhosis; fatty liver/NAFLD/NASH; and inherited liver disease. 
• 
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 
 
 
 
 
 
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hepatitis B core antigen] antibody test) are eligible. 
• 
Patients positive for HCV antibody are eligible only if polymerase chain reaction 
(PCR) is negative for HCV RNA. 
 Patients with active underlying autoimmune disease requiring systemic 
immunosuppressive medication (oral prednisone >10 mg/day or equivalent). Topical, 
inhaled, or intraarticular steroids or physiologic endocrine replacement (insulin, 
levothyroxine, etc.) are permitted. Patients with a history of autoimmune disease that is 
not currently active require consultation with the Protocol PI and/or CITN Coordinating 
Center.  
 
 
 
 
 Patients who have a history of idiopathic pulmonary fibrosis, pneumonitis (including 
drug induced), organizing pneumonia (bronchiolitis obliterans, cryptogenic organizing 
pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan. History 
of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 Patients who have known additional malignancies other than UBC within 2 years before 
initiation of study treatment. 
Exceptions include malignancies with a negligible risk of metastasis or death and treated 
with expected curative outcome (e.g., non–melanomatous skin cancers), or localized 
prostate cancer treated with curative intent and absence of prostate-specific antigen 
(PSA) relapse or incidental prostate cancer. 
 Patients with active tuberculosis (TB). 
 Patients who have leptomeningeal disease. 
 Patients who have severe infections within 4 weeks before initiation of study treatment, 
including, but not limited to, hospitalization for complications of infection, bacteremia, or 
severe pneumonia. 
Exception: Uncomplicated urinary tract infection will not be considered as a severe 
infection in these patients.  
 Patients who have signs or symptoms of infection within 2 weeks before initiation of 
study treatment. 
 Patients who have received oral or IV antibiotics within 2 weeks before initiation of study 
treatment. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary 
tract infection or chronic obstructive pulmonary disease) are eligible. 
 Patients who have major surgical procedure, other than for diagnosis, within 28 days 
before initiation of study treatment or anticipation of need for a major surgical procedure 
 
 
 
 
 
 
 
 
 
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during the course of the study. 
 Patients who have had a live, attenuated vaccine within 4 weeks before initiation of study 
treatment or anticipation that such a live, attenuated vaccine will be required during the 
study and up to 5 months after the last dose of atezolizumab. 
• 
Influenza vaccination should be given during influenza season only (approximately 
October to March). Patients must not receive live, attenuated influenza vaccine within 
4 weeks before initiation of study treatment or at any time during the study. 
 Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive 
heart failure (New York Heart Association Class III or IV), unstable angina pectoris, 
cardiac arrhythmia, recent myocardial infarction (within the last 6 months), or psychiatric 
illness/social situations that would limit compliance with study requirements. 
 Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for 
treatment of either a psychiatric or medical (e.g., infectious) illness. 
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
4. 
REGISTRATION PROCEDURES 
4.1 
Investigator and Research Associate Registration with CTEP 
 CTEP Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all investigators participating in any NCI-sponsored clinical trial to register 
and to renew their registration annually. To register, all individuals must obtain a Cancer 
Therapy Evaluation Program (CTEP) Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).  
RCR utilizes five person registration types. 
• IVR — MD, DO, or international equivalent; 
• NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
• AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System [RUMS], OPEN, Rave, 
acting as a primary site contact, or with consenting privileges; 
• Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
 
 
 
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continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory Office 
following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet (SSW) 
for Local Context to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to 
the CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory 
Office at CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be addressed 
to the CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• Holds an active CTEP status; 
• Active status at the site(s) on the IRB/REB approval (applies to US and Canadian 
sites only) on at least one participating organization’s roster; 
• If using NCI CIRB, active on the NCI CIRB roster under the applicable CIRB 
Signatory Institution(s) record; 
• Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile;  
• Lists all sites on the IRB/REB approval as Practice Sites in the Form FDA 1572 in the 
RCR profile; and 
• Holds the appropriate CTEP registration type for the protocol.  
Additional Requirements 
Additional site requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
participating organization (PO); and 
• 
An active roster affiliation with the NCI CIRB roster under at least one CIRB 
Signatory Institution (US sites only); and 
• 
Compliance with all protocol-specific requirements (PSRs). 
 Downloading Site Registration Documents 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted to the institutions and its associated investigators and 
staff on a participating roster. To view/download site registration forms:  
 
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• 
Log in to the CTSU members’ website (https://www.ctsu.org) using your CTEP-IAM 
username and password; 
• 
Click on Protocols in the upper left of your screen; 
• 
Either enter the protocol number in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand, then select CITN, and protocol 
CITN-14. 
• 
Click on Documents, Protocol Related Documents, and use the Document Type filter and 
select Site Registration to download and complete the forms provided. (Note: For 
sites under the CIRB, IRB data will load automatically to the CTSU.)  
 
 Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU members’ website.  
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately by phone or email: 1-866-651-
CTSU (2878), or CTSURegHelp@coccg.org in order to receive further instruction and 
support. 
 Checking Site Registration Status 
Site registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of your screen; 
• 
Click on Site Registration; and  
• 
Enter your 5-character CTEP Institution Code and click on Go; 
o Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling investigator’s 
status with the NCI or their affiliated networks. 
4.3 
Delegation of Tasks Log (DTL) 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using the 
DTL application in the Delegation Log section on the CTSU members’ website. The 
Clinical Investigator (CI) is required to review and electronically sign the DTL prior to 
the site receiving an approved site registration status and enrolling patients to the study. 
To maintain an approved site registration status the CI must re-sign the DTL at least 
annually and when a new version of the DTL is released; and to activate new task 
 
 
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assignments requiring CI sign-off. Any individual at the enrolling site on a participating 
roster may initiate the site DTL. Once the DTL is submitted for CI approval, only the 
designated DTL Administrators or the CI may update the DTL. Instructions on 
completing the DTL are available in the Help Topics button in the DTL application and 
include a Master Task List, which describes DTL task assignments, CI signature, and 
CTEP registration requirements. 
 
4.4 
Patient Enrollment 
 OPEN 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available to users on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster 
data and with the LPOs registration/randomization systems or the Theradex Interactive 
Web Response System (IWRS) for retrieval of patient registration/randomization 
assignment. OPEN will populate the patient enrollment data in NCI’s clinical data 
management system, Medidata Rave.  
Requirements for OPEN access:   
• A valid CTEP-IAM account; 
• To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role of 
Registrar. Registrars must hold a minimum of an Associate Plus (AP) registration 
type; 
• If a Delegation of Tasks Log (DTL) is required for the study, the registrars must hold 
the OPEN Registrar task on the DTL for the site; and 
• Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
Before accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
• 
All patients have signed an appropriate consent form and Health Insurance Portability 
and Accountability Act (HIPAA) authorization form (if applicable). 
Note: The OPEN system will provide the site with a printable confirmation of registration 
and treatment information. Please print this confirmation for your records. 
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU member’s 
website. Further instructional information is on the OPEN section of the CTSU website at 
 
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https://www.ctsu.org or at https://open.ctsu.org. For any additional questions contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
Patient enrollment for this study will be facilitated using the Slot Reservation System in 
conjunction with the registration system in OPEN. Prior to discussing protocol entry with 
the patient, all site staff must use the CTSU OPEN Slot Reservation System to ensure that 
a slot on the protocol is available to the patient. Once a slot reservation confirmation is 
obtained, site staff may then proceed to enroll the patient to this study.  
 
4.5 
General Guidelines 
After registration, patients should begin protocol treatment within 5 business days. Issues that 
would cause treatment delays should be discussed with the PI. If a patient does not receive 
protocol therapy after registration, the patient’s registration on the study may be canceled. The 
Clinical Research Site (CRS) must notify the CITN Coordinating Center of cancellations as soon 
as possible. 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
agents directly from CTEP. 
5. 
TREATMENT PLAN 
This is a phase II trial of atezolizumab (MPDL3280A) plus recombinant human IL-7 (CYT107) 
in patients with locally advanced or metastatic urothelial carcinoma. The trial follows a 
randomized, controlled trial design, with an initial ‘Safety Run-In’ phase designed to evaluate 
the acute safety profile of the investigational treatment combination. 
During the Safety Run-In phase, 6 patients will be assigned to the experimental arm 
(atezolizumab + CYT107) with staggered enrollment. This will be accomplished with an initial 3 
patient enrollment. All adverse events will be assessed by the Toxicity Evaluation Committee. If 
0-1 patient experiences a protocol-defined DLT (refer to Section 5.2) after completion of the 4-
week DLT window, an additional 3 patients will be enrolled. Once all 6 patients have completed 
the 4-week DLT window, the Toxicity Evaluation Committee will again assess all adverse 
events. If, at any time, 2 or more patients experience a protocol-defined DLT, further enrollment 
into the trial will be suspended. 
If the treatment combination of the experimental arm demonstrates an acceptable safety profile 
in the Safety Run-In (one or fewer patient experiences a protocol-defined DLT), randomized 
enrollment into the trial will begin. 
Patients will be randomly assigned to either the control arm (atezolizumab monotherapy) or 
experimental arm (atezolizumab + CYT107) of the trial.  
The first 6 subjects enrolled in the run-in phase of the study will have PK sampling done at 
baseline (prior to CYT107 administration), and at week 4 prior to CYT107 administration and at 
2 hours, 4 hours and 6 hours after the fourth CYT107 administration. 
Anti-drug antibody testing (ADA testing) will be done on all subjects who receive CYT107. 
Testing will be done at baseline (prior to CYT107 administration) and at week 8, (1 month after 
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For anaphylaxis precautions, see the management guidelines below. Atezolizumab 
infusions will be administered per the instructions outlined in the Table below. 
First Infusion 
Subsequent Infusions 
• 
No premedication is permitted prior to the 
atezolizumab infusion. 
• 
Vital signs (pulse rate, respiratory rate, blood 
pressure, and temperature) should be measured 
within 60 minutes prior to the infusion. 
• 
Atezolizumab should be infused over 60 (±15) 
minutes. 
• 
If clinically indicated, vital signs should be 
measured every 15 (±5) minutes during the 
infusion and at 30 (±10) minutes after the 
infusion. 
• 
Patients should be informed about the 
possibility of delayed post-infusion symptoms 
and instructed to contact their study physician if 
they develop such symptoms. 
• 
If the patient experienced an infusion−related 
reaction with any previous infusion, 
premedication with antihistamines, 
antipyretics, and/or analgesics may be 
administered for subsequent doses at the 
discretion of the investigator. 
• 
Vital signs should be measured within 
60 minutes prior to the infusion. 
• 
Atezolizumab should be infused over 
30 (±10) minutes if the previous infusion was 
tolerated without an infusion-related reaction, 
or 60 (±15) minutes if the patient experienced 
an infusion-related reaction with the previous 
infusion. 
• 
If the patient experienced an infusion−related 
reaction with the previous infusion or if 
clinically indicated, vital signs should be 
measured during the infusion and at 
30 (± 10) minutes after the infusion. 
 
For anaphylaxis precautions, use the following procedure: 
 
Equipment Needed 
• 
Monitoring devices: ECG monitor, blood pressure monitor, oxygen saturation 
monitor, and thermometer 
• 
Oxygen 
• 
Epinephrine for subcutaneous, IV, intramuscular, 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 atezolizumab infusion, the 
following procedures should be performed: 
• 
Stop the study drug infusion. 
• 
Call for additional medical assistance. 
• 
Maintain an adequate airway. 
• 
Ensure that appropriate monitoring is in place, with continuous ECG and pulse 
oximetry monitoring, if possible. 
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• 
Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge. 
• 
Continue to observe the patient and document observation. 
All patients randomly assigned to the experimental treatment arm in Part 2 will also 
receive CYT107 in addition to atezolizumab. 
 Recombinant Human IL-7 (CYT107) 
Patients enrolled in the Safety Run-in phase and patients randomly assigned to the 
experimental arm of the trial will receive recombinant human IL-7 (CYT107). The 
patients will receive 10 mcg/kg of IL-7 (CYT107) IM on days 1, 8, 15 and 22 of Cycle 1 
only. The CYT107 dose must be administered before atezolizumab on Day 8 of Cycle 1.  
For patient with a Body Mass Index (BMI) >30, an adjusted body weight will be used to 
calculate the final dose the patient will receive. Please refer to Appendix D for details on 
the adjusted body weight calculation. 
Patients receiving CYT107 will have their vital signs (heart rate, respiratory rate, blood 
pressure, and temperature) determined within 60 minutes before the first CYT107 
injection on day 1, and 2 hours (±15 minutes) after the injection. 
On day 8, vital signs will be monitored as described above (Section 5.1.1) following the 
guidelines for the first atezolizumab infusion. 
On days 15 and 22, vital signs will be determined within 60 minutes before and within 30 
minutes after the injection.  
Patients will be informed about the possibility of the development of an allergic reaction 
to CYT107 (hives, bronchospasm, rash, etc.) and instructed to contact their study 
physician if they develop such symptoms. 
 Other Procedures: Biopsy (core needle, punch or excisional) 
The rationale for the biopsy/tissue collection is to investigate changes in the tumor 
microenvironment that may correlate with response or provide information on potential 
actionable causes for lack of benefit.  
A pre-treatment biopsy/tissue collection will be obtained before the first dose of study 
treatment (atezolizumab or CYT107) assuming this can be carried out safely. 
Note: If an archival tumor sample (at least 0.5 × 0.5 × 0.5 cm) obtained within 2 years 
from screening visit is available, the pre-treatment biopsy is not required.  
A post-treatment tumor biopsy/tissue collection will be obtained if deemed relatively safe 
and technically feasible (core biopsy, punch biopsy or excisional biopsy). The tumor 
biopsy/tissue collection will be obtained prior to dosing on Cycle 4, Day 1or at the end of 
treatment visit, whichever occurs first.  
 
 
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The biopsies will be done according to clinical site Standard Operating Procedures 
(SOPs). 
 Other procedures:  Microbiome Sample Collection 
Pre-treatment and post-treatment microbiome samples will be collected by patients using 
standard, at home stool-collection procedures using standardized fecal swab/storage 
devices. The samples will be stored frozen at home by patient and returned to the clinical 
research site at their next study visit.    
Patients will be provided with fecal swab/storage devices and instructions (refer to 
Appendix E) at the screening visit and at the Cycle 3, Day 1 visit.  
5.2 
Safety Run-in: Definition of Dose-Limiting Toxicity 
Dose-limiting toxicity is defined as any adverse event (AE) occurring within the first 28 days 
(i.e., from Week 1 Day 1 through Week 4 Day 7), that is considered to be at least possibly 
related to the protocol treatment (atezolizumab, CYT107 or both), and that meets at least one of 
the non-hematologic or hematologic criteria below: 
 Hematologic toxicity 
The standard NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 
criteria will be replaced by these criteria: 
 
• 
Any Grade 4 event, including laboratory electrolyte abnormalities, that is not easily 
reversed without sequelae 
• 
Grade 4 neutropenia (Absolute Neutrophil Count (ANC) <0.5 × 109/L) 
• 
Grade 3 febrile neutropenia (ANC <1.0 × 109/L with a fever ≥38.3ºC) 
• 
Grade 4 thrombocytopenia (<25.0 × 109/L) lasting >4 days or that requires platelet 
transfusion 
• 
Grade ≥3 thrombocytopenia (<50.0–25.0 × 109/L) associated with Grade ≥3 bleeding 
• 
Grade 2 concurrent AST or ALT >3xULN and total bilirubin > 2xULN without 
evidence of cholestasis  
• 
Any toxicity resulting in death (i.e., Grade 5) 
Note: Peripheral lymphocytopenia after the first CYT107 injection is not a sign of 
toxicity; it reflects the lymphocytes “homing effect” of rhIL-7. Lymphocyte counts 
usually come back to baseline 5 to 7 days after the first injection. 
 Non-hematologic toxicity 
Any Grade ≥3 non-hematologic toxicity (CTCAE v5.0), except for the following, which 
will not constitute DLTs: 
• 
Grade ≥3 nausea or vomiting lasting ≤72 hours with the use of adequate/maximal 
medical intervention and/or prophylaxis 
 
 
 
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• 
Grade 3 diarrhea lasting ≤72 hours with the use of adequate/maximal medical 
intervention and/or prophylaxis 
• 
Grade 3 fatigue lasting ≤7 days 
• 
Grade 3 injection site reaction (unless operative intervention is required) 
• 
Grade 3 hyperglycemia lasting ≤72 hours with standard antidiabetic therapy 
• 
Grade 3 increases in liver transaminases (>5.0–20.0 × ULN) in patient with liver 
metastases 
• 
Clinical laboratory abnormalities that are reversible to ≤Grade 1 or baseline status 
within 72 hours with outpatient care and/or monitoring, or that are considered not 
clinically significant by the treating physician 
Management and dose modifications associated with the above AEs are outlined in 
Section 6. 
The AEs will be assessed by the Toxicity Evaluation Committee, which includes the 
PI(s), study sponsor(s), CTEP and the CITN Central Operating and Statistical Center 
(COSC).  
The patients must complete the full 4-week DLT window to be considered evaluable for 
DLTs. Patients who discontinue from the study before completion of the full 4-week 
DLT window for reasons other than the occurrence of a DLT (e.g., withdrawal of 
consent, rapid tumor progression, death due to rapid tumor progression, AE that does not 
meet DLT criteria) will not be considered evaluable for DLTs and will be replaced. 
All randomly assigned patients will be monitored for occurrence of DLT. Monitoring of 
all safety and toxicity data is done by the PI, the study Sponsor(s) and the CITN COSC 
on a real-time basis as data are entered into Medidata Rave using the Web Reporting 
Module. All participating sites must notify the PI and CITN COSC when a DLT has 
occurred. 
A delay due to toxicity in receiving the second cycle of therapy of >14 days will be 
considered a DLT in subjects enrolled in the safety run-in phase of the study. This does 
not apply to subsequent subjects enrolled in the randomized component of the study. 
5.3 
General Concomitant Medication and Supportive Care Guidelines 
Because there is a potential for interaction of Atezolizumab and CYT107 with other 
concomitantly administered drugs, the case report form must capture the concurrent use of all 
other drugs, over-the-counter medications, or alternative therapies. The PI should be alerted if 
the patient is taking any agent known to affect or with the potential for drug interactions. The 
study team should check a frequently updated medical reference for a list of drugs to avoid or 
minimize use of.  
Atezolizumab General Concomitant Medication Guidelines 
Concomitant therapy includes any prescription medications or over-the-counter 
preparations used by a patient between the 7 days preceding the baseline evaluation and 
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the treatment discontinuation visit. 
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 
receptor antagonist, as per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice). Serious infusion-associated 
events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation, or respiratory distress should be managed with supportive 
therapies as clinically indicated (e.g., supplemental oxygen and β2-adrenergic agonists; 
see Section 5.1.1). 
Systemic corticosteroids and TNFα 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. Megestrol administered as appetite stimulant is acceptable while the patient is 
enrolled in the study. 
Patients who use oral contraceptives, hormone-replacement therapy, prophylactic or 
therapeutic anticoagulation therapy (such as low-molecular-weight heparin or warfarin at 
a stable dose level) should continue their use. Males and females of reproductive 
potential should use highly effective means of contraception. 
 Atezolizumab Excluded Therapies 
Any concomitant therapy intended for the treatment of cancer, whether health authority 
approved or experimental, is prohibited unless it is specifically included in the treatment 
regimen described in this protocol. This includes but is not limited to the following: 
• 
Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy (except for maintenance therapies outlined in Section 5.3.1). 
– 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. 
• 
Herbal therapy intended as anticancer therapy must be discontinued ≥1 week before 
initiation of study treatment; 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. 
Initiation or increased dose of granulocyte colony stimulating factors (e.g., granulocyte 
colony stimulating factor, granulocyte/macrophage colony stimulating factor, and/or 
pegfilgrastim) is prohibited. 
 
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Patients are not allowed to receive immunostimulatory agents, including, but not limited 
to, IFN-α, IFN-γ, or IL-2, during the entire study. These agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions. 
Patients should also 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. 
 Recombinant Human IL-7 (CYT107) 
The excluded therapies listed above (Section 5.3.1) also apply to CYT107. 
Immunostimulatory and immunosuppressive agents are prohibited.  
Topical corticosteroids to treat injection site reaction are allowed. 
Studies performed to investigate the potential of CYT107 to inhibit or to act as a time 
dependent inhibitor of hepatic microsomal cytochrome P450 isozymes (see Investigator 
Brochure) concluded that at the concentration investigated, it is unlikely that CYT107 
will be involved in drug-drug interactions and CYT107 is not expected to cause clinically 
significant P450 inhibition or induction. However, the case report form (CRF) must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies including vitamins and nutritional supplements. 
5.4 
Duration of Therapy 
In the absence of treatment delays due to AE(s), treatment may continue for up to 2 years or until 
one of the following criteria applies: 
 
• 
Disease progression warranting alternative systemic therapy, 
Note: Patients with radiographic progressive disease (PD) who are otherwise stable 
without symptomatic progression may continue Atezolizumab until the next radiographic 
imaging time point (within 9 weeks) to assess for possible pseudoprogression. 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable AE(s), 
• 
Patient decides to withdraw from the study, 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator, 
• 
Patient noncompliance, 
• 
Dosing interruption lasting >12 weeks (see Section 6.1.1), 
• 
Pregnancy 
– All women of child-bearing potential should be instructed to contact the 
investigator immediately if they suspect they might be pregnant (e.g., missed 
or late menstrual period) at any time during study participation. 
– The investigator must immediately notify CTEP in the event of a confirmed 
pregnancy in a patient participating in the study. 
 
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• 
Termination of the study by sponsor(s), or 
• 
The drug manufacturer can no longer provide the study agent 
The reason(s) for protocol therapy discontinuation, the reason(s) for study removal, and the 
corresponding dates must be documented in the CRF. 
All patients who tolerate the protocol regimen and with either complete tumor response (CR), 
partial response (PR), or stable disease (SD) will be permitted to continue treatment with 
atezolizumab until confirmed disease progression or for up to 2 years. 
Discontinuation of treatment may be considered, at the discretion of the treating physician, for 
patients who have attained a confirmed CR that have been treated for at least 24 weeks with 
atezolizumab and had at least 2 treatments beyond the date when the initial CR was declared. 
5.5 
Study Treatment beyond Disease Progression 
Immunotherapeutic agents such as atezolizumab may produce antitumor effects by potentiating 
endogenous cancer-specific immune responses. The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents and 
can manifest as a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
Patients with radiographic PD who are otherwise stable without symptomatic progression may 
continue trial treatment as long as they meet the following criteria (following consultation with 
Protocol PI and/or CITN Coordinating Center): 
 
• 
Investigator-assessed clinical benefit 
• 
Tolerance of study treatment 
• 
Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression 
• 
No decline in ECOG performance status 
• 
Absence of rapid progression of disease or threat to vital organs 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention 
Patients should remain on the trial and continue to receive monitoring according to the Study 
Calendar (Section 10).  
5.6 
Duration of Follow-Up 
The active study will end when the last patient reaches 2 years. 
Disease status and overall survival data will be collected and reported every 12 weeks, either by 
in-person visit or by telephone assessment. 
Upon discontinuation of study treatment in patients without documented progression, every 
effort should be made to continue monitoring disease status by radiologic imaging at the 
investigative site or locally. Imaging will be collected and evaluated per RECIST 1.1. Patients 
will be followed for disease assessment for up to 2 years after discontinuation of study treatment.  
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Standard of care disease assessments will be collected until disease progression, start of new 
anticancer treatment, death or end of study, whichever occurs first.  
After disease progression or start of new anticancer treatment, patient will be followed for 
overall survival only. Survival follow-up will continue until death or the end of the study, 
whichever occurs first.   
Patients removed from study for unacceptable AE(s) will be followed until resolution or 
stabilization of the AE; in addition, the patients will be followed for disease status and overall 
survival, as described above.  
5.7 
Patient Replacement 
All randomly assigned patients who receive at least one dose of the investigational treatment will 
be considered evaluable for safety and included in the overall safety analysis. 
During the Safety Run-in Phase, patients who discontinue from the study before completion of 
the full 4-week DLT window for reasons other than the occurrence of a DLT (e.g., withdrawal of 
consent, rapid tumor progression, death due to rapid tumor progression, AE that does not meet 
DLT criteria) will not be considered evaluable for DLTs and will be replaced. 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
The NCI CTCAE Version 5.0 will be used to grade AEs. Patients enrolled in this study will be 
evaluated clinically and with standard laboratory tests before and at regular intervals during their 
participation in this study as specified in this section. 
Patients will be evaluated for AEs (all grades), serious AEs, and AEs requiring study drug 
interruption or discontinuation at each study visit for the duration of their participation in the 
study. 
6.1 
Atezolizumab (MPDL3280A) 
 General AE Management and Dose Modification Guidelines 
There will be no dose reduction for atezolizumab in this study. 
Patients may temporarily suspend study treatment for up to 84 days (12 weeks) 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 efficacy as specified in this protocol. If the AE resolves 
within 84 days and the patient is receiving corticosteroid therapy for the event, 
atezolizumab may be held for longer than 84 days (up to 4 weeks) in order to allow 
tapering of the steroid dose to ≤10 mg oral prednisone or equivalent. 
Dose interruptions for reasons other than toxicity, such as surgical procedures, may be 
allowed. The acceptable length of interruption will be at the discretion of the study PI in 
consultation with CTEP. 
 
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For detailed information regarding management of AEs associated with atezolizumab, 
please refer to the most current version of the Atezolizumab Investigator’s Brochure and 
the FDA product label. 
The primary approach to grade 1 to 2 irAEs is supportive and symptomatic care with 
continued treatment with atezolizumab; for higher-grade irAEs, atezolizumab should be 
withheld and oral and/or parenteral steroids administered. Recurrent grade 2 irAEs may 
also mandate withholding atezolizumab or the use of steroids. Assessment of the benefit-
risk balance should be made by the investigator, with consideration of the totality of 
information as it pertains to the nature of the toxicity and the degree of clinical benefit a 
given patient may be experiencing before further administration of atezolizumab. 
Atezolizumab should be permanently discontinued in patients with life-threatening irAEs. 
Patients should be assessed clinically (including review of laboratory values) for toxicity 
before, 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 Specific AEs 
Management of certain AEs of concern, including immune-related pneumonitis, hepatitis, 
colitis, endocrinopathies, pancreatitis, neuropathies, meningoencephalitis, and potential 
ocular toxicities are presented in the Atezolizumab Investigator’s Brochure. See Section 
5.1.1, including the ‘Administration of First and Subsequent Atezolizumab 
Infusions’ table for guidelines for the management of Infusion-Related Reactions and 
Anaphylaxis. 
Atezolizumab has been associated with risks such as the following: IRRs and 
immune−related hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, hypophysitis, Guillain-Barré 
syndrome, myasthenic syndrome or myasthenia gravis, meningoencephalitis, 
myocarditis, nephritis, myositis, and severe cutaneous adverse reactions. Immune-
mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis and macrophage activation syndrome. 
6.1.2.1 
Pulmonary events 
 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been associated 
with the administration of atezolizumab. Patients will be assessed for pulmonary signs and 
symptoms throughout the study and will have computed tomography (CT) scans of the chest 
performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension. Management 
guidelines for pulmonary events are provided in the table below. 
 
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Event 
Management 
Pulmonary event, 
Grade 1 
• 
Continue atezolizumab and monitor closely. 
• 
Re-evaluate on serial imaging. 
• 
Consider patient referral to pulmonary specialist. 
• 
For Grade 1 pneumonitis, consider withholding atezolizumab. 
Pulmonary event, 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• 
For recurrent events, or events with no improvement after 48–72 hours 
of corticosteroids, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab. c 
• 
Bronchoscopy or BAL is recommended. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
BAL  =  bronchoscopic alveolar lavage. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or 
appropriate delegate). 
6.1.2.2 
Hepatic events 
 
Immune-mediated hepatitis has been associated with the administration of atezolizumab.  
Patients eligible for study treatment must have adequate liver function, as manifested by 
measurements of total bilirubin and hepatic transaminases, and liver function will be monitored 
throughout study treatment.  Management guidelines for hepatic events are provided in the table 
below. 
 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting should 
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Event 
Management 
AST/ALT is within 
normal limits 
at baseline and 
increases to 
>3×ULN to 
≤10×ULN 
or 
AST/ALT is >ULN 
to ≤3×ULN 
at baseline and 
increases to 
>5×ULN to 
≤10×ULN 
or 
AST/ALT is 
>3×ULN to 
≤5×ULN at baseline 
and increases to 
>8×ULN to 
≤10×ULN 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Monitor LFTs more frequently until return to baseline values. 
• 
For events of > 5 days' duration, consider initiating treatment 
with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone. 
• 
If event resolves to baseline or to Grade 1 or better, resume 
atezolizumab. b 
• 
If event does not resolve to baseline or to Grade 1 or better 
while withholding atezolizumab, permanently discontinue 
atezolizumab. c 
AST or ALT 
increases to 
> 10 × ULN or total 
bilirubin increases to 
> 3× ULN 
• 
Permanently discontinue atezolizumab. c 
• 
Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
• 
Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day oral prednisone. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to baseline, taper corticosteroids over ≥1 
month. 
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Event 
Management 
LFT  =  liver function test. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) 
to allow for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral 
prednisone.  The acceptable length of the extended period of time must be based on an 
assessment of benefit−risk by the investigator and in alignment with the protocol requirements 
for the duration of treatment and documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥ 1 month to the equivalent 
of ≤10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re−challenge patients with 
atezolizumab should be based on investigator's assessment of benefit−risk and documented by 
the investigator (or an appropriate delegate). 
6.1.2.3 
Gastrointestinal events 
 
Immune-mediated colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in the table below. 
 
All events of diarrhea or colitis should be thoroughly evaluated for other more common 
etiologies.  For events of significant duration or magnitude or associated with signs of systemic 
inflammation or acute-phase reactants (e.g., increased C-reactive protein, platelet count, or 
bandemia): Perform sigmoidoscopy (or colonoscopy, if appropriate) with colonic biopsy, with 
three to five specimens for standard paraffin block to check for inflammation and lymphocytic 
infiltrates to confirm colitis diagnosis.  
 
Event 
Management 
Diarrhea or colitis, 
Grade 1 
• 
Continue atezolizumab. 
• 
Initiate symptomatic treatment. 
• 
Endoscopy is recommended if symptoms persist for >7 days. 
• 
Monitor closely. 
Diarrhea or colitis, 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Initiate symptomatic treatment. 
• 
Patient referral to GI specialist is recommended. 
• 
For recurrent events or events that persist  >5 days, initiate treatment 
with corticosteroids equivalent to 1−2 mg/kg/day oral prednisone.  
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
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Event 
Management 
Diarrhea or colitis, 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to GI specialist for evaluation and confirmatory biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Diarrhea or colitis, 
Grade 4 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to GI specialist for evaluation and confirmation biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 mg/kg/day IV 
methylprednisolone and convert to 1-2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating corticosteroids, 
consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over ≥1 
month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
6.1.2.4 
Endocrine disorders 
 
Thyroid disorders, adrenal insufficiency, diabetes mellitus, and pituitary disorders have been 
associated with the administration of atezolizumab. Management guidelines for endocrine events 
are provided in the table below 
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, 
constipation, or mental status changes should be investigated for the presence of thyroid, 
pituitary, or adrenal endocrinopathies. The patient should be referred to an endocrinologist if an 
endocrinopathy is suspected. Thyroid stimulating hormone (TSH) and free triiodothyronine (T3) 
and thyroxine (T4) levels should be obtained to determine whether thyroid abnormalities are 
present. Pituitary hormone levels and function tests (e.g., TSH, growth hormone, luteinizing 
hormone, follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone 
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[ACTH] levels, and ACTH stimulation test) and magnetic resonance imaging (MRI) of the brain 
(with detailed pituitary sections) may help to differentiate primary pituitary insufficiency from 
primary adrenal insufficiency. 
Event 
Management 
Asymptomatic 
hypothyroidism 
• 
Continue atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH closely. 
Symptomatic 
hypothyroidism 
• 
Withhold atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH closely. 
• 
Consider patient referral to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
Asymptomatic 
hyperthyroidism 
TSH ≥0.1 mU/L and <0.5 mU/L: 
• 
Continue atezolizumab. 
• 
Monitor TSH every 4 weeks. 
• 
Consider patient referral to endocrinologist. 
 
TSH <0.1 mU/L: 
• 
Follow guidelines for symptomatic hyperthyroidism. 
• 
Consider patient referral to endocrinologist. 
Symptomatic 
hyperthyroidism 
• 
Withhold atezolizumab. 
• 
Initiate treatment with anti-thyroid drug such as methimazole or 
carbimazole as needed. 
• 
Consider patient referral to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled and thyroid 
function is improving. 
• 
Permanently discontinue atezolizumab. c 
Symptomatic adrenal 
insufficiency, Grade 2−4 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to endocrinologist. 
• 
Perform appropriate imaging. 
• 
Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• 
If event resolves to Grade 1 or better and patient is stable on 
replacement therapy, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better or patient is not 
stable on replacement therapy while withholding atezolizumab, 
permanently discontinue atezolizumab. c 
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Hyperglycemia, Grade 1 
or 2 
• 
Continue atezolizumab. 
• 
Investigate for diabetes.  In the absence of corticosteroids or 
diabetes medication non-adherence may be an indication of beta-
cell destruction and atezolizumab-induced diabetes.  If patient 
has Type 1 diabetes (e.g. new-onset diabetes in the absence of 
corticosteroids or another inciting medication), treat as a Grade 3 
event.   
• 
Exercise caution in utilizing non-insulin hypoglycemic agents in 
this setting, as new-onset hyperglycemia in the absence of 
corticosteroids may be an indication of beta-cell destruction and 
atezolizumab-induced diabetes.  After a thorough investigation of 
other potential causes which may involve a referral to an 
endocrinologist, follow institutional guidelines. 
• 
Monitor for glucose control. 
Hyperglycemia, Grade 3 
or 4 
• 
Withhold atezolizumab. 
• 
Initiate treatment with insulin. 
• 
Monitor for glucose control. 
• 
Strongly consider referral to endocrinologist, particularly if 
patient is deemed to have atezolizumab-induced diabetes; if so, 
obtain C-peptide level paired with glucose, autoantibody levels 
(e.g. GAD65, islet cell autoantibodies), and hemoglobin A1C 
level. 
• 
If patient is found to have diabetic ketoacidosis or hyperglycemic 
hyperosmolar syndrome, treat as per institutional guidelines with 
appropriate management and laboratory values (e.g. anion gap, 
ketones, blood pH, etc.) reported.   
• 
Resume atezolizumab when symptoms resolve and glucose levels 
are stable. 
Hypophysitis (pan-
hypopituitarism), Grade 2 
or 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to endocrinologist. 
• 
Perform brain MRI (pituitary protocol). 
• 
Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 1-2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• 
Initiate hormone replacement if clinically indicated. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• 
For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis (pan-
hypopituitarism), Grade 4 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to endocrinologist. 
• 
Perform brain MRI (pituitary protocol). 
• 
Initiate treatment with corticosteroids equivalent to 1-2 
mg/kg/day IV methylprednisolone and convert to 12 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• 
Initiate hormone replacement if clinically indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone. 
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a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
6.1.2.5 
Ocular Events 
 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in the table below. 
Event 
Management 
Ocular event, 
Grade 1 
• 
Continue atezolizumab. 
• 
Patient referral to ophthalmologist is strongly recommended. 
• 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• 
If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Patient referral to ophthalmologist is strongly recommended. 
• 
Initiate treatment with topical corticosteroid eye drops and topical 
immunosuppressive therapy. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Ocular event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to ophthalmologist. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day oral 
prednisone.   
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
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c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
6.1.2.6 
Immune-mediated Myocarditis 
 
Immune-mediated myocarditis has been associated with the administration of atezolizumab.  
Immune-mediated myocarditis should be suspected in any patient presenting with signs or 
symptoms suggestive of myocarditis, including, but not limited to, laboratory (e.g., B-type 
natriuretic peptide) or cardiac imaging abnormalities, dyspnea, chest pain, palpitations, fatigue, 
decreased exercise tolerance, or syncope.  Myocarditis may also be a clinical manifestation of 
myositis and should be managed accordingly.  Immune-mediated myocarditis needs to be 
distinguished from myocarditis resulting from infection (commonly viral, e.g., in a patient who 
reports a recent history of gastrointestinal illness), ischemic events, underlying arrhythmias, 
exacerbation of preexisting cardiac conditions, or progression of malignancy.   
All patients with possible myocarditis should be urgently evaluated by performing cardiac 
enzyme assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as 
appropriate per institutional guidelines.  A cardiologist should be consulted.  An endomyocardial 
biopsy may be considered to enable a definitive diagnosis and appropriate treatment, if clinically 
indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in the table below. 
Event 
Management 
Immune-mediated 
myocarditis, Grade 2−4 
• 
Permanently discontinue atezolizumab. a 
• 
Refer patient to cardiologist. 
• 
Initiate treatment as per institutional guidelines and consider 
antiarrhythmic drugs, temporary pacemaker, ECMO, or VAD as 
appropriate. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
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6.1.2.7 
Infusion-Related Reactions and Cytokine-Release Syndrome 
 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction (IRR) or cytokine-release syndrome (CRS) 
with atezolizumab may receive premedication with antihistamines, anti-pyretics, and/or 
analgesics (e.g., acetaminophen) for subsequent infusions.  Metamizole (dipyrone) is prohibited 
in treating atezolizumab-associated IRRs because of its potential for causing agranulocytosis. 
IRRs are known to occur with the administration of monoclonal antibodies and have been 
reported with atezolizumab.  These reactions, which are thought to be due to release of cytokines 
and/or other chemical mediators, occur within 24 hours of atezolizumab administration and are 
generally mild to moderate in severity. 
 
CRS is defined as a supraphysiologic response following administration of any immune therapy 
that results in activation or engagement of endogenous or infused T cells and/or other immune 
effector cells.  Symptoms can be progressive, always include fever at the onset, and may include 
hypotension, capillary leak (hypoxia), and end-organ dysfunction (Lee et al., 2019).  CRS has 
been well documented with chimeric antigen receptor T-cell therapies and bispecific T-cell 
engager antibody therapies but has also been reported with immunotherapies that target PD-1 or 
PD-L1 (Rotz et al., 2017; Adashek and Feldman, 2019), including atezolizumab. 
 
There may be significant overlap in signs and symptoms of IRRs and CRS, and in recognition of 
the challenges in clinically distinguishing between the two, consolidated guidelines for medical 
management of IRRs and CRS are provided in the table below. 
 
Severe COVID-19 appears to be associated with a CRS involving the inflammatory cytokines 
interleukin (IL)-6, IL-10, IL-2, and IFN-γ (Merad and Martin, 2020).  If a patient develops 
suspected CRS during the study, a differential diagnosis should include COVID-19, which 
should be confirmed or refuted through assessment of exposure history, appropriate laboratory 
testing, and clinical or radiologic evaluations per investigator judgment.  If a diagnosis of 
COVID-19 is confirmed, the disease should be managed as per local or institutional guidelines. 
 
Event 
Management 
Grade 1 a 
Fever b with or 
without 
constitutional 
symptoms 
• 
Immediately interrupt infusion. 
• 
Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
• 
If the infusion is tolerated at the reduced rate for 30 minutes, the infusion 
rate may be increased to the original rate. 
• 
If symptoms recur, discontinue infusion of this dose. 
• 
Administer symptomatic treatment, c including maintenance of IV fluids 
for hydration. 
• 
In case of rapid decline or prolonged CRS (>2 days) or in patients with 
significant symptoms and/or comorbidities, consider managing as per 
Grade 2. 
• 
For subsequent infusions, consider administration of oral premedication 
with antihistamines, anti-pyretics, and/or analgesics, and monitor closely 
for IRRs and/or CRS. 
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Event 
Management 
Grade 2 a 
Fever b with 
hypotension not 
requiring 
vasopressors 
and/or 
Hypoxia requiring 
low-flow oxygen d 
by nasal cannula or 
blow-by 
• 
Immediately interrupt infusion. 
• 
Upon symptom resolution, wait for 30 minutes and then restart infusion 
at half the rate being given at the time of event onset. 
• 
If symptoms recur, discontinue infusion of this dose. 
• 
Administer symptomatic treatment. c 
• 
For hypotension, administer IV fluid bolus as needed. 
• 
Monitor cardiopulmonary and other organ function closely (in the ICU, if 
appropriate).  Administer IV fluids as clinically indicated, and manage 
constitutional symptoms and organ toxicities as per institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• 
Consider IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 
Consider anti-cytokine therapy. 
• 
Consider hospitalization until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 3, that is, hospitalize 
patient (monitoring in the ICU is recommended), permanently 
discontinue atezolizumab. e 
• 
If symptoms resolve to Grade 1 or better for 3 consecutive days, the next 
dose of atezolizumab may be administered.  For subsequent infusions, 
consider administration of oral premedication with antihistamines, 
anti-pyretics, and/or analgesics and monitor closely for IRRs and/or 
CRS. 
• 
If symptoms do not resolve to Grade 1 or better for 3 consecutive days, 
contact the investigator. 
Grade 3 a 
Fever b with 
hypotension 
requiring a 
vasopressor (with or 
without 
vasopressin) 
and/or 
Hypoxia requiring 
high-flow oxygen d 
by nasal cannula, 
face mask, 
non-rebreather 
mask, or Venturi 
mask 
• 
Permanently discontinue atezolizumab. e 
• 
Administer symptomatic treatment. c 
• 
For hypotension, administer IV fluid bolus and vasopressor as needed. 
• 
Monitor cardiopulmonary and other organ function closely; monitoring 
in the ICU is recommended.  Administer IV fluids as clinically indicated, 
and manage constitutional symptoms and organ toxicities as per 
institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• 
Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 
Consider anti-cytokine therapy. 
• 
Hospitalize patient until complete resolution of symptoms.  If no 
improvement within 24 hours, manage as per Grade 4, that is, admit 
patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed; for patients who 
are refractory to anti-cytokine therapy, experimental treatments may be 
considered at the discretion of the investigator. 
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Event 
Management 
Grade 4 a 
Fever b with 
hypotension 
requiring multiple 
vasopressors 
(excluding 
vasopressin) 
and/or 
Hypoxia requiring 
oxygen by positive 
pressure (e.g., 
CPAP, BiPAP, 
intubation and 
mechanical 
ventilation) 
• 
Permanently discontinue atezolizumab. e 
• 
Administer symptomatic treatment. c 
• 
Admit patient to ICU and initiate hemodynamic monitoring, mechanical 
ventilation, and/or IV fluids and vasopressors as needed.  Monitor other 
organ function closely.  Manage constitutional symptoms and organ 
toxicities as per institutional practice. 
• 
Rule out other inflammatory conditions that can mimic CRS 
(e.g., sepsis).  If no improvement within 24 hours, initiate workup and 
assess for signs and symptoms of HLH or MAS as described in this 
appendix. 
• 
Administer IV corticosteroids (e.g., methylprednisolone 2 mg/kg/day or 
dexamethasone 10 mg every 6 hours). 
• 
Consider anti-cytokine therapy.  For patients who are refractory to 
anti-cytokine therapy, experimental treatments f may be considered at the 
discretion of the investigator. 
• 
Hospitalize patient until complete resolution of symptoms. 
ASTCT = American Society for Transplantation and Cellular Therapy; BiPAP = bi-level positive airway 
pressure; CAR = chimeric antigen receptor; CPAP = continuous positive airway pressure; 
CRS = cytokine-release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; 
eCRF = electronic Case Report Form; HLH = hemophagocytic lymphohistiocytosis; ICU = intensive care 
unit; IRR = infusion-related reaction; MAS = macrophage activation syndrome; NCCN = National Cancer 
Comprehensive Network; NCI = National Cancer Institute. 
Note:  These management guidelines have been adapted from NCCN guidelines for management of CAR 
T-cell−related toxicities (Version 2.2019). 
a Grading system for these management guidelines is based on ASTCT consensus grading for CRS.  NCI 
CTCAE v5.0 should be used when reporting severity of IRRs, CRS, or organ toxicities associated with 
CRS on the Adverse Event eCRF.  Organ toxicities associated with CRS should not influence overall 
CRS grading. 
b Fever is defined as temperature ≥38°C not attributable to any other cause.  In patients who develop CRS 
and then receive anti-pyretic, anti-cytokine, or corticosteroid therapy, fever is no longer required when 
subsequently determining event severity (grade).  In this case, the grade is driven by the presence of 
hypotension and/or hypoxia. 
c Symptomatic treatment may include oral or IV antihistamines, anti-pyretics, analgesics, bronchodilators, 
and/or oxygen.  For bronchospasm, urticaria, or dyspnea, additional treatment may be administered as per 
institutional practice. 
d Low flow is defined as oxygen delivered at ≤6 L/min, and high flow is defined as oxygen delivered at 
>6 L/min. 
e Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
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should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate).  For subsequent infusions, administer oral premedication with antihistamines, anti-
pyretics, and/or analgesics, and monitor closely for IRRs and/or CRS.  Premedication with corticosteroids 
and extending the infusion time may also be considered after assessing the benefit−risk ratio. 
f Refer to Riegler et al. (2019). 
 
6.1.2.8 
Pancreatic Events 
 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate workup should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in the 
table below. 
Event 
Management 
Amylase and/or lipase 
elevation, Grade 2 
Amylase and/or lipase >1.5−2.0 × ULN: 
• 
Continue atezolizumab. 
• 
Monitor amylase and lipase weekly. 
• 
For prolonged elevation (e.g., >3 weeks), consider treatment 
with corticosteroids equivalent to 10 mg/day oral prednisone. 
 
Asymptomatic with amylase and/or lipase >2.0−5.0 × ULN: 
• 
Treat as a Grade 3 event. 
Amylase and/or lipase 
elevation, Grade 3 or 4 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to GI specialist. 
• 
Monitor amylase and lipase every other day. 
• 
If no improvement, consider treatment with corticosteroids 
equivalent to 1−2 mg/kg/day oral prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
• 
For recurrent events, permanently discontinue atezolizumab. c 
Immune-mediated pancreatitis, 
Grade 2 or 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to GI specialist. 
• 
Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while 
withholding atezolizumab, permanently discontinue 
atezolizumab. c 
• 
For recurrent events, permanently discontinue atezolizumab. c 
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Event 
Management 
Immune-mediated pancreatitis, 
Grade 4 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to GI specialist. 
• 
Initiate treatment with corticosteroids equivalent to 
1−2 mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids 
over ≥1 month. 
GI = gastrointestinal. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
6.1.2.9 
Dermatologic Events 
 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limiting, with or without pruritus.  Although uncommon, cases of 
severe cutaneous adverse reactions such as Stevens-Johnson syndrome and toxic epidermal 
necrolysis have been reported with atezolizumab.  A dermatologist should evaluate persistent 
and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in the table below. 
 
Event 
Management 
Dermatologic event, 
Grade 1 
• 
Continue atezolizumab. 
• 
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, 
Grade 2 
• 
Continue atezolizumab. 
• 
Consider patient referral to dermatologist for evaluation and, if 
indicated, biopsy. 
• 
Initiate treatment with topical corticosteroids. 
• 
Consider treatment with higher-potency topical corticosteroids if event 
does not improve. 
• 
If unresponsive to topical corticosteroids, consider oral prednisone 
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0.5 mg/kg/day. 
Dermatologic event, 
Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to dermatologist for evaluation and, if indicated, biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 10 mg/day oral 
prednisone, increasing dose to 1−2 mg/kg/day if event does not 
improve within 48−72 hours. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Dermatologic event, 
Grade 4 
• 
Permanently discontinue atezolizumab. c 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
(any grade) 
Additional guidance for Stevens-Johnson syndrome or toxic epidermal 
necrolysis: 
• 
Withhold atezolizumab for suspected Stevens-Johnson syndrome or 
toxic epidermal necrolysis. 
• 
Confirm diagnosis by referring patient to a specialist (dermatologist, 
ophthalmologist, or urologist as relevant) for evaluation and, if 
indicated, biopsy. 
• 
Follow the applicable treatment and management guidelines above. 
• 
If Stevens-Johnson syndrome or toxic epidermal necrolysis is 
confirmed, permanently discontinue atezolizumab. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
6.1.2.10 
Immune-mediated Meningoencephalitis 
 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab. Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness. Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process. 
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All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed 
safe by the treating physician, a lumbar puncture should be performed, and a neurologist should 
be consulted. 
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in the table below. 
Event 
Management 
Immune-mediated 
meningoencephalitis, 
all grades 
• 
Permanently discontinue atezolizumab. a 
• 
Refer patient to neurologist. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 
mg/kg/day IV methylprednisolone and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-mediated event.  The decision to re−challenge patients with 
atezolizumab should be based on investigator's assessment of benefit−risk and documented by the 
investigator (or an appropriate delegate). 
 
6.1.2.11 
Neurologic disorders 
 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent 
atezolizumab. Patients may present with signs and symptoms of sensory and/or motor 
neuropathy. Diagnostic work-up is essential for an accurate characterization to differentiate 
between alternative etiologies. Management guidelines for neurologic disorders are provided in 
table below. 
Event 
Management 
Immune-mediated 
neuropathy, Grade 1 
• 
Continue atezolizumab. 
• 
Investigate etiology. 
Immune-mediated 
neuropathy, Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Investigate etiology and refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Immune-mediated 
neuropathy, Grade 3 
or 4 
• 
Permanently discontinue atezolizumab. c  
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
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Myasthenia gravis and 
Guillain-Barré 
syndrome (any grade) 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of corticosteroids equivalent to 1−2 mg/kg/day 
oral or IV prednisone. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of ≤10 
mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
6.1.2.12 
Renal Events 
 
Immune-mediated nephritis has been associated with the administration of atezolizumab.  
Eligible patients must have adequate renal function.  Renal function, including serum creatinine, 
should be monitored throughout study treatment.  Patients with abnormal renal function should 
be evaluated and treated for other more common etiologies (including prerenal and postrenal 
causes, and concomitant medications such as non-steroidal anti-inflammatory drugs).  Refer the 
patient to a renal specialist if clinically indicated.  A renal biopsy may be required to enable a 
definitive diagnosis and appropriate treatment. 
 
Patients with signs and symptoms of nephritis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in the table below. 
 
Event 
Management 
Renal event, Grade 1 
• 
Continue atezolizumab. 
• 
Monitor kidney function, including creatinine and urine protein, 
closely until values resolve to within normal limits or to baseline 
values. 
Renal event, Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to renal specialist. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
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Renal event, Grade 3 
or 4 
• 
Permanently discontinue atezolizumab.  
• 
Refer patient to renal specialist and consider renal biopsy. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
oral prednisone. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of 
≤10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
6.1.2.13 
Immune-Mediated Myositis 
 
Immune-mediated myositis has been associated with the administration of atezolizumab.  
Myositis or inflammatory myopathies are a group of disorders sharing the common feature of 
inflammatory muscle injury; dermatomyositis and polymyositis are among the most common 
disorders.  Initial diagnosis is based on clinical (muscle weakness, muscle pain, skin rash in 
dermatomyositis), biochemical (serum creatine kinase increase), and imaging 
(electromyography/MRI) features, and is confirmed with a muscle biopsy.  Patients with possible 
myositis should be referred to a rheumatologist or neurologist.  Patients with possible myositis 
should be monitored for signs of myocarditis. 
Patients with signs and symptoms of myositis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in the table below 
Event 
Management 
Immune-mediated 
myositis, Grade 1 
• 
Continue atezolizumab. 
• 
Refer patient to rheumatologist or neurologist.  
• 
Initiate treatment as per institutional guidelines. 
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Event 
Management 
Immune-mediated 
myositis, Grade 2 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to rheumatologist or neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone and convert to 1−2 mg/kg/day oral prednisone 
or equivalent upon improvement. 
• 
If corticosteroids are initiated and event does not improve within 
48 hours after initiating corticosteroids, consider adding an 
immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
Immune-mediated 
myositis, Grade 3 
• 
Withhold atezolizumab for up to 12 weeks after event onset. a 
• 
Refer patient to rheumatologist or neurologist. 
• 
Initiate treatment as per institutional guidelines.   
• 
Respiratory support may be required in more severe cases. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day IV 
methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, resume atezolizumab. b 
• 
If event does not resolve to Grade 1 or better while withholding 
atezolizumab, permanently discontinue atezolizumab. c 
• 
For recurrent events, treat as a Grade 4 event. 
Immune-mediated 
myositis, Grade 4 
• 
Permanently discontinue atezolizumab. c 
• 
Refer patient to rheumatologist or neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Respiratory support may be required in more severe cases. 
• 
Initiate treatment with corticosteroids equivalent to 1−2 mg/kg/day 
IV methylprednisolone, or higher-dose bolus if patient is severely 
compromised (e.g., cardiac or respiratory symptoms, dysphagia, or 
weakness that severely limits mobility); convert to 1−2 mg/kg/day oral 
prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
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Event 
Management 
a Atezolizumab may be withheld for a longer period of time (i.e., >12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to the equivalent of ≤10 mg/day oral prednisone.  The 
acceptable length of the extended period of time must be based on an assessment of benefit−risk by the 
investigator and in alignment with the protocol requirements for the duration of treatment and 
documented by the investigator. 
b If corticosteroids have been initiated, they must be tapered over ≥1 month to the equivalent of 
≤10 mg/day oral prednisone before atezolizumab can be resumed. 
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-mediated event.  The decision to re−challenge patients with atezolizumab 
should be based on investigator's assessment of benefit−risk and documented by the investigator (or an 
appropriate delegate). 
 
6.1.2.14 
Hemophagocytic Lymphohistiocytosis and Macrophage Activation Syndrome 
 
Immune-mediated reactions may involve any organ system and may lead to hemophagocytic 
lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), which are considered 
to be potential risks for atezolizumab.   
 
Patients with suspected HLH should be diagnosed according to published criteria by McClain 
and Eckstein (2014).  A patient should be classified as having HLH if five of the following eight 
criteria are met: 
• Fever ≥38.5°C 
• Splenomegaly 
• Peripheral blood cytopenia consisting of at least two of the following: 
− 
Hemoglobin <90 g/L (9 g/dL) (<100 g/L [10 g/dL] for infants <4 weeks old) 
− 
Platelet count <100 × 109/L (100,000/mcL) 
− 
ANC <1.0 × 109/L (1000/mcL) 
• Fasting triglycerides >2.992 mmol/L (265 mg/dL) and/or fibrinogen <1.5 g/L 
(150 mg/dL) 
• Hemophagocytosis in bone marrow, spleen, lymph node, or liver 
• Low or absent natural killer cell activity 
• Ferritin >500 mg/L (500 ng/mL) 
• Soluble interleukin 2 (IL-2) receptor (soluble CD25) elevated ≥ 2 standard deviations 
above age-adjusted laboratory-specific norms 
 
Patients with suspected MAS should be diagnosed according to published criteria for systemic 
juvenile idiopathic arthritis by Ravelli et al. (2016).  A febrile patient should be classified as 
having MAS if the following criteria are met: 
• Ferritin >684 mg/L (684 ng/mL) 
• At least two of the following: 
− 
Platelet count ≤181 × 109/L (181,000/mcL) 
− 
AST ≥48 U/L 
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− 
Triglycerides >1.761 mmol/L (156 mg/dL) 
− 
Fibrinogen ≤3.6 g/L (360 mg/dL) 
 
Patients with suspected HLH or MAS should be treated according to the guidelines in the 
table below. 
 
Event 
Management 
Suspected HLH or 
MAS 
• 
Permanently discontinue atezolizumab. 
• 
Consider patient referral to hematologist. 
• 
Initiate supportive care, including intensive care monitoring if 
indicated per institutional guidelines. 
• 
Consider initiation of IV corticosteroids, an immunosuppressive agent, 
and/or anti-cytokine therapy. 
• 
If event does not respond to treatment within 24 hours, initiate 
treatment as appropriate according to published guidelines (La Rosée 
2015; Schram and Berliner 2015; La Rosée et al., 2019). 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
≥1 month. 
HLH = hemophagocytic lymphohistiocytosis; MAS = macrophage activation syndrome. 
 
6.2 
Recombinant Human IL-7 (CYT107) 
There will be no dose reduction for CYT107 in this study. 
Delays in dosing will be allowed for delays such as weather factors resulting in delays getting to 
the clinic or hospital, travel delays, clinic schedules, or emergencies. A delay of up to 72 hours 
will be allowed on one occasion during the course of a treatment cycle. 
Patients will come off protocol therapy if any CYT107 or treatment-related grade 3 or 4 AEs by 
CTCAE Version 5.0 criteria occur with the exception of transient lymphopenia. Three cases of 
Grade 3 lymphopenia have been documented with CYT107. Peripheral lymphopenia after the 
first CYT107 injection is a sign of CYT107 activity; reflecting the rhIL-7 ‘homing effect’ of 
lymphocytes to deep tissues. 
For purposes of this trial, since peripheral lymphopenia is a transient event, a Grade 3 
‘lymphocyte count decrease’ to <500-200 cells/mm3 and a Grade 4 ‘lymphocyte count decrease’ 
to <200 cells/mm3 will not require patients coming off protocol provided the lymphocyte count 
returns to a minimum of 500 cells/mm3 by the time of the scheduled start of the next weekly dose 
within the treatment phase. A Grade 3 or 4 ‘lymphocyte count decrease’ will require patients 
coming off protocol if the count fails to return to a minimum of 500 cells/mm3 by the time of the 
scheduled start of the next weekly dose. 
Dose modifications for Adverse Events: Substantial AEs are not expected and thus dose 
modifications are not planned or recommended. In all human trials with CYT107, AEs were 
frequent, but transient and grade 2 or less (as noted in the Adverse Event list, Section 7.1.2). 
These include injection site reactions, lymphadenopathy, pyrexia, rash, and fatigue. 
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 Adverse Event List(s) for Commercial Agent(s): N/A 
7.2 
Adverse Event Characteristics 
• 
CTCAE term (AE description) and grade: The descriptions and grading scales 
found in the revised NCI CTCAE version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. 
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• 
For expedited reporting purposes only: 
– AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed 
in the SPEER column, Section 7.1.1) should be reported through CTEP-AERS 
only if the grade is above the grade provided in the SPEER. 
– Other AEs for the protocol that do not require expedited reporting are outlined 
in Section 7.3.4. 
• 
Attribution of the AE: 
– Definite – The AE is clearly related to the study treatment. 
– Probable – The AE is likely related to the study treatment. 
– Possible – The AE may be related to the study treatment. 
– Unlikely – The AE is doubtfully related to the study treatment. 
– Unrelated – The AE is clearly NOT related to the study treatment. 
7.3 
Expedited Adverse Event Reporting 
 Rave-CTEP-AERS Integration 
The Rave Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS) Integration enables evaluation of Adverse Events (AE) entered in Rave to 
determine whether they require expedited reporting and facilitates entry in CTEP-AERS 
for those AEs requiring expedited reporting. Sites must initiate all AEs for this study in 
Medidata Rave.  
 
Treatment-emergent AEs: All AEs that occur after start of treatment are collected in 
Medidata Rave using the Adverse Event form, which is available for entry at each 
treatment course or reporting period and is used to collect AEs that start during the period 
or persist from the previous reporting period. AEs that occur 30 Days after the Last 
Administration of the Investigational Agent/Intervention are collected using the Late 
Adverse Event form. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
• The reporting period (course/cycle) is correct; and 
• AEs are recorded and complete (no missing fields) and the form is query free.  
 
 
 
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The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and 
protocol-specific reporting rules evaluate the AEs submitted for expedited reporting. A 
report is initiated in CTEP-AERS using information entered in Medidata Rave for AEs 
that meet reporting requirements. The CRA completes the report by accessing CTEP-
AERS via a direct link on the Medidata Rave Expedited Reporting Evaluation form. 
Contact the CTSU Help Desk at 1-888-823-5923 or by email at ctsucontact@westat.com 
if you have any issues submitting an expedited report in CTEP-AERS. 
 
In the rare occurrence that internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497. Once internet connectivity is restored, the 
24-hour notification that was phoned in must be entered immediately into CTEP-AERS 
using the direct link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU 
members’ website: 
 
• Study specific documents:   Protocols > Documents> Protocol Related 
Documents> Adverse Event Reporting, and   
• Additional resources: Resources > CTSU Operations Information> User Guides 
& Help Topics. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
 
• NCI Guidelines for Investigators:  Adverse Event Reporting Requirements is 
available at 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/docs/aeguid
elines.pdf. 
 
 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: PI and Adverse Event Coordinator(s) (if applicable) of the 
Corresponding Organization or Lead Organization, the local treating physician, and the 
Reporter, and Submitter. CTEP-AERS provides a copy feature for other email recipients. 
 Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note: A death on study requires both routine and expedited reporting, regardless of 
causality. Attribution to treatment or other cause must be provided. 
 
 
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 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions: N/A 
 Adverse Events of Special Interest in Atezolizumab Studies 
The following AEs are considered of special interest in patients receiving atezolizumab 
and must be reported expeditiously through CTEP-AERS, irrespective of regulatory 
seriousness criteria: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy’s 
Law and based on the following observations:  
• 
Treatment-emergent ALT or AST > 3 x ULN (or > 3 x baseline value in disease 
states where LFTs may be elevated at baseline) in combination with total bilirubin 
> 2 x ULN (of which ≥ 35% is direct bilirubin)  
• 
Treatment-emergent ALT or AST > 3 x ULN (or > 3 x baseline value in disease 
states where LFTs may be elevated at baseline) in combination with clinical 
jaundice    
• 
Suspected transmission of an infectious agent by the study treatment, as defined 
below: 
• 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent. A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product. This term applies only when a 
contamination of study treatment is suspected. 
• 
Pneumonitis 
• 
Colitis 
• 
Endocrinopathies: diabetes mellitus, pancreatitis, hyperthyroidism, hypophysitis, and 
adrenal insufficiency 
• 
Hepatitis, including AST or ALT >10 x ULN 
• 
Systemic lupus erythematosus 
• 
Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• 
Events suggestive of hypersensitivity, cytokine release syndrome, influenza-like 
illness, systemic inflammatory response syndrome, systemic immune activation, or 
infusion-related reactions 
• 
Nephritis 
• 
Ocular toxicities (e.g., uveitis, retinitis, optic neuritis) 
• 
Myositis 
• 
Myopathies, including rhabdomyolysis 
• 
Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
• 
Vasculitis 
• 
Autoimmune hemolytic anemia 
 
 
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• 
Severe cutaneous reactions (e.g., Stevens-Johnson syndrome, dermatitis, bullous, toxi 
epidermal necrolysis) 
7.4 
Routine Adverse Event Reporting 
All AEs must be reported in routine study data submissions. AEs reported expeditiously 
through CTEP-AERS must also be reported in routine study data submissions. 
AE data collection and reporting, which are required as part of every clinical trial, are done to 
ensure the safety of patients enrolled in the studies as well as those who will enroll in future 
studies using similar agents. AEs are reported in a routine manner at scheduled times during the 
trial using Medidata Rave. For this trial the Adverse Event CRF is used for routine AE reporting 
in Rave. 
7.5 
Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS. In addition, the Pregnancy Information Form included within 
the NCI Guidelines for Adverse Event Reporting Requirements must be completed and 
submitted to CTEP. Any pregnancy occurring in a patient or patient’s partner from the time of 
consent to 150 days after the last dose of study drug must be reported and then followed for 
outcome. Newborn infants should be followed until 30 days old. Please see the “NCI Guidelines 
for Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP 
INDs and IDEs” (at http://ctep.cancer.gov/protocolDevelopment/adverse effects.htm) for more 
details on how to report pregnancy and its outcome to CTEP. 
7.6 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur after treatment with an agent under an NCI 
IND/IDE be reported expeditiously via CTEP-AERS. Three options are available to describe the 
event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia [AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also be 
reported via the routine reporting mechanisms outlined in each protocol. 
7.7 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT a 
metastasis from the initial malignancy). Second malignancies require ONLY routine AE 
reporting unless otherwise specified. 
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8. 
PHARMACEUTICAL INFORMATION 
A list of the AEs and potential risks associated with the investigational agents administered in 
this study can be found in Section 7.1. 
8.1 
CTEP IND Agent(s) 
 Atezolizumab (NSC 783608) 
Other Names: TecentriqTM, MPDL3280A 
Classification: monoclonal antibody 
M.W.: 150 KD 
Mode of Action: anti-PD-L1 
Description: 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of 2 heavy chains 
(448 amino acids) and 2 light chains (214 amino acids). Atezolizumab targets human PD-
L1 and inhibits its interaction with its receptor PD-1. Atezolizumab also blocks the 
binding of PD-L1 to B7.1, an interaction that is reported to provide additional inhibitory 
signals to T cells (Butte et al. 2007). 
How Supplied: 
Atezolizumab is provided by Genentech/F.Hoffmann-La Roche LTD and distributed by 
the Pharmaceutical Management Branch, CTEP, NCI. The agent is supplied in a single-
use, 20-mL glass vial as a colorless-to-slightly-yellow, sterile, preservative-free clear 
liquid solution intended for IV administration. Each 20 mL vial contains 1200 mg of 
atezolizumab and is formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), 
polysorbate 20 (8 mg), and sucrose (821.6 mg), with a pH of 5.8. 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. 
Preparation: 
The prescribed dose of atezolizumab should be diluted 0.9% NaCl to a concentration 
between 3.2 mg/mL and 16.8 mg/mL and infused with or without a low-protein binding 
0.2 or 0.22 micrometer in-line filter. The IV bag may be constructed of polyvinyl 
chloride (PVC), polyolefin (PO), or polyethylene (PE).The prepared solution may be 
stored at 2°C–8°C for up to 24 hours or at ambient ≤ 25°C (77°F) for 6 hours from the 
time of preparation. If the dose solution is stored at 2°C–8°C (36°C–46°F), it should be 
removed from refrigeration and allowed to reach room temperature prior to 
administration. These times include the storage and administration times for the infusion. 
Do not shake or freeze infusion bags containing the dose solution.  
Storage: 2°C–8°C (36°F–46°F). Vial contents should not be frozen or shaken and should 
be protected from direct sunlight. 
 
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If a storage temperature excursion is identified, promptly return atezolizumab to 2°C-8°C 
(36°F-46°F) and quarantine the supplies. Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Stability studies are ongoing. 
CAUTION: No preservative is used in atezolizumab; therefore, the vial is intended for 
single use only. Discard any unused portion of drug remaining in a vial. 
Route of Administration: IV infusion 
Method of Administration: 
Atezolizumab is administered as an IV infusion over 60 minutes. If the first infusion is 
tolerated, all subsequent infusions may be delivered over 30 minutes. Do not administer 
atezolizumab as an IV push or bolus. No premedication is indicated for administration of 
Cycle 1 of atezolizumab. Patients who experience an infusion-related reaction with Cycle 
1 of atezolizumab may receive premedication with subsequent infusions. 
Potential Drug Interactions: 
Cytochrome P450 enzymes as well as conjugation/glucuronidation reactions are not 
involved in the metabolism of atezolizumab. No drug interaction studies for atezolizumab 
have been conducted or are planned. There are no known interactions with other 
medicinal products or other form of interactions. 
Patient Care Implications: 
Male patients and female patients of childbearing potential should utilize contraception 
and take active measures to avoid pregnancy while undergoing atezolizumab treatment 
and for at least 5 months (150 days) after the last dose of atezolizumab. 
Availability: 
Atezolizumab is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
Atezolizumab is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.4). 
 CYT107 (Recombinant Glycosylated Human Interleukin-7) (NSC 767713) 
Other Names: Human Interleukin-7, Lymphopoietin-1, rHuIL-7  
Classification: Cytokine 
M.W.: 22kDa 
Mode of Action: Multifunctional cytokine critical for T-cell development and 
homeostasis. 
 
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Description: 
Glycosylated 152 amino acid recombinant protein containing three N-glycosylation sites 
and one O-glycosylation site, with 3 disulfide bridges: Cys2- Cys 92, Cys 34- Cys 129, 
and Cys 47- Cys 141. CYT107 is produced using a Chinese Hamster Ovary cell line. 
How Supplied: CYT107 is supplied by RevImmune and distributed by the 
Pharmaceutical Management Branch, CTEP, DCTD, NCI. Each single-use 0.6 mL vial 
contains 1200 mcg of CYT107 at a concentration of 2000 mcg/mL, as a sterile, clear, 
colorless solution containing 10mM Sodium Acetate, 100mM Sodium chloride, 50mM 
Glutamic acid, 50mM Arginine, pH approximately 5. 
 
CYT107 is provided to the NCI under a Collaborative Agreement between the 
Pharmaceutical Collaborator and the DCTD, NCI (see Section 12.4). 
Preparation: Do not shake vials. Remove number of vials required for dose preparation 
from the freezer and thaw at refrigerated temperature (2-8°C) for 1 hour prior to dose 
preparation. Once thawed, inspect vials for any visible particulate matter. If observed, 
discard vials. Aseptically withdraw the required dose volume into a syringe for 
administration.  
 
Storage: Store vials in their original box frozen at -20°C. 
 
If a storage temperature excursion is identified, promptly return CYT107 vials to -20°C 
freezer and quarantine the supplies. Provide a detailed report of the excursion (including 
documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Stability studies of the intact vials are ongoing. Do not re-freeze thawed vials. 
Intact vials may be removed from the freezer and kept at refrigerated temperature for a 
maximum of 12 hours prior to dose administration. Once dose is withdrawn into a 
syringe, administer immediately. If necessary, prepared syringes may be stored 
refrigerated for up to 6 hours prior to administration. Vials are for single-use only. 
Destroy any remaining contents following dose preparation.  
 
Route and Method of Administration: Intramuscular (IM) injection. Inject slowly (over 
10-20 seconds) into Deltoid muscle or muscle of the thighs or buttocks, away from joints, 
nerves or bones. Rotate injection sites with each injection.  
Potential Drug Interactions: In-vitro, CYT107 did not inhibit isoenzymes CYP1A2, 
CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. In 
vitro, CYT107 did not induce isoenzymes CYP1A, CYP2B6 and CYP3A4. At 
concentrations tested, it is unlikely CYT107 will cause drug-drug interactions.  
 
Patient Care Implications: Advise study participants to use effective contraception 
while receiving study treatment and for at least 2 months after the last dose.  
 
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For patient with a Body Mass Index (BMI) >30, an adjusted body weight will be used to 
calculate the final dose to be administered. Please refer to Appendix D for details on the 
adjusted body weight calculation. 
 
 Agent Ordering and Agent Accountability 
NCI-supplied agents may be requested by the PI (or their authorized designee) at each 
participating institution. Pharmaceutical Management Branch (PMB) policy requires that 
agent be shipped directly to the institution where the patient is to be treated. PMB does 
not permit the transfer of agents between institutions (unless prior approval from PMB is 
obtained). The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents. The responsible investigator at each participating 
institution must be registered with CTEP, DCTD through an annual submission of FDA 
Form 1572 (Statement of Investigator), Biosketch/Curriculum Vitae, Supplemental 
Investigator Data Form (IDF), and Financial Disclosure Form (FDF). If there are several 
participating investigators at one institution, CTEP-supplied investigational agents for the 
study should be ordered under the name of one lead investigator at that institution. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application. Access to OAOP requires the establishment of a CTEP 
IAM account and the maintenance of an “active” account status and a “current” 
password. For questions about drug orders, transfers, returns, or accountability, call or 
email PMB any time. Refer to the PMB’s website for specific policies and guidelines 
related to agent management. 
8.1.3.1 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must maintain 
a careful record of the receipt, dispensing and final disposition of all agents received 
from the PMB using the appropriate NCI Investigational Agent (Drug) Accountability 
Record (DARF) available on the CTEP forms page. Store and maintain separate NCI 
Investigational Agent Accountability Records for each agent, strength, formulation, 
and ordering investigator on this protocol. 
 Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB OAOP application. Access to OAOP requires the 
establishment of a CTEP-IAM account and the maintenance of an “active” account status 
and a “current” password. Questions about IB access may be directed to the PMB IB 
Coordinator via email. 
 Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 
• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
 
 
 
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• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• 
PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx 
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/ 
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov 
• 
IB Coordinator: IBCoordinator@mail.nih.gov 
• 
PMB email: PMBAfterHours@mail.nih.gov 
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
Specimens will be collected for several planned correlative studies. Many samples will be 
processed and stored to be run in batches. The CITN Immune Monitoring Laboratory will 
provide lab kits and shipping supplies. Specific instructions on numbers and types of tubes 
required for each visit are provided in the CITN-14 Laboratory Manual.  
When blood volume or specimen material is limited, the correlative studies will be considered 
secondary to tests needed to make clinical decisions. Prioritization of secondary tests will be 
made based on technical considerations, total amount of sample from each individual subject, 
total number of samples acquired, total number of each assay performed, and information gained 
from the assays performed to date. The anticipated priority correlatives are: 
Plasma/serum-based studies 
1. Multiplex Cytokines – Multiplex ELISA 
2. Kynurenine and tryptophan (Kyn/Trp) ratios and  
Cell associated studies 
1. Evaluation of peripheral CD4+ and CD8+ T-cell counts 
2. T-Cell Receptor Repertoire Analysis – TCR sequencing 
3. Evaluation of the effect of atezolizumab with and without CYT107 on circulating 
Lymphocyte and Monocyte numbers and Phenotype 
4. Tumor-Associated Neoantigen discovery – Whole Exome Sequencing and RNAseq and 
Antigen Prediction 
5. Antitumor Immune T-cell Responses 
Biopsy associated studies 
1. Slide-Based Immune Phenotype Panel – Multispectral IHC 
2. Assessment of tumor biopsy by gene expression analysis -- Interferon γ (INFγ) Gene 
Expression Signature - NanoString® nCounter® Human Immunology V2 Panel and the 
nCounter® PanCancer Immune Profiling Panel 
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3. Assessment of PD-L1 expression at Baseline and Post-treatment – 
Immunohistochemistry (IHC) 
4. Tumor-Associated Neoantigen discovery – Whole Exome Sequencing and RNAseq and 
Antigen Prediction 
9.1 
Integrated Correlative Studies 
 Evaluation of peripheral CD4+ and CD8+ T-cell counts – Integrated Laboratory 
Correlative Study #1 
9.1.1.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects in Red-Top or 
Gold SST or other blood draw tubes as specified per local site SOP. 
9.1.1.2 
Handling of Specimens(s) 
Blood Samples will be collected at room temperature and shipped ambient to the 
local clinical lab. 
9.1.1.3 
Shipping of Specimen(s) 
Blood collection tubes will be shipped at ambient temperature to the designated local 
clinical, CLIA compliant laboratory the same day as the blood draw. 
9.1.1.4 
Site(s) Performing Correlative Study 
Assays will be performed at each local clinical site. Assays are to be performed at 
each site by a CLIA compliant laboratory. The specific technique is not specified in 
the protocol. 
 
 Slide-Based Immune Phenotype Panel – Multispectral IHC – Integrated Laboratory 
Correlative Study #2 
9.1.2.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor obtained 
within 2 years from the screening visit will be identified by the clinical site at the 
relevant pathology laboratories where they were processed and stored. Tissue blocks 
are preferred, however FFPE slides can substitute if blocks are unavailable. 
Alternatively, patients will undergo a pre-treatment biopsy (core, punch, or 
excisional) as part of this protocol. Patient will undergo a post-treatment biopsy (core, 
punch, or excisional) if deemed relatively safe and technically feasible as part of this 
protocol.  
9.1.2.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by fax 
and phone by the clinical site from the relevant pathology laboratory by providing the 
patient’s name, consent form, and date of collection. If patients undergo biopsy as 
part of this protocol, tissue will be placed in formalin for overnight shipping to the 
CIML. 
 
 
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9.1.2.3 
Shipping of Specimen(s) 
For archival samples, clinical sites will arrange for the formalin-fixed, paraffin-
embedded tumor blocks or FFPE slide to be shipped at ambient temperature to the 
CIML. For biopsies done as part of this protocol, tissue in formalin will be shipped 
overnight at ambient temperature to the CIML. Clinical sites will utilize a web-based 
specimen system (BSI-Web) to communicate with the CIML. After sectioning at the 
CIML, the CIML will coordinate shipment of unstained slides to Dr.
at 
Fred Hutch. 
9.1.2.4 
Site(s) Performing Correlative Study 
Assays will be performed by Dr.
at Fred Hutch. 
 
 Assessment of tumor biopsy by gene expression analysis -- Interferon γ (INFγ) Gene 
Expression Signature - NanoString® nCounter® Human Immunology V2 Panel and the 
nCounter® PanCancer Immune Profiling Panel – Integrated Laboratory Correlative 
Study #3 
9.1.3.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor obtained 
within 2 years from the screening visit will be identified by the clinical site at the 
relevant pathology laboratories where they were processed and stored. Alternatively, 
patients will undergo a pre-treatment biopsy (core, punch, or excisional) as part of 
this protocol. Patients will undergo a post-treatment biopsy (core, punch, or 
excisional) if deemed relatively safe and technically feasible as part of this protocol. 
9.1.3.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by fax 
and phone by the clinical site from the relevant pathology laboratory by providing the 
patient’s name, consent form, and date of collection. If patients undergo biopsy as 
part of this protocol, tissue will be placed in formalin for overnight shipping to the 
CIML. 
9.1.3.3 
Shipping of Specimen(s) 
For archival samples, clinical sites will arrange for the formalin-fixed, paraffin-
embedded tumor blocks (preferred) or FFPE slides (if blocks are unavailable) to be 
shipped at ambient temperature to the CIML. For biopsies done as part of this 
protocol, tissue in formalin will be shipped overnight at ambient temperature to the 
CIML. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CIML. After sectioning at the CIML, the CIML will 
coordinate shipment of unstained slides (or RNA) to NanoString®. Depending on the 
specific contract, RNA will be extracted from FFPE slides, either at NanoString® or 
the CIML, using established protocols (MAN-10050-02 Preparing Nucleic Acid from 
FFPE Samples for Use with nCounter® Assays). 
 
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9.1.3.4 
Site(s) Performing Correlative Study 
Assays will be performed by NanoString® Technologies in Seattle, WA, and analyzed 
using qualified analytic tools at the immunopathology lab of Fred Hutch. 
 T-Cell Receptor Repertoire Analysis – TCR sequencing – Integrated Laboratory 
Correlative Study #4 
9.1.4.1 
Collection of Specimen(s) 
Specimens will include archived and prospectively obtained tumor biopsies and blood 
samples. Blood draws will be performed by venipuncture. 
9.1.4.2 
Handling of Specimens(s) 
Biopsy samples will be placed in formalin and shipped to the CIML. Blood collection 
tubes will be shipped on day of blood draw for overnight delivery to the CIML. 
9.1.4.3 
Shipping of Specimen(s) 
Whole blood and biopsies in formalin will be shipped ambient to the CIML. Blood 
will be processed to PBMC as described above. Clinical sites will utilize a web-based 
specimen system (BSI-Web) to communicate with the CIML. The CIML will 
coordinate shipment of samples to Adaptive Biosciences. 
9.1.4.4 
Site(s) Performing Correlative Study 
Samples will be analyzed at Adaptive Bioscience in Seattle, WA, or other agreed 
upon vendor or collaborator. 
 
 Tumor-Associated Neoantigen discovery – Whole Exome Sequencing and RNAseq and 
Antigen Prediction – Integrated Laboratory Correlative Study #5 
9.1.5.1 
Collection of Specimen(s) 
Specimens will include archived tumor blocks (or FFPE slides) and prospectively 
obtained tumor biopsies and blood samples. Blood draws will be performed by 
venipuncture. 
9.1.5.2 
Handling of Specimens(s) 
For archival samples, clinical sites will arrange for the formalin-fixed, paraffin 
embedded tumor specimens to be shipped at ambient temperature to the CIML. For 
biopsies done as part of this protocol, tissue in formalin will be shipped overnight at 
ambient temperature to the CIML where they will be embedded in paraffin. Paraffin 
blocks (or FFPE slides) will be stored at 4oC under desiccant.  
Blood collection tubes will be shipped on day of blood draw for overnight delivery to 
the CIML. Blood will be processed to PBMC as described above and stored in liquid 
nitrogen. Nucleic acid will be extracted from PBMC and from biopsy specimens 
using vendor-specific protocols.  
 
 
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9.1.5.3 
Shipping of Specimen(s) 
Whole blood, archival tumor blocks (or FFPE slides) and biopsies in formalin will be 
shipped ambient to the CIML. Clinical sites will utilize a web-based specimen system 
(BSI-Web) to communicate with the CIML. The CIML will coordinate shipment of 
samples to the Fred Hutch immunopathology lab and/or agreed upon vendor. 
9.1.5.4 
Site(s) Performing Correlative Study 
These analyses will be performed using qualified analytes and analytic tools at the 
immunopathology lab and shared resources of the Fred Hutch or at a vendor to be 
determined. 
 
 Antitumor Immune T-cell Responses -- ELISPOT – Integrated Laboratory Correlative 
Study #6 
9.1.6.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects just before, during, 
and at end of treatment. 
9.1.6.2 
Handling of Specimens(s) 
Blood collection tubes (for subsequent PBMC isolation) will be shipped on day of 
blood draw for overnight delivery to the CIML. 
9.1.6.3 
Shipping of Specimen(s) 
Blood collection tubes will be shipped overnight at ambient temperature to the CIML 
using CIML established SOPs. Clinical sites will utilize a web-based specimen 
system (BSI-Web) to communicate with the CIML. The CIML will coordinate 
shipment via cryoport of cryopreserved PBMC in the event that a vendor or 
collaborator performs these studies. 
9.1.6.4 
Site(s) Performing Correlative Study 
Assays will be performed in the CIML at Fred Hutch under the direction of Dr. 
 or an agreed upon vendor or collaborator. 
9.2 
Exploratory Correlative Studies 
 Assessment of PD-L1 expression at Baseline and Post-treatment -- 
Immunohistochemistry (IHC) – Exploratory Laboratory Correlative Study #1 
9.2.1.1 
Collection of Specimen(s) 
Formalin-fixed, paraffin-embedded archival tissue block(s) from tumor obtained 
within 2 years from the screening visit will be identified by the clinical site at the 
relevant pathology laboratories where they were processed and stored. Tissue blocks 
are preferred, however FFPE slides can substitute if blocks are unavailable. 
Alternatively, patients will undergo a pre-treatment biopsy (core, punch, or 
excisional) as part of this protocol. Patients will undergo a post-treatment biopsy 
 
 
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(core, punch, or excisional) if deemed relatively safe and technically feasible as part 
of this protocol. 
9.2.1.2 
Handling of Specimens(s) 
Formalin-fixed, paraffin-embedded archival tumor blocks will be requested by fax 
and phone by the clinical site from the relevant pathology laboratory by providing the 
patient’s name, consent form, and date of collection. If patients undergo biopsy as 
part of this protocol, tissue will be placed in formalin for overnight shipping to the 
CIML. 
9.2.1.3 
Shipping of Specimen(s) 
For archival samples, clinical sites will arrange for the formalin-fixed, paraffin-
embedded tumor blocks (preferred) or FFPE slides (if blocks are unavailable) to be 
shipped at ambient temperature to the CIML. For biopsies done as part of this 
protocol, tissue in formalin will be shipped overnight at ambient temperature to the 
CIML. Clinical sites will utilize a web-based specimen system (BSI-Web) to 
communicate with the CIML. After sectioning at the CIML, the CIML will 
coordinate shipment of unstained slides to HistoGeneX (Naperville, IL)or other 
agreed upon vendor. 
9.2.1.4 
Site(s) Performing Correlative Study 
Assays will be performed by HistoGeneX or other agreed upon vendor. Samples 
would be run in batches. 
 
 Evaluation of the effect of atezolizumab with and without CYT107 on circulating 
Lymphocyte and Monocyte numbers and Phenotype – Exploratory Laboratory 
Correlative Study #2 
9.2.2.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects just before, during, 
and at end of treatment. 
9.2.2.2 
Handling of Specimens(s) 
Blood Samples will be collected at room temperature and shipped ambient to the 
CIML the same day as the blood draw. The sample must be received at the CIML 
within 24 hours of blood draw. 
9.2.2.3 
Shipping of Specimen(s) 
Blood collection tubes will be shipped at ambient temperature to the CIML. Clinical 
sites will utilize a web-based specimen system (BSI-Web) to communicate with the 
CIML. 
9.2.2.4 
Site(s) Performing Correlative Study 
Quantification of PBMC and T-cell subsets will be performed under the direction of 
Dr. 
 in the CIML at Fred Hutch. 
 
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 Multiplex Cytokines -- Multiplex ELISA – Exploratory Laboratory Correlative Study #3 
9.2.3.1 
Collection of Specimen(s) 
Whole blood will be collected into red-top tubes by venipuncture. 
9.2.3.2 
Handling of Specimens(s) 
Blood samples will be processed to frozen serum at the local labs and stored frozen at 
-80°C. 
9.2.3.3 
Shipping of Specimen(s) 
Frozen serum vials will be shipped from clinical sites to the CIML. Clinical sites will 
utilize a web-based specimen system (BSI-Web) to communicate with the CIML. The 
CIML will coordinate shipments of serum to the Fred Hutch Shared Resource facility 
or other collaborator, as needed. 
9.2.3.4 
Site(s) Performing Correlative Study 
Assays will be performed at the Fred Hutch Shared Resource facility or other agreed 
upon collaborator or vendor. 
 
 Kynurenine and tryptophan (Kyn/Trp) Ratios and Plasma Arginine levels – Exploratory 
Laboratory Correlative Study #4 
9.2.4.1 
Collection of Specimen(s) 
Blood draws will be performed by venipuncture on study subjects at time points 
before, during, and after treatment. 
9.2.4.2 
Handling of Specimens(s) 
Plasma will be isolated by the local laboratory and frozen at -80°C. 
9.2.4.3 
Shipping of Specimen(s) 
Plasma samples will be batch shipped overnight on dry ice to the CIML. Sites will 
utilize a web-based specimen system (BSI-Web) to communicate with the CIML. The 
CIML will coordinate the shipment of samples to the agreed upon collaborator or 
vendor. 
9.2.4.4 
Site(s) Performing Correlative Study 
Kynurenine and tryptophan and Arginine levels will be assessed at an agreed upon 
collaborator or vendor to be determined.  
 
 
 
 
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 Microbiome Analyses – Exploratory Laboratory Correlative Study #5 
9.2.5.1 
Collection of Specimen(s) 
Fecal samples will be collected by patients pre-treatment and post-treatment using 
standard, at home stool-collection procedures using standardized fecal swab/storage 
devices. 
9.2.5.2 
Handling of Specimens(s) 
Samples will be initially stored frozen at home by patients and returned to the clinical 
research site at their next study visit and stored at the local site at -80°C. 
9.2.5.3 
Shipping of Specimen(s) 
Frozen samples will be batch shipped overnight on dry ice to the CIML. Sites will 
utilize a web-based specimen system (BSI-Web) to communicate with the CIML. The 
CIML will coordinate the shipment of samples to Dr. 
 at Fred Hutch. 
9.2.5.4 
Site(s) Performing Correlative Study 
Assays will be performed in collaboration with Dr. 
 at Fred Hutch or 
other collaborator. 
9.3 
Special Studies 
 Immunogenicity Testing 
The formation of anti-drug antibodies (ADA) and neutralizing anti-drug antibodies 
(NADA) to glyco-rhIL-7 (CYT107) will be evaluated in the Safety Run-In/Experimental 
Arm subjects only, on Cycle 1, Day 1 before the first CYT107 injection and on Cycle 3, 
Day 1. If positive on Cycle 3, Day 1, immunogenicity testing will be repeated at the end 
of the study. 
 
9.3.1.1 
Collection of specimen(s) 
Blood draws will be performed by venipuncture on study subjects before, during and 
at end of treatment. 
 
 
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9.3.1.2 
Handling of specimen(s)   
Plasma will be isolated by the local laboratory and frozen at -80C. 
9.3.1.3 
Shipping of Specimen(s)  
Plasma samples will be batch shipped overnight on dry ice to the CIML (Seattle, 
WA). Sites will utilize a web-based specimen system (BSI-Web) to communicate 
with the CIML. The CIML will coordinate the shipment of samples to the agreed 
upon collaborator or vendor.  
9.3.1.4 
 Site(s) Performing Immunogenicity Testing 
ADA and NADA to glyco-rhIL-7 (CYT107) will be performed by Eurofins Scientific 
(Vergeze, France) who will perform both ELISA Binding (non-neutralizing) and 
neutralizing antibody assays according to their Standard Operating Procedure.  
 
 CYT107 Pharmacokinetics 
The pharmacokinetic profile of CYT107 levels will be assessed to determine if 
Atezolizumab has an effect on CYT107 PK levels. The samples will be collected before 
CYT107 treatment on Cycle 1, Day 1 and again on Cycle 1, Day 22.  
9.3.2.1 
Collection of specimen(s)   
Blood draws will be performed by venipuncture on study subjects before and during 
study treatment. 
Table 9.3.2 Pharmacokinetics timepoints  
Cohort 
Pharmacokinetic timepoints for CYT107  
Safety Run-in subjects 
Day 1, Immediate Pre-dose CYT107 
Safety Run-in subjects 
Day 1, 2 hours (± 15 mins) after CYT107 administration is complete 
Safety Run-in subjects 
Day 1, 4 hours (± 15 mins) after CYT107 administration is complete 
Safety Run-in subjects 
Day 1, 6 hours (± 15 mins) after CYT107 administration is complete 
Safety Run-in subjects 
Day 22, Immediate Pre-dose CYT107 and Atezolizumab 
Safety Run-in subjects 
Day 22, 2 hours (± 15 mins) after CYT107 administration is complete* 
Safety Run-in subjects 
Day 22, 4 hours (± 15 mins) after CYT107 administration is complete* 
Safety Run-in subjects 
Day 22, 6 hours (± 15 mins) after CYT107 administration is complete* 
*Blood draws are timed after CYT107 administration is complete, not completion of Atezolizumab 
infusion. 
 
9.3.2.2 
Handling of Specimens(s) 
Plasma will be isolated by the local laboratory and frozen at -80°C. 
 
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9.3.2.3 
Shipping of Specimen(s) 
Plasma samples will be batch shipped overnight on dry ice to the CIML (Seattle, 
WA). Sites will utilize a web-based specimen system (BSI-Web) to communicate 
with the CIML. The CIML will coordinate the shipment of samples to the agreed 
upon collaborator or vendor. 
9.3.2.4 
Site(s) Performing Pharmacokinetics Testing  
PK of glyco-rhIL-7 (CYT107) will be performed by Eurofins Scientific (Vergeze, 
France) who will perform assays according to their Standard Operating Procedures.  
 
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11. 
MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 9 weeks. 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eisenhauer 2009]. Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in 
the RECIST criteria. 
This study will also evaluate response and progression using immune-related response criteria 
(irRC) [Wolchok 2009]. See Appendix C for a detailed description of the evaluation criteria. 
 Definitions 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their 
first treatment with atezolizumab and/or CYT107. 
Evaluable for objective response. Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response. These patients will have their 
response classified according to the definitions stated below. (Note: Patients who exhibit 
objective disease progression before the end of cycle 1 will also be considered evaluable.) 
Evaluable Non-Target Disease Response. Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions. 
 Disease Parameters 
Measurable disease. Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥20 mm (≥2 cm) 
by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. 
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis when assessed by CT scan (CT scan 
slice thickness recommended to be no greater than 5 mm [0.5 cm]). At baseline and in 
follow-up, only the short axis will be measured and followed. 
 
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Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm [<1 cm] or pathological lymph nodes with ≥10 to <15 mm [≥1 
to <1.5 cm] short axis), are considered non-measurable disease. Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, and abdominal masses (not followed by 
CT or MRI), are considered as non-measurable. 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if 
noncystic lesions are present in the same patient, these are preferred for selection as 
target lesions. 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements. It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. A sum of the diameters (longest for nonnodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and reported 
as the baseline sum diameters. If lymph nodes are to be included in the sum, then only the 
short axis is added into the sum. The baseline sum diameters will be used as reference to 
further characterize any objective tumor regression in the measurable dimension of the 
disease. 
Non-target lesions. All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline. Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up. 
 Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
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Clinical lesions Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm (≥1 cm) diameter 
as assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
Chest x-ray Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable. 
Conventional CT and MRI This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm (0.5 cm) or less. If CT 
scans have slice thickness greater than 5 mm (0.5 cm), the minimum size for a 
measurable lesion should be twice the slice thickness. MRI is also acceptable in certain 
situations (e.g., for body scans). 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease. Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence. It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases. Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans. Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements. However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time. Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed. 
Ultrasound Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement. Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 
assessment to the next. If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised. If there is concern about radiation exposure 
at CT, MRI may be used instead of CT in selected instances. 
Endoscopy, Laparoscopy The utilization of these techniques for objective tumor 
evaluation is not advised. However, such techniques may be useful to confirm complete 
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pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence after CR or surgical resection is an endpoint. 
Tumor markers Tumor markers alone cannot be used to assess response. If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered 
in complete clinical response. Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer)[Rustin 2004] and PSA response (in recurrent prostate cancer) [Bubley 
1999; Scher 2008] have been published. In addition, the Gynecologic Cancer Intergroup 
has developed CA-125 progression criteria which are to be integrated with objective 
tumor assessment for use in first-line trials in ovarian cancer [Vergote 2000]. 
Cytology, Histology These techniques can be used to differentiate between PR and CR in 
rare cases (e.g., residual lesions in tumor types, such as germ cell tumors, where known 
residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and PD. 
FDG-PET While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease). New lesions on the basis 
of FDG-PET imaging can be identified according to the following algorithm: 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy 
in cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring. The use of FDG-PET in this circumstance should be prospectively described 
in the protocol and supported by disease-specific medical literature for the indication. 
However, it must be acknowledged that both approaches may lead to false positive 
CR due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note: A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
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 Response Criteria 
11.1.4.1 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm (<1 cm). 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm (0.5 cm). 
(Note: the appearance of one or more new lesions is also considered progressions). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
11.1.4.2 
Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization 
of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm 
[<1 cm] short axis). 
Note: If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance 
of tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions. Unequivocal progression 
should not normally trump target lesion status. It must be representative of overall 
disease status change, not a single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or PI). 
11.1.4.3 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
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For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response 
when Confirmation is 
Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once 
>4 wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR, or CR 
Any 
PD*** 
Yes or No 
PD 
 
Any 
Any 
Yes 
PD 
 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration.” Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as an endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised 
 
 Duration of Response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
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The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
Duration of stable disease: SD is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements. 
 Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 Response Review 
Radiological images will be collected for a possible review of response by an expert(s) 
independent of the study. Measurement of tumor response by a trained radiologist/nuclear 
medicine physician at each clinical site will be chronicled and reported unless or until a 
central expert review takes place. 
11.2 
Other Response Parameters: Immune-Related Response Criteria (irRC) 
See Appendix C for a detailed description of the evaluation criteria. 
12. 
STUDY OVERSIGHT AND DATA REPORTING / REGULATORY 
REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Study Oversight 
This protocol is monitored at several levels, as described elsewhere in this section. The Protocol 
PI is responsible for monitoring the conduct and progress of the clinical trial, including the 
ongoing review of accrual, patient-specific clinical and laboratory data, and routine and serious 
AEs; reporting of expedited AEs; and accumulation of reported AEs from other trials testing the 
same drug(s). The Protocol PI and statistician have access to the data at all times. 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via the mechanism described elsewhere in this section. 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
12.2 
Data Submission/Reporting 
Medidata Rave is a clinical data management system being used for data collection for this 
trial/study. Access to the trial in Rave is controlled through the CTEP-IAM system and role 
assignments.  
 
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Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and  
• 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave CRA, Rave 
Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave Investigator.  
 
Rave role requirements: 
• 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as an Non-Physician Investigator (NPIVR) or 
Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates (A) registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration types and 
documentation required. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those requiring write access to Rave 
must also be assigned the appropriate Rave tasks on the DTL. 
 
Upon initial site registration approval for the study in Regulatory Support System (RSS), all 
persons with Rave roles assigned on the appropriate roster will be sent a study invitation email 
from iMedidata. To accept the invitation, site users must either click on the link in the email or 
log in to iMedidata via the CTSU members’ website  under Data Management > Rave Home and 
click to accept the invitation in the Tasks pane located in the upper right corner of the iMedidata 
screen. Site staff will not be able to access the study in Rave until all required Medidata and 
study specific trainings are completed. Trainings will be in the form of electronic learnings 
(eLearnings) and can be accessed by clicking on the eLearning link in the Tasks pane located in 
the upper right corner of the iMedidata screen. If an eLearning is required for a study and has not 
yet been taken, the link to the eLearning will appear under the study name in the Studies pane 
located in the center of the iMedidata screen; once the successful completion of the eLearning 
has been recorded, access to the study in Rave will be granted, and a Rave EDC link will replace 
the eLearning link under the study name. 
Site staff that have not previously activated their iMedidata/Rave account at the time of initial 
site registration approval for the study in RSS will also receive a separate invitation from 
iMedidata to activate their account. Account activation instructions are located on the CTSU 
website, Rave tab under the Rave resource materials (Medidata Account Activation and Study 
Invitation Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ website under the Rave tab at www.ctsu.org/RAVE/ or by contacting the CTSU Help 
Desk at 1-888-823-5923 or by email at ctsucontact@westat.com. 
 Method 
This study will be monitored by the CTMS. Data will be submitted to CTMS at least 
once every 2 weeks via Medidata Rave (or other modality if approved by CTEP). 
Information on CTMS reporting is available at: 
http://www.theradex.com/clinicalTechnologies/?National-Cancer-Institute-NCI-11.  
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For CTMS monitored studies, after users have activated their accounts, please contact the 
Theradex Help Desk at (609) 619-7862 or by email at CTMSSupport@theradex.com for 
additional support with Rave and completion of CRFs. 
 Responsibility for Data Submission 
For trials monitored by CTMS, a quarterly report of data will be provided by Theradex to 
the Coordinating Center. 
12.3 
CTEP Multicenter Guidelines 
This protocol will adhere to the policies and requirements of the CTEP Multicenter Guidelines. 
The specific responsibilities of the PI and the Coordinating Center (Study Coordinator) and the 
procedures for auditing are presented in Appendix B. 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports received from CTEP to all participating institutions for submission 
to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied agents directly from CTEP. Agents may be ordered by a participating site only after 
the initial IRB approval for the site has been forwarded by the Coordinating Center to the 
CTEP PIO (PIO@ctep.nci.nih.gov) except for Group studies. 
12.4 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) and 
shall be maintained as such by the investigators. The protocol documents for studies 
utilizing Agents contain confidential information and should not be shared or distributed 
without the permission of the NCI. If a copy of this protocol is requested by a patient or 
patient’s family member participating on the study, the individual should sign a 
confidentiality agreement. A suitable model agreement can be downloaded from: 
http://ctep.cancer.gov. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to 
and use of data by each Collaborator shall be as follows (data pertaining to such 
combination use shall hereinafter be referred to as "Multi-Party Data”): 
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a. NCI will provide all Collaborators with prior written notice regarding the existence 
and nature of any agreements governing their collaboration with NCI, the design of 
the proposed combination protocol, and the existence of any obligations that would 
tend to restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical 
trial by any other Collaborator solely to the extent necessary to allow said other 
Collaborator to develop, obtain regulatory approval, or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must 
agree in writing before the commencement of the trials that it will use the Multi-Party 
Data solely for development, regulatory approval, and commercialization of its own 
Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as described 
in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). Additionally, 
all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable 
Health Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to 
the NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is 
a DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by 
the Group office for Cooperative Group studies or by the PI for non–Cooperative Group 
studies for immediate delivery to Collaborator(s) for advisory review and comment 
before submission for publication. Collaborator(s) will have 30 days from the date of 
receipt for review. Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected. Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three (3) 
days before submission, but in any case, before presentation at the meeting or publication 
in the proceedings. Press releases and other media presentations must also be forwarded 
to CTEP before release. Copies of any manuscript, abstract and/or press release/ media 
presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
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The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 
12.5 
Genomic Data Sharing Plan: N/A 
13. 
STATISTICAL CONSIDERATIONS 
This section outlines the statistical analysis strategy and methods for the study. If, after the study 
has begun, but before the conduct of any analysis, changes are made to primary and/or key 
secondary hypotheses or the statistical methods related to those hypotheses, then the protocol 
will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-
confirmatory analyses made after the protocol has been finalized, along with an explanation as to 
when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. 
Post hoc exploratory analyses will be clearly identified in the CSR. No separate Statistical 
Analysis Plan (SAP) will be issued for this study. 
13.1 
Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of Fred 
Hutch as part of the CITN. 
13.2 
Study Design/Objectives 
This is a phase II trial of atezolizumab (MPDL3280A) plus recombinant human IL-7 (CYT107) 
in patients with locally advanced or metastatic urothelial carcinoma. The trial follows a 
randomized, controlled trial design, with an initial ‘Safety Run-In’ phase designed to evaluate 
the acute safety profile of the investigational treatment combination. The Safety Run-In phase is 
designed to demonstrate that the incidence of DLTs is 16.7% or less in 6 patients receiving the 
investigational combination. These patients will not be included as part of the overall analysis 
since they are not randomized. Due to the non-randomized nature of the enrollment for these six 
patients, the inclusion of these patients in the overall analysis could confound and bias results of 
any randomized comparisons. Hence, these 6 patients will be analyzed and reported separately 
both for safety and for efficacy. However, toxicity data from all patients will be reviewed in the 
aggregate at the time of the interim and final analysis to evaluate overall patterns. 
The randomized trial is designed to evaluate the improvement in the objective response rate 
(ORR) of CYT107 + atezolizumab compared to atezolizumab alone in patients with 
advanced/unresectable bladder cancer who have progressive disease after a platinum-based 
chemotherapy regimen. An interim futility analysis will be conducted when 50% of planned 
sample size have their first disease assessment and survival information. An exploratory analysis 
will be conducted to evaluate the ORR after all patients have been followed up for 2 years.  
 Primary Objective 
The primary endpoint will be the ORR, defined by CR or PR as measured by RECIST 
v1.1. 
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For patients with disease that progressed after at least one platinum-based treatment 
regimen, the ORR for atezolizumab monotherapy is 14.8%.  
The Cochran Mantel Haenszel test will be conducted to compare ORR in the 
experimental arm (atezolizumab + CYT107) to the ORR in the control arm (atezolizumab 
monotherapy). A one-sided significance level of 0.10 will be considered for the test. 
13.3 
Sample Size/Accrual Rate 
During the Safety Run-In phase, 6 patients will be assigned to the experimental arm 
(atezolizumab + CYT107) with staggered enrollment (refer to Section 5 for details). The AEs 
will be assessed by the Toxicity Evaluation Committee. If, at any time, 2 or more patients 
experience a protocol-defined DLT (refer to Section 5.2), further enrollment into the trial will be 
suspended. 
If the treatment combination of the experimental arm demonstrates an acceptable safety profile 
in the Safety Run-In (1 or fewer patient experiences a protocol-defined DLT), randomized 
enrollment into the trial will begin. 
A total of 54 patients will be enrolled in this study; 6 patients in the Safety Run-In and 48 
patients in the randomized portion of the study. The expected accrual is 4 patients per month 
total at approximately 8 CITN sites. A study with 48 randomly assigned patients (1:1 
randomization) will meet the following statistical parameters: Hnull = 14.8%; Halt = 45%; one-
sided alpha of 0.10; power 88%. 
The interim futility analysis will be conducted when 24 randomized patients have their first 
disease assessment and survival information. The futility analysis is based on an O’Brien-
Fleming boundary, and the futility boundary will be considered to be crossed when the 
difference of ORR in the experimental arm – ORR in the control arm is less than -0.0063. Under 
the null hypothesis, the probability of crossing the futility boundary is 48.2%.  
Safety Population: All patients who receive at least 1 dose of the investigational regimen will be 
considered evaluable for safety and included in the overall safety analysis. For the Safety Run-in 
phase, in the absence of a DLT, patients must complete the full 28-day DLT window period to be 
considered evaluable for DLTs. Patients who discontinue from the study before the completion 
of the full 28-day DLT window for reasons other than the occurrence of a DLT (e.g., withdrawal 
of consent, rapid tumor progression, death due to rapid tumor progression, AE that does not meet 
DLT criteria) will not be considered evaluable for DLTs and will be replaced. 
Efficacy Population: The efficacy analysis will be conducted on all randomized patients, based 
upon the intent-to-treat population. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
 
Not Hispanic or Latino 
Hispanic or Latino 
Totals 
 
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The endpoints will include the evaluation of the effect of the investigation treatment 
combination on the immune-bias of the tumor microenvironment, based upon baseline 
and post-baseline tumor biopsy comparisons of: 
• 
Number, distribution, and phenotype of tumor-infiltrating cells 
• 
PD-L1 expression 
• 
Expression of Interferon γ (IFNγ) and associated proinflammatory gene expression in 
the tumor microenvironment 
Analyses may be also performed to explore the effect of the investigational treatment 
combination on the number and phenotype of tumor-specific T cells in the peripheral 
blood, investigate for evidence that the investigational treatment combination increases 
the exposure of bladder cancer-specific antigens (e.g., Cancer/Testis Antigens or 
neoantigens), and investigate changes in tumor microenvironment that correlate with 
response or provide information on potential actionable causes for lack of clinical benefit. 
The effect of CYT107 on the infiltrating T cells will be assessed using the paired baseline 
and post-baseline results of the patients. The patient’s baseline result will serve as the 
control for the comparison. Log-transformed values will be considered for the 
comparison of the number of infiltrating T cells.  
 
It was established that the CYT107 dose regimen can double the number of peripheral 
blood T cells. There had been no prior information on the effect of CYT107 on 
infiltrating T cells. Assuming the CYT107 dose regimen also similarly doubles the 
number of infiltrating T cells, standard error of the effect size in the log scale (i.e. 
log(post-baseline) – log(baseline)) being 1, and a two-sided alpha of 0.10, a sample size 
of 13 paired samples will have 80% power to detect any difference between baseline and 
post-baseline. 
 
13.6 
Reporting and Exclusions 
 Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
atezolizumab and/or CYT107. 
 Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible. Each patient will be 
assigned one of the following categories: (1) complete response, (2) partial response, 
(3) stable disease, (4) progressive disease, (5) early death from malignant disease, 
(6) early death from toxicity, (7) early death because of other cause, or (9) unknown (not 
assessable, insufficient data). [Note: By arbitrary convention, category 9 usually 
designates the “unknown” status of any type of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
 
 
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response rate. Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression). Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate. Precise 
definitions for categories 4-9 will be protocol specific. 
All conclusions should be based on all eligible patients. Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major protocol 
deviations have been identified (early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.). However, these subanalyses may not serve as 
the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis should be clearly reported. The 95% confidence 
intervals should also be provided. 
 
 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
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APPENDIX B 
CTEP MULTICENTER GUIDELINES 
If an institution wishes to collaborate with other participating institutions in performing a CTEP-
sponsored research protocol, then the guidelines below must be followed. 
Responsibility of the Protocol Chair 
• The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO). The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments. The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair. There will be only one 
version of the protocol, and each participating institution will use that document. The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress. All reporting requirements to CTEP are the 
responsibility of the Protocol Chair. 
• The Protocol Chair is responsible for the timely review of AE to ensure safety of the patients. 
• The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
Responsibilities of the Coordinating Center 
• Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH. The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site. 
• Before the activation of the protocol at each participating institution, an OHRP form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• The Coordinating Center is responsible for central patient registration. The Coordinating 
Center is responsible for ensuring that IRB approval has been obtained at each participating 
site before the first patient registration from that site. 
• The Coordinating Center is responsible for the preparation of all submitted data for review by 
the Protocol Chair. 
• The Coordinating Center will maintain documentation of AE reports. There are 2 options for 
AE reporting: (1) participating institutions may report directly to CTEP with a copy to the 
Coordinating Center, or (2) participating institutions report to the Coordinating Center who 
in turn report to CTEP. The Coordinating Center will submit AE reports to the Protocol Chair 
for timely review. 
• Audits may be accomplished in one of 2 ways: (1) source documents and research records for 
selected patients are brought from participating sites to the Coordinating Center for audit, or 
(2) selected patient records may be audited on-site at participating sites. If the NCI chooses to 
have an audit at the Coordinating Center, then the Coordinating Center is responsible for 
having all source documents, research records, all IRB approval documents, NCI Drug 
Accountability Record forms, patient registration lists, response assessments scans, x-rays, 
etc., available for the audit. 
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Inclusion of Multicenter Guidelines in the Protocol 
• The protocol must include the following minimum information: 
 The title page must include the name and address of each participating institution and the 
name, telephone number, and email address of the responsible investigator at each 
participating institution. 
 The Coordinating Center must be designated on the title page. 
 Central registration of patients is required. The procedures for registration must be stated 
in the protocol. 
 Data collection forms should be of a common format. Sample forms should be submitted 
with the protocol. The frequency and timing of data submission forms to the 
Coordinating Center should be stated. 
 Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
 Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions. 
Agent Ordering 
• Except in very unusual circumstances, each participating institution will order DCTD-
supplied investigational agents directly from CTEP. Investigational agents may be ordered by 
a participating site only after the initial IRB approval for the site has been forwarded by the 
Coordinating Center to the CTEP PIO. 
 
 
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APPENDIX C 
IMMUNE-RELATED RESPONSE CRITERIA 
Introduction 
Increasing clinical experience indicates that traditional response criteria (e.g., Response 
Evaluation Criteria in Solid Tumors, Version 1.1 [RECIST v1.1][Eisenhauer 2009] and World 
Health Organization [WHO]) may not be sufficient to fully characterize activity in the new era of 
target therapies and/or biologics. In studies with cytokines, cancer vaccines, and monoclonal 
antibodies, CR, PR, or SD has been shown to occur after an increase in tumor burden as 
characterized by progressive disease by traditional response criteria. Therefore, conventional 
response criteria may not adequately assess the activity of immunotherapeutic agents because 
progressive disease (by initial radiographic evaluation) does not necessarily reflect therapeutic 
failure. Long term effect on the target disease must also be captured. The immune-related 
response criteria (irRC) are criteria that attempt to do that by enhancing characterization of new 
response patterns that have been observed with immunotherapeutic agents (i.e., ipilimumab) 
[Wolchok 2009]. (Note: The irRC only index and measurable new lesions are taken into 
account.) 
Glossary 
Term 
Definition 
SPD 
sum of the products of the 2 largest perpendicular diameters 
Tumor burden 
SPDindex lesions + SPDnew, measurable lesions 
Nadir 
minimally recorded tumor burden 
irCR 
immune-related complete response 
irPD 
immune-related progressive disease 
irPR 
immune-related partial response 
irSD 
immune-related stable disease 
irBOR 
immune-related best overall response 
 
Baseline Assessment Using irRC 
Step 1. Identify the index lesions (5 lesions per organ, up to 10 visceral lesions and 5 cutaneous 
lesions). 
Step 2. Calculate the SPD of all of these index lesions: 
× (Second largest diameter of lesion i)" 
SPD = 
Post-Baseline Assessments Using irRC 
Step 1. Calculate the SPD of the index lesions. 
Step 2. Identify new, measurable lesions (≥5 × 5 mm; up to 5 new lesions per organ: 5 new 
cutaneous lesions and 10 visceral lesions). 
Step 3. Calculate the SPD of the new, measurable lesions. 
෍(Largest diameter of lesion i)
i
 
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Step 4. Calculate the tumor burden: 
Tumor burden = SPDindex lesions + SPDnew, measurable lesions 
Step 5. Calculate the change in tumor burden relative to baseline and the change in tumor burden 
relative to nadir. 
Step 6. Derive the overall response using the table below. 
Overall Response 
Criterion 
irCR 
Complete disappearance of all lesions (whether measurable or not, and no new 
lesions) confirmed by a repeat, consecutive assessment ≥4 weeks from the date 
first documented 
irPR 
Decrease in tumor burden ≥50% relative to baseline confirmed by a consecutive 
assessment ≥4 weeks from the date first documented 
irSD 
Criteria for irCR, irPR, and irPD are not met; does not require confirmation 
irPD 
Increase in tumor burden ≥25% relative to nadir confirmed by a consecutive 
assessment ≥4 weeks from the date first documented 
irCR = immune-related complete response; irPD = immune-related progressive disease; irPR = 
immune-related partial response; irSD = immune-related stable disease. 
Determination of irBOR 
Once a patient has completed all tumor assessments, his/her irBOR may be determined: 
Condition 
irBOR 
At least one irCR 
irCR 
At least one irPR and no irCR 
irPR 
At least one irSD and no irCR and no irPR 
irSD 
At least one irPD and no irCR, no irPR, and no irSD 
irPD 
irBOR = immune-related best overall response; irCR = immune-related complete response; 
irPD = immune-related progressive disease; irPR = immune-related partial response; 
irSD = immune-related stable disease. 
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If BMI >30, proceed with the following steps: 
• Determine Ideal Weight (1 kg = 2.2 lbs) 
Males: 50 kg + (2.3 kg/inch over 5 feet) 
Females: 45.5 kg + (2.3 kg/inch over 5 feet) 
(Patients less than 5 feet: subtract 2.3 kg/inch) 
•  
Determine Adjusted Body Weight: 
Ideal Weight + 0.25 (actual weight – ideal weight) = Adjusted Body Weight 
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APPENDIX E 
MICROBIOME SAMPLE COLLECTION 
Patient Instructions: The clinical research team will provide you with fecal swab/storage devices 
and the instructions sheet at the screening visit and at the Cycle 3 (Week 8) visit.  
1. Collect the sample at home using the standardized fecal swab/storage devices provided.  
2. Store the sample in the freezer at home.  
3. Return the sample to the clinical research team at your next study visit.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
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APPENDIX F 
ABBREVIATIONS LIST 
AE 
 
adverse event 
AP 
 
Associate Plus 
BAL  
bronchoscopic alveolar lavage 
CAEPR 
Comprehensive Adverse Events and Potential Risks 
CBR  
clinical benefit rate 
CDUS  
Clinical Data Update System 
CIML  
CITN Immune Monitoring Laboratory 
CITN  
Cancer Immunotherapy Trials Network 
CNS  
central nervous system 
COPD  
chronic obstructive pulmonary disease 
COSC  
Central Operating and Statistical Center 
CR 
 
complete response 
CRF 
 
case report form 
CRS 
 
clinical research site 
CSR 
 
clinical study report 
CT 
 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP  
Cancer Therapy Evaluation Program 
CTMS  
Clinical Trials Monitoring Service 
CTSU  
Cancer Trials Support Unit 
DLT 
 
dose-limiting toxicities 
DMC  
data monitoring committee 
DOR  
duration of response 
FDA  
Food and Drug Administration 
FDF 
 
financial disclosure form 
FFPE  
formalin-fixed paraffin-embedded 
FWA  
Federal Wide Assurance 
HAART 
highly active antiretroviral therapy 
HBV  
hepatitis B virus 
HCV  
hepatitis C virus 
HIV 
 
human immunodeficiency virus 
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HSCT  
hematopoietic stem cell transplantation 
IAM 
 
Identity and Access Management 
ICF 
 
informed consent form 
IDF 
 
Investigator Data Form 
IME 
 
important medical events 
IRB 
 
Institutional Review Board 
LCMV  
lymphocytic choriomeningitis virus 
LPO 
 
Lead Protocol Organization 
MDSC  
myeloid-derived suppressor cells 
MTD  
maximum tolerated dose 
NCI 
 
National Cancer Institute 
NK 
 
natural killer (cells) 
OAOP  
Online Agent Order Processing 
OHRP  
Office for Human Research Protection 
OPEN  
Oncology Patient Enrollment Network 
ORR  
objective response rate 
OS 
 
overall survival 
PCR 
 
polymerase chain reaction 
PD 
 
progressive disease 
PFS 
 
progression-free survival 
PI 
 
principal investigator 
PIO 
 
Protocol and Information Office 
PMB  
Pharmaceutical Management Branch 
PR 
 
partial response 
PSA 
 
prostate-specific antigen 
RCC  
renal cell carcinoma 
RCR  
Registration and Credential Repository 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RSS 
 
Regulatory Support System 
SAP 
 
statistical analysis plan 
SD 
 
stable disease 
SOC  
system organ class 
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SPEER 
Specific Protocol Exceptions to Expedited Reporting 
TCR 
 
T-cell receptor 
TIL 
 
tumor-infiltrating lymphocyte 
TNBC  
triple-negative breast cancer 
TSH 
 
thyroid-stimulating hormone 
UBC  
urothelial bladder cancer 
UC 
 
urothelial carcinoma 
ULN  
upper limit of normal 
WGS  
whole genome shotgun 
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