Clinical trial NCT02921269
Conditions: Cervical Adenocarcinoma Cervical Adenosquamous Carcinoma Cervical Squamous Cell Carcinoma, Not Otherwise Specified Recurrent Cervical Carcinoma Stage IV Cervical Cancer AJCC v6 and v7 Stage IVA Cervical Cancer AJCC v6 and v7 Stage IVB Cervical Cancer AJCC v6 and v7
Sponsor: National Cancer Institute (NCI)
Start date: 2017-03-10; Completion date: 2021-01-13
Enrollment: 11 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well atezolizumab and bevacizumab work in treating patients with cervical cancer that has come back, remains despite treatment, or has spread to other places in the body. Monoclonal antibodies, such as atezolizumab and bevacizumab, may shrink tumor cell and interfere with the ability of tumor cells to grow and spread.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the anti-tumor activity (proportion of patients with objective response by Response Evaluation Criteria in Solid Tumors version 1.1 \[RECIST 1.1\] criteria) of atezolizumab and bevacizumab in patients with recurrent, persistent or metastatic cervical cancer.

SECONDARY OBJECTIVES:

I. To estimate the duration of progression free survival (PFS) and overall survival (OS).

II. To assess safety by Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0).

III. To describe the efficacy of the combination of atezolizumab and bevacizumab as measured by objective response, by PD-L1 expression on tumor and immune cells measured by semi-quantitative immunohistochemistry (IHC).

IV. To describe the efficacy of the combination of atezolizumab and bevacizumab as measured by objective response, by intratumoral and peripheral T-cell receptor (TCR) clonality and tumor infiltrating lymphocyte proportion.

OUTLINE:

Patients receive atezolizumab intravenously (IV) over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Arms: arm 1: Patients receive atezolizumab IV over 30-60 minutes and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Atezolizumab intervention 2: Bevacizumab intervention 3: Laboratory Biomarker Analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
NCI Protocol #: 10010 
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SUMMARY OF CHANGES – Protocol 
 
For Protocol Amendment: A Phase 2 Study of Atezolizumab (MPDL3280A) in Combination 
with Bevacizumab in Patients with Recurrent, Persistent or Metastatic Cervical Cancer 
 
NCI Protocol #:10010 
 
NCI Version Date: 02/06/2018 
Protocol Version Date: 02/06/2018 
 
# 
Section/ Page 
Comments 
1 
N/A 
The protocol version date was updated to 02/06/2018 throughout the 
protocol.  
2 
N/A 
Formatting and editorial changes were made throughout the protocol. 
3 
Title Page 
Stella Krawiec added as LAO Protocol Liaison. 
4 
9.1.1.2 
Pre-treatment/biopsy sample shipping address updated.  
5 
Study Calendar 
Treatment window revised.  
6 
Table of Contents 
Table of Contents page numbers revised.  
7 
1.2.2 
 
7.2  
 
7.3.3 
 
13.1 
 
13.4 
CTCAE version changed from 4.0 to 5.0 throughout the protocol to 
reflect CTEP updated amendment request dated 01/25/2018. 


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NCI Protocol #: 
10010 
 
Local Protocol #: 
17-183 
 
ClinicalTrials.gov Identifier:  TBD 
 
TITLE:  A Phase 2 Study of Atezolizumab (MPDL3280A) in Combination with Bevacizumab in 
Patients with Recurrent, Persistent or Metastatic Cervical Cancer 
 
Corresponding Organization: LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer 
Center   
 
Principal Investigator: 
Claire Friedman, MD 
Memorial Sloan Kettering Cancer Center 
1275 York Ave 
New York, NY 10065 
646-888-4247 
friedmac@mskcc.org 
 
Participating Organizations: 
LAO-11030 / University Health Network Princess Margaret Cancer Center LAO 
LAO-CA043 / City of Hope Comprehensive Cancer Center LAO 
LAO-CT018 / Yale University Cancer Center LAO 
LAO-MA036 / Dana-Farber - Harvard Cancer Center LAO 
LAO-MD017 / JHU Sidney Kimmel Comprehensive Cancer Center LAO 
LAO-MN026 / Mayo Clinic Cancer Center LAO 
LAO-NC010 / Duke University - Duke Cancer Institute LAO 
LAO-NJ066 / Rutgers University - Cancer Institute of New Jersey LAO 
LAO-OH007 / Ohio State University Comprehensive Cancer Center LAO 
LAO-PA015 / University of Pittsburgh Cancer Institute LAO 
LAO-TX035 / University of Texas MD Anderson Cancer Center LAO 
LAO-NCI / National Cancer Institute LAO 
 
Statistician: 
 
Study Coordinator: 
 
Alexia Iasonos, PhD 
Leigh Gaffney 
 
485 Lexington Ave 
633 Third Ave, 15th Floor 
 
New York, NY 10017 
New York, NY 10017 
 
646-888-8255 
646-227-2131 
 
iasonosa@mskcc.org 
frigugll@mskcc.org 
 
Responsible Research Nurse: 
Responsible Data Manager: 
 
Krysten Soldan, APN 
Joyce Guillen 
 
160 East 53rd St 
300 E. 66th Street 


NCI Protocol #: 10010 
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New York, NY  10022 
New York, NY 10065 
 
212-610-0379 
646-888-4446 
 
soldank@mskcc.org 
guillenj@mskcc.org 
 
LAO Protocol Liaison: 
Stella Krawiec, M.A. 
Johns Hopkins University 
550 N. Broadway, Suite 409 
Baltimore, MD 21205 
Telephone: (410) 502-1962 
Fax: (410) 502-9933 
skrawie1@jhmi.edu  
 
NCI-Supplied Agent(s):  Atezolizumab (MPDL3280A; NSC 783608), Bevacizumab (NSC 
704865) 
 
 
IND Sponsor:  DCTD, NCI   
 
Protocol Type / Version # / Version Date: 
Original / Version 1 / 08/01/2016 
 
 
 
 
Amended / Version 2 / 12/15/2016  
 
 
 
 
Amended / Version 3 / 02/01/2017 
 
 
 
 
Amended / Version 4 / 03/23/2017 
 
 
 
 
Amended / Version 5 / 05/25/2017 
 
 
 
 
Amended / Version 6 / 06/09/2017 
 
 
 
 
      Amended / Version 7 / 08/10/2017  
 
 
 
 
      Amended / Version 8 / 02/06/2018 
 


NCI Protocol #: 10010 
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STUDY SCHEMA 
 
This is a Phase II, multi-institution study entitled, “Phase II study of Atezolizumab and 
Bevacizumab in Patients with Recurrent, Persistent or Metastatic Cervical Cancer.”  In this study, 
patients with recurrent, persistent or metastatic cervical cancer who have received one to two prior 
therapies in the recurrent, persistent or metastatic disease setting will be treated with the 
combination of bevacizumab 15mg/kg intravenous (IV) every 3 weeks and atezolizumab 1200mg 
IV every 3 weeks until progression of disease (POD), unacceptable toxicity or withdrawal from 
study.  All treatments will be administered in the outpatient setting.  The primary objective is to 
measure the objective response rate (ORR, either partial or complete response) defined by RECIST 
v1.1 criteria.  Secondary endpoints include progression-free survival (PFS), overall survival (OS) 
and safety. 
 
Recurrent, Persistent or Metastatic 
Cervical Cancer
1-2 Prior therapies
Measurable Disease
Bevacizumab 15 mg/kg IV q 3 weeks
Atezolizumab 1200 mg IV q 3 weeks
Pre-treatment tumor biopsy 
 
Pre-treatment blood sample 


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TABLE OF CONTENTS 
 
STUDY SCHEMA ...................................................................................................................3 
1. 
OBJECTIVES ...................................................................................................................6 
1.1 
Primary Objectives ...............................................................................................6 
1.2 
Secondary Objectives ...........................................................................................6 
2. 
BACKGROUND ..............................................................................................................6 
2.1 
Study Disease(s) ...................................................................................................6 
2.2 
CTEP IND Agent .................................................................................................9 
2.3 
Rationale ............................................................................................................21 
2.4 
Correlative Studies Background ..........................................................................22 
3. 
PATIENT SELECTION ..................................................................................................23 
3.1 
Eligibility Criteria...............................................................................................23 
3.2 
Exclusion Criteria...............................................................................................24 
3.3 
Inclusion of Minorities........................................................................................28 
4. 
REGISTRATION PROCEDURES ..................................................................................28 
4.1 
Investigator and Research Associate Registration with CTEP...............................28 
4.2 
Site Registration .................................................................................................30 
4.3 
Patient Registration ............................................................................................31 
4.4 
General Guidelines .............................................................................................32 
5. 
TREATMENT PLAN .....................................................................................................32 
5.1 
Agent Administration .........................................................................................32 
5.2 
General Concomitant Medication and Supportive Care Guidelines .......................34 
5.3 
Duration of Therapy ...........................................................................................36 
5.4 
Duration of Follow Up........................................................................................36 
5.5 
Criteria for Removal from Study .........................................................................37 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................37 
6.1 
Atezolizumab (MPDL3280A) .............................................................................37 
6.2 
Bevacizumab......................................................................................................55 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS...............................59 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) ................59 
7.2 
Adverse Event Characteristics.............................................................................68 
7.3 
Expedited Adverse Event Reporting ....................................................................69 
7.4 
Routine Adverse Event Reporting .......................................................................71 
7.5 
Secondary Malignancy .......................................................................................71 
7.6 
Second Malignancy ............................................................................................72 
8. 
PHARMACEUTICAL INFORMATION .........................................................................72 
8.1 
CTEP IND Agent(s) ...........................................................................................72 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..........................................76 


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9.1 
Exploratory/Ancillary Correlative Studies ...........................................................76 
10. STUDY CALENDAR .....................................................................................................78 
11. MEASUREMENT OF EFFECT ......................................................................................80 
11.1 Antitumor Effect – Solid Tumors ........................................................................80 
12. STUDY OVERSIGHT AND DATA REPORTING / REGULATORY REQUIREMENTS86 
12.1 Study Oversight..................................................................................................86 
12.2 Data Reporting ...................................................................................................87 
12.3 Collaborative Agreements Language ...................................................................88 
12.4 Genomic Data Sharing Plan ................................................................................88 
13. STATISTICAL CONSIDERATIONS..............................................................................89 
13.1 Study Design/Endpoints......................................................................................89 
13.2 Sample Size/Accrual Rate ...................................................................................89 
13.3 Stratification Factors...........................................................................................90 
13.4 Analysis of Secondary Endpoints ........................................................................90 
13.5 Reporting and Exclusions ...................................................................................91 
14. REFERENCES ...............................................................................................................92 
APPENDIX A PERFORMANCE STATUS CRITERIA........................................................98 
Appendix B 
Examples ON HOW TO ASSESS TUMOR RESPONSES .............................99 
Appendix C 
Collaborative Agreements Language ...........................................................103 
 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 
To assess the anti-tumor activity (proportion of patients with objective response by RECIST 1.1 
criteria) of atezolizumab and bevacizumab in patients with recurrent, persistent or metastatic 
cervical cancer. 
 
1.2 
Secondary Objectives 
 
1.2.1 To estimate the duration of progression free survival (PFS) and overall survival (OS) 
 
1.2.2 To assess safety by CTCAE v.5.0 
 
1.2.3 Integrated Biomarker:  To describe the efficacy of the combination of atezolizumab and 
bevacizumab as measured by objective response, by PD-L1 expression on tumor and 
immune cells measured by semi-quantitative immunohistochemistry (IHC) 
 
1.2.4 Exploratory Biomarker:  To describe the efficacy of the combination of atezolizumab and 
bevacizumab as measured by objective response, by intratumoral and peripheral TCR 
clonality and tumor infiltrating lymphocyte proportion 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
2.1.1 Cervical Cancer 
 
In the United States, it is estimated that 12,990 women will be diagnosed with cervical 
cancer and 4,120 women will die of the disease in 2016 
(http://www.ncbi.nlm.nih.gov/pubmed/26742998).  Worldwide, cervical cancer is the 
fourth most common cancer and the most common cause of mortality in women, with 
528,000 new cases and an estimated 266,000 deaths in 2012 
(http://www.ncbi.nlm.nih.gov/pubmed/25220842). 
 
The human papilloma virus (HPV) is recognized to be the primary etiologic agent for 
cervical carcinogenesis.  However, the majority of HPV-infected individuals have an 
asymptomatic course, with clearance of the virus occurring within 1 or 2 years in 90% of 
cases.  Ten percent of individuals experience persistent HPV infection, which increases 
their risk of developing invasive cancers.  Ultimately, approximately one half of the 10% 
of individuals with persistent HPV infection will develop malignant disease, a process 
that may take up to 30 years (http://www.ncbi.nlm.nih.gov/pubmed/21282563).  Although 
many HPV types have been associated with cervical neoplasia, types 16, 18, 31, 35, 39, 
45, 51, 52, 56, and 58 cause most invasive cancers and are considered “high-risk” HPV-
genotypes.  HPV-16 accounts for approximately 53% of invasive cervical cancer cases in 
most countries, followed by HPV-18, which accounts for approximately 13% 
(http://www.ncbi.nlm.nih.gov/pubmed/19318628).  The high-risk HPV genotypes 


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produce 2 oncoproteins, designated E6 and E7, which bind and inactivate the tumor 
suppressor’s p53 and retinoblastoma protein (pRB), respectively.  The E6 mediated 
inhibition of p53 blocks apoptosis, whereas E7 inhibition of pRB abrogates cell cycle 
arrest leading to dysregulated cellular proliferation and ultimately malignancy 
(http://www.ncbi.nlm.nih.gov/pubmed/12502868). 
 
Outcomes for patients with recurrent, persistent or metastatic cervical cancer are poor.  
First-line therapy with bevacizumab in combination with paclitaxel/cisplatin or 
paclitaxel/topotecan is been approved by the Food and Drug Administration (FDA) based 
on GOG 240 (http://www.ncbi.nlm.nih.gov/pubmed/24552320).  Treatment with this 
combination increased overall survival from 13.3 to 17 months, (HR 0.71 [98% CI, 0.54-
0.95; p=0.004]), and the ORR increased from 36 to 48% (p=0.008) when compared to 
chemotherapy without bevacizumab.  Seventy-five percent of patients entering GOG240 
had prior concurrent chemotherapy and radiation therapy (CCRT) with cisplatin.  The 
remaining 25% were treatment naïve.  Following this first line treatment with 
chemotherapy with or without bevacizumab, there is no usual care second line therapy 
with significant activity.  In GOG 227C, a phase II study of single agent bevacizumab (in 
patients without prior bevacizumab), treatment was shown to be well-tolerated and active 
in the second and third-line treatment of patients with recurrent cervical cancer (23.9% 
PFS at 6 months and 10.9% response rate, n=46 patients) 
(http://www.ncbi.nlm.nih.gov/pubmed/19139430). 
 
2.1.2 Cervical Cancer and Immunotherapy 
 
Cervical cancers have a lower median mutational burden than other checkpoint-blockade 
sensitive malignancies (range of approximately 1-10 mutations per megabase, as 
compared to 1 to 100 in melanoma, (http://www.ncbi.nlm.nih.gov/pubmed/23945592). To 
increase the proportion of benefiting patients, cervical cancer must be made “visible” to 
the immune system, which may require targeting of disease specific immune targets 
and/or target enhancement through judicious combinations.  Strategies to improve activity 
of PD-L1/PD-1 blockade include immune combinations (e.g., CTLA4/ipilimumab), 
chemotherapy combinations and targeted therapy combinations (e.g., anti-vascular). 
 
Results to date show modest activity for single agent anti-PD-1 and anti-CTLA4 
therapies.  A study of single agent anti-PD-1 treatment with nivolumab in recurrent, 
persistent or metastatic cervix cancer has completed accrual and is in follow-up (NRG 
GY002, NCT02257528), n=26 patients.  A phase I/II study of ipilimumab in metastatic or 
recurrent cervical carcinoma has completed accrual.  Preliminary results of 42 enrolled 
patients, presented at ASCO 2015, showed one confirmed partial response (J Clin Oncol 
33, 2015 (suppl; abstr 3061)).  Cervical squamous cell cancer is under evaluation in the 
Phase Ib KEYNOTE-028 study (pembrolizumab).  Preliminary results presented at ASCO 
2016 show ORR of 12.5% (3/24) (J Clin Oncol 34, 2016 (suppl; abstr 5515)).  Further 
evaluation of pembrolizumab is planned in the KEYNOTE-158 study (NCT02628067). 
 
Evaluation of combinations holds promise.  A study of nivolumab and nivolumab plus 
ipilimumab in viral-associated tumors (NCT02488759) is ongoing.  SWOG is planning a 
trial of nivolumab and ipilimumab in treating patients with rare tumors (NCT02834013), 


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that will include cervical cancer, vaginal cancer and vulvar cancer cohorts. 
 
2.1.3 Rationale for Atezolizumab in Advanced Cervix Cancers 
 
Given the parallels in disease pathogenesis and treatment between HPV associated cervix 
and head and neck cancers (HNSCC), their comparison may be informative. Promising 
data from HNSCC suggest that checkpoint blockade therapies may be effective in cervical 
cancer.   
 
PD-L1 has been found to be upregulated in cervical intraepithelial neoplasias (CINs) 
(20/21 cases) and cervical squamous cell cancers (56/70) relative to normal cervical 
epithelia (0/55) (http://www.ncbi.nlm.nih.gov/pubmed/26403783).  While one study 
found PD-L1 expression to be associated with HPV positivity 
(http://www.ncbi.nlm.nih.gov/pubmed/23521696), in another 
(http://www.ncbi.nlm.nih.gov/pubmed/19825956), PD-L1 was only expressed in 19% of 
cervical carcinomas; however, a tissue microarray was used for this study which may 
underestimate PD-L1 prevalence in a given sample. PD-L1 expression does not appear to 
be different between HPV (+) and (-) oropharyngeal squamous cell cancers 
(http://www.ncbi.nlm.nih.gov/pubmed/26511814).  Nonetheless, the success of TIL 
therapy in a small study of HPV (+) patients (ORR 3/9 with 2 CRs, 
http://www.ncbi.nlm.nih.gov/pubmed/25823737) suggests that there is potential for an 
effective anti-tumor T cell response in this disease.  
 
In terms of the clinical significance of HPV positivity, in HNSCC, a history of infection 
may impact long term outcome but not response rate to checkpoint blockade.  This could 
be, in part, due to the fact that most HPV (-) HNSCC are associated with cigarette 
exposure, and thus tumors are likely to have a higher mutational burden.  In a Phase IB 
study of pembrolizumab at 10mg/kg q2 weeks in patients with HNSCC, the ORR was 
20% overall and 50% in the 12 patients with high PD-L1 expression (Chow LQ et al Ann 
Oncol 25(suppl 4):S1–S41).  The ORR was 4/23 (20%) in the HPV (+) patients, and 7/38 
(19%) in HPV (-).  However, the PFS and OS were longer in HPV positive patients: PFS 
(95% CI) of 17.1 (8-41.7) vs 8.1 (7.9-15.6) weeks in HPV (+) versus HPV (-), and OS of 
not reached (9.6-NR) vs. 9.5 (3.9-12.6) weeks in HPV (+) versus HPV (-), respectively.  
While it is not possible to ascertain whether the drug or inherent disease behavior was 
responsible for this difference, it is nonetheless promising that those patients with HPV+ 
disease fared better.   
 
In a study of pembrolizumab in HNSCC, of 99 evaluable patients, the RR was 24.8% with 
an additional 24.8% of patients having stable disease, yielding a DCR of 49.6% (Seiwart 
et al J Clin Oncol Vol 33, 2015).  In that study, the response rate was slightly lower in 
HPV (+) patients (20.6%, 95% CI 8.7-37.9) compared to HPV (-) (27.2%, 95% CI 17.9-
38.2).  This study did not report PFS/OS in HPV (+) versus negative patients.  In another 
study of MEDI4736 in 62 patients with HNSCC, the ORR was 11% (18% in PD-L1 
positive tumors; 8% in PD-L1 negative tumors) (Segal et al J Clin Oncol 33, 2015), and 
was not different between HPV (+) and (-) patients.   
 


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2.2 
CTEP IND Agent 
 
2.2.1 Atezolizumab (MPDL3280A) 
 
Atezolizumab (MPDL3280A) is a human immunoglobulin (Ig) G1 monoclonal antibody 
consisting of two heavy chains (448 amino acids) and two light chains (214 amino acids) 
and is produced in Chinese hamster ovary cells (Investigator’s Brochure, 2015).  
Atezolizumab was engineered to eliminate Fc-effector function via a single amino acid 
substitution (asparagine to alanine) at position 298 on the heavy chain, which results in a 
non-glycosylated antibody that has minimal binding to Fc receptors and prevents Fc-
effector function at expected concentrations in humans.  Atezolizumab targets human 
programmed death-ligand 1 (PD-L1) and inhibits its interaction with its receptor, 
programmed death-1 (PD-1).  Atezolizumab also blocks the binding of PD-L1 to B7.1, an 
interaction that is reported to provide additional inhibitory signals to T cells. 
 
Atezolizumab is being investigated as a potential therapy against solid tumors and 
hematologic malignancies in humans. 
 
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 et al., 2006; Hamanashi et al., 
2007; Okazaki and Honjo 2007; Hino et al., 2010).  PD-L1 binds to two 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 et al., 
2005; Keir et al., 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 anti-tumor immunity, resulting in immune evasion (Blank and 
Mackensen, 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. 
 
Unlike PD-L1, programmed death-ligand 2 (PD-L2) is primarily expressed in normal 
tissues such as the lung.  As a result, targeting tumor-overexpressed PD-L1 is a more 
promising strategy than targeting PD-1, as it preserves the immune homeostatic PD-
L2:PD-1 interaction in normal tissues while dually inhibiting the PD-L1:PD-1 and PD-
L1:B7.1 pathways to enhance anti-tumor 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 et al., 2002; 
Strome et al., 2003).  These data suggest that tumor-specific T cells may be present in the 
tumor microenvironment in an inactive or 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 


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(AEs) reported from the two recent studies were consistent with the role of the PD-
L1/PD-1 pathway in regulating peripheral tolerance. 
 
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 
 
Current clinical studies of atezolizumab include one ongoing phase 1a monotherapy 
study, three ongoing combination studies, five phase 2 studies, and one phase 3 study.  
Details of all ongoing studies can be found in the 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 (Investigator’s Brochure, 2015).  At doses ≥1 mg/kg, the 
mean maximum plasma concentration (Cmax) increased in a dose-proportional manner and 
was 26.0 mcg/mL for the 1 mg/kg dose group and 472 mcg/mL for the 20 mg/kg dose 
group.  Similarly, at doses ≥1 mg/kg, the group mean area under the concentration-time 
curve from time zero extrapolated to infinity (AUC0-inf) had a range of 340 to 6050 day × 
mcg/mL and was approximately dose proportional, as evidenced by similar clearance 
(CL) across the dose range.  For the 1 mg/kg and 20 mg/kg dose groups, the mean 
apparent CL and the mean steady-state volume of distribution (Vss) had a range of 3.20 to 
4.44 mL/day/kg and 48.1 to 65.7 mL/kg, respectively, which is consistent with the 
expected profile of an IgG1 antibody in humans. 
 
The development of anti-therapeutic 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) (Investigator’s Brochure, 2015).  Patients dosed at the 
10-, 15-, and 20-mg/kg dose levels maintained the expected target trough levels of drug 
despite the detection of ATAs.  Accordingly, the development of detectable ATAs does 
not appear to have a clinically significant impact on PK for doses from 10 to 20 mg/kg.  
To date, no relationship between the development of measurable ATAs and safety or 


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efficacy has been observed. 
 
2.2.1.3.2. 
Clinical Safety Summary 
 
As of 10 May 2016, an estimated total of 6053 patients with solid tumor and hematologic 
malignancies have received atezolizumab in clinical trial participation as a single agent or 
in combination with cytotoxic chemotherapy and/or targeted therapy.   
 
Safety findings of single-agent atezolizumab across multiple tumor types in the clinical 
development program are consistent with the known mechanism of action of 
atezolizumab and the underlying disease.  Overall, treatment with atezolizumab is well 
tolerated, with a manageable adverse event profile.  Currently, no maximum tolerated 
dose, no dose-limiting toxicities, and no clear dose-related trends in the incidence of 
adverse events have been determined.  Across all studies and tumor types, the most 
commonly reported adverse events with single-agent atezolizumab include fatigue, 
nausea, decreased appetite, diarrhea, constipation, and cough.   
 
The adverse events observed with atezolizumab in combination with chemotherapy and/or 
targeted therapies are consistent with the known risks of each study treatment.  Systemic 
immune activation, characterized by an excessive immune response, is a potential risk 
associated with atezolizumab when used in combination with another immunomodulating 
compound. 
 
The percentage of patients who discontinued atezolizumab due to any adverse event is 
consistent when used as a single agent or in combination with chemotherapy (e.g., 5.4% 
in Study PCD4989g and 5.8% in Study GP28328, respectively).  The percentage of 
patients with any Grade 5 adverse event was similar when used as a single agent or in 
combination with chemotherapy (e.g., 1.6% in Study PCD4989g and 1.0% in 
Study GP28328).        
 
Immune-related adverse events are consistent with the role of the PD-L1/PD-1 pathway in 
regulating peripheral tolerance.  Given the mechanism of action of atezolizumab, events 
associated with inflammation and/or immune-related adverse events are closely 
monitored during the atezolizumab clinical program. 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, and meningoencephalitis.  Immune-
related adverse events and guidance regarding the management of immune-related 
adverse events are provided below: 
 
Management of Atezolizumab-Specific Adverse Events 
 
Toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, should be used to evaluate for a possible immunogenic etiology. 
 


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Although most immune-related adverse events observed with immunomodulatory agents 
have been mild and self-limiting, such events should be recognized early and treated 
promptly to avoid potential major complications.  Discontinuation of atezolizumab may 
not have an immediate therapeutic effect, and in severe cases, immune-related toxicities 
may require acute management with topical corticosteroids, systemic corticosteroids, or 
other immunosuppressive agents. The investigator should consider the benefit-risk 
balance prior to further administration of atezolizumab.  In patients who have met the 
criteria for permanent discontinuation, resumption of atezolizumab may be considered if 
the patient is deriving clinical benefit and has fully recovered from the immune-related 
event.  Patients can be rechallenged with atezolizumab only after careful consideration of 
benefit-risk balance and medical judgment by the investigator. For detailed information 
regarding management of adverse events associated with atezolizumab, please refer 
to the most current version of the Atezolizumab Investigator’s Brochure. 
 
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 (Investigator’s Brochure, 2015).  These include potential dermatologic, 
hepatic, endocrine, gastrointestinal, and respiratory events as well as events of 
hepatitis/elevated liver function tests (LFTs) and influenza-like illness.  Expected adverse 
drug reactions associated with atezolizumab include the following:  
hepatitis/transaminitis, hypothyroidism, infusion-related reactions (IRRs), pneumonitis, 
influenza-like illness, and dermatologic reactions.  Potential adverse drug reactions 
include the following:  ATAs, colitis, endocrine disorders, hypersensitivity, neurologic 
disorders, and pericardial effusion.  Pericardial and pleural involvement with associated 
effusions is common in patients with cancer and has the theoretical potential to be 
exacerbated by inflammation associated with antitumor immunity following PD-L1 
blockade.  Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have 
been associated with the administration of atezolizumab and have primarily been 
observed in patients with underlying NSCLC. 
 
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 non-small cell lung cancer (NSCLC), renal cell 
carcinoma (RCC), and bladder cancer (Investigator’s Brochure, 2015).  Objective 
responses with atezolizumab monotherapy were observed in a broad range of 
malignancies, including NSCLC, RCC, melanoma, urothelial bladder cancer (UBC), 
colorectal cancer, head and neck cancer, gastric cancer, breast cancer, and sarcoma.  
Objective responses were recorded for 20 of 88 (22.7%) response-evaluable patients with 
NSCLC, including responses in squamous and non-squamous patients (4/21 and 16/67, 
respectively).  A total of 8 of the 20 responding NSCLC patients continued to respond at 
the time of the clinical data cutoff.   
 


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Analyses of tumor cells and tumor-infiltrating immune cells for PD-L1 expression on 
baseline tumor tissue have been performed for study PCD4989g, including expansion 
cohorts of patients with NSCLC (88 efficacy-evaluable patients), UBC (87 efficacy-
evaluable patients), and RCC (62 efficacy-evaluable patients) (Powles et al., 2014; Herbst 
et al., 2014; Investigator’s Brochure, 2015).  Preliminary results suggest that PD-L1 
expression in tumor-infiltrating T cells is likely to be associated with response to 
atezolizumab.  An objective response rate (ORR) of 43% (13 of 30 patients, including 2 
complete responses) was observed in UBC patients with tumor-infiltrating immune cells 
with PD-L1 immunohistochemistry (IHC) scores of 2 or 3, whereas the ORR among IHC 
0/1 UBC patients was 11% (4 of 35) (Powles et al., 2014).  While the median had not 
been reached as of January 1, 2014, the duration of response ranged from 0.1+ to 30.3+ 
weeks for patients with IHC 2/3 tumor-infiltrating immune populations and from 0.1+ to 
6.0+ weeks for patients with IHC 0/1.  Response to atezolizumab in the UBC cohort was 
associated with the tumor-infiltrating immune cell IHC scores (P=0.026) but not with 
tumor cell IHC scores (P=0.93).  Similarly, a preliminary analysis of the NSCLC cohort 
(53 evaluable patients) and the total patient population (175 evaluable patients) of 
PCD4989g found that response was significantly associated with PD-L1 IHC score in 
tumor-infiltrating immune cells (P=0.015 in NSCLC, P=0.007 in all tumors) but not with 
IHC score in tumor cells (P=0.920 in NSCLC, P=0.079 in all tumors) (Herbst et al., 
2014).  Eighty-three percent of NSCLC patients with an IHC score of 3 (tumor-infiltrating 
immune cell) responded to treatment, whereas 43% of NSCLC patients with IHC 2 were 
limited to disease stabilization. 
 
2.2.2 Bevacizumab 
 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all 
biologically active isoforms of human vascular endothelial growth factor (VEGF, or 
VEGF-A) with high affinity (Kd=1.1 nM) (Presta et al., 1997).  The antibody consists of a 
human IgG1 framework and the antigen-binding complementarity-determining regions 
from the murine anti-VEGF MAb A.4.6.1 (AvastinTM [bevacizumab] Investigators 
Brochure, 2008; Kim et al., 1993; Presta et al., 1997). 
 
2.2.2.1 
Mechanism of Action 
 
Of known proangiogenic factors, VEGF is one of the most potent and specific, and has 
been identified as a crucial regulator of both normal and pathological angiogenesis. 
VEGF is a secreted, heparin-binding protein that exists in multiple isoforms.  Action of 
VEGF is primarily mediated through binding to the receptor tyrosine kinases, VEGFR-1 
(Flt-1) and VEGFR-2 (KDR/Flk-1).  The biological effects of VEGF include endothelial 
cell mitogenesis and migration, increased vascular permeability, induction of proteinases 
leading to remodeling of the extracellular matrix, and suppression of dendritic cell 
maturation. Neutralization of VEGF by A.4.6.1 or bevacizumab has been shown to inhibit 
the VEGF-induced proliferation of human endothelial cells in vitro, and decrease 
microvessel density and interstitial pressure in tumor xenografts in vivo. In patients, 
preliminary results from a neoadjuvant trial in rectal cancer demonstrated a decrease in 
blood perfusion/permeability and interstitial fluid pressure in tumors after one dose of 
bevacizumab (Willett et al., 2004). 


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2.2.2.2 
Nonclinical Studies 
 
The murine parent MAb of bevacizumab, A4.6.1, has demonstrated potent growth 
inhibition in vivo in a variety of human cancer xenograft and metastasis models, including 
those for SK-LMS-1 leiomyosarcoma, G55 glioblastoma multiforme, A673 
rhabdomyosarcoma, Calu-6, and MCF-7 cell lines (Borgstrom et al., 1999; Kabbinavar, 
1995; Kim et al., 1993; Presta et al., 1997).  The antitumor activity was enhanced with the 
combination of A4.6.1 and chemotherapeutic agents compared to either agent alone.  
Combined blockage of the VEGF and other growth factor pathways (e.g., epidermal 
growth factor receptor [EGFR] or Platelet Derived Growth Factor Receptor [PDGFR]) 
has also demonstrated additive effects in vivo (Bergers et al., 2003; Shaheen et al., 2001). 
Associated with the anti-tumor activity of anti-VEGF MAbs were findings of reduced 
intratumoral endothelial cells and microcapillary counts as well as reduced vascular 
permeability and interstitial pressure. 
   
Nonclinical toxicology studies have examined the effects of bevacizumab on female 
reproductive function, fetal development, and wound healing.  Fertility may be impaired 
in cynomolgus monkeys administered bevacizumab, which led to reduced endometrial 
proliferation and uterine weight as well as a decrease in ovarian weight and number of 
corpora lutea.  Bevacizumab is teratogenic in rabbits, with increased frequency of fetal 
resorption, and specific gross and skeletal alterations. In juvenile cynomolgus monkeys 
with open growth plates, bevacizumab induced physeal dysplasia which was partially 
reversible upon cessation of therapy.  Bevacizumab also delays the rate of wound healing 
in rabbits, and this effect appeared to be dose-dependent and characterized by a reduction 
of wound tensile strength. 
 
2.2.2.3 
Clinical Studies 
 
Pharmacokinetics and MTD: The pharmacokinetics (PK) of bevacizumab have been 
characterized in several phase 1 and phase 2 clinical trials, with doses ranging from 1 to 
20 mg/kg administered weekly, every 2 weeks, or every 3 weeks.  The estimated half-life 
of bevacizumab is approximately 21 days (range 11-50 days).  The predicted time to 
reach steady state was 100 days.  The volume of distribution is consistent with limited 
extravascular distribution.    
 
The maximum tolerated dose (MTD) of bevacizumab has not been determined; however, 
the dose level of 20 mg/kg was associated with severe headaches (Cobleigh et al., 2003).  
The dose schedule of either 10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks is used 
in most phase 2 or 3 trials with only a few exceptions (e.g., the pivotal phase 3 trial in 
colorectal cancer, in which bevacizumab was given at 5 mg/kg every 2 weeks). 
 
Clinical efficacy of bevacizumab: Clinical proof of principle for anti-VEGF therapy with 
bevacizumab has been observed in several solid tumors.  In first- and second-line 
metastatic colorectal cancer (mCRC), the combination of bevacizumab with 5-FU-based 
chemotherapy improved the overall survival (OS), progression-free survival (PFS), and 
response rate (RR) as compared to chemotherapy alone (Hurwitz et al. 2004; Giantonio et 


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al., 2007).  There was also improved overall survival in first-line non-small cell lung 
cancer (NSCLC) patients (E4599) treated with carboplatin/paclitaxel + bevacizumab 
compared with chemotherapy alone.  Bevacizumab in combination with chemotherapy 
has been approved by the Food and Drug Administration (FDA) for treatment in mCRC 
(first and second lines) and in NSCLC. 
 
In untreated advanced and metastatic breast cancer, addition of bevacizumab to paclitaxel 
also significantly improved the RR and PFS (E2100; Miller et al., 2005).  However, in the 
phase 3 trial in doxorubicin- and paclitaxel-refractory metastatic breast cancer, the 
addition of bevacizumab to capecitabine did not show an improvement in PFS despite an 
increase in the RR (Miller et al., 2002). In locally advanced and metastatic pancreatic 
cancer, a Phase 3 also failed to demonstrate an overall survival (OS) or PFS advantage by 
adding bevacizumab to gemcitabine (CALGB-80303) (Kindler et al., 2007). 
Bevacizumab has been studied as monotherapy in renal cell cancer (RCC).  In a three-
arm, double-blind, placebo-controlled phase 2 trial (Yang et al., 2003), patients with 
previously treated stage IV RCC were randomized to high-dose (HD) bevacizumab (10 
mg/kg every 2 weeks), low-dose (LD) bevacizumab (3 mg/kg every 2 weeks), or placebo.  
The study demonstrated a highly significant prolongation of time to progression (TTP) in 
the HD arm (4.8 months) as compared with the placebo (2.6 months) (hazard ratio 
[HR]=2.55, P=0.0002); the LD arm was associated with a smaller difference in TTP (3.0 
months) of borderline significance.  The tumor response rate was 10% in the HD arm but 
0% in the LD and placebo groups.   
 
A Phase 3 study (BO17705) with bevacizumab (10 mg/kg every 2 weeks) plus interferon-
α2a versus interferon-α2a plus placebo as first-line therapy in patients with advanced 
and/or  metastatic RCC demonstrated statistically significant and clinically relevant 
improvements in PFS (10.2 vs. 5.4 months), and objective response rate (ORR) (31.4 vs. 
12.8%).  
 
The Phase 3 study BO17706 indicated no statistically significant improvement in OS 
when bevacizumab (5 mg/kg every 2 weeks) was added to the gemcitabine/erlotinib 
combination in the first-line treatment of advanced pancreatic cancer.  The Phase 3 NCI-
sponsored CALGB-80303 study investigating the use of bevacizumab (10 mg/kg every 2 
weeks) combined with gemcitabine was prematurely terminated after the CALGB Data 
Safety Monitoring Board (DSMB) concluded that the futility boundary defined for the 
primary efficacy parameter (OS) had been crossed in a protocol-specified interim analysis 
(dated June 16th, 2006).  
 
Additional clinical trials are ongoing in a variety of solid tumors and hematological 
malignancies using bevacizumab as monotherapy or in combination with chemotherapy, 
radiation, or other targeted/biological agents. 
 
2.2.2.4 
Safety Profile 
 
Based on clinical trials with bevacizumab as monotherapy or in combination with 
chemotherapy, the most common adverse events (AEs) of any severity included asthenia, 
pain, headache, hypertension, diarrhea, stomatitis, constipation, epistaxis, dyspnea, 


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dermatitis, and proteinuria.  The most common grade 3-4 AEs were asthenia, pain, 
hypertension, diarrhea, and leukopenia. 
 
The major bevacizumab-associated AEs identified in phase 1 to phase 3 trials include 
hypertension, proteinuria, arterial thromboembolic events (ATEs), hemorrhage, 
congestive heart failure (CHF), gastrointestinal (GI) perforations, and wound healing 
complications.  Other serious AEs (SAEs) observed with bevacizumab therapy include 
reversible posterior leukoencephalopathy syndrome (RPLS) and fistula formation. 
The following details a description of major AEs associated with bevacizumab therapy.  
In addition, a list of Comprehensive Adverse Events and Potential Risks (CAEPR) in 
NCI-Common Terminology Criteria for Adverse Events (CTCAE) terms is included in 
Section 7.1 of the protocol.  Reference may also be made to the Investigators’ Brochure 
and the FDA package insert (www.fda.gov/cder/foi/label/2004/125085lbl.pdf).  
 
Infusion-Related Reactions:  Infusion reactions with bevacizumab were uncommon 
(<3%) and rarely severe (0.2%).  Infusion reactions may include rash, urticaria, fever, 
rigors, hypertension, hypotension, wheezing, or hypoxia.  Currently, there is no adequate 
information on the safety of retreatment with bevacizumab in patients who have 
experienced severe infusion-related reactions.  
 
Hypertension:  Hypertension is common in patients treated with bevacizumab, with an 
incidence of 20-30% (all grades) across trials, with a mean increase of +5.5mmHg to 
+8.4mmHg for systolic pressure, or +4.1mmHg to +5.4mmHg for diastolic pressure.  
Incidence of grade 3 (hypertension requiring initiation of or increase in hypertensive 
medications) ranges from 7.8 to 17.9%.  Grade 4 hypertension (hypertensive crisis) 
occurred in up to 0.5% of bevacizumab-treated patients. 
 
Hypertension associated with bevacizumab can generally be controlled with routine oral 
drugs while bevacizumab is continued.  However, incidents of hypertensive crisis with 
encephalopathy (including RPLS) or cardiovascular sequelae have been rarely reported.  
Blood pressure (BP) should be closely monitored during bevacizumab therapy and the 
goal of BP control should be consistent with standard medical practice (Chobanian et al, 
2003).  Bevacizumab therapy should be suspended in the event of uncontrolled 
hypertension. 
 
Proteinuria:  Proteinuria has been seen in all bevacizumab studies to date, ranging in 
severity from mild asymptomatic increase in urine protein (incidence of about 38%) to 
rare instances of grade 3 proteinuria (>3.5gm/24 hour urine) (3%) or nephrotic syndrome 
(1.4%).  Pathologic findings on renal biopsies in two patients showed proliferative 
glomerulonephritis.  The risk of proteinuria may be higher in patients with advanced RCC 
or history of hypertension.  There is also evidence from dose-finding trials that the rate of 
proteinuria may be dose related.   
 
Renal thrombotic microangiopathy:  Thrombotic microangiopathy (TMA) has been 
described in biopsy samples from case reports of patients treated with bevacizumab and 
other anti-VEGF agents.  The presentation was mostly localized to the kidney, and 
systemic manifestations (e.g., thrombocytopenia or schistocytosis) were present only in 


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some of these patients.  As renal biopsies were rarely performed in patients with 
proteinuria or renal insufficiency, the true rate of renal-localized or subclinical TMA is 
not assessable. Available data indicate that systemically evident TMA (i.e., with evidence 
of hemolysis or thrombocytopenia) is very rare. However, the use of more than one anti-
VEGF agent in combination might enhance the risk.  In a phase 1 dose escalation trial of 
concurrent bevacizumab (10 mg/kg every 2 weeks) and escalating doses of sunitinib (25 
mg, 37.5 mg or 50 mg daily for 4 out of 6 weeks) in patients with RCC, 5 of the 12 
patients at the highest dose level developed systemic TMA, or microangiopathic 
hemolytic anemia; clinical presentations in these cases included thrombocytopenia, 
schistocytes, hypertension, and varying degrees of proteinuria. 
 
Hemorrhage:  Overall, grade 3 and 4 events associated with bleeding or hemorrhage were 
observed in 4.0% of 1,132 patients treated with bevacizumab in a pooled database from 
eight phase 1, 2, and 3 clinical trials in multiple tumor types.  The hemorrhagic events 
that have been observed in bevacizumab clinical studies were predominantly tumor-
associated hemorrhage and minor mucocutaneous hemorrhage. 
 
Tumor-associated hemorrhage - Major or massive pulmonary hemorrhage/hemoptysis 
has been observed primarily in patients with NSCLC.  In a phase 2 study in NSCLC, 6 
cases of life-threatening (4 fatal) hemoptysis were reported among 66 patients treated 
with bevacizumab and chemotherapy (Novotny et al., 2001); squamous cell histology was 
identified as the risk factor.  In the phase 3 trial in non-squamous NSCLC (E4599), the 
rate of Grade ≥3 broncho-pulmonary hemorrhage was <1% in the control arm 
(carboplatin/paclitaxel) versus 2.3% in the chemotherapy plus bevacizumab arm (10/427 
patients, including 7 deaths). 
 
GI hemorrhages, including rectal bleeding and melena have been reported in patients with 
CRC, and have been assessed as tumor-associated hemorrhages.  In the pivotal phase 3 
trial in advanced CRC, the rate of GI (duodenal, ileal, cecal and colonic) hemorrhage (all 
grades) was 24% in the irinotecan, fluorouracil, and leucovorin (IFL)/bevacizumab arm 
compared to 6% in the IFL alone arm; grade 3-4 hemorrhage was 3.1% for 
IFL/bevacizumab and 2.5% for IFL.   
 
Serious tumor associated bleedings have also been observed in patients with pancreatic 
cancer, gastric cancer, central nervous system (CNS) metastases, hepatoma, or varices 
treated with bevacizumab.  
 
Mucocutaneous hemorrhage - Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%-40% of patients treated.  These were most commonly 
NCI-CTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical 
intervention, and did not require any changes in bevacizumab treatment regimen. 
There have also been less common events of minor mucocutaneous hemorrhage in other 
locations, such as gingival bleeding and vaginal bleeding. 
 
Thromboembolic Events, Arterial (ATE):  The risk of ATEs is increased with 
bevacizumab therapy; such events included cerebral infarction, transient ischemic attack 
(TIA), myocardial infarction (MI), and other peripheral or visceral arterial thrombosis.  A 


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pooled analysis of five randomized studies showed a two-fold increase in these events 
(3.8% vs. 1.7%).  ATE led to a fatal outcome in 0.8% patients with bevacizumab (vs. 
0.5% without bevacizumab).  The rate of cerebrovascular accidents (including TIA) was 
2.3% vs. 0.5%, and the rates of MI 1.7% vs. 0.7%.  Certain baseline characteristics, such 
as age and prior arterial ischemic events, appear to confer additional risk (Skillings et al., 
2005).  In patients >65 years treated with bevacizumab and chemotherapy, the rate of 
ATE was approximately 8.5%.  
 
Aspirin is a standard therapy for primary and secondary prophylaxis of ATE in patients at 
high risk of such events, and the use of aspirin ≤325 mg daily was allowed in the five 
randomized studies discussed above though safety analyses specifically regarding aspirin 
use were not preplanned.  Due to the relatively small numbers of aspirin users and ATE 
events, retrospective analyses of the ability of aspirin to affect the risk of ATE were 
inconclusive.  Further analyses of the effects of concomitant use of bevacizumab and 
aspirin are ongoing. 
 
Thromboembolic Events, Venous (VTE) (including deep venous thrombosis, pulmonary 
embolism, and thrombophlebitis):  In the phase 3 pivotal trial in mCRC, there was a 
slightly higher rate of VTE in patients treated with chemotherapy plus bevacizumab 
compared with chemotherapy alone (19% vs. 16%).  The incidence of NCI-CTC Grade3 
VTEs in one NSCLC trial (E4599) was higher in the bevacizumab-containing arm 
compared to the chemotherapy control arm (5.6% vs. 3.2%).  
 
In clinical trials across all indications, the overall incidence of VTEs ranged from 2.8% to 
17.3% in the bevacizumab-containing arms compared to 3.2% to 15.6% in the 
chemotherapy control arms. The use of bevacizumab with chemotherapy does not 
substantially increase the risk of VTE compared with chemotherapy alone. However, 
patients with mCRC who receive bevacizumab and experienced VTE may be at higher 
risk for recurrence of VTE. 
 
Perforations of GI tract:  GI perforations/fistula are rare but have occurred at an increased 
rate in bevacizumab-containing therapies.  The majority of such events required surgical 
intervention, and some were associated with a fatal outcome.  In the pivotal phase 3 trial 
in CRC (AVF2107), the incidence of bowel perforation was 2% in patients receiving 
IFL/bevacizumab and 4% in patients receiving fluorouracil (5-FU)/bevacizumab 
compared to 0.3% in patients receiving IFL alone.  GI perforation has also been reported 
in non-CRC tumors (e.g., gastric/esophageal, pancreatic, and ovarian cancers) or 
nonmalignant conditions such as diverticulitis and gastric ulcer.  GI perforation should be 
included in the differential diagnosis of patients on bevacizumab therapy presenting with 
abdominal pain or rectal/abdominal abscess. 
 
GI Fistula:  Fistula formations, including events resulting in death, have been observed in 
patients receiving bevacizumab in clinical studies and post-marketing reports.  Fistulae in 
the GI tract are common (1-10% incidence) in patients with certain metastatic tumors 
such as CRC or cervical, but uncommon (0.1-1%) or rare (0.01-0.1%) in other 
indications.  
 


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In GOG 240, the rate of GI vaginal fistula was 8.2%. 
 
In addition, fistulae that involve areas other than the GI tract have also been observed 
(e.g. tracheoesophageal, bronchopleural, urogenital, and biliary).  Events were reported at 
various time points during treatment, ranging from 1 week to 1 year following initiation 
of bevacizumab, with most events occurring within the first 6 months of therapy. 
Tracheoesophageal (TE) fistula:  Life-threatening or fatal TE fistula has been reported in 
patients with small cell lung cancer (SCLC) treated with concurrent chemoradiation and 
bevacizumab.  In a phase 2 trial of bevacizumab plus irinotecan, carboplatin, and 
radiation therapy (RT) followed by maintenance bevacizumab that accrued 25 patients, 
there have been two confirmed cases of TE fistula (one fatal) and a third case of fatal 
upper aerodigestive tract hemorrhage, with TE fistula suspected but not confirmed.  All 
three events occurred during the bevacizumab maintenance phase (1.5 to 4 months after 
completion of chemoradiation).  While pulmonary fistula (including TE fistula) has also 
been observed in advanced NSCLC or SCLC patients receiving bevacizumab and 
chemotherapy (without RT), the incidence was extremely low.   
 
Wound Healing Complications:  Bevacizumab delays wound healing in rabbits, and it 
may also compromise or delay wound healing in patients.  Bowel anastomotic dehiscence 
and skin wound dehiscence have been reported in clinical trials with bevacizumab.   
The appropriate interval between surgery and initiation of bevacizumab required to avoid 
the risk of impaired wound healing has not been determined.  Across mCRC trials, at least 
28 days must have elapsed following major surgery before bevacizumab could be 
initiated; data suggested initiation of bevacizumab 29-60 days following surgery did not 
appear to increase the risk of wound healing complications compared to those treated with 
chemotherapy alone.   
 
The optimal interval between termination of bevacizumab and subsequent elective 
surgery has not been determined.  In the pivotal study in CRC, among patients who 
underwent major surgery while on study therapy, there was an increased rate of 
significant post-operative bleeding or wound healing complications in the IFL plus 
bevacizumab arms vs. IFL alone [10% (4/40) vs. 0% (0/25)] (Scappaticci et al., 2005).  
Decisions on the timing of elective surgery should take into consideration the half-life of 
bevacizumab (average 21 days, range 11-50 days). 
 
If patients receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure.  
Patients undergoing a major surgical procedure should not begin/restart bevacizumab 
until 4 weeks after that procedure (in the case of high-risk procedures such as liver 
resection, thoracotomy, or neurosurgery, it is recommended that chemotherapy be 
restarted no earlier than 6 weeks and bevacizumab no earlier than 8 weeks after surgery). 
 
Heart failure (HF):  The risk of left ventricular dysfunction may be increased in patients 
with prior or concurrent anthracycline treatment.  In phase 3 trials in metastatic breast 
cancer (AVF 2119g) in which all patients had received prior anthracyclines, congestive 
heart failure (CHF) or cardiomyopathy were reported in 3% in the bevacizumab plus 
capecitabine arm compared to 1% in the capecitabine-only arm (Miller et al. 2005).  In a 


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Phase 3 trial of patients with previously untreated metastatic breast cancer (E2100), the 
incidence of left ventricular ejection fraction (LVEF) decrease (defined as NCI-CTC 
Grade 3 or 4) in the paclitaxel plus bevacizumab arm was 0.3% versus 0% for the 
paclitaxel alone arm  
 
In phase 2 study of 48 patients with refractory acute myelogenous leukemia treated with 
cytarabine, mitoxantrone, and bevacizumab, five cases of cardiac dysfunction (CHF) or 
LVEF decreases to <40% were reported. All but one of these subjects had significant 
prior exposure to anthracyclines as well.  Two additional studies investigated concurrent 
administration of anthracyclines and bevacizumab.  In 21 patients with inflammatory 
breast cancer treated with neoadjuvant docetaxel, doxorubicin (cumulative doses at 240 
mg/m2), and bevacizumab, no patients developed clinically apparent CHF; however, 
patients had asymptomatic decreases in LVEF to 40% (Wedam et al., 2006).  In a small 
phase 2 study in patients with soft tissue sarcoma, 2 of the 17 patients treated with 
bevacizumab and high-dose doxorubicin (75 mg/m2) developed CHF (one Grade 3 event 
after a cumulative doxorubicin dose of 591 mg/m2 and one Grade 4 event after a 
cumulative doxorubicin dose of 420 mg/m2); an additional 4 patients had asymptomatic 
decreases in LVEF (D’Adamo et al. 2004).  Patients receiving anthracyclines or with 
prior exposure to anthracyclines should have a baseline Multi Gated Acquisition Scan 
(MUGA) or echocardiogram (ECHO) with a normal ejection fraction.   
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS), Posterior Reversible 
Encephalopathy Syndrome (PRES), or similar leukoencephalopathy syndrome:  
RPLS/PRES are clinical syndromes related to vasogenic edema of the white matter and 
have rarely reported in association with bevacizumab therapy (<1%).  Clinical 
presentations may include altered mental status, seizure, visual disturbance or cortical 
blindness, with or without associated hypertension.  MRI scans are required for diagnosis.  
[Typical findings are vasogenic edema (enhanced intensity in T2 and FLAIR sequences 
on non-contrast magnetic resonance imaging [MRI]) predominantly in the white matter of 
the posterior parietal and occipital lobes, and less frequently, in the anterior distributions 
and the gray matter].   
 
RPLS/PRES is potentially reversible, but timely correction of the underlying causes, 
including control of BP and interruption of the offending drug, is important in order to 
prevent irreversible tissue damage.  The safety of reinitiating bevacizumab therapy in 
patients previously experiencing RPLS is not known (Glusker et al., 2006; Ozcan et al., 
2006).   
 
Neutropenia:  In the phase 3 trial with IFL plus or minus bevacizumab in CRC, Grade 3-4 
neutropenia was 21% with bevacizumab plus IFL vs. 14% with IFL alone (Grade 4 
neutropenia was 3% vs. 2%).  Increased rates of severe neutropenia, febrile neutropenia, 
or infection with severe neutropenia (including some fatalities) have been observed in 
patients treated with some myelotoxic chemotherapy regimens plus bevacizumab.  In a 
phase 3 trial in NSCLC, the carboplatin and paclitaxel plus bevacizumab arm was 
associated with increased rate of Grade 4 neutropenia (27% vs. 17%), febrile neutropenia 
(5.4% vs. 1.8%), and infection with neutropenia (4.4% vs. 2.0%) with three fatal cases 
(Sandler et al., 2006). 


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Bone metaphyseal dysplasia in children with active (open) growth plates:  Inhibitors of 
VEGF/VEGFR pathways have been shown to induce physeal dysplasia in juvenile 
cynomolgus monkeys with open growth plates.  Asymptomatic metaphyseal bone lesions 
were also observed in a 4.5-month old infant after 4 doses (8 weeks) of bevacizumab for 
treatment of cutaneovisceral angiomatosis with thrombocytopenia (CAT).  The 
radiographic findings included lytic lesions in the metaphyses of upper and lower 
extremity long bones, which reversed following cessation of bevacizumab (Smith et al, 
2008).  In a phase 1 pediatric study with bevacizumab, metaphyseal expansion was not 
observed in the three patients with open growth plates at baseline; however, the duration 
of treatment was limited (Bender et al., 2008).  At this time, experience is limited for 
prolonged treatment with bevacizumab in children, and no data are available for the long 
term impact of bevacizumab on growth.    
 
Additional Adverse Events:  See the bevacizumab Investigator Brochure for additional 
details regarding the safety experience with bevacizumab. 
 
Fertility and Pregnancy:  Clinical data are lacking regarding the immediate or long-term 
effect of bevacizumab on fertility and pregnancy.  However, bevacizumab is known to be 
teratogenic and detrimental to fetal development in animal models.  In addition, 
bevacizumab may alter corpus luteum development and endometrial proliferation, thereby 
having a negative effect on fertility.  As an IgG1, it may also be secreted in human milk.  
Therefore, fertile men and women on bevacizumab studies must use adequate 
contraceptive measures and women should avoid breast feeding.  The duration of such 
precautions after discontinuation of bevacizumab should take into consideration the half-
life of the agent (average 21 days, ranging from 11 to 50 days). 
 
Immunogenicity:  As a therapeutic protein, there is a potential for immunogenicity with 
bevacizumab.  With the currently available assay with limited sensitivity, high titer 
human anti-bevacizumab antibodies have not been detected in approximately 500 patients 
treated with bevacizumab. 
 
2.3 
Rationale 
 
Preclinical data illustrate the immunosuppressive effects of VEGF, which are reversed by VEGF 
blockade.  VEGF is thought to induce myeloid derive suppressor cells (MDSC), which suppress 
the anti-tumor T-cell and dendritic cell response 
(http://www.ncbi.nlm.nih.gov/pubmed/22437938). VEGF blockade may increase T cell 
trafficking to tumors, increase anti-tumor populations of T cells (CD8+ and CD4+ central 
memory) and decrease pro-tumor immune populations (myeloid-derived suppressor cells and 
regulatory T cells) (http://www.ncbi.nlm.nih.gov/pubmed/18566400, 
http://www.ncbi.nlm.nih.gov/pubmed/24018532, 
http://www.ncbi.nlm.nih.gov/pubmed/17606729, 
http://www.ncbi.nlm.nih.gov/pubmed/20631075).  In addition, anti-VEGF therapies may reduce 
suppressive cytokines, tumor-infiltrating T regulatory cells and MDSC 
(http://www.ncbi.nlm.nih.gov/pubmed/19888452). 
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
22 
 
Several clinical studies have illustrated the potential advantage of adding anti-angiogenic agents 
to checkpoint blockade therapy. A Phase II study of bevacizumab with the anti-CTLA-4 agent 
ipilimumab in melanoma showed a DCR of 67.4% and median survival of 25.1 months, which 
was substantially better than historical controls.  Furthermore, on-treatment biopsies exhibited 
inflammation and lymphocyte infiltration (http://www.ncbi.nlm.nih.gov/pubmed/24838938).  In a 
Phase Ib study of 12 patients with renal cell carcinoma treated with bevacizumab and 
atezolizumab, 40% had an objective response, which appeared to occur independent of PD-L1 
IHC staining (Figure 1, McDermott et al, ESMO 2014, Abstract 809O; Sznol et al, JClin Oncol 
33, 2015 Abstract 410).  A phase III trial is in progress (A phase III, open label, randomized 
study of atezolizumab [anti-PD-L1 antibody] in combination with bevacizumab versus sunitinib 
in patients with untreated advanced renal cell carcinoma).  Renal cell carcinomas (RCC), like 
cervix cancers, do not harbor a particularly high mutational burden, and are treated with 
bevacizumab as a standard of care.   
 
The combination of atezolizumab and bevacizumab has already provided an excellent safety 
signal.  In Study GP28328, the grade 3-5 AE rate was 1/35 patients (2.9%).  The one >= grade 3 
event was neutropenia.    
 
2.4 
Correlative Studies Background 
 
2.4.1 PD-L1 Expression (integrated biomarker) 
 
The expression of PD-L1 has been previously demonstrated to be associated with 
improved clinical benefit from therapies targeting the PD-1/PD-L1 pathway (reviewed in 
https://www.ncbi.nlm.nih.gov/pubmed/24714771). The utility of PD-L1 expression as a 
predictive biomarker, however, has been debated as it is highly dynamic and can be up-
regulated in response to immune activating factors. In this trial, tumor and immune cell 
PD-L1 staining will be evaluated by immunohistochemistry (IHC) in formalin-fixed, 
paraffin-embedded (FFPE) tumor tissue from an archived sample and a pre-treatment 
biopsy per patient. In patients in whom biopsy tissue is insufficient, this evaluation will be 
performed only on archived tissue. If responses occur predominantly in patients with PD-
L1 positive tumors, this would suggest it should be explored in larger studies; whereas, if 
there no association between PD-L1 and response, this would suggest either the sample 
size was too small to detect the association, or that there is not a strong association. 
 
2.4.2 TCR sequencing (exploratory biomarker) 
TCR sequencing (TCRSeq) will be performed on the tumor and peripheral blood 
mononuclear cells (PBMC) at baseline. Genomic DNA will be purified from total 
PBMCs; FFPE slides from pre-treatment tumor biopsy samples will be used for 
intratumoral TCR sequencing. If biopsy tissue is insufficient, archived tissue may be 
used. The TCRCDR3 regions will be amplified and sequenced using ImmunoSEQ 
technology (Adaptive Biotechnologies, Seattle, WA) as previously described 
(https://www.ncbi.nlm.nih.gov/pubmed/19706884). If baseline intratumoral or peripheral 
TCR clonality associates with response to therapy, as has been seen in other solid tumors, 
this could provide a complementary or improved biomarker relative to PD-L1. If no such 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
23 
 
association were seen, this would suggest either the sample size was too small to detect 
the association, or that there is not a strong association. 
3. PATIENT SELECTION 
 
3.1 Eligibility Criteria  
 
3.1.1 Patients must have measurable disease per RECIST 1.1.  See Section 11 for the evaluation 
of measurable disease. 
 
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥10 mm (≥1 cm) with CT scan, MRI, or 
calipers by clinical exam.  To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm (≥1.5 cm) in short axis. 
 
3.1.2 Patients must have had one prior systemic chemotherapeutic regimen for management of 
recurrent, persistent or metastatic carcinoma of the cervix (e.g.; paclitaxel/cisplatin, 
paclitaxel/cisplatin/bevacizumab), at least one of which must have contained 
bevacizumab 
 
NOTE: Patients are allowed to receive 1-2 two prior regimens for management of 
recurrent, persistent or metastatic carcinoma of the cervix.  Patients who have 
received more than two prior systemic regimens for management of recurrent, 
persistent or metastatic carcinoma of the cervix are NOT eligible. 
 
NOTE:  Prior adjuvant therapy is NOT counted as a systemic chemotherapeutic 
regimen for management of recurrent, persistent or metastatic carcinoma of the 
cervix.  Adjuvant therapy includes cisplatin given concurrent with primary radiation 
therapy (CCRT) and adjuvant chemotherapy given following the completion of 
concurrent chemotherapy and radiation therapy (e.g., paclitaxel and carboplatin for up 
to 4 cycles).   
 
3.1.3 Age ≥18 years. Because no dosing or adverse event data are currently available on the use 
of atezolizumab in combination with bevacizumab in patients <18 years of age, children 
are excluded from this study, but will be eligible for future pediatric trials. 
 
3.1.4 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
 
3.1.5 Patients must have normal organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥1,500/mcL 
− 
platelets 
≥100,000/mcL  
− 
hemoglobin 
≥9 g/dL 
− 
total bilirubin 
≤1.5 × institutional upper limit of normal (ULN) 
(however, patients with known Gilbert disease who 
have serum bilirubin level 3  ULN may be enrolled) 
− 
AST(SGOT)/ALT(SGPT) 
≤3 × ULN 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
24 
 
− 
alkaline phosphatase   
≤2.5 × ULN 
− 
creatinine  
 
 
≤1.5 × ULN  
− 
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.) 
− 
urine protein 
Must be screened by urinalysis. If protein is 2+ or 
higher, 24-hour urine protein should be obtained and the 
level should be <1000 mg for patient enrollment. 
 
3.1.6 Patient must have recurrent, persistent or metastatic cervical cancer including squamous 
cell, adenocarcinoma and adenosquamous histologies.  Mesonephric carcinoma, minimal 
deviation/adenoma malignum, clear cell carcinoma and gastric type are excluded.  
 
3.1.7 Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk 
to the human fetus, including embryo-lethality.  Women of child-bearing potential must 
agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of study participation, and for 5 months 
(150 days) after the last dose of atezolizumab.  
 
Bevacizumab is detrimental to fetal growth.  For this reason and because anti-VEGF 
inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, 
fertile women must agree to use adequate contraceptive measures during study therapy 
and for at least 6 months after the completion of bevacizumab therapy.   
 
Should a woman become pregnant or suspect she is pregnant while she is participating in 
this study, she should inform her treating physician immediately. 
 
3.1.8 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.9 Tumors within previous radiated field will be designated “non-target” lesions unless 
progression is documented or a biopsy is obtained to confirm persistence at least 90 days 
following completion of radiation therapy. 
 
3.1.10 Willingness to undergo a tumor biopsy. 
 
 
3.2 
Exclusion Criteria 
 
3.2.1 Patients with prior allogeneic bone marrow transplantation or prior solid organ 
transplantation. 
 
3.2.2 Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered 
from adverse events (other than alopecia) due to agents administered more than 4 weeks 
earlier.  However, the following therapies are allowed: 
• 
Hormone-replacement therapy or oral contraceptives 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
25 
 
• 
Herbal therapy 1 week prior to Cycle 1, Day 1 (herbal therapy intended as 
anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1) 
 
3.2.3 Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway-targeting 
agents. 
 
3.2.4 Prior treatment with anti-CTLA-4 therapeutic antibody or pathway-targeting agents. 
 
3.2.5 Treatment with any other investigational agent within 4 weeks prior to Cycle 1, Day 1. 
 
3.2.6 Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon [IFN]- or interleukin [IL]-2) within 6 weeks) prior to Cycle 1, Day 1. 
 
3.2.7 Treatment with systemic immunosuppressive medications (including, but not limited to, 
prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor 
necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1, Day 1. 
• Patients who have received acute, low dose, systemic immunosuppressant 
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. 
 
3.2.8 Patients taking bisphosphonate therapy for symptomatic hypercalcemia.  Use of 
bisphosphonate therapy for other reasons (e.g., bone metastasis or osteoporosis) is 
allowed. 
 
3.2.9 Patients with known brain metastases should be excluded from this clinical trial because 
of their poor prognosis and because they often develop progressive neurologic 
dysfunction that would confound the evaluation of neurologic and other adverse events. 
 
3.2.10 Known hypersensitivity to Chinese hamster ovary cell products or other recombinant 
human antibodies. 
 
3.2.11 History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or 
humanized antibodies or fusion proteins. 
 
3.2.12 History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to bevacizumab or atezolizumab. 
 
3.2.13 Known clinically significant liver disease, including active viral, alcoholic, or other 
hepatitis; cirrhosis; fatty liver; 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 
hepatitis B core antigen] antibody test) are eligible. 
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if 
polymerase chain reaction (PCR) is negative for HCV RNA. 
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
26 
 
3.2.14 History or risk of autoimmune disease, including, but not limited to, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis 
associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s 
syndrome, Bell’s palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid 
disease, vasculitis, or glomerulonephritis. 
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid 
replacement hormone may be eligible. 
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may 
be eligible. 
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis would be 
excluded) are permitted provided that they meet the following conditions: 
o Patients with psoriasis must have a baseline ophthalmologic exam to rule out 
ocular manifestations 
o Rash must cover less than 10% of body surface area (BSA) 
o Disease is well controlled at baseline and only requiring low potency topical 
steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, 
flucinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) 
o No acute exacerbations of underlying condition within the last 12 months 
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral 
steroids) 
 
3.2.15 History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), 
organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, 
etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) 
scan.  History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 
 
3.2.16 Patients with active tuberculosis (TB) are excluded. 
 
3.2.17 Severe infections within 4 weeks prior to Cycle 1, Day 1, including, but not limited to, 
hospitalization for complications of infection, bacteremia, or severe pneumonia. 
 
3.2.18 Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1. 
 
3.2.19 Received oral or intravenous (IV) antibiotics within 2 weeks prior to Cycle 1, Day 1.  
Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection 
or chronic obstructive pulmonary disease) are eligible. 
 
3.2.20 Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need 
for a major surgical procedure during the course of the study. 
 
3.2.21 Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or 
anticipation that such a live, attenuated vaccine will be required during the study and up 
to 5 months after the last dose of aztezolizumab. 
• Influenza vaccination should be given during influenza season only 
(approximately October to March).  Patients must not receive live, attenuated 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
27 
 
influenza vaccine within 4 weeks prior to Cycle 1, Day 1 or at any time during the 
study. 
 
3.2.22 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.23 Patients positive for human immunodeficiency virus (HIV) are NOT excluded from this 
study, but HIV-positive patients must have: 
a. A stable regimen of highly active anti-retroviral therapy (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 
 
3.2.24 Pregnant women are excluded from this study because atezolizumab and/or bevacizumab 
are agents with the potential for teratogenic or abortifacient effects.  Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to treatment of 
the mother with atezolizumab and/or bevacizumab, breastfeeding should be discontinued 
if the mother is treated with atezolizumab and/or bevacizumab. 
 
3.2.25 Malignancies other than the cervical cancer within 5 years prior to cycle 1, day 1, with the 
exception of those with a negligible risk of metastasis or death, such as adequately 
controlled basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in 
situ of the breast. 
 
3.2.26 Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent 
peripheral arterial thrombosis) within 6 months prior to Day 1. 
 
3.2.27 Patients with clinically significant cardiovascular disease are excluded.  
• Inadequately controlled HTN (SBP ≥160mmHg and/or DBP ≥90 mmHg despite 
antihypertensive medication) 
• History of CVA within 6 months 
• Myocardial infarction or unstable angina within 6 months 
• New York heart association class II or greater congestive heart failure  
• Serious and inadequately controlled cardiac arrhythmia 
• Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection) 
• Clinically significant peripheral vascular disease 
 
3.2.28 History of abdominal/pelvic fistula, gastrointestinal perforation and/or intraabdominal 
abscess within 6 months prior to day 1. 
 
3.2.29 Evidence of bleeding diathesis or clinically significant coagulopathy. 
 
3.2.30 Serious or non-healing wound, active ulcer or bone fracture. 
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
28 
 
3.2.31 Patients requiring treatment with a RANKL inhibitor (e.g. denosumab) who cannot 
discontinue it before treatment with atezolizumab. 
 
3.3 
Inclusion of Minorities 
 
NIH policy requires that members of minority groups and their subpopulations be included in all 
NIH-supported biomedical and behavioral research projects involving NIH-defined clinical 
research unless a clear and compelling rationale and justification establishes to the satisfaction of 
the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the 
health of the subjects or the purpose of the research.  Exclusion under other circumstances must 
be designated by the Director, NIH, upon the recommendation of an IC Director based on a 
compelling rationale and justification.  Cost is not an acceptable reason for exclusion except 
when the study would duplicate data from other sources.  Women of childbearing potential 
should not be routinely excluded from participation in clinical research.  Please see 
http://grants.nih.gov/grants/funding/phs398/phs398.pdf. 
 
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
2 
0 
0 
0 
2 
Native Hawaiian or 
Other Pacific Islander 
 
 
 
 
 
Black or African 
American 
2 
0 
2 
0 
4 
White 
12 
0 
2 
0 
14 
More Than One Race 
1 
0 
1 
0 
2 
Total 
17 
0 
5 
0 
22 
PHS 398 / PHS 2590 (Rev. 08/12 Approved Through 8/31/2015)  
OMB No. 0925-0001/0002 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
Investigator and Research Associate Registration with CTEP 
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
29 
 
4.1.1 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. 
 
Registration requires the submission of: 
 
• a completed Statement of Investigator Form (FDA Form 1572) with an original 
signature 
• a current Curriculum Vitae (CV) 
• a completed and signed Supplemental Investigator Data Form (IDF) 
• a completed Financial Disclosure Form (FDF) with an original signature 
 
Fillable PDF forms and additional information can be found on the CTEP website at 
http://ctep.cancer.gov/investigatorResources/investigator_registration.htm. 
 
For questions about Investigator Registration, please contact the CTEP Investigator 
Registration Help Desk by email at pmbregpend@ctep.nci.nih.gov. 
 
4.1.2 CTEP Associate Registration Procedures / CTEP-IAM Account 
 
The Cancer Therapy Evaluation Program (CTEP) Identity and Access Management 
(IAM) application is a web-based application intended for use by both Investigators (i.e., 
all physicians involved in the conduct of NCI-sponsored clinical trials) and Associates 
(i.e., all staff involved in the conduct of NCI-sponsored clinical trials). 
 
Associates will use the CTEP-IAM application to register (both initial registration and 
annual re-registration) with CTEP and to obtain a user account. 
 
Investigators will use the CTEP-IAM application to obtain a user account only.  (See 
CTEP Investigator Registration Procedures above for information on registering with 
CTEP as an Investigator, which must be completed before a CTEP-IAM account can be 
requested.) 
 
An active CTEP-IAM user account is required to access all CTEP applications and, if 
applicable (e.g., all Network trials), all Cancer Trials Support Unit (CTSU) applications 
and websites. 
 
Additional information can be found on the CTEP website at 
http://ctep.cancer.gov/branches/pmb/associate_registration.htm. 
 
For questions about Associate Registration or CTEP-IAM Account Creation, please 
contact the CTEP Associate Registration Help Desk by email at 
ctepreghelp@ctep.nci.nih.gov. 
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
30 
 
4.2 
Site Registration 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
Each investigator or group of investigators at a clinical site must obtain IRB approval for this 
protocol and submit IRB approval and supporting documentation to the CTSU Regulatory Office 
before they can be approved to enroll patients.  Assignment of site registration status in the 
CTSU Regulatory Support System (RSS) uses extensive data to make a determination of whether 
a site has fulfilled all regulatory criteria including but not limited to: an active Federal Wide 
Assurance (FWA) number, an active roster affiliation with the Lead Network or a participating 
organization, a valid IRB approval, and compliance with all protocol specific requirements. 
 
Sites participating on the NCI CIRB initiative that are approved by the CIRB for this study are 
not required to submit IRB approval documentation to the CTSU Regulatory Office. For sites 
using the CIRB, IRB approval information is received from the CIRB and applied to the RSS in 
an automated process.  Signatory Institutions must submit a Study Specific Worksheet for Local 
Context (SSW) to the CIRB via IRBManager to indicate their intent to open the study locally.  
The CIRB’s approval of the SSW is then communicated to the CTSU Regulatory Office.  In 
order for the SSW approval to be processed, the Signatory Institution must inform the CTSU 
which CIRB-approved institutions aligned with the Signatory Institution are participating in the 
study. 
 
4.2.1 Downloading Regulatory Documents 
 
Site registration forms may be downloaded from the NCI protocol #10010 protocol page 
located on the CTSU Web site.  Permission to view and download this protocol is 
restricted and is based on person and site roster data housed in the CTSU RSS.  To 
participate, Investigators and Associates must be associated with the Corresponding or 
Participating protocol organization in the RSS.  
 
• Go to https://www.ctsu.org and log in using your CTEP-IAM username and 
password. 
• Click on the Protocols tab in the upper left of your screen.  
• Either enter the protocol # in the search field at the top of the protocol tree, or 
• Click on the By Lead Organization folder to expand, then select LAO-MD017, 
and protocol NCI Protocol # 10010. 
• Click on LPO Documents, select the Site Registration documents link, and 
download and complete the forms provided.  (Note: For sites under the CIRB 
initiative, IRB data will automatically load to RSS.) 
 
4.2.2 Requirements For NCI protocol #10010 Site Registration: 
 
• CTSU Transmittal Sheet (optional) 
• IRB approval (For sites not participating via the NCI CIRB; local IRB 
documentation, an IRB-signed CTSU IRB Certification Form, Protocol of Human 
Subjects Assurance Identification/IRB Certification/Declaration of Exemption 
Form, or combination is accepted ) 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
31 
 
 
4.2.3 Submitting Regulatory Documents 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be 
entered and tracked in the CTSU RSS.   
ONLINE:  www.ctsu.org (members’ section) → Regulatory Submission Portal 
(Note:  Use of the Regulatory Submission Portal will be mandatory 
beginning in early 2017.) 
EMAIL:    CTSURegulatory@ctsu.coccg.org (for regulatory document submission 
only) 
FAX:    
215-569-0206 
MAIL:  
CTSU Regulatory Office 
       
1818 Market Street, Suite 1100 
       
Philadelphia, PA 19103 
 
4.2.4 Checking Site Registration Status 
 
You can verify your site registration status on the members’ section of the CTSU website.   
 
• Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM 
username and password 
• Click on the Regulatory tab at the top of your screen 
• Click on the Site Registration tab 
• Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional 
compliance with protocol-specific requirements as outlined by the Lead Network. 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 
Patient Registration 
 
4.3.1 OPEN / IWRS 
 
Patient enrollment will be facilitated using the Oncology Patient Enrollment Network 
(OPEN).  OPEN is a web-based registration system available to users on a 24/7 basis.  It 
is integrated with the CTSU Enterprise System for regulatory and roster data interchange 
and with the Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment.  Patient enrollment data entered by Registrars in 
OPEN / IWRS will automatically transfer to the NCI’s clinical data management system, 
Medidata Rave. 
 
The OPEN system will provide the site with a printable confirmation of registration and 
treatment information.  Please print this confirmation for your records.  
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
32 
 
4.3.2 OPEN/IWRS User Requirements 
 
OPEN/IWRS users must meet the following requirements: 
• Have a valid CTEP-IAM account (i.e., CTEP username and password). 
• To enroll patients or request slot reservations:  Be on an ETCTN Corresponding or 
Participating Organization roster with the role of Registrar. 
• To approve slot reservations or access cohort management:  Be identified to 
Theradex as the “Client Admin” for the study.  
• Have regulatory approval for the conduct of the study at their site. 
 
Prior to accessing OPEN/IWRS, site staff should verify the following: 
• All eligibility criteria have been met within the protocol stated timeframes.   
• If applicable, all patients have signed an appropriate consent form and HIPAA 
authorization form. 
 
4.3.3 OPEN/IWRS Questions? 
 
Further instructional information on OPEN is provided on the OPEN tab of the CTSU 
website at 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.  
 
4.4 
General Guidelines 
 
Following registration, patients should begin protocol treatment within 5 days.  Issues that would 
cause treatment delays should be discussed with the Principal Investigator.  If a patient does not 
receive protocol therapy following registration, the patient’s registration on the study may be 
canceled.  The Study Coordinator should be notified of cancellations as soon as possible. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration 
 
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the patient's 
malignancy. 
 
Enrolled patients with initiate treatment with atezolizumab and bevacizumab beginning Day 1 of 
Cycle 1.  A cycle is 21 days.  See below for details regarding administration of each agent.  
Atezolizumab will be administered first, followed by bevacizumab. 
 
While on study, patients will return for assessments every week during the first cycle, then every 
3 weeks. 
 
Patients that require discontinuation of one study agent (atezolizumab or bevacizumab), but meet 
criteria to continue the other study agent (atezolizumab or bevacizumab) may do so after 
discussion with the study chair. 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
33 
 
 
During screening, every 9 weeks (+/- 7 days) for the first year then every 12 weeks (+/-7 days), 
and at the end of study, patients will have a CT or MRI of the abdomen and pelvis and a CT of 
the chest performed.  
 
A patient will be permitted to have a new cycle of chemotherapy delayed up to 7 days (without 
this being considered to be a protocol violation) for major life events (e.g., serious illness in a 
family member, major holiday, vacation which is unable to be re-scheduled).  Documentation to 
justify this decision should be provided. 
 
It will be acceptable for a new cycle of therapy (and all associated tests and procedures) to be 
delivered within a 3 day window before and after the protocol defined date. 
 
5.1.1 Atezolizumab 
 
Administration of atezolizumab will be performed in a setting with emergency medical 
facilities and staff who are trained to monitor for and respond to medical emergencies. 
 
The initial dose of atezolizumab will be delivered over 60 (15) minutes.  If the 
first infusion is tolerated without infusion-associated AEs, the second infusion may be 
delivered over 30 (10) minutes.  If the 30-minute infusion is well tolerated, 
all subsequent infusions may be delivered over 30 (10) minutes. Anaphylactic 
precautions should be observed during atezolizumab administration. 
Premedication is not permitted for the first dose of atezolizumab.  Premedication with 
antihistamines or antipyretics/analgesics (e.g., acetaminophen) may be administered for 
subsequent infusions at the discretion of the treating physician.  The management of 
Infusion Related Reactions will be according to severity as per Table 6: Management 
Guidelines for Infusion-Related Reactions. 
 
5.1.2 Bevacizumab 
 
Bevacizumab is administered by intravenous (IV) infusion.  The dose should be based on 
the patient’s actual body weight; the dose will be recalculated if there is a weight change 
of >10% from baseline. 
 
Bevacizumab doses can be “rounded” according to institutional standards without being 
considered a protocol violation (most institutions use a rule of approximately +/- 5% of 
the calculated dose). 
 
The first dose of bevacizumab should be given over 90 minutes.  If well tolerated, the 
second dose can be given over 60 minutes.  If this dose is well-tolerated, then all 
subsequent infusions can be administered over 30 minutes.  If an infusion reaction occurs, 
subsequent doses of bevacizumab should be administered over the shortest period that 
was well tolerated.  
 
Special Precautions/Safety Issues: 
Prior to each treatment, the patient should be carefully assessed with special attention to 


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BP, proteinuria, bleeding and cardiovascular events, as well as symptoms or signs of 
bowel perforation and RPLS.  Decisions for retreatment or dose modification/interruption 
should follow the dose modification guidelines. 
 
Patients who have an ongoing study agent-related SAE upon study completion or at 
discontinuation from the study will be contacted by the investigator or his/her designee 
periodically until the event is resolved or determined to be irreversible. 
 
Infusional reactions:  Routine premedication is not required for the first dose of 
bevacizumab.  If infusional reactions occur, acetaminophen, diphenhydramine, steroids, 
or other medications may be given for symptom control and for premedication as needed.  
Anaphylactic precautions should be observed during bevacizumab administration. 
 
Hypertension:   Patients should have BP monitored prior to each infusion of bevacizumab.  
Hypertensive mediation should be initiated or increased for optimal BP control according 
to standard public heath guidelines. 
 
Proteinuria:  Proteinuria should be monitored per protocol. 
 
Surgery and wound complication issues and surgery:  The appropriate interval from 
discontinuation of bevacizumab to subsequent elective surgery required to reduce the risk 
of impaired wound healing has not been determined.  Decision on such an interval should 
take into consideration the half-life of bevacizumab.  It is generally recommended that 
bevacizumab should be discontinued at least 4-8 weeks prior to major elective surgery.  In 
addition, bevacizumab should not be restarted until at least 4 weeks after major surgery 
provided that the wound has adequately healed; in cases of high risk procedures such as 
liver resection, thoracotomy, or neurosurgery, it is recommended that bevacizumab be 
resumed no earlier than 8 weeks after surgery. 
 
5.1.3 Other Modality(ies) or Procedures 
 
N/A 
 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
 
5.2.1 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 screening evaluation and 
the treatment discontinuation visit. 
 
Patients who experience infusion-associated symptoms may be treated symptomatically 
with acetaminophen, ibuprofen, diphenhydramine, and/or cimetidine or another H2 
receptor antagonist, as per standard practice (for sites outside the United States, 
equivalent medications may be substituted per local practice).  Serious infusion associated 
events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, 
reduced oxygen saturation, or respiratory distress should be managed with supportive 


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therapies as clinically indicated (e.g., supplemental oxygen and 2-adrenergic agonists; 
see Section 5.1.1). 
 
Systemic corticosteroids and TNF inhibitors may attenuate potential beneficial 
immunologic effects of treatment with atezolizumab but may be administered at the 
discretion of the treating physician.  If feasible, alternatives to corticosteroids should be 
considered.  Premedication may be administered for Cycles ≥2 at the discretion of the 
treating physician.  The use of inhaled corticosteroids and mineralocorticoids (e.g., 
fludrocortisone) for patients with orthostatic hypotension or adrenocortical insufficiency 
is allowed.  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), or other allowed maintenance therapy (see Section 3.2) should 
continue their use.  Females of reproductive potential should use highly effective means 
of contraception. 
 
5.2.2 Atezolizumab Excluded Therapies 
 
Any concomitant therapy intended for the treatment of cancer, whether health 
authority-approved or experimental, is prohibited.  This includes but is not limited to the 
following: 
• Chemotherapy, hormonal therapy, immunotherapy, radiotherapy, investigational 
agents, or herbal therapy (except for maintenance therapies outlined in Section 3.2 
and Section 5.2.1). 
 
It is strongly recommended that:  
• Traditional herbal medicines not be administered because the ingredients of many 
herbal medicines are not fully studied and their use may result in unanticipated 
drug-drug interactions that may cause, or confound assessment of, toxicity. 
• The use of a RANKL inhibitor (denosumab) be discontinued during the study; 
this agent could potentially alter the activity and the safety of atezolizumab. 
 
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 for patients with solid malignancies. 
 
Patients are not allowed to receive immunostimulatory agents, including, but not limited 
to, IFN-, IFN-, or IL-2, during the entire study.  These agents, in combination with 
atezolizumab, could potentially increase the risk for autoimmune conditions. 
 
Patients should 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.  Systemic 
corticosteroids and anti-TNF agents may attenuate potential beneficial immunologic 
effects of treatment with atezolizumab but may be administered at the discretion of the 


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treating physician.  If feasible, alternatives to these agents should be considered. 
 
In addition, all patients (including those who discontinue the study early) should not 
receive other immunostimulatory agents for 10 weeks after the last dose of atezolizumab. 
 
5.3 
Duration of Therapy 
 
In the absence of treatment delays due to adverse event(s), treatment may continue for an 
unlimited number of cycles or until one of the following criteria applies: 
 
• 
Disease progression, 
• 
Intercurrent illness that prevents further administration of treatment, 
• 
Unacceptable adverse event(s), 
• 
Patient decides to withdraw from the study, or 
• 
General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
 
5.3.1 Treatment Beyond Progression 
 
Refer to Appendix B for samples.  
 
Treatment may be continued in cases of radiologic progression at the first 9 week (+/- 7 days) CT 
if all of the following criteria are satisfied: 
• No decrease in performance status 
• No requirement for immediate alternative treatment or urgent palliative treatment 
• Progression limited to an increase of 40% in the sum of diameters of target lesions 
(including up to 4 new lesions added to the sum) 
• No more than 4 new lesions included in the sum. 
 
NOTE:  If treatment is continued in the case of radiologic progression at the first 9 week 
(+/- 7 days) CT, a reassessment scan must be performed at 4 weeks (+/- 7 days) to rule out 
ongoing progression. 
 
For patients who continue treatment in the case of radiologic progression at the first 9 week (+/- 7 
days) CT: 
• At any subsequent CT scan patients who have stable disease as compared to the 9 
week (+/- 7 days) CT scan will be allowed to continue on study treatment. 
• Patients who continue treatment in the case of radiologic progression at the first 9 
week (+/- 7 days) CT, and later experience a PR or CR (as compared to baseline CT) 
will be recorded as delayed responses. 
 
5.4 
Duration of Follow Up 
 
Patients will be followed for vital status every 3 months for two years, after removal from 
treatment or until death, whichever occurs first.  The every three month follow up for two years 
can be by phone call or clinic visit.  Follow-up will cease when study is terminated.  Patients 
removed from treatment for unacceptable adverse event(s) will be followed until resolution or 


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stabilization of the adverse event. 
 
5.5 
Criteria for Removal from Study 
 
Patients will be removed from treatment when any of the criteria listed in Section 5.3 applies.  
The reason for treatment and study removal and the date the patient was removed must be 
documented in the Case Report Form. 
 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
NOTE:  Patients that require discontinuation of one study agent (atezolizumab or bevacizumab), 
but meet criteria to continue the other study agent (atezolizumab or bevacizumab) may do so 
after discussion with the study chair. 
 
NOTE:  Upon occurrence of perforation and/or fistula (defined below) study therapy should be 
held, and the Study Chair and Research Coordinator should be notified within 48 hours.  CTEP 
will be notified within 7 days of study chair notification of each instance of perforation and/or 
fistula.  The study chair will consult CTEP and the study statistician to review the history of the 
affected patient and the perforation and/or fistula toxicities for the trial as a whole before 
proceeding with the recommendation to resume protocol therapy for the affected patient with 
single agent atezolizumab.  Per section 6.2.2 below, bevacizumab must be discontinued for 
perforation (GI, or any other organ), any grade AND/OR fistula (GI, pulmonary or any other 
organ), any grade.  
 
Definition of perforation and fistula: 
• Perforation (GI, or any other organ), any grade 
• Fistula (GI, pulmonary or any other organ), any grade 
 
6.1 
Atezolizumab (MPDL3280A) 
 
6.1.1 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. 
 
Please note:  Tumor measurements must continue on schedule (see study calendar, section 
10.1) during temporary suspension (Tumor measurements are repeated every 9 weeks (+/- 
7 days) for 12 months, then every 12 weeks (+/- 7 days) thereafter.).  Patients with 
progression will be discontinued from study treatment. 


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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. 
 
Atezolizumab must be permanently discontinued if the patient experiences any of the 
following events, regardless of benefit: 
 
• Grade 4 pneumonitis 
• AST or ALT >5×ULN or total bilirubin >3×ULN  
• Grade 4 diarrhea or colitis 
• Grade 4 hypophysitis 
• Any grade myasthenic syndrome/myasthenia gravis, Guillain-Barré or 
meningoencephalitis 
• Grade 4 ocular inflammatory toxicity 
• Grade 4 pancreatitis or any grade of recurrent pancreatitis 
• Grade 4 rash 
• Any grade myocarditis 
 
Treatment may, under limited and compelling circumstances, be resumed in patients who 
have recovered from the following events, but only after consultation with the trial 
Principal Investigator: 
• Grade 3 pneumonitis 
• Grade 3 ocular inflammatory toxicity 
• Grade 3 or 4 infusion-related reactions 
 
Any toxicities associated or possibly associated with atezolizumab treatment should be 
managed according to standard medical practice.  Additional tests, such as autoimmune 
serology or biopsies, may be used to determine a possible immunogenic etiology.  
Although most immune-related adverse events (irAEs) observed with immunomodulatory 
agents have been mild and self-limiting, such events should be recognized early and 
treated promptly to avoid potential major complications (Di Giacomo et al., 2010).  
Discontinuation of atezolizumab may not have an immediate therapeutic effect, and there 
is no available antidote for atezolizumab.  In severe cases, immune-related toxicities may 
be acutely managed with topical corticosteroids, systemic corticosteroids, or other 
immunosuppressive agents. The investigator should consider the benefit-risk balance 
prior to further administration of atezolizumab. 
For detailed information regarding management of adverse events 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 


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a given patient may be experiencing prior to 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 
prior to, during, and after each infusion.  If unmanageable toxicity due to atezolizumab 
occurs at any time during the study, treatment with atezolizumab should be discontinued. 
 
Systemic Immune Activation 
 
Systemic immune activation is a rare condition characterized by an excessive immune 
response. Given the mechanism of action of atezolizumab, systemic immune activation is 
considered a potential risk when given in combination with other immunomodulating 
agents.  Systemic immune activation should be included in the differential diagnosis for 
patients who, in the absence of an alternative etiology, develop a sepsis-like syndrome 
after administration of atezolizumab, and the initial evaluation should include the 
following: 
• CBC with peripheral smear 
• PT, PTT, fibrinogen, and D-dimer 
• Ferritin 
• Triglycerides 
• AST, ALT, and total bilirubin 
• LDH 
• Complete neurologic and abdominal examination (assess for hepatosplenomegaly) 
 
If systemic immune activation is still suspected after the initial evaluation, contact the 
Principal Investigator for additional recommendations. 
 
 
6.1.2 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 Table 6 for guidelines for the 
management of Infusion Related Reactions and Anaphylaxis. 
 
For recommendations to hold atezolizumab and begin corticosteroid treatment, use the following 
guidance for tapering the corticosteroid and resuming atezolizumab therapy after resolution of the 
event: 
 
• Corticosteroids must be tapered over 1 month to 10 mg/day oral prednisone or 
equivalent before atezolizumab can be resumed. 
• Atezolizumab may be held for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to 10 mg/day oral prednisone or equivalent. 
 
 
 
1. Pulmonary Events 


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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.   
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, heart 
failure, chronic obstructive pulmonary disease, or pulmonary hypertension.  Management 
guidelines for pulmonary events are provided in Table 1. 
Table 1: Management Guidelines for Pulmonary Events, Including Pneumonitis 
Event 
Management 
Pulmonary event, 
Grade 1  
• 
Continue atezolizumab and monitor closely. 
• 
Re-evaluate on serial imaging. 
• 
Consider patient referral to pulmonary specialist. 
• 
For recurrent pneumonitis, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 2 
• 
Withhold atezolizumab. 
• 
Refer patient to pulmonary and infectious disease specialists and 
consider bronchoscopy or BAL. 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 
Resume atezolizumab if event resolves to Grade 1 or better within 12 
weeks. a, b 
• 
Permanently discontinue atezolizumab and contact Study Chair if 
event does not resolve to Grade 1 or better within 12 weeks.a, b, c 
• 
For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact Study Chair. c 
• 
Bronchoscopy or BAL is recommended. 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or equivalent. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over  1 
month. 
Myocarditis 
All grades 
• 
Permanently discontinue atezolizumab. Patient may not resume 
treatment, regardless of benefit. 
BAL = bronchoscopic alveolar lavage; IVIG = intravenous immunoglobulin 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids 
to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.  
 
 
2. Hepatic Events 


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Immune-related hepatitis has been associated with the administration of atezolizumab.  Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin and 
hepatic transaminases, and liver function will be monitored throughout study treatment.  
Management guidelines for hepatic events are provided in Table 2. 
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have LFTs performed immediately and reviewed before administration of the next dose 
of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate. 
Table 2: Management Guidelines for Hepatic Events 
Event 
Management 
Hepatic event, 
Grade 1 
• 
Continue atezolizumab. 
• 
Monitor LFTs until values resolve to within normal limits.  
Hepatic event, 
Grade 2 
All events: 
• 
Monitor LFTs more frequently until return to baseline 
values.  
Events of   5 days’ duration: 
• 
Withhold atezolizumab. 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
• 
Resume atezolizumab if event resolves to Grade 1 or 
better within 12 weeks. a, b 
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better within 
12 weeks.a, b, c 
Hepatic event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact Study 
Chair. c 
• 
Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury.  
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
LFT = liver function tests. 
a If corticosteroids have been initiated, they must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.   


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3. Gastrointestinal Events 
Immune-related colitis has been associated with the administration of atezolizumab.  
Management guidelines for diarrhea or colitis are provided in Table 3. 
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 CRP, 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.  


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Table 3: Management Guidelines for Gastrointestinal Events  


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Event 
Management 
Acute abdominal 
pain 
• 
Symptoms of abdominal pain associated with elevations of 
amylase and lipase, suggestive of pancreatitis, have been 
associated with administration of other immunomodulatory 
agents.  The differential diagnosis of acute abdominal pain 
should include pancreatitis.  Appropriate workup should 
include an evaluation for obstruction, as well as serum 
amylase and lipase tests.  See the guidelines for “Amylase 
and/or lipase increase” and “Immune-related pancreatitis” 
elsewhere in this table, as needed. 
• 
Right upper-quadrant abdominal pain and/or unexplained 
nausea or vomiting should be evaluated for potential 
hepatotoxicity (see the “Hepatotoxicity” guideline elsewhere 
in this table). 
Diarrhea or 
colitis, Any 
grade 
• 
Patients should be advised to inform the investigator if any 
diarrhea occurs, even if it is mild. 
• 
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 CRP, 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. 
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. 
• 
Initiate symptomatic treatment. 
• 
Patient referral to GI specialist is recommended. 
• 
For recurrent events or events that persist  5 days, initiate 
treatment with 1−2 mg/kg/day oral prednisone or equivalent.  
• 
Resume atezolizumab if event resolves to Grade 1 or better 
within 12 weeks. a,b 
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better within 12 
weeks.a,b,c 


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Diarrhea or 
colitis, Grade 3 
• 
Withhold atezolizumab. 
• 
Refer patient to gastrointestinal specialist for evaluation and 
confirmatory biopsy. 
• 
Initiate treatment with 1−2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
Resume atezolizumab if event resolves to Grade 1 or better 
within 12 weeks. a, b 
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better within 12 
weeks.a, b, c 


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Table 3: Management Guidelines for Gastrointestinal Events (cont.) 
 
Event 
Management 
Diarrhea or 
colitis, Grade 4 
• 
Permanently discontinue atezolizumab and contact Study Chair. 
Patient may not resume treatment, regardless of benefit. 
• 
Refer patient to gastrointestinal specialist for evaluation and 
confirmation biopsy. 
• 
Initiate treatment with 1−2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 1−2 mg/kg/day 
oral prednisone or equivalent upon improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.   
 
 
4. Endocrine Events 
Thyroid disorders or adrenal insufficiency has been associated with the administration of 
atezolizumab.  Management guidelines for endocrine events are provided in Table 4. 
Patients with unexplained symptoms such as fatigue, myalgias, impotence, mental status 
changes, or constipation should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies.  The patient should be referred to an endocrinologist if an endocrinopathy is 
suspected.  Thyroid-stimulating hormone (TSH) and free T3 and T4 levels should be measured 
to determine whether thyroid abnormalities are present.  TSH, prolactin, and a morning cortisol 
level will help to differentiate primary adrenal insufficiency from primary pituitary insufficiency. 


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Table 4: Management Guidelines for Endocrine Events 
Event 
Management 
Asymptomatic 
hypothyroidism, Grade 1 
• 
Continue atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH weekly. 
Symptomatic 
hypothyroidism, Grade 
2+ 
• 
Withhold atezolizumab. 
• 
Initiate treatment with thyroid replacement hormone. 
• 
Monitor TSH weekly. 
• 
Consider patient referral to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
Asymptomatic 
hyperthyroidism, Grade 1 
TSH  0.1 mU/L and  0.5 mU/L: 
• 
Continue atezolizumab. 
• 
Monitor TSH every 4 weeks. 
TSH  0.1 mU/L: 
• 
Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic 
hyperthyroidism, Grade 
2+ 
• 
Withhold atezolizumab. 
• 
Initiate treatment with anti-thyroid drug such as methimazole 
or carbimazole as needed. 
• 
Consider patient referral to endocrinologist. 
• 
Resume atezolizumab when symptoms are controlled and 
thyroid function is improving. 
• 
Permanently discontinue atezolizumab and contact Study 
Chair for life-threatening immune-related hyperthyroidism. c 
Symptomatic adrenal 
insufficiency, Grade 2−4  
• 
Withhold atezolizumab.a 
• 
Refer patient to endocrinologist. 
• 
Perform appropriate imaging. 
• 
Initiate treatment with 1−2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
Resume atezolizumab if event resolves to Grade 1 or better 
and patient is stable on replacement therapy (if required) 
within 12 weeks. a, b  
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better or patient 
is not stable on replacement therapy within 12 weeks.a, b, c 
Hyperglycemia,  Grade 1 
or 2  
• 
Continue atezolizumab. 
• 
Initiate treatment with insulin if needed. 
• 
Monitor for glucose control. 


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Table 4: Management Guidelines for Endocrine Events (cont.) 
Hyperglycemia, 
Grade 3 or 4 
• 
Withhold atezolizumab. 
• 
Initiate treatment with insulin. 
• 
Monitor for glucose control. 
• 
Resume atezolizumab when symptoms resolve and glucose 
levels are stable. 
TSH = thyroid-stimulating hormone;  
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day oral 
prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids 
to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.   
 
5. Ocular events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events).  
Management guidelines for ocular events are provided in Table 5. 


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Table 5: Management Guidelines for Ocular Events 
Event 
Management 
Ocular event, 
Grade 1  
• 
Continue atezolizumab. 
• 
Patient referral to ophthalmologist is strongly recommended. 
• 
Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• 
If symptoms persist, treat as a Grade 2 event. 
Ocular event, 
Grade 2 
• 
Withhold atezolizumab. 
• 
Patient referral to ophthalmologist is strongly recommended. 
• 
Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
• 
Resume atezolizumab if event resolves to Grade 1 or better 
within 12 weeks. a, b 
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better within 
12 weeks.a, b, c 
Ocular event, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact Study 
Chair. c 
• 
Refer patient to ophthalmologist. 
• 
Initiate treatment with 1−2 mg/kg/day oral prednisone or 
equivalent.   
• 
If event resolves to Grade 1 or better, taper corticosteroids 
over  1 month. 
a If corticosteroids have been initiated, they must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.   
 
6. Infusion-Related Reactions 
No premedication is indicated for the administration of Cycle 1 of atezolizumab.  However, 
patients who experience an infusion-related reaction with Cycle 1 of atezolizumab may receive 
premedication with antihistamines or antipyretics/analgesics (e.g., acetaminophen) for 
subsequent infusions. 
Guidelines for medical management of infusion-related reactions during Cycle 1 are provided in 
Table 6.  For subsequent cycles, infusion-related reactions should be managed according to 
institutional guidelines. 
 


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Table 6: Management Guidelines for Infusion-Related Reactions 
Event 
Management 
IRR, Grade 1 
during Cycle 1 
• 
Reduce infusion rate to half the rate being given at the time 
of event onset. 
• 
After the event has resolved, the investigator should wait for 
30 minutes while delivering the infusion at the reduced rate. 
• 
If the infusion is tolerated at the reduced rate for 30 minutes 
after symptoms have resolved, the infusion rate may be 
increased to the original rate. 
IRR, Grade 2 or 
flushing, fever, or 
throat pain 
• 
Interrupt atezolizumab infusion. 
• 
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
• 
After symptoms have resolved to baseline, resume infusion 
at half the rate being given at the time of event onset. 
• 
For subsequent infusions, administer oral premedication with 
antihistamine and anti-pyretic and monitor closely for IRRs. 
IRR, Grade 3 or 4 
• 
Stop infusion. 
• 
Administer aggressive symptomatic treatment (e.g., oral or IV 
antihistamine, anti-pyretic, glucocorticoids, epinephrine, 
bronchodilators, oxygen). 
• 
Permanently discontinue atezolizumab and contact Study 
Chair.a 
IRR = infusion-related reaction; IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.   
 
7. Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of atezolizumab.  The differential 
diagnosis of acute abdominal pain should include pancreatitis.  Appropriate work-up should 
include an evaluation for ductal obstruction, as well as serum amylase and lipase tests.  
Management guidelines for pancreatic events, including pancreatitis, are provided in Table 7. 
 


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Table 7: Management Guidelines for Pancreatic Events, Including Pancreatitis  
Event 
Management 
Amylase and/or lipase 
increased, Grade 1 
• 
Continue atezolizumab 
• 
Monitor amylase and lipase prior to dosing 
Amylase and/or lipase 
increased, Grade 2 
• 
Continue atezolizumab 
• 
Monitor amylase and lipase weekly 
• 
For prolonged elevation (e.g., 3 weeks), consider 
treatment with 10 mg/day oral prednisone or equivalent. 
Amylase and/or lipase 
increased, Grade 3 or 4 
• 
Hold atezolizumab. 
• 
Refer patient to gastrointestinal (GI) specialist. 
• 
Monitor amylase and lipase every other day. 
• 
If no improvement, consider treatment with 
1−2 mg/kg/day oral prednisone or equivalent. 
• 
If event resolves to grade 1 or better within 12 weeks, 
taper corticosteroids and resume atezolizumab 
according to the guidelines above. 
• 
Permanently discontinue atezolizumab if event does not 
resolve to grade 1 or better within 12 weeks. 
• 
For recurrent events, permanently discontinue 
atezolizumab. c 
Immune-related pancreatitis, 
Grade 2 or 3 
 
• 
Withhold atezolizumab. 
• 
Refer patient to gastrointestinal specialist. 
• 
Initiate treatment with 1−2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
Resume atezolizumab if event resolves to Grade 1 or 
better within 12 weeks. a, b 
• 
Permanently discontinue atezolizumab and contact 
Study Chair if event does not resolve to Grade 1 or 
better within 12 weeks.a, b, c 
• 
For recurrent events, permanently discontinue 
atezolizumab and contact Study Chair. c  


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Table 7: Management Guidelines for Pancreatic Events, Including Pancreatitis (cont.)
 
 
Event 
Management 
Immune-related pancreatitis, 
Grade 4 
• 
Permanently discontinue atezolizumab and contact 
Study Chair. c 
• 
Refer patient to gastrointestinal specialist. 
• 
Initiate treatment with 1−2 mg/kg/day intravenous 
methylprednisolone or equivalent and convert to 
1−2 mg/kg/day oral prednisone or equivalent upon 
improvement. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
• 
If event resolves to Grade 1 or better, taper 
corticosteroids over  1 month. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 mg/day 
oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit and 
have fully recovered from the immune-related event.  
 
8. Dermatologic events 
Treatment-emergent rash has been associated with atezolizumab.  The majority of cases of rash 
were mild in severity and self-limited, with or without pruritus.  A dermatologist should evaluate 
persistent and/or severe rash or pruritus.  A biopsy should be considered unless contraindicated.  
Management guidelines for dermatologic events are provided in Table 8. 


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Table 8: Management Guidelines for Dermatologic Events  
Event 
Management 
Dermatologic 
event, Grade 1  
• 
Continue atezolizumab. 
• 
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic 
event, Grade 2  
• 
Continue atezolizumab. 
• 
Consider patient referral to dermatologist. 
• 
Initiate treatment with topical corticosteroids. 
• 
Consider treatment with higher-potency topical 
corticosteroids if event does not improve 
Dermatologic 
event, Grade 3  
• 
Withhold atezolizumab. 
• 
Refer patient to dermatologist. 
• 
Initiate treatment with 10 mg/day oral prednisone or 
equivalent, increasing dose to 1−2 mg/kg/day if event does 
not improve within 48−72 hours. 
• 
Resume atezolizumab if event resolves to Grade 1 or 
better within 12 weeks. a, b 
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better within 
12 weeks.a, b, c 
Dermatologic 
event, Grade 4 
• 
Permanently discontinue atezolizumab and contact Study 
Chair.c 
Persistent and/or 
severe rash or 
pruritus, any 
grade 
• 
A dermatologist should evaluate the event. A biopsy 
should be performed unless contraindicated. 
a If corticosteroids have been initiated, they must be tapered over  1 month to 
 10 mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  
 
9. 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 9. 


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Table 9: Management Guidelines for Neurologic Disorders 
Event 
Management 
Immune-related 
neuropathy, 
Grade 1 
• 
Continue atezolizumab. 
• 
Evaluate for alternative etiologies. 
Immune-related 
neuropathy, 
Grade 2  
• 
Withhold atezolizumab. 
• 
Evaluate for alternative etiologies. 
• 
Initiate treatment as per institutional guidelines. 
• 
Resume atezolizumab if event resolves to Grade 1 or better 
within 12 weeks. a, b 
• 
Permanently discontinue atezolizumab and contact Study 
Chair if event does not resolve to Grade 1 or better within 
12 weeks.a, b, c 
Immune-related 
neuropathy, 
Grade 3 or 4 
• 
Permanently discontinue atezolizumab and contact Study 
Chair. c  
• 
Initiate treatment as per institutional guidelines. 
Myasthenia 
gravis and 
Guillain-Barré 
syndrome (any 
grade) 
• 
Permanently discontinue atezolizumab and contact Study 
Chair.c 
• 
Refer patient to neurologist. 
• 
Initiate treatment as per institutional guidelines. 
• 
Consider initiation of 1−2 mg/kg/day oral or intravenous 
prednisone or equivalent. 
a If corticosteroids have been initiated, they must be tapered over  1 month to  10 
mg/day oral prednisone or equivalent before atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for 
corticosteroids to be reduced to  10 mg/day oral prednisone or equivalent.   
c Resumption of atezolizumab may be considered in patients who are deriving benefit 
and have fully recovered from the immune-related event.  
 
10. Immune-related meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
atezolizumab.  Immune-related meningoencephalitis should be suspected in any patient 
presenting with signs or symptoms suggestive of meningitis or encephalitis, including, but not 
limited to, headache, neck pain, confusion, seizure, motor or sensory dysfunction, and altered or 
depressed level of consciousness.  Encephalopathy from metabolic or electrolyte imbalances 
needs to be distinguished from potential meningoencephalitis resulting from infection (bacterial, 
viral, or fungal) or progression of malignancy, or secondary to a paraneoplastic process.   
All patients being considered for meningoencephalitis should be urgently evaluated with a CT 
scan and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema.  If 
deemed safe by the treating physician, a lumbar puncture should be performed and a 
neurologist should be consulted. 


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Patients with signs and symptoms of meningoencephalitis, in the absence of an identified 
alternate etiology, should be treated according to the guidelines in Table 10. 
Table 10: Management Guidelines for Immune-Related Meningoencephalitis 
Event 
Management 
Immune-related 
meningoencephalitis, 
all grades 
• 
Permanently discontinue atezolizumab and contact Study Chair. 
a 
• 
Refer patient to neurologist. 
• 
Initiate treatment with 1−2 mg/kg/day IV methylprednisolone or 
equivalent and convert to 1−2 mg/kg/day oral prednisone or 
equivalent upon improvement. 
• 
If event resolves to Grade 1 or better, taper corticosteroids over 
 1 month. 
• 
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive agent. 
IV = intravenous. 
a Resumption of atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event.   
 
The safety profile remains consistent based on the known mechanism of action of atezolizumab.  
As more data are generated in atezolizumab’s growing clinical development plan, further updates 
will be provided on the incidence of these adverse events in patients taking atezolizumab. As 
with all investigational products, unknown side effects may occur. Patients should be monitored 
closely throughout their participation in clinical studies with atezolizumab.  
6.2 
Bevacizumab 
 
6.2.1 General AE Management and Dose Modification Guidelines 
 
There will be no dose reduction for bevacizumab in this study. Treatment should be 
interrupted or discontinued for certain adverse events, as described below. If bevacizumab 
is interrupted for ANY reasons for >4 weeks (unless otherwise specified), the patient 
should discontinue bevacizumab therapy on protocol. 
 
6.2.2    Management of Specific AEs 
  


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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE. V4 
Grade 
Action to be Taken 
Allergic reactions  
Or  
Infusion-related reactions 
Or  
Anaphylaxis 
Grade 1-2  
• Infusion of bevacizumab should be 
interrupted for subjects who develop dyspnea 
or clinically significant hypotension.  
• For infusion-associated symptoms not 
specified above, infusion should be slowed to 
50% or less or interrupted.  Upon complete 
resolution of the symptoms, infusion may be 
continued at no more than 50% of the rate 
prior to the reaction and increased in 50% 
increments every 30 minutes if well 
tolerated.  Infusions may be restarted at the 
full rate during the next cycle.  
• Subjects who experience bronchospasm 
(regardless of grade) should discontinue 
bevacizumab. 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Arterial), arterial  ischemia  
- Cardiac ischemia 
- Myocardial  infraction 
- CNS ischemia (TIA, CVA) 
- Any peripheral or visceral 
arterial ischemia/thrombosis 
Grade 2 (new or 
worsening since 
bevacizumab 
Discontinue bevacizumab 
Grade 3-4 
Discontinue bevacizumab 
Thromboembolic Event 
(Venous) 
 
 
 
Grade 3 
OR 
asymptomatic 
Grade 4 
• Hold bevacizumab treatment.  If the 
planned duration of full-dose 
anticoagulation is <2 weeks, 
bevacizumab should be held until the 
full-dose anticoagulation period is over. 
• If the planned duration of full-dose 
anticoagulation is >2 weeks, 
bevacizumab may be resumed during 
full-dose anticoagulation IF all of the 
criteria below are met: 
• The subject must not have pathological 
conditions that carry high risk of bleeding 
(e.g. tumor involving major vessels or 
other conditions) 
• The subject must not have had 
hemorrhagic events while on study 
• The subject must be on stable dose of 
heparin or have an in-range INR (usually 
2-3) on a stable dose of warfarin prior to 
restarting bevacizumab. 


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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE. V4 
Grade 
Action to be Taken 
• If thromboemboli worsen/recur upon 
resumption of study therapy, discontinue 
bevacizumab 
Grade 4 
(symptomatic) 
Discontinue bevacizumab 
Hypertension 
[Treat with anti-hypertensive medication as needed.  The goal 
of BP control should be consistent with general medical 
practice] 
Grade 1 
(SBP 120-139 
mmHg or DBP 
80-89 mmHg) 
Consider increased BP monitoring; start 
anti-hypertensive medication if appropriate 
Grade 2 
asymptomatic 
(SBP 140-159 
mmHg or DBP 
90-99 mmHg) 
Begin anti-hypertensive therapy and 
continue bevacizumab 
• Grade 2 
symptomatic 
(SBP 140-159 
mmHg or DBP 
90-99 mm Hg) 
 
• Grade 3 
(SBP >160 
mmHg or 
DBP >100 
mmHg) 
• Start or adjust anti-hypertensive 
medication 
• Hold bevacizumab until symptoms 
resolve AND BP < 160/90mmHg 
• For hypertension that is refractory 
requiring delay of bevacizumab for > 4 
weeks, discontinue bevacizumab  
 
 
Grade 4  
(Hypertensive 
crisis or 
malignant 
hypertension) 
Discontinue bevacizumab 
Heart Failure  
OR 
Left Ventricular (LV) 
dysfunction 
• Heart failure 
>Grade 2 
• LV 
dysfunction 
>Grade 3 
Discontinue bevacizumab 
Proteinuria 
Proteinuria will be monitored 
by urine analysis dipstick. If 
Dipstick >2+ proteinuria, 24-
Dipstick > 2+ 
Hold bevacizumab and obtain 24 hour urine 
protein 
If 24-h urine 
protein <2g 
Continue bevacizumab 


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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE. V4 
Grade 
Action to be Taken 
hour urine protein should be 
obtained 
If 24-h urine 
protein >2 g 
• Hold bevacizumab until 24-hour urine 
protein <2.0 g   
• Discontinue bevacizumab if urine protein 
does not recover to < 2.0 g after 8 weeks 
of bevacizumab interruption 
Nephrotic 
syndrome 
Discontinue bevacizumab. 
Hemorrhage (intracranial or 
pulmonary)  
Grade 2-4 
• Discontinue bevacizumab 
Grade 1 
• Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
• For patients not on full-dose 
anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- the bleeding has resolved and 
hemoglobin is stable 
- there is no bleeding diathesis that 
would increase the risk of therapy 
• there is no anatomic or pathologic 
condition that could increase the risk of 
hemorrhage recurrence 
Hemorrhage (not CNS or 
pulmonary) 
Grade 3  
 
• Patients receiving full-dose 
anticoagulation should discontinue 
bevacizumab. 
• For patients not on full-dose 
anticoagulation, hold bevacizumab until 
ALL of the following criteria are met: 
- the bleeding has resolved and 
hemoglobin is stable 
- there is no bleeding diathesis that 
would increase the risk of therapy 
- there is no anatomic or pathologic 
condition that could increase the risk 
of hemorrhage recurrence. 
• Patients who experience recurrence of 
grade 3 hemorrhage should discontinue 
study therapy. 
Grade 4 
Discontinue bevacizumab 
RPLS (Reversible Posterior 
Leukoencephalopathy 
syndrome  
OR 
Any Grade 
Discontinue bevacizumab upon diagnosis 
of RPLS.   


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Treatment Modification for Bevacizumab-Related Adverse Events 
Event 
CTCAE. V4 
Grade 
Action to be Taken 
PRES (Posterior Reversible 
Encephalopathy Syndrome) 
Wound dehiscence 
OR 
 Wound complications  
Grade 2 
Hold bevacizumab until healing  
Grade 3-4 
Discontinue bevacizumab 
Perforation (GI, or any other 
organ) 
Any Grade 
Discontinue bevacizumab 
Fistula (GI, pulmonary or any 
other organ) 
Any Grade 
Discontinue bevacizumab 
Obstruction of GI tract 
Grade 2 
requiring 
medical 
intervention 
Hold bevacizumab until complete 
resolution  
 
Grade 3-4 
• Hold bevacizumab until complete 
resolution 
• If surgery is required, patient may restart 
bevacizumab after 28 days and full 
recovery from surgery, and at 
investigator’s discretion 
Other Unspecified 
bevacizumab-related AEs 
(except controlled 
nausea/vomiting). 
Grade 3 
• Hold bevacizumab until symptoms 
resolve to<Grade 1 
Grade 4 
• Discontinue bevacizumab 
• Upon consultation with the study 
chair, resumption of bevacizumab may 
be considered if a patient is benefiting 
from therapy, and the Grade 4 toxicity is 
transient, has recovered to <Grade 1 and 
unlikely to recur with retreatment. 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2 and 
7.3) will determine whether the event requires expedited reporting via the CTEP Adverse Event 
Reporting System (CTEP-AERS) in addition to routine reporting. 
 
7.1 
Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of 
reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column and 
is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events that are 


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protocol specific exceptions to expedited reporting to NCI (except as noted below).  Refer to the 
'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf  for 
further clarification. Frequency is provided based on 1369 patients. Below is the CAEPR for 
Atezolizumab (MPDL3280A). 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple 
investigational agents and has an AE listed on different SPEERs, use the lower of the grades 
to determine if expedited reporting is required. 
 
 
7.1.1 CAEPRs for CTEP IND Agent(s) 
 
7.1.1.1 
Atezolizumab 
 
Version 2.1, June 7, 20171 
 
 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 4.0 Term) 
[n= 1369] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
CARDIAC DISORDERS 
 
 
Heart failure2 
 
 
Myocarditis2 
 
 
Pericardial effusion2 
 
 
Pericardial tamponade2  
 
 
Pericarditis2 
 
ENDOCRINE DISORDERS 
 
 
Adrenal insufficiency2 
 
 
Endocrine disorders - Other 
(diabetes)2 
 
 
Endocrine disorders - Other 
(hypophysitis)2 
 
Hyperthyroidism2 
 
 
Hypothyroidism2 
 
 
EYE DISORDERS 
 
 
Eye disorders - Other (ocular 
inflammatory toxicity)2 
 
 
Uveitis2 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 Abdominal pain (Gr 2) 
 
Colitis2 
 
Diarrhea 
 
 Diarrhea (Gr 2) 
Dysphagia 
 
 
Nausea 
 
 Nausea (Gr 2) 
 
Pancreatitis2 
 
Vomiting 
 
 Vomiting (Gr 2) 


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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 4.0 Term) 
[n= 1369] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
 
 
 Fatigue (Gr 2) 
Fever3 
 
 
Flu like symptoms3 
 
 
Infusion related reaction3 
 
 
HEPATOBILIARY DISORDERS 
 
 
Hepatic failure2 
 
 
Hepatobiliary disorders - Other 
(hepatitis)2 
 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction3 
 
 
 
Anaphylaxis3 
 
 
Cytokine release syndrome3 
 
 
Immune system disorders - Other 
(systemic immune activation)2 
 
INFECTIONS AND INFECTATIONS 
 
 
Meningitis2 
 
INVESTIGATIONS 
 
Alanine aminotransferase increased2 
 
 
Alkaline phosphatase increased 2 
 
 
Aspartate aminotransferase increased 2  
 
Blood bilirubin increased 2 
 
 
GGT increased2 
 
 
Lipase increased* 
 
 
 
Platelet count decreased 
 
Serum amylase increased* 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia2 
 
Hypokalemia 
 
 
Hyponatremia 
 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia2 
 
 
 
Generalized muscle weakness 
 
Myalgia2 
 
 
 
Myositis2 
 
NERVOUS SYSTEM DISORDERS 
 
 
Ataxia2 
 
 
Encephalopathy2 
 
 
Nervous system disorders - Other 
(encephalitis non-infective)2 
 
 
Nervous system disorders - Other 
(Guillain-Barre syndrome)2 
 
 
Nervous system disorders - Other 
(meningitis non-infective)2 
 


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 Adverse Events with Possible  
 Relationship to Atezolizumab (MPDL3280A) 
 (CTCAE 4.0 Term) 
[n= 1369] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
Nervous system disorders - Other 
(myasthenia gravis)2 
 
 
Paresthesia2 
 
 
Peripheral motor neuropathy2 
 
 
Peripheral sensory neuropathy2 
 
RENAL AND URINARY DISORDERS 
 
 
Renal and urinary disorders - Other 
(nephritis)2 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 Cough (Gr 2) 
Dyspnea 
 
 
Hypoxia 
 
 
Nasal congestion 
 
 Nasal congestion (Gr 2) 
 
Pleural effusion2 
 
Pneumonitis2 
 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
 
Bullous dermatitis2 
 
Pruritus 
 
 
Rash acneiform 
 
 
Rash maculo-papular 
 
 
Skin and subcutaneous tissue 
disorders - Other (lichen planus)2 
 
 
 
*Denotes adverse events that are <3%. 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Atezolizumab, being a member of a class of agents involved in the inhibition of “immune checkpoints,” 
may result in severe and possibly fatal immune-mediated adverse events probably due to T-cell activation 
and proliferation.  Immune-mediated adverse reactions have been reported in patients receiving 
atezolizumab.  Adverse events potentially related to atezolizumab may be manifestations of immune-
mediated adverse events.  In clinical trials, most immune-mediated adverse reactions were reversible and 
managed with interruptions of atezolizumab, administration of corticosteroids and supportive care. 
 
3Infusion reactions, including high-grade hypersensitivity reactions, anaphylaxis, and cytokine release 
syndrome, which have been observed following administration of atezolizumab, may manifest as fever, 
chills, shakes, itching, rash, hypertension or hypotension, or difficulty breathing during and immediately 
after administration of atezolizumab. 
 
 
Adverse events reported on atezolizumab (MPDL3280A) trials, but for which there is insufficient 
evidence to suggest that there was a reasonable possibility that atezolizumab (MPDL3280A) 
caused the adverse event: 
 
CARDIAC DISORDERS - Cardiac arrest 


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GASTROINTESTINAL DISORDERS - Constipation; Ileus 
GENERAL DISORDERS AND ADMINISTRATION SITE conditions - Chills; Edema limbs; Malaise; Pain 
INFECTIONS AND INFESTATIONS - Lung infection; Sepsis; Urinary tract infection 
INVESTIGATIONS - Weight loss; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hypophosphatemia; Tumor lysis syndrome 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Bone pain 
NERVOUS SYSTEM DISORDERS - Headache 
PSYCHIATRIC DISORDERS - Confusion; Insomnia; Suicide attempt 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; 
Pulmonary hypertension 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin2; Hyperhidrosis 
VASCULAR DISORDERS - Hypertension; Hypotension; Thromboembolic event 
 
 
Note: Atezolizumab (MPDL3280A) in combination with other agents could cause an exacerbation of any 
adverse event currently known to be caused by the other agent, or the combination may result in events 
never previously associated with either agent. 
 
 
7.1.1.2 
Bevacizumab 
 
 Adverse Events with Possible  
 Relationship to Bevacizumab (rhuMAb VEGF) 
 (CTCAE 4.0 Term) 
[n= 3540] 
 
 Specific Protocol Exceptions 
to Expedited Reporting 
(SPEER)  
Likely 
(>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
Anemia (Gr 3) 
Blood and lymphatic system 
disorders - Other (renal thrombotic 
microangiopathy) 
 
Febrile neutropenia 
Febrile neutropenia (Gr 3) 
CARDIAC DISORDERS 
 
Acute coronary syndrome2 
 
Cardiac disorders - Other 
(supraventricular 
arrhythmias)3 
Cardiac disorders - Other 
(supraventricular arrhythmias)3 
(Gr 3) 
Heart failure 
 
Left ventricular systolic dysfunction  
Myocardial infarction2 
 
Ventricular arrhythmia 
 
Ventricular fibrillation 
 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
Abdominal pain (Gr 3) 
Colitis 
Colitis (Gr 3) 
Constipation 
Constipation (Gr 3) 
Diarrhea 
Diarrhea (Gr 3) 
Dyspepsia 
Dyspepsia (Gr 2) 
Gastrointestinal fistula4 
 
Gastrointestinal hemorrhage5
Gastrointestinal hemorrhage5 (Gr 
2) 
 
Gastrointestinal obstruction6  
 
 
Gastrointestinal perforation7 
 


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Gastrointestinal ulcer8 
 
Ileus 
 
 
Mucositis oral 
Mucositis oral (Gr 3) 
Nausea 
Nausea (Gr 3) 
Vomiting 
Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Fatigue 
Fatigue (Gr 3) 
Infusion related reaction 
Infusion related reaction (Gr 2) 
Non-cardiac chest pain 
Non-cardiac chest pain (Gr 3) 
Pain 
Pain (Gr 3) 
IMMUNE SYSTEM DISORDERS 
 
Allergic reaction 
Allergic reaction (Gr 2) 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
Infection9 
Infection9 (Gr 3) 
 
Infections and infestations - Other 
(necrotizing fasciitis) 
 
Infections and infestations - 
Other (peri-rectal abscess) 
 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
Injury, poisoning and procedural 
complications – Other 
(anastomotic leak)10 
 
Wound complication 
Wound complication (Gr 2) 
Wound dehiscence 
Wound dehiscence (Gr 2) 
INVESTIGATIONS 
 
Alanine aminotransferase 
increased 
Alanine aminotransferase 
increased (Gr 3) 
Alkaline phosphatase 
increased 
Alkaline phosphatase increased 
(Gr 3) 
Aspartate aminotransferase 
increased 
Aspartate aminotransferase 
increased (Gr 3) 
Blood bilirubin increased 
Blood bilirubin increased (Gr 2) 
Cardiac troponin I increased 
 
Neutrophil 
count 
decreased 
Neutrophil count decreased (Gr 3) 
Platelet count decreased 
Platelet count decreased (Gr 4) 
Weight loss 
Weight loss (Gr 3) 
White blood cell decreased 
White blood cell decreased (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
Anorexia (Gr 3) 
Dehydration 
Dehydration (Gr 3) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
Arthralgia (Gr 3) 
Musculoskeletal and 
connective tissue disorder -  
Other (bone metaphyseal 
dysplasia)11 
 
Myalgia 
Myalgia (Gr 3) 
Osteonecrosis of jaw12 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
Dizziness (Gr 2) 
Headache 
Headache (Gr 3) 
Intracranial hemorrhage 
 


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Ischemia cerebrovascular2 
 
Peripheral sensory 
neuropathy13 
 
Reversible posterior 
leukoencephalopathy syndrome 
 
Syncope 
 
RENAL AND URINARY DISORDERS 
 
Acute kidney injury 
 
Hematuria 
Hematuria (Gr 3) 
Proteinuria 
Proteinuria (Gr 2) 
Renal and urinary disorders - 
Other (Nephrotic Syndrome) 
 
Urinary fistula 
 
 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 
 
Reproductive 
system and 
breast 
disorders - 
Other (ovarian 
failure)14 
 
Vaginal fistula 
 
Vaginal hemorrhage 
Vaginal hemorrhage (Gr 3) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Allergic rhinitis 
Allergic rhinitis (Gr 3) 
Bronchopleural fistula 
 
Bronchopulmonary hemorrhage 
 
Cough 
Cough (Gr 3) 
Dyspnea 
Dyspnea (Gr 2) 
Epistaxis 
Epistaxis (Gr 3) 
Hoarseness 
Hoarseness (Gr 3) 
Respiratory, thoracic and 
mediastinal disorders - Other 
(nasal-septal perforation) 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(tracheo-esophageal fistula) 
 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Pruritus 
Pruritus (Gr 2) 
Rash maculo-papular 
Rash maculo-papular (Gr 2) 
Urticaria 
Urticaria (Gr 2) 
VASCULAR DISORDERS 
 
Hypertension  
Hypertension (Gr 3) 
Thromboembolic event 
Thromboembolic event (Gr 3) 
Vascular disorders - Other (arterial 
thromboembolic event)2,15 
 
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates 
will be distributed to all Principal Investigators at the time of revision.  The current 
version can be obtained by contacting PIO@CTEP.NCI.NIH.GOV.  Your name, 
the name of the investigator, the protocol and the agent should be included in the 
e-mail. 
2The risks of arterial thrombosis such as cardiac or CNS ischemia are increased 
in elderly patients and in patients with a history of diabetes. 
3Supraventricular arrhythmias may include supraventricular tachycardia, atrial 


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fibrillation and atrial flutter. 
4Gastrointestinal fistula may include: Anal fistula, Colonic fistula, Duodenal fistula, 
Esophageal fistula, Gastric fistula, Gastrointestinal fistula, Rectal fistula, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
5Gastrointestinal hemorrhage may include: Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Oral 
hemorrhage, Rectal hemorrhage, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
6Gastrointestinal obstruction may include: Colonic obstruction, Duodenal 
obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Rectal 
obstruction, Small intestinal obstruction, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
7Gastrointestinal perforation may include: Colonic perforation, Duodenal 
perforation, Esophageal perforation, Gastric perforation, Jejunal perforation, 
Rectal perforation, Small intestinal perforation, and other sites under the 
GASTROINTESTINAL DISORDERS SOC. 
8Gastrointestinal ulcer may include: Duodenal ulcer, Esophageal ulcer, Gastric 
ulcer, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
9Infection may include any of the 75 infection sites under the INFECTIONS AND 
INFESTATIONS SOC. 
10Anastomotic leak may include Gastric anastomotic leak; Gastrointestinal 
anastomotic leak; Large intestinal anastomotic leak; Rectal anastomotic leak; 
Small intestinal anastomotic leak; Urostomy leak; Vaginal anastomotic leak 
11Metaphyseal dysplasia was observed in young patients who still have active 
epiphyseal growth plates. 
12Cases of osteonecrosis of the jaw (ONJ) have been reported in cancer patients 
in association with bevacizumab treatment, the majority of whom had received 
prior or concomitant treatment with i.v. bisphosphonates. 
13Increased rate of peripheral sensory neuropathy has been observed in trials 
combining bevacizumab and chemotherapy compared to chemotherapy alone.  
14Ovarian failure, defined as amenorrhea lasting 3 or more months with follicle-
stimulating hormone (FSH) elevation (≥30 mIU/mL), was increased in patients 
receiving adjuvant bevacizumab plus mFOLFOX compared to mFOLFOX alone 
(34% vs. 2%).  After discontinuation of bevacizumab, resumption of menses and 
an FSH level <30 mIU/mL was demonstrated in 22% (7/32) of these 
women.  Long term effects of bevacizumab exposure on fertility are unknown. 
 
15Arterial thromboembolic event includes visceral arterial ischemia, peripheral 
arterial ischemia, heart attack and stroke. 
Also reported on bevacizumab (rhuMAb VEGF) trials but with the 
relationship to bevacizumab (rhuMAb VEGF) still undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (idiopathic thrombocytopenia purpura); Bone marrow 
hypocellular; Disseminated intravascular coagulation; Hemolysis 
CARDIAC DISORDERS - Atrioventricular block complete; Atrioventricular block 
first degree; Cardiac arrest; Myocarditis; Pericardial effusion; Restrictive 


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cardiomyopathy; Right ventricular dysfunction 
EAR AND LABYRINTH DISORDERS - Ear and labyrinth disorders - Other 
(tympanic membrane perforation); Hearing impaired; Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Hyperthyroidism; Hypothyroidism 
EYE DISORDERS - Blurred vision; Cataract; Dry eye; Extraocular muscle 
paresis; Eye disorders - Other (blindness); Eye disorders - Other (conjunctival 
hemorrhage); Eye disorders - Other (corneal epithelial defect); Eye disorders - 
Other (floaters); Eye disorders - Other (ischemic CRVO); Eye disorders - Other 
(macular pucker); Eye disorders - Other (transient increased IOP > or =30 mm 
Hg); Eye disorders - Other (vitreous hemorrhage); Eye pain; Keratitis; Optic nerve 
disorder; Photophobia; Retinal detachment; Retinal tear; Retinopathy; Watering 
eyes 
GASTROINTESTINAL DISORDERS - Ascites; Cheilitis; Colonic stenosis; Dry 
mouth; Dysphagia; Enterocolitis; Esophageal pain; Esophageal stenosis; 
Flatulence; Gastrointestinal disorders - Other (peritonitis); Oral pain; Pancreatitis; 
Proctitis; Rectal mucositis; Rectal stenosis; Typhlitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Death 
NOS; Edema face; Edema limbs; Edema trunk; Facial pain; Fever; Flu like 
symptoms; Gait disturbance; Injection site reaction; Localized edema; Multi-organ 
failure; Sudden death NOS 
HEPATOBILIARY DISORDERS - Cholecystitis; Gallbladder necrosis; 
Gallbladder obstruction; Hepatic failure; Hepatic necrosis 
INFECTIONS AND INFESTATIONS - Infections and infestations - Other (aseptic 
meningitis) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Arterial injury; 
Bruising; Burn; Dermatitis radiation; Fracture 
INVESTIGATIONS - Activated partial thromboplastin time prolonged; Blood 
antidiuretic hormone abnormal; CD4 lymphocytes decreased; CPK increased; 
Carbon monoxide diffusing capacity decreased; Electrocardiogram QT corrected 
interval prolonged; Forced expiratory volume decreased; GGT increased; INR 
increased; Lipase increased; Lymphocyte count decreased; Serum amylase 
increased; Weight gain 
METABOLISM AND NUTRITION DISORDERS - Acidosis; Hypercalcemia; 
Hyperglycemia; Hyperkalemia; Hypermagnesemia; Hypernatremia; 
Hypertriglyceridemia; Hyperuricemia; Hypoalbuminemia; Hypocalcemia; 
Hypokalemia; Hypomagnesemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthritis; 
Back pain; Bone pain; Chest wall pain; Fibrosis deep connective tissue; 
Generalized muscle weakness; Head soft tissue necrosis; Joint effusion; Muscle 
weakness lower limb; Muscle weakness upper limb; Musculoskeletal and 
connective tissue disorder - Other (aseptic necrotic bone); Musculoskeletal and 
connective tissue disorder - Other (myasthenia gravis); Musculoskeletal and 
connective tissue disorder - Other (polymyalgia rheumatica); Neck pain; Pain in 
extremity; Pelvic soft tissue necrosis; Soft tissue necrosis lower limb 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Arachnoiditis; Ataxia; Central nervous 


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system necrosis; Cerebrospinal fluid leakage; Cognitive disturbance; Depressed 
level of consciousness; Dysesthesia; Dysgeusia; Dysphasia; Encephalopathy; 
Extrapyramidal disorder; Facial nerve disorder; Hydrocephalus; 
Leukoencephalopathy; Memory impairment; Nervous system disorders - Other 
(increased intracranial pressure); Paresthesia; Peripheral motor neuropathy; 
Pyramidal tract syndrome; Seizure; Somnolence; Tremor; Vasovagal reaction 
PSYCHIATRIC DISORDERS - Agitation; Anxiety; Confusion; Depression; 
Insomnia; Libido decreased; Psychosis 
RENAL AND URINARY DISORDERS - Bladder spasm; Chronic kidney disease; 
Cystitis noninfective; Renal and urinary disorders - Other (dysuria); Renal and 
urinary disorders - Other (ureterolithiasis); Renal hemorrhage; Urinary frequency; 
Urinary incontinence; Urinary retention; Urinary tract obstruction; Urinary tract 
pain 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Breast pain; Erectile 
dysfunction; Irregular menstruation; Pelvic pain; Vaginal discharge 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult 
respiratory distress syndrome; Atelectasis; Hypoxia; Nasal congestion; 
Pulmonary fibrosis; Pulmonary hypertension; Respiratory failure; Respiratory, 
thoracic and mediastinal disorders - Other (dry nares); Respiratory, thoracic and 
mediastinal disorders - Other (pulmonary infarction) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Nail loss; Pain of skin; Palmar-plantar erythrodysesthesia 
syndrome; Photosensitivity; Purpura; Rash acneiform; Skin and subcutaneous 
tissue disorders - Other (diabetic foot ulcer); Skin and subcutaneous tissue 
disorders - Other (skin breakdown/ decubitus ulcer); Skin hyperpigmentation; 
Skin induration; Skin ulceration; Stevens-Johnson syndrome 
VASCULAR DISORDERS - Flushing; Hot flashes; Hypotension; Lymphocele; 
Phlebitis; Vasculitis  
Note: Bevacizumab (rhuMAb VEGF) in combination with other agents could 
cause an exacerbation of any adverse event currently known to be caused by the 
other agent, or the combination may result in events never previously associated 
with either agent. 
 
7.2 
Adverse Event Characteristics  
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be utilized until March 31, 2018 for AE reporting. CTCAE version 5.0 will be 
utilized for AE reporting beginning April 1, 2018. 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. 


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- 
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 
 
7.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (https://eapps-
ctep.nci.nih.gov/ctepaers).  The reporting procedures to be followed are presented in the 
“NCI Guidelines for Investigators: Adverse Event Reporting Requirements for DCTD 
(CTEP and CIP) and DCP INDs and IDEs” which can be downloaded from the CTEP 
Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)
.  These requirements are briefly outlined in the tables below (Section 7.3.3). 
 
In the rare occurrence when 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 phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
 
7.3.2 Distribution of Adverse Event Reports 
 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator 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 e-mail recipients.  
 
7.3.3 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. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”   
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  


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Pregnancy loss is defined in CTCAE as “Death in utero.” Any pregnancy loss should be 
reported expeditiously, as Grade 4 “Pregnancy loss” under the Pregnancy, puerperium 
and perinatal conditions SOC. A pregnancy loss should NOT be reported as a Grade 5 
event under the Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse Events 
that Occur on Studies under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or not 
they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via electronic 
submission within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o 
“24-Hour; 5 Calendar Days” - The AE must initially be submitted electronically within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
o 
“10 Calendar Days” - A complete expedited report on the AE must be submitted electronically within 10 
calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• 
Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 


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7.3.4 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:  
 
• Pneumonitis 
• Colitis 
• Endocrinopathies:  diabetes mellitus, pancreatitis, hyperthyroidism, hypophysitis, 
and adrenal insufficiency 
• Hepatitis 
• ALT 10  ULN  
• Systemic lupus erythematosus 
• Neurological disorders: Guillain-Barré syndrome, myasthenic syndrome or 
myasthenia gravis, and meningoencephalitis 
• Nephritis 
• Events suggestive of hypersensitivity, cytokine release, influenza-like illness, 
systemic inflammatory response syndrome, systemic immune activation, or 
infusion related reactions 
• Ocular toxicities (e.g., uveitis, retinitis) 
• Myositis 
• Myopathies, including rhabdomyolysis 
• Grade ≥2 cardiac disorders (e.g., atrial fibrillation, myocarditis, pericarditis) 
 
7.4 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
Adverse event 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 
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 following treatment with an agent under an 
NCI IND/IDE be reported expeditiously via CTEP-AERS.  Three options are available to 
describe the event:  
 


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• 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.  
 
Loading of the pathology report is required. 
 
7.6 
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. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events 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) 
 
8.1.1 Atezolizumab (NSC 783608) 
 
Other Names: MPDL3280A 
 
Classification: monoclonal antibody 
 
M.W.: 150 KD 
 
Mode of Action: anti-PD-L1 
 
Description: 
Atezolizumab is a humanized IgG1 monoclonal antibody consisting of two heavy chains 
(448 amino acids) and two 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. Atezolizumab is formulated as 60 mg/mL 
atezolizumab in 20 mM histidine acetate, 120 mM sucrose, 0.04% polysorbate 20, at 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. 


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Preparation:   
The prescribed dose of atezolizumab should be diluted in 250 mL 0.9% NaCl and infused 
through a 0.2 micrometer in-line filter. The IV bag may be constructed of PVC or PO; the 
IV infusion line may be constructed of PVC or PE; and the 0.2 micrometer in-line filter 
may be constructed of PES.  The prepared solution may be stored at 2°C-8°C or room 
temperature for up to 8 hours. 
 
Storage:  
2°C-8°C (36°F-46°F) Vial contents should not be frozen or shaken and should be 
protected from direct sunlight. 
 
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 intravenous 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 intravenous 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 
antihistamines or antipyretics/analgesics (e.g. acetaminophen) for 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 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. 
 


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8.1.2 Bevacizumab (NSC 704865) 
 
Other Names: rhuMAb VEGF, Avastin® 
 
Classification: Recombinant humanized monoclonal antibody 
 
MW: Approximate molecular weight is 149,000 daltons 
 
Mode of Action:   
Bevacizumab blocks the binding of vascular endothelial growth factor (VEGF) to its 
receptors resulting in inhibition of angiogenesis. 
 
Description:  
Bevacizumab is a recombinant humanized anti-VEGF monoclonal antibody consisting of 
93% human and 7% murine amino acid sequences. The agent is composed of human IgG 
framework and murine antigen-binding complementarity-determining regions. 
 
How Supplied:   
Bevacizumab is supplied as a clear to slightly opalescent, sterile liquid for parenteral 
administration. Each 400 mg (25mg/ml – 16 mL fill) glass vial contains bevacizumab 
with phosphate, trehalose, polysorbate 20, and Sterile Water for Injection, USP. 
   
Preparation:   
Vials contain no preservatives and are intended for single use only. Place the calculated 
dose in 100 mL of 0.9% sodium chloride for injection.  
 
 
 
Storage:  
Upon receipt, refrigerate bevacizumab (2 to 8 C).  Do not freeze.  Do not shake. 
 
Stability:  
Shelf-life studies of rhuMAb VEGF are ongoing.  The sterile single use vials contain no 
antibacterial preservatives.  Discard vials 8 hours after initial entry. Once diluted in 0.9% 
sodium chloride, administer solutions of bevacizumab within 8 hours. 
   
Route of Administration: Intravenous 
 
Method of Administration:  
Administer the initial dose over a minimum of 90 minutes.  If no adverse reactions occur, 
administer the second dose over a minimum of 60 minutes. If no adverse reactions occur 
after the second dose, administer subsequent doses over a minimum of 30 minutes. If 
infusion-related adverse reactions occur, all subsequent infusions should be administered 
over the shortest period that was well tolerated.  
 
Availability:   
Bevacizumab is an investigational agent supplied to investigators by the Division of 
Cancer Treatment and Diagnosis (DCTD), NCI. 
 


NCI Protocol #: 10010 
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75 
 
8.1.3 Agent Ordering and Agent Accountability 
 
8.1.3.1 
NCI-supplied agents may be requested by the Principal Investigator (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. 
 
In general, sites may order initial agent supplies when a subject is being screened for 
enrollment onto the study. 
 
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 Identity and Access Management (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.   
 
8.1.3.2 
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. 
 
8.1.3.3 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  PMBRegPend@ctep.nci.nih.gov 
• 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://eapps-
ctep.nci.nih.gov/iam/ 
• CTEP Associate Registration and IAM account help:  
ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
76 
 
between 8:30 am and 4:30 pm (ET) 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
9.1 
Exploratory/Ancillary Correlative Studies 
 
9.1.1 PD-L1Immunohistochemistry and T-cell Receptor Sequencing 
 
9.1.1.1 
Collection of Specimen(s) 
 
Formalin-fixed, paraffin embedded (FFPE) tissue should be the most representative of the 
biospecimen type (primary, metastatic, recurrent, persistent). Primary (FP01) and metastatic 
(FM01) tumor should be collected prior to all treatment. Recurrent and persistent tumor should 
be collected prior to the study treatment. Recurrent or persistent tumor collected from the site of 
primary disease should be labeled recurrent primary (FRP01) or persistent primary (FPP01), 
respectively. Recurrent or persistent tumor collected from a site other than the site of primary 
disease (e.g., lymph node) should be labeled recurrent metastatic (FRM01) or persistent 
metastatic (FPM01), respectively. Only one block may be submitted per tissue type. 
 
Biopsy tissue sampling instructions and requirements:  A minimum of one core biopsy sample 
should be attained, for the purposes of Hematoxylin and eosin (H and E) staining, PD-L1 IHC 
and TCR sequencing. Bone metastases, final needle aspirates, cytology specimens and alcohol-
fixed specimens are not suitable for PD-L1 IHC or TCR sequencing. 
For both archived and fresh biopsy tissue, every attempt should be made to provide a block; 
however, if a block cannot be provided then unstained slides (9 charged, 4 µm) should be 
submitted. For PD-L1 staining, 4 charged, 4µm, sections must be cut fresh and only shipped 
when requested by the study team. Blocks or fresh cut (not older than 60 days) sections of FFPE 
tumor will be shipped to a designated CLIA laboratory upon closure of each trial phase.  For the 
H&E, one of the 9 slides is needed, and for TCR sequencing 4 of 9 slides are needed. The H and 
E slides will be collected and reviewed for tumor content by a pathologist. 
Peripheral blood will be collected prior to the first dose of therapy; genomic DNA will be 
purified from total PBMCs.  PBMC DNA will be isolated from whole blood for TCR sequencing 
according to the following steps: 7-10mL of blood should be drawn into a lavender/purple top 
tube(s) labeled with the patient’s study ID. A minimum of 3mL is needed for processing. 
Immediately after collection, gently invert the tube 5-10 times to mix the blood and EDTA.  Ship 
whole blood to the address below on the day the biospecimen is collected. If the whole blood 
absolutely cannot be shipped the day it is collected, the tube(s) should be refrigerated (4°C) and 
shipped within 24 hours. 
Dr. Friedman and colleagues will isolate whole blood DNA from these samples. DNA will then 
be shipped to Adaptive Biotechnologies for sequencing.  
The slides of tumor tissue for TCR sequencing will be sent to Adaptive Biotechnologies for DNA 
isolation, sequencing and data generation. The TCRCDR3 regions will be amplified and 


NCI Protocol #: 10010 
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77 
 
sequenced using ImmunoSEQ technology (Adaptive Biotechnologies, Seattle, WA) as previously 
described (https://www.ncbi.nlm.nih.gov/pubmed/19706884). In brief, bias-controlled V and J 
gene primers are used to amplify rearranged V(D)J segments for high-throughput sequencing. 
After correcting sequencing errors via a clustering algorithm, CDR3 segments are annotated to 
identify the V, D, and J genes that contributed to each rearrangement. The estimated TIL content 
will be calculated as previously described (https://www.ncbi.nlm.nih.gov/pubmed/25428505). 
For each sample, Shannon entropy will be calculated on the clonal abundance of all productive 
TCR sequences in the data set.  
The type of biospecimen (block, slides) should be specified. If submitting slides, the slide type, 
thickness, and count should also be specified.  
 
Labeling formalin-fixed, paraffin-embedded tissue 
A waterproof permanent marker or printed label should be used to label each translational science 
biospecimen with: 
NCI Protocol number 10010 
Biospecimen code (see above) 
Collection date (mm/dd/yyyy) 
Surgical pathology accession number 
Block number 
 
Note: if labeling slides, only label on the top, front portion of the slide. Do not place a label on 
the back of the slide or over the tissue. The label must fit on the slide and should not be wrapped 
around the slide or hang over the edge. 
 
9.1.1.2 
Shipping of Specimen(s) 
 
Pre-treatment blood samples are to be shipped to:  
 
Rosemarie Ramsawak/Kevin Crawford/Phillip Wong 
Immune Monitoring Facility, Room ZRC-1513 
Memorial Sloan Kettering Cancer Center 
408 East 69th Street 
New York, NY 10021 
Lab Phone 1: 1-646-888-2114  
Lab Phone 2: 1-646-888-3106 
 
Fresh pre-treatment biopsies and archived tissue is to be shipped to:  
 
Merghoub Lab 
C/O: Beatrice Yin 
417 E 68th St 
Rm: Z1525 
New York, NY 10065 
 
 
 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
78 
 
 
 
9.1.1.3 
Site(s) Performing Correlative Study 
 
Claire Friedman, MD 
Memorial Sloan Kettering Cancer Center 
300 E. 66th Street 
New York, NY 10065 
646-888-4247 
friedmac@mskcc.org 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  
Baseline radiographic tumor assessment must be done within 30 days prior to the start of therapy.  
Patients receiving atezolizumab and bevacizumab will be assessed for pulmonary signs and 
symptoms throughout the study.  Patients will also have CT scans of the chest at every tumor 
assessment.  It will be acceptable for a new cycle of therapy (and all associated tests and 
procedures) to be delivered within a 4 day window before and after the protocol defined date (see 
section 5.1).  If screening laboratory assessments are performed within 4 days prior to Cycle 1, 
Day 1 they do not need to be repeated at Cycle 1, Day 1. 
 
  
Pre-Study 
Off 
Studyc 
Cycle 1, 
Day 1 
(week 1) 
+/- 4 days 
Cycle 1, Wk 2  
+/- 4 days 
Cycle 1, 
Wk 3     
+/- 4 days 
Cycle 2, Day 1 
+/- 4 days 
Cycle 3, Day 1 
+/- 4 days 
Cycle 4+, Day 1 
+/- 4 days 
Atezolizumab 
  
A 
  
  
A 
A 
A 
  
Bevacizumab 
  
B 
  
  
B 
B 
B 
  
Informed consentg 
X 
  
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
Concurrent meds 
X 
X---------------------------------------------------------------------------------X 
 X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
  
  
  
  
  
  
  
Weight 
X 
X 
 X 
X 
 X 
X 
X  
X 
Performance status 
X 
X 
 X 
X 
 X 
X 
X  
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
PT (INR)/PTT 
X 


NCI Protocol #: 10010 
Protocol Version Date: 02/06/2018 
79 
 
TSH 
X 
X 
X 
X 
Urinalysisd 
X 
X 
EKG  
X 
  
  
  
  
  
  
  
Adverse event 
evaluation 
  
X---------------------------------------------------------------X 
X 
Tumor 
measurements 
X 
Tumor measurements are repeated every 9 weeks (+/- 7 days) for 12 months, then every 12 weeks 
(+/- 7 days) thereafter.  Documentation (radiologic) must be provided for patients removed from 
treatment for progressive disease.f 
X 
B-HCG 
Xb 
  
  
  
  
  
  
  
Archived FFPE 
Submissione 
Xe 
  
  
  
  
  
  
  
Pre-Treatment 
Biopsy 
Xe 
Pre-Treatment 
Research Blood 
Xe 
 
 
 
 
 
 
 
A:Atezolizumab 1200mg IV 
B: Bevacizumab 15mg/kg IV 
a: Na, K, Cl, CO2, BUN, creatinine, Ca, glucose, total bilirubin, total protein, albumin, alkaline phosphatase,  
AST, ALT 
b: Serum pregnancy test (women of childbearing potential). 
c: Off-study evaluation (30 days +/- 7 days after last dose) 
d:  Urinalysis for urine protein prior to every other cycle (odd cycles, e.g., prior to Cycle 3, 5, 7, ect) 
        e:  Pre-treatment biopsy formalin fixed paraffin embedded (FFPE) should be submitted for each patient.  If pre-treatment biopsy results in 
insufficient material, patient may still proceed with protocol treatment.  Archived formalin fixed paraffin embedded (FFPE) tissue should be 
confirmed as available for all patients.  TCR sequencing will be performed on biopsy tissue or, where insufficient, archived tumor tissue.  PD-L1 
tumor and immune cell staining will be performed on both biopsy and archived tissue.  TCR sequencing will be performed on PBMC collected at 
baseline. Pre-treatment research blood can be drawn anytime during screening or on Cycle 1, Day 1 prior to treatment administration.  
 
Submission will be requested at the end of the study to allow for IHC to be performed within  60 days of slides being cut.  From the time of request, sites 
will have 30 days to submit tissue. 
        f:  See Section 5.3.1, Section 11.1 and Appendix B for guidance on treatment beyond progression 
 
        g: Informed consent to be obtained within 30 days prior to the start of protocol therapy.  
 
 
 
 
 


NCI Protocol #: 10010 
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80 
 
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 (+/- 7 
days).  In addition to a baseline scan, confirmatory scans should also be obtained, not less than 4 
weeks following initial documentation of objective response. 
 
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 et al., 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. 
 
Treatment may be continued in cases of radiologic progression at the first 9 week (+/- 7 
days) CT if all of the following criteria are satisfied (see Section 5.3.1 and Appendix B): 
• No decrease in performance status 
• No requirement for immediate alternative treatment or urgent palliative treatment 
• Progression limited to an increase of 40% in the sum of diameters of target lesions (including 
up to 4 new lesions added to the sum) 
• No more than 4 new lesions included in the sum. 
 
NOTE:  If treatment is continued in the case of radiologic progression at the first 9 week 
(+/- 7 days) CT, a reassessment scan must be performed at 4 weeks (+/- 7 days) to rule out 
ongoing progression. 
 
For patients who continue treatment in the case of radiologic progression at the first 9 week 
(+/- 7 days) CT: 
• At any subsequent CT scan patients who have stable disease as compared to the 9 week (+/- 7 
days) CT scan will be allowed to continue on study treatment. 
• Patients who continue treatment in the case of radiologic progression at the first 9 week (+/- 7 
days) CT, and later experience a PR or CR (as compared to baseline CT) will be recorded as 
delayed responses. 
 
11.1.1 Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with atezolizumab and/or bevacizumab. 
 
Evaluable for objective response.  All patients will be evaluable for response from the 
time of their first treatment with atezolizumab and/or bevacizumab.  Patients will have 
their response classified according to the definitions stated below.  (Note:  Patients who 
exhibit objective disease progression prior to 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 


NCI Protocol #: 10010 
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81 
 
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.  
 
11.1.2 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.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
 
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. 
 
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 non-
cystic 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 non-nodal 
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 


NCI Protocol #: 10010 
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82 
 
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.  
 
11.1.3 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. 
 
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 


NCI Protocol #: 10010 
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83 
 
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.  Furthermore, the PET portion of the CT introduces additional data which 
may bias an investigator.  For this reason, PET-CT is not an option for tumor 
measurements in this study. 
 
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 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology These techniques can be used to differentiate between partial 
responses (PR) and complete responses (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 progressive disease. 
 
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 


NCI Protocol #: 10010 
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84 
 
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. 
 
11.1.4 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 


NCI Protocol #: 10010 
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85 
 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
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. 
 
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. 
***  Radiographic responses or stable disease must be confirmed 4 or greater weeks after the 
first scan documenting that status. 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 


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 
‘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 
 
11.1.5 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). 
 
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:  Stable disease 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.  
 
11.1.6 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
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 in this section.  The Protocol Principal 
Investigator 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 adverse events; reporting of expedited adverse events; and accumulation of reported 
adverse events from other trials testing the same drug(s).  The Protocol Principal Investigator and 
statistician have access to the data at all times through the CTMS web-based reporting portal.   
 
All Study Investigators at participating sites who register/enroll patients on a given protocol are 
responsible for timely submission of data via Medidata Rave and timely reporting of adverse 
events for that particular study.  This includes timely review of data collected on the electronic 
CRFs submitted via Medidata Rave. 
 
All studies are also reviewed in accordance with the enrolling institution’s data safety monitoring 
plan. 
 
Investigators (or, when unavailable, a qualified representative from each institution) will meet via 


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teleconference every 2 weeks.  
 
12.2 
Data Reporting 
 
Data collection for this study will be done exclusively through Medidata Rave.  Access to the 
trial in Rave is granted through the iMedidata application to all persons with the appropriate roles 
assigned in the Regulatory Support System (RSS).  To access Rave via iMedidata, the site user 
must have an active CTEP IAM account (https://eapps-ctep.nci.nih.gov/iam) and the appropriate 
Rave role (Rave CRA, Read-Only, or Site Investigator) on either the Corresponding Organization 
or Participating Organization roster at the enrolling site.   
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned 
on the appropriate roster will be sent a study invitation e-mail from iMedidata.  To accept the 
invitation, site users must log into the Select Login (https://login.imedidata.com/selectlogin) 
using their CTEP-IAM user name and password, and click on the “accept” link in the upper right-
corner of the iMedidata page.  Please note, site users 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 link in the upper 
right pane of the iMedidata screen.   
 
Users 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 or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-
mail at ctsucontact@westat.com. 
 
12.2.1 Method 
 
This study will be monitored by the Clinical Trials Monitoring Service (CTMS).  Data 
will be submitted to CTMS at least once every two weeks via Medidata Rave (or other 
modality if approved by CTEP).  Information on CTMS reporting is available at 
http://www.theradex.com/CTMS.  On-site audits will be conducted three times annually 
(one annual site visit and two data audits).  For CTMS monitored studies, after users have 
activated their accounts, please contact the Theradex Help Desk at (609) 799-7580 or by 
email at ctms@theradex.com for additional support with Rave and completion of CRFs. 
 
 
 
12.2.2 Responsibility for Data Submission 
 
For ETCTN trials, it is the responsibility of the PI(s) at the site to ensure that all 
investigators at the ETCTN Sites understand the procedures for data submission for each 
ETCTN protocol and that protocol specified data are submitted accurately and in a timely 
manner to the CTMS via the electronic data capture system, Medidata Rave.   
 


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Data are to be submitted via Medidata Rave to CTMS on a real-time basis, but no less 
than once every 2 weeks.  The timeliness of data submissions and timeliness in resolving 
data queries will be tracked by CTMS.  Metrics for timeliness will be followed and 
assessed on a quarterly basis.  For the purpose of Institutional Performance Monitoring, 
data will be considered delinquent if it is greater than 4 weeks past due. 
 
Data from Medidata Rave and CTEP-AERS is reviewed by the CTMS on an ongoing 
basis as data is received.  Queries will be issued by CTMS directly within Rave.  The 
queries will appear on the Task Summary Tab within Rave for the CRA at the ETCTN to 
resolve.  Monthly web-based reports are posted for review by the Drug Monitors in the 
IDB, CTEP.  Onsite audits will be conducted by the CTMS to ensure compliance with 
regulatory requirements, GCP, and NCI policies and procedures with the overarching goal 
of ensuring the integrity of data generated from NCI-sponsored clinical trials, as 
described in the ETCTN Program Guidelines, which may be found on the CTEP 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)  
and CTSU websites. 
 
An End of Study CRF is to be completed by the PI, and is to include the recommended 
phase 2 dose (RP2D), and a description of any dose-limiting toxicities (DLTs).  CTMS 
will utilize a core set of eCRFs that are Cancer Data Standards Registry and Repository 
(caDSR) compliant (http://cbiit.nci.nih.gov/ncip/biomedical-informatics-
resources/interoperability-and-semantics/metadata-and-models).  Customized eCRFs will 
be included when appropriate to meet unique study requirements.  The PI is encouraged 
to review the eCRFs, working closely with CTMS to ensure prospectively that all 
required items are appropriately captured in the eCRFs prior to study activation.  CTMS 
will prepare the eCRFs with built-in edit checks to the extent possible to promote data 
integrity. 
 
CDUS data submissions for ETCTN trials activated after March 1, 2014, will be carried 
out by the CTMS contractor, Theradex.  CDUS submissions are performed by Theradex 
on a monthly basis.  The trial’s lead institution is responsible for timely submission to 
CTMS via Rave, as above. 
 
Further information on data submission procedures can be found in the ETCTN Program 
Guidelines 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm)
. 
12.3 
Collaborative Agreements Language 
 
N/A 
 
12.4 
Genomic Data Sharing Plan 
 
N/A 
 


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13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
Primary Objectives 
To assess the anti-tumor activity (proportion of patients with objective response by RECIST 1.1 
criteria) of atezolizumab and bevacizumab in patients with recurrent, persistent or metastatic 
cervical cancer. 
 
Secondary Objectives 
To estimate the duration of progression free survival (PFS) and overall survival (OS) 
 
To assess safety by CTCAE v.5.0 
 
Integrated Biomarker 
Integrated Biomarker:  To describe the efficacy of the combination of atezolizumab and 
bevacizumab as measured by objective response, by PD-L1 expression on tumor and immune 
cells measured by semi-quantitative immunohistochemistry (IHC) 
 
Exploratory Biomarker 
To describe the efficacy of the combination of atezolizumab and bevacizumab as measured by 
objective response, by intratumoral and peripheral TCR clonality and tumor infiltrating 
lymphocyte proportion 
 
13.2 
Sample Size/Accrual Rate 
 
Primary objective: 
Objective response rate (ORR, either partial or complete response) defined by RECIST v1.1 
criteria. 
 
Null hypothesis: The administration of atezolizumab with bevacizumab to patients with 
persistent, metastatic or recurrent cervical cancer does not yield an overall response (ORR) 
greater than 15 percent. 
 
Alternative hypothesis: The administration of atezolizumab with bevacizumab to patients with 
persistent, metastatic or recurrent cervical cancer yields an overall response (ORR) of 40% or 
greater. 
 
Statistical Considerations: 
A Simon 2-stage Phase II design will be used to address the primary endpoint of ORR.  The 
unacceptable response rate is 0.15; desirable response rate is 0.40.  With an error rate of (Type I 
error of 0.1, Type II error of 0.1), 22 patients are needed.  With 22 patients, there is a 90% power 
to show a difference in response rate from 15 to 40%.  The trial will continue to stage two only if 
two or more out of 10 patients show a response in the first stage.  Six or more patients out of 22 
must exhibit a response for the study to be positive.  The ORR (either partial or complete 
response) defined by RECIST v1.1 will be calculated assuming binomial proportions and a 90% 
confidence interval will be provided.  


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Early stopping rule.  We will stop for safety if >=3/10 DLTs are observed or at the end of the 
study if >=5 DLTs out of 22 patients are seen we will deem the regimen not safe. These 
boundaries were calculated assuming 0.1 and 0.30 as safe and unacceptably safe rates 
respectively (https://www.ncbi.nlm.nih.gov/pubmed/16011702).  
 
Definition of a Dose-Limiting Toxicity (DLT) 
For the early stopping rule for safety component of this study a DLT is defined as: 
Any Grade 4 immune related adverse event 
Any >= grade 3 colitis 
Any Grade 3 or 4 noninfectious pneumonitis (irrespective of duration) 
Liver transaminase (ALT and/or AST) elevation > 8 x ULN or total bilirubin > 5 x 
ULN 
Any >= grade 3 non immune related adverse event except for the exclusion list below 
Any Grade 3 or higher fistula/leak/bowel perforation 
Treatment related death 
 
A DLT does not include: 
Grade 3 fatigue 
Grade 3 endocrine disorders (thyroid, pituitary, and/or adrenal insufficiency) that is 
managed with or without systemic corticosteroid therapy and/or hormone replace 
therapy 
Grade 3 infusion related reaction 
Grade 3 or 4 neutropenia (that is not associated with fever or infection) lasting <= 7 
days 
Grade 3 or 4 lymphopenia 
Grade 3 thrombocytopenia that is not associated with clinically significant bleeding 
Isolated grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention 
Grade 3 hypertension 
 
Accrual rate is estimated to be 4 patients/month. 
 
13.3 
Stratification Factors 
 
N/A 
 
13.4 
Analysis of Secondary Endpoints 
 
Progression-Free survival (PFS), defined as time from the date of start of treatment to the 
investigator determined date of progression (determined by RECIST v1.1 criteria), or death due 
to any cause, whichever occurs first.  For individuals who are alive and progression free, PFS 
will be defined as the time from the study enrollment date to the date of the patient’s last 
radiographic disease assessment.   The expected median duration of PFS in this population is 3.5-
4.5 months. 
 
Overall survival (OS), defined as time from the date of start of treatment to death. 


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Safety endpoint: safety as measured by frequency and severity of adverse events by Common 
Terminology Criteria for Adverse Events (CTCAE) v.5.0 assessed in those patients who initiate 
their study treatment.  
 
Integrated biomarker:  PD-L1 IHC:  We will describe the efficacy of the combination of 
atezolizumab and bevacizumab as measured by objective response, in patients according to PD-
LI expression.  PD-L1 expression will be assessed following a pre-specified scoring algorithm for 
tumor cells and immune cells.  The association of PD-L1 expression, baseline demographics and 
clinical outcome will be determined. 
 
Exploratory biomarker:  We will describe the efficacy of the combination of atezolizumab and 
bevacizumab as measured by objective response, by intratumoral and peripheral TCR clonality 
and tumor infiltrating lymphocyte proportion. 
 
13.5 
Reporting and Exclusions 
 
13.5.1 Evaluation of Toxicity 
 
All patients will be evaluable for toxicity from the time of their first treatment with 
atezolizumab and/or bevacizumab. 
 
13.5.2 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 exception of those who 
received no study medication) should be included in the main analysis of the 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. 
 
All conclusions will 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 (e.g., early death due to other reasons, early discontinuation of 
treatment, major protocol violations, etc.).  However, these subanalyses will not serve as 
the basis for drawing conclusions concerning treatment efficacy, and the reasons for 
excluding patients from the analysis will be clearly reported.  The 95% confidence 
intervals will be provided.  
 
 
 


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in a pooled analysis of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) with 
chemotherapy.  Proc. Am. Soc. Clin. Oncol.  24:A3019 
 
Smith, A.R., J.M. Hennessy, M.A. Kurth, and S.C. Nelson.  (2008).  Reversible skeletal changes 
after treatment with bevacizumab in a child with cutaneovisceral angiomatosis with 
thrombocytopenia syndrome.  Pediatr Blood Cancer.  51:418-20 
 
Wedam, S.B., J.A. Low, S.X. Yang, et al.  (2006).  Antiangiogenic and antitumor effects of 
bevacizumab in patients with inflammatory and locally advanced breast cancer.  J Clin Oncol.  
24:769-77.  
 
Willett, C.G., Y. Boucher, E. di Tomaso, et al. (2004). Direct evidence that the VEGF-specific 
antibody bevacizumab has antivascular effects in human rectal cancer. Nat. Med. 10:145-147. 
 


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Yang, J.C., L. Haworth, R.M. Sherry, et al.  (2003).  A randomized trial of bevacizumab, an anti-
vascular endothelial growth factor antibody, for metastatic renal cancer.  N. Engl. J. Med.  
349:427-434. 
 
 
 


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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 
EXAMPLES ON HOW TO ASSESS TUMOR RESPONSES 
 
The methods used to assess tumor response follow to a large extent RECIST 1.1 but are 
modified at the first scan (performed at 9 weeks +/- 7 days) to allow for temporary inflammation 
of the tumors that could result from activation of an immune response system. Below are 
examples of hypothetical cases which can be used as a guide for evaluating your patient. 
 
The protocol specifies continuation of treatment in cases of radiologic progression at 
the first 9 week (+/- 7 days) CT if all of the following criteria are satisfied: 
• No decrease in performance status 
• No requirement for immediate alternative treatment or urgent palliative treatment 
• Progression limited to an increase of 40% in the sum of diameters of target lesion (including 
up to 4 new lesions added to the sum) 
• No more than 4 new lesions included in the sum 
 
NOTE:  If treatment is continued in the case of radiologic progression at the first 9 week 
(+/- 7 days) CT, a reassessment scan must be performed at 4 weeks (+/- 7 days) to rule out 
ongoing progression. 
 
For patients who continue treatment in the case of radiologic progression at the first 9 
week (+/- 7 days) CT: 
• At any subsequent CT scan patients who have stable disease as compared to the 9 week 
(+/- 7 days) CT scan will be allowed to continue on study treatment. 
• Patients who continue treatment in the case of radiologic progression at the first 9 week 
(+/- 7 days) CT, and later experience a PR or CR (as compared to baseline CT) will be 
recorded as delayed responses. 
 
Example 1 
 
Patient obtains a baseline measurement on 12/31/2015, enrolls onto study, and starts therapy on 
01/01/2016. 
 ………………………………………………………………………………… 
Date of Evaluation: 12/31/2015              Baseline Tumor Measurement 
 
 
 
Notes: The nadir is 10 cm. Partial response will occur if the total is ≤ 7 cm (> 30% or greater 
decrease from nadir of 10). Progression will occur if the total is > 14 cm (>40% or greater 
increase from nadir of 10). 
……………………………………………………………………………… 
Site of Lesion Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 


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Date of Evaluation: 3/4/2016                Nine Week Assessment 
Site of Lesion   Tumor Size 
 
Site 1 
6 cm 
Site 2 
7 cm 
Total 
13 cm 
 
Time point response: Neither progression nor response since 7cm < total < =14 cm. Although 
the total > 12 cm (> 20% or greater increase from nadir of 10), an allowance is made for this type 
of therapy at this time. The nadir is revised to 13 cm. The threshold for progression is now > 15.6 
cm (> 20% or greater increase from nadir of 13). Partial response can be obtained if the total is ≤ 7 
cm, same as before. 
 
……………………………………………………………………………… 
Date of Evaluation: 5/6/2016                18 Week Assessment 
 
Site of Lesion Tumor Size 
Site 1 
8 cm 
Site 2 
8 cm 
Total 
16 cm 
 
Time point response: Progression since 16 cm > 15.6 cm. The date of progression is 3/4/2016, 
not 5/6/2016. 
 
Example 2 
 
Patient obtains a baseline measurement on 12/31/2015, enrolls onto study, and starts therapy on 
01/01/2016. 
 
……………………………………………………………………………… 
Date of Evaluation: 12/31/2015              Baseline Tumor Measurement 
 
Site of Lesion Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 
 
Notes: The nadir is 10 cm. Partial response will occur if the total is ≤ 7 cm (> 30% or greater 
decrease from nadir of 10). Progression will occur if the total is > 14 cm (> 40% or greater 
increase from nadir of 
10). 
 
……………………………………………………………………………… 
Date of Evaluation: 3/4/2016                9 Week Assessment 


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Site of Lesion Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Site 3 
4 cm 
Total 
14 cm 
 
Time point response: Neither progression nor response since 7 cm < total <= 14 cm. Up to 4 
additional target tumors are allowed. Nadir revised to 14 cm. The threshold for progression is 
revised to > 16.8 cm. 
 
……………………………………………………………………………… 
Date of Evaluation: 5/6/2016                18 Week Assessment 
 
Site of Lesion Tumor Size 
Site 1 
4 cm 
Site 2 
4 cm 
Site 3 
3 cm 
Total 
11 cm 
 
Time point response: Neither progression nor response since 7 cm < total < 16.8 cm. Note, the 
nadir is revised to 11 cm. The threshold for progression is now > 13.2 cm. In order for the 
patient to respond, all 3 tumors must sum to ≤ 7 cm. 
 
……………………………………………………………………………… 
Date of Evaluation: 7/8/2016                27 Week Assessment 
 
Site of Lesion Tumor Size 
Site 1 
2 cm 
Site 2 
2 cm 
Site 3 
2 cm 
Total 
6 cm 
 
Time point response: Partial Response since total ≤ 7 cm. The patient’s response will 
need to be confirmed ≥ 4 weeks later with a total ≤ 7 cm. If confirmed, her date of partial 
response will be 7/8/2016. Note, the nadir is now 6 cm. Disease progression would occur 
if the total is ≥ 7.2 cm. 
 
Example 3 
 
Patient obtains a baseline measurement on 12/31/2015, enrolls onto study, and starts therapy on 
01/01/2016. 
 
………………………………………………………………………………… 


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Date of Evaluation: 12/31/2015              Baseline Tumor Measurement 
 
Site of Lesion Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 
 
Notes: The nadir is 10 cm. Partial response will occur if the total is ≤ 7 cm (> 30% or greater 
decrease from nadir of 10). Progression will occur if the total is > 14 cm (> 40% or greater 
increase from nadir of 10). 
……………………………………………………………………………… 
Date of Evaluation:  3/4/2016                9 Week Assessment 
Site of lesion 
Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 
 
 
Site of Lesion Non-target 
Site 3 
Present 
 
 
Time point response: Neither progression nor response. This patient’s measurable lesions 
remained the same but she acquired a new non-target lesion. 
………………………………………………………………………………… 
Date of Evaluation: 5/6/2016                18 Week Assessment 
Site of lesion 
Tumor Size 
Site 1 
5 cm 
Site 2 
5 cm 
Total 
10 cm 
 
 
Site of Lesion Non-target 
Site 3 
Present 
 
Time point response: Neither progression nor response. New lesions that appear during week 9 
will be carried forward as if they were at baseline.
 
 


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APPENDIX C 
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”): 
 
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 prior to 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. 
 


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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 principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to 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 prior to submission, but in 
any case, prior to presentation at the meeting or publication in the proceedings. Press releases 
and other media presentations must also be forwarded to CTEP prior to release. Copies of 
any manuscript, abstract and/or press release/ media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov  
 
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.