CA209-382 A Randomized Phase 2 Open Label Study of Nivolumab Plus Standard Dose Bevacizumab Versus Nivolumab Plus Low Dose Bevacizumab in Recurrent Glioblastoma (GBM)
Phase: PHASE2
Conditions: Glioblastoma
Sponsor: David Peereboom

 
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STUDY NUMBER:  CASE 1317 
 
ClinicalTrials.gov NCT #:  NCT 03452579 
 
Version Date:   Protocol Date 10/05/2017 
                          Protocol Date 10/24/2017 
                          Protocol Date Amendment 1 05/03/2018 
                          Protocol Date Amendment 2 05/21/2018 
                          Protocol Date Amendment 3 01/06/2020 
                          Protocol Date Amendment 4 03/20/2020 
                          Protocol Date Amendment 5 07/14/2021 
 
STUDY TITLE:  CA209-382 A Randomized Phase 2 Open Label Study of Nivolumab plus 
standard dose Bevacizumab versus Nivolumab plus low dose Bevacizumab in Recurrent 
Glioblastoma (GBM) 
 
 
 
 
PRINCIPAL INVESTIGATOR: David Peereboom M.D. 
 
 
 
 
Case Comprehensive Cancer Center 
Cleveland Clinic 
 
 
 
 
Taussig Cancer Center 
9500 Euclid Avenue, CA-51  
 
 
Cleveland, OH 44195 
 
 
 
 
 
 
 
CO-PI: 
 
 
            David A. Reardon, M.D. 
                                                      Center for Neuro-Oncology 
                                                      Dana-Farber Cancer Institute 
                                                      450 Brookline Avenue, D2134 
                                                      
 
                                                      
 

 
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STATISTICIAN:  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
STUDY COORDINATOR: 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
SPONSOR:  
 
 
Case Comprehensive Cancer Center  
 
 
 
 
 
 
SUPPORT/FUNDING: 
 
Cleveland Clinic/Bristol Myers Squibb 
 
SUPPLIED AGENT: 
 
Nivolumab 
 
IND #:  
 
 
 
 
 
 
 
 
OTHER AGENT:  
            Bevacizumab 
 
 
 
 
 
 
 
 
 
 
 

 
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SUMMARY OF CHANGES 
 
 
Protocol 
Date 
Section 
Change 
10/05/2017 
 
Initial IRB approval 
10/24/2017 
Table 
9.2-1 
 
Table 9.2-1 
Correlative Study information inadvertently omitted from table 9.2-1 
Cytokine/chemokine/PBMC Correlative studies and Tumor Tissue 
added to screening assessments 
10/24/2017 
Page 6 
Removal of the word monotherapy 
10/24/2017 
Page 28
Corrected nivolumab monotherapy to state nivolumab + standand 
bevacizumab 
10/24/2017 
Page 39 
6.5.1 
Corrected nivolumab to state nivolumab plus standard bevacizumab 
 
10/24/2017 
Page 39 
6.5.1 1-
1 
Corrected nivolumab monotherapy to state Nivolumab (BMS-936558) 
plus standard bevacizumab 
05/03/2018 
 
Page 1 
NCT # added, Updated protocol version date added, updated 
statistician contact information  
05/03/2018 
Page 16
Appendices updated to include 7.0 NANO Scale 
05/03/2018 
 
Page 30
Information required for subject randomization updated  
05/03/2018 
 
Page 30
Patients name updated to Patients Initials, Patient Medical Record # 
updated to Patient ID 
05/03/2018 
 
Page 32
® added after Mirena 
05/03/2018 
 
Page 33 
section 
4.2 
Exclusion Criteria 1 updated to “more than one recurrences of GBM” 
05/03/2018 
 
Page 36
Typo of sequelae corrected 

 
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Protocol 
Date 
Section 
Change 
05/03/2018 
 
Page 41 
Section 
6.5.1 
Drug names of nivolumab and bevacizumab updated from upper case 
to lower case  
05/03/2018 
 
Page 41
Time of infusion changed from 30 minutes after completion of the 
nivolumab infusion to 10 minutes 
05/03/2018 
 
Page 63
Injection solution typo corrected 
05/03/2018 
 
Page 68 
Table 
9.2-1 
MGMT added, Tumor biopsy changed to tumor tissue, notes for tumor 
tissue details amended, oxygen saturation by pulse oximetry. Pulse 
oximetry at rest and after exertion deleted, physical measurements of 
Karnofsky performance score changed to KPS, laboratory tests 
amended-serum urea level deleted, B/C(HBVsAG, HCV antibody 
deleted, HIV,HepVsAg,HCV added 
05/03/2018 
 
Page 70 
Table 
9.2-2 
Window updated to 3-4 days, Physical exam amended to day 1 of 
each cycle +/-4 days, vital signs and oxygen saturation amended, 
clarification regarding C1D1 labs added, clarification of labs after C1 
D1 added 
05/03/2018 
 
Page 71 
Table 
9.2-2 
Cytokine/chemokine/PBMC Correlative Studies added to on study 
assessments. To be obtained at Week 4, Week 8, then at every MRI 
visit until progression 
05/03/2018 
 
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Table 
9.2-3 
Deletion of Oxygen saturation by pulse oximetry. Pulse oximetry at 
rest and after exertion 
 
05/03/2018 
 
Pages 
75-81 
Statistical Section of the protocol amended  
Section 12.1 Amended 
Section 12.2.5 Amended 
05/03/2018 
Page 
115 
Appendix 7 Cytokine/chemokine/PBMC Correlative Studies amended 
to include details of tissue slides, location of tissue submission, blood 
collection details clarified  
05/03/2018 
Page 
118 
Appendix 9 NANO Scale added  
05/03/2018 
 
CTCAE version updated to CTCAE v 5.0 throughout  protocol 
05/03/2018 
Pages 
7,26,27
,31,74 
First or second recurrence amended to state only first recurrence   

 
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Protocol 
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05/03/2018 
Page 34 
4.2 
Exclusion criteria amended to > NCI CTCAE Grade 3 within 6 
months prior to start of study treatment  
05/21/2018 Inclusion 
criteria d First or second recurrence amended to state only first recurrence   
05/21/2018 Inclusion 
criteria g Deleted  
01/06/2020 
Cover 
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footer 
Updated to include Amendment number and version date  
01/06/2020 All 
Protocol 
Patients amended to Subjects throughout protocol  
01/06/202 
Study 
Design 
Deleted “may have up to 2 recurrences” amended to state “Subjects 
must have received previous treatment with radiotherapy and one 
recurrence” 
01/06/2020 
3.2 
Number 
of 
Subjects 
Arm B (nivolumab + reduced dose bevacizumab) amended to Arm B 
(nivolumab + low dose bevacizumab) 
01/06/2020 3.3 Study
Phases 
Arm B (nivolumab + reduced dose bevacizumab) amended to Arm B 
(nivolumab + low dose bevacizumab) 
The second infusion will be bevacizumab, and will start no sooner 
than 30 minutes amended to no sooner than 10 minutes 
All of the laboratory tests and vital signs will be collected prior to 
study drug dosing at the time points specified in Section amended 
from 10.0 to 9.2 
Study drug dosing may be delayed for toxicity. See Section 7 
amended to 6.6 
01/06/2020 3.4 
After verifying each patient’s eligibility status and administering 
informed consent, the patient will be enrolled into the study by the 
study coordinator to obtain the subject number amended to study 
coordinator “or research nurse” 
Added sentence -If the subject withdraws or screen fails before 
starting treatment, the assigned subject number will not be re-issued 
Surgery type amended to complete resection, near complete resection 
or biopsy  
01/06/2020 4.0 
Gender,Age,Race deleted  

 
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Protocol 
Date 
Section 
Change 
01/06/2020 4.1 
Applies to covered entities in the USA only deleted 
Addition of bullet point i) Up to ten unstained slides of 5 microns 
thickness or a block of tissue will be required to be sent if tissue is 
available. If the tissue is not available then Principal investigator 
permissions is required prior to enrollment 
Bullet point d) and e) amended.  Bullet point g) and h) deleted  
Deleted-Acceptable 
alternate 
methods 
of 
highly 
effective 
contraception must be discussed in the event that the subject chooses 
to forego complete abstinence  
Section Women of Child Bearing Potential (WOCBP) amended  
  
01/06/2020 
4.2 
Bullet point h) amended from (defined as systolic blood pressure ≥150 
mmHg and /or diastolic blood pressure ≥100 mmHg) to (defined as 
systolic blood pressure ≥160 mmHg and /or diastolic blood pressure 
≥100 mmHg)  
Bullet point l) amended from ≥ NCI CTCAE Grade 3 within 6 months 
to within 3 months  
01/06/2020 4.4 
Section Deleted         
01/06/2020 4.5.2 
Appendix 6 amended to added hepatoxicity article  
01/06/2020 5.0 
Language added for studies using the Forte EDC (Overture) for data 
collection  
01/06/2020 
6.5.1 
Arm B amended to state Arm B( nivolumab plus low dose 
bevacizumab) 
Table 6.5.1-2: “in combination” deleted and replaced with “plus low 
dose” 
Nivolumab will be given every two weeks at a dose of 3mg/kg 
amended to 240mg 
01/06/2020 
6.5.2 
The dose of bevacizumab will be based on with at study entry 
amended to based on weight at screening.   
“guidelines” amended to “or per institutional guidelines.”  
01/06/2020 6.5.3 
Section 7 amended to Section 6.8 
01/06/2020 7.4 
Language added to clarify that all SAEs are to be reported to Sponsor-
Investigator Manmeet Ahluwalia M.D. 
01/06/2020 Table 8 
Venous Thrombosis.  If the planned duration of full-dose 
anticoagulation amended from >2 weeks to ≥ 2 weeks 

 
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Protocol 
Date 
Section 
Change 
01/06/2020 9.1.2 
Amended Arm B form reduced dose bevacizumab to low dose 
bevacizumab 
01/06/20 
20 
9.2.1 
Amended Study Calendar, deleted HIV, footnote bb added, footnote q 
will remain blank  
01/06/2020 15.0 
Appendix numbers amended.   
01/06/2020 Appendix 
6 
Hepatotoxicity article added  
01/06/2020 Appendix 
10  
Appendix added to include corrected NANO scale   
01/06/2020 All 
Protocol 
Updated protocol where is states reduced dose bevacizumab to low 
dose bevacizumab for consistency  
01/06/2020 Table of
Contents Corrected numbering of section 12.0  
03/20/2020 Cover 
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footer 
Updated to include Amendment number and version date 
 
 
03/20/2020 Section 
9.1.2 
Added: In view of the Covid 19 crisis, all in person visits can be 
substituted for virtual visit.   All nursing toxicity checks can be 
performed over the phone rather than in person 
 
03/20/2020 
Section 
9.2 Study
Calendar
cc superscript added to Physical & Neurological exam, vital signs, 
Performance Status (KPS) 
 
03/20/2020 
 
Section 
9.2 Study
Calendar
cc superscript details added: in view of covid-19 crisis, virtual visits 
will be allowed and the need for physical exam as long as patients is 
asymptomatic will be waived 
07/14/2021 Cover 
page 
Updated Sponsor-Investigator to David Peereboom M.D. 
 
07/14/2021 Cover 
page 
Updated Statistician to Wei Wei (Austin)  
07/14/2021 Section 
5.0 
Updated EDC language to The Advarra EDC™ and OnCore™ 
databases 
07/14/2021 7.8 
Updated Sponsor-Investigator to David Peereboom M.D. 
07/14/2021 Section 
11.1 
Updated EDC language to The Advarra EDC™ and OnCore™ 
databases 

 
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Protocol 
Date 
Section 
Change 
07/14/2021 Section 
9.2 
dd superscript details added to tumor assessments: patients who 
remain on study after 3 years, MRIs to be done every 12 weeks (+/- 1 
week)  
07/14/2021 Appendix 
8 
Updated Sponsor-Investigator to David Peereboom M.D. 
 
 

 
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STUDY SCHEMA 
 
SYNPOSIS 
Background 
 
The outcome for glioblastoma (GBM) remains dismal with a median survival of approximately 
15 months and nearly all cases recur despite progress in surgical techniques, radiation and 
chemotherapies1,2. A number of single arm phase II studies using immunotherapy approaches 
in subjects with GBM provide support for considering an immunotherapy3-7 particularly a 
strategy designed to reverse cancer-mediated immune suppression8. T cells have access to 
antigens within the CNS, and the blood brain barrier does not form an absolute barrier to 
immune responses; the concept of “immunologic privilege” in the CNS has been refuted9. 
Subjects with GBM have a variety of mechanisms that contribute to an overall state of immune 
suppression.  Primed CD8+ cytotoxic T cells gain CNS access, however, the cells are 
functionally impaired as evidenced by the lack of tumor eradication. Ex vivo studies 
demonstrate a lack of effector/activated T cells in the glioma microenvironment10.  Gliomas 
secrete factors such as prostaglandin E2 and TGF β that are capable of suppressing cytotoxic 
responses of T cells against tumor targets. Co-stimulatory inhibitory molecules like B7-H1 are 
expressed in malignant gliomas and can further inhibit immune responses11. T-regulatory cells, 
which suppress effector T-cell responses, are increased in the peripheral circulation and within 
the tumors of subjects with glioma12,13 and more profound immunosuppression is associated 
with worse outcome14. 
 
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of 
immuno-oncology and treatment with investigational agents targeting this mechanism has 
induced regressions in several types of cancer. The programmed death 1 (PD-1) receptor is an 
important cellular target that play a key role in regulating adaptive immunity. Glioblastoma is 
an aggressive brain tumor with high mortality and morbidity despite current treatments. The 
significant unmet clinical need for subjects and preclinical data suggesting involvement of 
immunologic factors in GBM disease course support the investigation of checkpoint inhibitors 
for therapeutic potential. Nivolumab monotherapy has demonstrated clinical activity across 
several tumor types, including advanced melanoma, NSCLC, and RCC. Nivolumab has 
demonstrated a manageable safety profile in subjects > 700 subjects across all clinical trials. 
The most common AEs included fatigue, rash, pruritus, diarrhea, and nausea. 
 
Bevacizumab (Avastin; Genentech, South San Francisco, CA) is a humanized monoclonal 
antibody that inhibits VEGF and is the first antiangiogenic therapy to be approved for use in 
subjects with cancer. The BRAIN study, a phase II randomized trial evaluated the role of 

 
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bevacizumab (alone or in combination with irinotecan) in 167 subjects with recurrent GBM. 
The progression free survival (PFS) at 6 months (PFS-6) was 42.6% and 50.3%, objective 
response rate (ORR) was 28.2% and 37.8% and median overall survival (OS) was 9.2 months 
and 8.7 months in the monotherapy and combination arms respectively. In a study done at the 
National Cancer Institute (NCI), 48 subjects with recurrent GBM were treated with 
bevacizumab producing a response rate (RR) of 35%, PFS-6 of 29% and a median OS of 31 
weeks. Clinical benefit was also evident with decreasing cerebral edema, tapering steroid doses 
and improvement in neurological function in nearly half of the subjects. Nonetheless, the 
optimal dose of bevacizumab for GBM subjects remains unclear. A recent retrospective 
analysis of 219 subjects confirmed that lower dosing was associated with enhanced survival.15 
In this study, subjects treated with < 10 mg/kg every other week of bevacizumab had a median 
OS of 9 months compared to only 5 months for those treated with standard 10 mg/kg biweekly 
(p=0.001). Similar improved survival benefit associated with lower bevacizumab dosing was 
confirmed in a validation cohort (n=109 subjects). The exact mechanism of improved survival 
is unclear but standard bevacizumab dosing can significantly decrease perfusion and tumor 
vasculature permeability, leading to intratumoral hypoxia which may in turn drive GBM 
invasion and infiltration.16-20 In contrast, lower doses of anti-angiogenic agents can normalize 
tumor vasculature leading to enhanced intratumoral immune cell infiltration.21,22 
 
The rationale for combining nivolumab with bevacizumab includes increasing data 
demonstrating that VEGF inhibition can enhance the anti-tumor benefit of immunotherapies by 
decreasing immunosuppression, enhancing dendritic cell and T cell activity and decreasing 
Treg activity.23-25,26-29  Enhanced anti-tumor immune responses have also been demonstrated in 
preclinical models following VEGF blockade22,24-35  and a clinical trial has recently 
demonstrated that bevacizumab improved therapeutic outcome of CTLA-4 blockade among 
metastatic melanoma subjects.36 
 
The current study will evaluate the anti-tumor activity as well as safety of nivolumab in 
combination with bevacizumab administered according to standard and reduced dosage 
schedules for recurrent glioblastoma subjects. Although the hypothesis is that VEGF blockade 
will enhance the anti-tumor activity of anti-PD-1/PD-L1 therapy, a currently unanswered 
critical question is whether there is an optimized dosing schedule of bevacizumab to do so. 
Standard bevacizumab dosing, administered as single agent therapy, represents the approved 
schedule for recurrent GBM based on durable radiographic responses.37  In fact, as a 
monotherapeutic, a higher dosing schedule of bevacizumab may be required to achieve a 
sufficient anti-angiogenic effect to translate into anti-tumor benefit. However, higher 
(standard) dosing has also been shown to significantly decrease perfusion and tumor 
vasculature permeability, leading to intratumoral hypoxia which may in turn drive GBM 
invasion and infiltration.16,17,38-40  In contrast, a lower dosing schedule has been shown to 

 
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normalize rather than eradicate tumor vasculature, leading to improved blood flow, less 
hypoxia and enhanced delivery of co-administered anti-tumor agents in preclinical cancer 
models including GBM.41,42 Normalized vasculature has also been associated with enhanced 
survival among cancer subjects including those with GBM treated with anti-VEGF therapy.43,44  
Furthermore, additional preclinical studies demonstrate that normalized tumor vasculature 
following reduced anti-VEGF therapy also leads to enhanced intratumoral immune cell 
infiltration.22,45  Finally, a recently published preclinical study evaluating lower versus higher 
doses of anti-VEGF therapy showed that only lower anti-VEGF therapy dosing led to enhanced 
immune infiltrate and improved survival following co-administration with an anti-tumor 
immunotherapeutic.22  
 
A prospective evaluation of standard versus reduced bevacizumab dosing has not been 
conducted for subjects with GBM. However, a retrospective review of 219 subjects treated 
with bevacizumab showed that subjects treated with lower dose intensity (< 5 mg/kg per week) 
of bevacizumab had longer PFS and OS when compared with those treated with the standard 
10 mg/kg biweekly dosing. 46 
 
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment 
with Investigational Product(s): 
 
 Nivolumab (BMS-936558) administered IV over 30 minutes at 240 mg flat dose and 
bevacizumab administered IV at 10 mg/kg every 2 weeks until progression (Arm A) 
 Nivolumab (BMS-936558) administered IV over 30 minutes at 240 mg flat dose and 
bevacizumab administered IV at 3 mg/kg every 2 weeks until progression (Arm B) 
 
Study design 
 
This is a randomized, open-label, phase 2 safety study of nivolumab and bevacizumab 
administered according to standard and low dosage schedules in adult (≥ 18 years) subjects 
with a first recurrence of glioblastoma (GBM). Subjects must have received previous treatment 
with radiotherapy and one recurrence.  The study will allow subjects that require decadron up 
to 4 mg/ day to participate.    
 
 
 
 
 
 

 
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PROTOCOL SUMMARY 
 
Protocol Number/Title 
Case 1317/ CA209-382 A Randomized Phase 2 Open Label 
Study of Nivolumab plus standard dose Bevacizumab 
versus Nivolumab plus low dose Bevacizumab in Recurrent 
Glioblastoma (GBM) 
Study Phase 
Phase 2  
Brief Background/Rationale
 
 
 
The outcome for recurrent glioblastoma (GBM) remains 
dismal despite progress in surgical techniques, radiation 
and chemotherapies1,2. A number of single arm phase II 
studies using immunotherapy approaches in subjects with 
GBM provide support for considering an immunotherapy3-7 
particularly a strategy designed to reverse the prominent 
cancer-mediated immune suppression8. T cells have access 
to antigens within the CNS, and the blood brain barrier does 
not form an absolute barrier to immune responses; the 
concept of “immunologic privilege” in the CNS has been 
refuted9. Subjects with GBM have a variety of mechanisms 
that contribute to an overall state of immune suppression.  

 
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Primed CD8+ cytotoxic T cells gain CNS access, however, 
the cells are functionally impaired as evidenced by the lack 
of tumor eradication. Ex vivo studies demonstrate a lack of 
effector/activated T cells in the glioma microenvironment10.  
Gliomas secrete factors such as prostaglandin E2 and TGF 
β that are capable of suppressing cytotoxic responses of T 
cells against tumor targets. Co-stimulatory inhibitory 
molecules like B7-H1 are expressed in malignant gliomas 
and can further inhibit immune responses11. T-regulatory 
cells, which suppress effector T-cell responses, are 
increased in the peripheral circulation and within the 
tumors of subjects with glioma12,13 and the subjects with 
more profound immunosuppression is associated with 
worse outcome14. 
Immune checkpoint blockade is a rapidly advancing 
therapeutic approach in the field of 
immuno-oncology and treatment with investigational agents 
targeting this mechanism has 
induced regressions in several types of cancer. Cytotoxic T-
lymphocyte–associated antigen 4(CTLA-4) and 
programmed death 1 (PD-1) receptor are two important 
cellular targets that play complementary roles in regulating 
adaptive immunity. Whereas PD-1 contributes to T-cell 
exhaustion in peripheral tissues, CTLA-4 inhibits at earlier 
points in T-cell activation63.  
 
Nivolumab (BMS-936558; anti-PD-1 monoclonal antibody) 
is a fully human monoclonal 
immunoglobulin (Ig) G4 antibody that binds to the PD-1 
cell surface membrane receptor, a negative regulatory 
molecule expressed by activated T and B lymphocytes. 
Inhibition of the interaction between PD-1 and its ligands 
promote immune responses and antigen-specific T cell 
responses to both foreign and self-antigens. PD-1 receptor 
blockade by nivolumab is a new approach for 
immunotherapy of tumors. Nivolumab monotherapy has 
demonstrated clinical activity across several tumor types, 
including advanced melanoma, NSCLC, and RCC. 

 
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Increasing data suggests that VEGF inhibition can enhance 
the anti-tumor benefit of immunotherapies. First, VEGF is 
known to significantly contribute to the immunosuppressive 
ability of tumors.23-25 Specifically, VEGF can inhibit 
dendritic cell maturation and antigen presentation, induce 
apoptosis of CD8+ T cells, enhance Treg activity and 
diminish infiltration of T cells across tumor endothelium.26-
29 
 
Second, 
preclinical 
studies 
demonstrate 
that 
immunotherapeutics may be combined with VEGF 
inhibitors to generate enhanced anti-tumor benefit.22,24-35 
Specifically, 
VEGF 
inhibition 
can 
diminish 
immunosuppressive features of tumors26-29,32,34,35 and 
enhance the anti-tumor activity of immunotherapies.30-
32,34,35 Third, preclinical strategies to normalize tumor 
vasculature, including administration of ant-VEGF therapy, 
can shift tumor-associated macrophages from an M2 
immune-inhibitory phenotype to an immune-stimulatory 
M1-phenotype, as well as increase tumor infiltrating CD8+ 
T cells and enhance survival following whole tumor cell 
vaccination.22 Finally, data from a recently published phase 
I study among metastatic melanoma subjects revealed that 
administration of bevacizumab with ipilimumab, an 
inhibitor of the CTLA-4 immune checkpoint, led to 
improved overall survival as well as increased immune cell 
trafficking into tumor sites.36 
 
The rationale for evaluating two dose levels of 
bevacizumab in combination with standard nivolumab 
dosing is based on several factors. First, although a lower 
bevacizumab dose schedule has not been prospectively 
evaluated among recurrent glioblastoma subjects, a recent 
retrospective analysis of 219 subjects confirmed that lower 
dosing was associated with enhanced survival.15 In this 
study, subjects treated with < 10 mg/kg every other week of 
bevacizumab had a median OS of 9 months compared to 
only 5 months for those treated with standard 10 mg/kg 
biweekly (p=0.001). Similar improved survival benefit 
associated with lower bevacizumab dosing was confirmed 

 
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in a validation cohort (n=109 subjects).  
 
Second, although standard bevacizumab dosing, 
administered as single agent therapy at 10 mg/kg every 2 
weeks, represents the approved schedule for recurrent GBM 
based on durable radiographic responses37 higher (standard) 
dosing has also been shown to significantly decrease 
perfusion and tumor vasculature permeability, leading to 
intratumoral hypoxia which may in turn drive GBM 
invasion and infiltration.16-20  In contrast, a lower dosing 
schedule has been shown to normalize rather than eradicate 
tumor vasculature, leading to improved blood flow, less 
hypoxia and enhanced delivery of co-administered anti-
tumor agents in preclinical cancer models including 
GBM.41,42 Normalized vasculature has also been associated 
with enhanced survival among cancer subjects including 
those with GBM treated with anti-VEGF therapy.43,64  
Furthermore, additional preclinical studies demonstrate that 
normalized tumor vasculature following reduced anti-
VEGF therapy also leads to enhanced intratumoral immune 
cell infiltration.21,22  Finally, a recently published preclinical 
study evaluating lower versus higher doses of anti-VEGF 
therapy showed that only lower anti-VEGF therapy dosing 
led to enhanced immune infiltrate and improved survival 
following co-administration with an anti-tumor 
immunotherapeutic.22  
 
In addition to these potential advantages, bevacizumab at 
either standard or reduced dosing, is expected to decrease 
tumor vessel permeability62 which may lessen the cerebral 
edema that typically accompanies GBM recurrence. By 
decreasing cerebral edema, bevacizumab may reduce the 
need for systemic corticosteroids such as dexamethasone 
which are routinely used to treat symptomatic cerebral 
edema 
but 
which 
may 
also 
abrogate 
anti-tumor 
immunoreactivity generated by PD-1 blockade. 
Primary Objective  
Primary Endpoint(s) 
To evaluate the efficacy of nivolumab when administered 
with standard and reduced bevacizumab dosing among 

 
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recurrent glioblastoma subjects as measured by the rate of 
overall survival at twelve months (OS-12). 
Secondary Objective(s) 
Secondary Endpoint(s) 
To evaluate the safety and tolerability of nivolumab in 
combination with bevacizumab administered according to 
standard and reduced dosage schedules for recurrent 
glioblastoma subjects.  
To compare progression free survival (PFS) at 6 months of 
nivolumab when administered with standard and reduced 
bevacizumab dosing for recurrent glioblastoma subjects. 
To compare the overall survival rate of nivolumab when 
administered with standard and reduced bevacizumab 
dosing for recurrent glioblastoma. 
To compare progression free survival (PFS) of when 
administered with standard and reduced bevacizumab 
dosing for recurrent glioblastoma subjects.  
To compare the objective response rate (ORR) of 
nivolumab and bevacizumab administered according to 
standard and reduced dosage schedules for recurrent 
glioblastoma subjects 
Exploratory Objective(s) 
Exploratory Endpoints (s) 
To evaluate whether baseline values or subsequent changes 
in circulating immunologic parameters (including but not 
limited to the number of T, B and NK cells; the number of 
T cell subsets; soluble circulating cytokines) are associated 
with outcome. 
 
To assess neurologic functioning in the treatment arms 
using the Neurologic Assessment in Neuro-Oncology 
(NANO).  
To assess the perfusion and diffusion base imaging to 
correlate with changes and response to nivolumab when 
administered with standard and reduced bevacizumab 

 
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dosing. 
To assess response using the immunotherapy response 
assessment in neuro-oncology criteria relative to survival. 
 
 
 
 

 
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ABBREVIATIONS  
 
 
 
CCCC Case Comprehensive Cancer Center 
CRF 
Case Report Form 
DCRU
Dahm’s Clinical Research Unit 
DSTC 
Data Safety and Toxicity Committee 
FDA 
Food and Drug Administration 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
PRMC
Protocol Review and Monitoring Committee
SOC 
Standard of Care 
CCF 
Cleveland Clinic Foundation 
UH 
University Hospitals 
 
 

 
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TABLE OF CONTENTS 
 
1.0  
INTRODUCTION  
 
1.1 
Background of Glioblastoma  
1.2  
Name/description of Nivolumab 
1.2.1    Preclinical Data  
1.2.2    Clinical Data  
1.2.3    Clinical Pharmacokinetics of Nivolumab 
1.3  
Name/description of Bevacizumab 
1.3.1    Pharmaceutical and Therapeutic Background 
1.3.2    Preclinical and Clinical Data  
1.4 
Drug Prohibited during the study  
1.5  
Rationale   
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 
2.2  
Secondary Objective(s) 
2.3 
Exploratory Objectives(s) 
 
3.0 
STUDY DESIGN-Investigational Plan 
3.1 
Study Design and Duration  
3.2 
Number of Subjects 
3.3 
Study Phases 
3.4 
Method of assigning subject identification  
3.5       Review of Safety  
 
 
4.0  
PATIENT SELECTION 
4.1 
Inclusion Criteria 
4.2  
Exclusion Criteria 
4.3 
Inclusion of Women and Minorities 
4.4       Woman of Child Bearing Potential (WOCBP) 
4.5       Concomitant Treatments 
4.5.1    Steroids 
4.5.2    Other Permitted Therapy 
4.5.3    Prohibited and/or Restricted Treatment 
4.5.4    Other Restrictions and Precautions  
 
5.0 
REGISTRATION  
 
 

 
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6.0  
TREATMENT  
6.1 
Investigational Product  
6.2 
Non Investigational Product  
6.3  
Storage, Handling and Dispensing of Investigational Product 
6.3.1    Nivolumab (BMS-936558) 
6.3.2    Bevacizumab 
6.4 
Destruction or Return of Investigational Product 
6.5 
Study Drug Administration  
6.5.1    Dosing Schedule and Administration 
6.5.2    Dosing Calculation 
6.5.3    Dosing Modifications 
6.5.4    Antiemetic Pre-Medications 
6.6 
Dose Delay 
6.6.1    Dose Delay Criteria for Nivolumab 
6.6.2    Criteria to Delay or Continue Bevacizumab 
6.6.3    Criteria to resume treatment 
6.6.4    Management Algorithms 
6.7       Discontinuation Criteria 
6.8       Treatment of Nivolumab related infusion reactions 
6.9       Cerebral Edema 
6.10    Treatment Beyond Initial Radiologic Assessment of Disease Progression 
6.10.1 Central Neuropathologic Review of Tumor Samples After Biopsy or Resection  
6.11    Blinding/Unblinding 
6.12    Treatment Compliance 
 
7.0 
ADVERSE EVENTS: List and Reporting Requirements  
7.1  
Adverse Events and Potential Risks  
7.1.1 Nivolumab 
7.1.2 Bevacizumab: Adverse Event Profile 
7.2 
Definitions  
7.2.1    Adverse Events 
7.2.2 Serious Adverse Events 
7.3 
Reporting Procedures for All Adverse Events  
7.4 
Serious Adverse Event Reporting Procedures 
7.4.1    Bristol-Myers Squibb Company Serious Adverse Event Reporting  
7.4.2    FDA Reporting 
7.5       Data Safety Toxicity Committee 
 
8.0 
PHARMACEUTICAL INFORMATION  

 
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8.1 
Nivolumab 
 
8.2 
Bevacizumab 
 
9.0 
Study Parameters and Calendar  
9.1  
Study Parameters 
9.1.1 Screening Evaluation 
9.1.2  Treatment Period  
9.2       Calendar 
 
10.0 
Measurement of Effect 
10.1 
RANO Criteria 
 
11.0 
Data Reporting/Regulatory Considerations 
11.1     Data Reporting 
11.2     Regulatory Considerations 
11.2.1  Written Informed Consent 
11.2.2   Subject Data Protection 
11.2.3   Retentions of Records 
11.2.4   Audits and inspections 
11.2.5   Data Safety and Monitoring Plan 
 
 
12.0 
STATISTICAL CONSIDERATIONS 
12.1     Statistical Analysis Plan Summary 
12.1.1  Efficacy Analysis 
12.1.2  Safety Analysis 
12.2     Statistical Analysis Plan 
12.2.1  Responsibility for Analyses 
12.2.1  Efficacy Endpoints 
12.2.2  Safety Endpoints 
12.2.3  Analysis of Demographics and Baseline Characteristics 
12.2.4  Analysis of Immunocorrelative Data  
12.2.5  Power and Sample Size  
 
13.0    Ethical Considerations 
13.1    Good Clinical Practice  
13.2    Institutional Review Board/Independent Ethics Committee 
 
14.  REFERENCES 
 
  

 
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15.  APPENDICES  
1.0   Karnofsy and ECOG Performance Status Scales 
 
2.0   Immunotherapy response assessment in neuro-oncology (IRANO) criteria 
3.0   Sample of drug ordering and pharmacy reference manual 
4.0   Adverse event reporting 
5.0   Recommended MRI sequences  
6.0   Hepatoxicity Article 
7.0   AE Management Algorithms  
8.0   Correlative Studies 
9.0      Laboratory Requisition   
10.0    NANO Scale 
           

 
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1.0 
Introduction  
 
1.1 
Background of Study Disease  
Glioblastoma (GBM) 
 
The outcome for glioblastoma (GBM) remains dismal with a median survival of approximately 
15 months and nearly all cases recur despite progress in surgical techniques, radiation and 
chemotherapies1,2. A number of single arm phase II studies using immunotherapy approaches 
in subjects with GBM provide support for considering an immunotherapy 3-7particularly a 
strategy designed to reverse the prominent cancer-mediated immune suppression8.  
T 
cells have access to antigens within the CNS, and the blood brain barrier does not form an 
absolute barrier to immune responses; thus, the concept of “immunologic privilege” in the 
CNS has been refuted 9. Subjects with GBM have a variety of mechanisms that contribute to an 
overall state of immune suppression.  Primed CD8+ cytotoxic T cells gain CNS access, 
however, the cells are functionally impaired as evidenced by the lack of tumor eradication. Ex 
vivo studies demonstrate a lack of effector/activated T cells in the glioma microenvironment 10.  
Gliomas secrete factors such as prostaglandin E2 and TGF β that are capable of suppressing 
cytotoxic responses of T cells against tumor targets. Co-stimulatory inhibitory molecules like 
B7-H1 are expressed in malignant gliomas and can further inhibit immune responses11. T-
regulatory cells, which suppress effector T-cell responses, are increased in the peripheral 
circulation and within the tumors of subjects with glioma 12,13, and the subjects with more 
profound immunosuppression is associated with worse outcome14 
 
1.2  
Name and Description of Investigational Agent 
Nivolumab  
 
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of 
immuno-oncology and treatment with investigational agents targeting this mechanism has 
induced regressions in several types of cancer. Cytotoxic T-lymphocyte–associated antigen 4 
(CTLA-4) and programmed death 1 (PD-1) receptor are two important cellular targets that play 
complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell 
exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation [Curran 
2010).  
 
Nivolumab (BMS-936558; anti-PD-1 monoclonal antibody) is a fully human monoclonal 

 
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immunoglobulin (Ig) G4 antibody that binds to the PD-1 cell surface membrane receptor, a 
negative regulatory molecule expressed by activated T and B lymphocytes. Inhibition of the 
interaction between PD-1 and its ligands promote immune responses and antigen-specific T 
cell responses to both foreign and self-antigens. PD-1 receptor blockade by nivolumab is a new 
approach for immunotherapy of tumors. Nivolumab monotherapy has demonstrated clinical 
activity across several tumor types, including advanced melanoma, NSCLC, and RCC. 
Nivolumab has demonstrated a manageable safety profile in subjects > 700 subjects across all 
clinical trials. The most common AEs included fatigue, rash, pruritus, diarrhea, and nausea. 
Nivolumab monotherapy is currently being studied in phase 3 clinical trials in advanced 
melanoma, renal cell carcinoma (RCC) and non-small cell lung carcinoma (NSCLC). 
 
1.2.1  Preclinical Data  
 
Pharmacology 
 
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal 
antibodies (mAbs) can enhance the anti-tumor immune response and result in tumor rejection. 
Antitumor activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors 
that are negative for the expression of PD-L1. This suggests that host mechanisms (.ie. 
expression of PD-L1 in antigen-presenting cells) limit the antitumor response. Consequently, 
both PD-L1 positive and negative tumors may be targeted using this approach. In humans, 
constitutive PD-L1 expression is normally limited to macrophage-lineage cells, although 
expression of PD-L1 can be induced on other hematologic cells as well, including activated T 
cells. However aberrant expression of PD-L1 by tumor cells has been reported in a number of 
human malignancies. PD-L1 expressed by tumor cells has been shown to enhance apoptosis of 
activated tumor-specific T cells in vitro. Moreover, the expression of PD-L1 may protect the 
tumor cells from the induction of apoptosis by effector T cells. 
 
Based upon the mechanistic rationale discussed above and promising results from a 
preliminary clinical study (CA209004) using the combination of nivolumab and ipilimumab in 
subjects with un-resectable or metastatic melanoma, the safety and efficacy of nivolumab as a 
single agent or in combination with ipilimumab in subjects with recurrent GBM was evaluated 
in a clinical trial that has completed accrual and the final results are awaited (NCT02017717). 
 
1.2.2 Clinical Data 
 
Although the efficacy of check point inhibitors such as nivolumab have not previously been 
studied in GBM, a multicenter Phase 2 study to evaluate the response of brain metastases to 
ipilimumab was previously performed (CA184042). Subjects (N = 71) with advanced Stage IV 

 
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melanoma and measureable active brain metastases were randomized to ipilimumab 
monotherapy. The study demonstrated that ipilimumab had clinical activity in subjects with 
melanoma brain metastases - with some subjects showing prolonged clinical responses, disease 
control, and prolonged survival. Ipilimumab did not cause unexpected neurological toxicity in 
subjects with brain metastases. There is a large ongoing study of Randomized Phase 3 Open 
Label Study of Nivolumab versus Bevacizumab and a Safety Study of Nivolumab or 
Nivolumab in Combination with Ipilimumab in Adult Subjects with Recurrent Glioblastoma 
(NCT 02017717).  
 
1.2.3 Clinical Pharmacokinetics of Nivolumab 
 
Safety Pharmacology 
The overall safety experience with nivolumab, as a monotherapy or in combination with other 
therapeutics, is based on experience in approximately 4,000 subjects treated to date. For 
monotherapy, the safety profile is similar across tumor types. The only exception is pulmonary 
inflammation adverse events (AEs), which may be numerically greater in subjects with 
NSCLC, because in some cases, it can be difficult to distinguish between nivolumab-related 
and unrelated causes of pulmonary symptoms and radiographic changes. There is no pattern in 
the incidence, severity, or causality of AEs to nivolumab dose level (Reference: 
INVESTIGATOR BROCHURE Nivolumab, BMS-936558, MDX1106 Version 13, July 2014) 
 
      Pharmacokinetics and Absorption, Distribution, Metabolism, and Excretion 
 
The single-dose pharmacokinetics (PK) of nivolumab was linear and dose-proportional in the 
range of 0.3 mg/kg to 10 mg/kg. The multiple-dose PK of nivolumab was linear with 
dose-proportional increases in maximum serum concentration (Cmax) and area under the 
concentration-time curve over the dosing interval (AUC[TAU]) in the range of 0.1 mg/kg to 10 
mg/kg. Both elimination and distribution of nivolumab in the dose range studied appear to be 
independent of dose in the dose-ranging studies, while the end of infusion and minimum serum 
concentration (Cmin) after the first dose were approximately dose proportional. Based on 
population PK (PPK) results (preliminary data), clearance of nivolumab is independent of dose 
in the dose range (0.1 mg/kg to 10 mg/kg) and tumor types studied. Body weight normalized 
dosing showed approximately constant trough concentrations over a wide range of body 
weights and, therefore, is appropriate for future clinical trials with nivolumab. 
 
Single-dose PK of nivolumab was studied in 39 subjects with cancer. The single-dose PK of 
nivolumab was linear and dose-proportional in the range of 0.3 mg/kg to 10 mg/kg. The mean 
terminal T-HALF of nivolumab ranged between 17 and 25 days across the dose range of 0.3 

 
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mg/kg to 10 mg/kg. Geometric mean total clearance varied from 0.13 mL/h/kg to 0.19 
mL/h/kg, while mean volume of distribution varied between 83 mL/kg and 113 mL/kg across 
doses. The clearance and half-life of nivolumab are consistent with that of IgG4. 
 
The multiple-dose PK of nivolumab given Q2W was determined from MDX1106-03 study as 
well as by population PK using data from 669 subjects across nivolumab studies. 
Multiple-dose PK of nivolumab following Q2W dosing was linear with dose-proportional 
increase in Cmax and AUC(TAU) in the studied range of 0.1 mg/kg to 10 mg/kg. Nivolumab 
accumulation with Q2W dosing frequency was in the range of 2.9 to 3.3 based on AUC(TAU), 
2.0 to 2.4 based on Cmax, and 3.1 to 4.8 based on Cmin. A PPK model was developed by 
nonlinear mixed effect modeling using data from 669 subjects.  
 
Nivolumab concentration-time data were well described by a linear, 2-compartment, 0-order 
IV infusion model with first-order elimination. Nivolumab PK was found to be linear, dose 
independent, and time invariant. The geometric mean of terminal T-HALF was 25.6 days and 
the typical clearance was 8.8 mL/h, which are consistent with those of full human 
immunoglobulin antibodies. Clearance of nivolumab is independent of dose in the dose range 
(0.1 mg/kg to 10 mg/kg) and tumor types studied. Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body weights. 
 
Nivolumab monotherapy has been extensively studied in a number of tumor types including 
NSCLC, MEL, RCC, and CRC with body weight normalized dosing (mg/kg). Nivolumab 
pharmacokinetics (PK) and exposures of subjects in these studies have been characterized by 
population pharmacokinetic (PPK) analysis of data collected these studies, together with PK 
data from several phase 1, 2, and 3 clinical studies of nivolumab monotherapy in solid tumors. 
Population PK (PPK) analyses have shown that the PK of nivolumab are linear, with dose 
proportional exposures over a dose range of 0.1 mg/kg to 10 mg/kg, and are similar across 
tumor types. Nivolumab clearance and volume of distribution were found to increase with 
increasing body weight, but the increase was less than proportional, indicating that a mg/kg 
dose represents an over-adjustment for the effect of body weight on nivolumab PK. Given the 
relationship between nivolumab PK and body weight, a flat dose is expected to lead to lower 
exposures in heavier subjects, relative to the exposures in lighter subjects.  
 
Using the PPK model, nivolumab steady-state trough, peak and time-averaged concentration 
(Cminss, Cmaxss, and Cavgss, respectively) were predicted for a flat nivolumab dose of 240 
mg Q2W and compared to those following administration of 3 mg/kg Q2W in NSCLC 
subjects. A dose of 240 mg nivolumab is identical to a dose of 3 mg/kg for subjects weighing 
80 kg, which is the approximate median body weight of NSCLC subjects in the 3 Phase 2 and 
3 BMS clinical studies of nivolumab monotherapy.  The geometric mean values of Cminss, 

 
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Cmaxss, and Cavgss with flat dosing are slightly (< 15%) higher than that produced by a 3 
mg/kg dose, and the coefficient of variation (cv%) in these measures of exposure are only 
slightly (< 10%) greater than that of 3 mg/kg dosing.  
 
Across the various tumor types in the BMS clinical program, nivolumab has been shown to be 
safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab 
exposure produced by 3 mg/kg and efficacy has been found to be relatively flat. Taken 
together, the PK, safety, and efficacy data indicate that the safety and efficacy profile of 240 
mg nivolumab will be similar to that of 3 mg/kg nivolumab. 
 
Thus a flat dose of 240 mg every 2 weeks is recommended for investigation in this study 
 
1.3  
Bevacizumab 
 
Bevacizumab is a humanized IgG1 monoclonal antibody (MAb) that binds all biologically 
active isoforms of human VEGF (or VEGF-A) with high affinity (kd = 1.1 nM). The antibody 
consists of a human IgG1 framework and the antigen-binding complementarity- determining 
regions from the murine anti-VEGF MAb A.4.6.1.16-18. Bevacizumab is commercially 
available and FDA approved for subjects with recurrent glioblastoma. Refer to the package 
insert for more detailed information on bevacizumab. 
 
1.3.1 Pharmaceutical and Therapeutic Background 
 
VEGF is one of the most potent and specific angiogenic factors, and it 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 
biologic 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 to decrease microvessel density and interstitial pressure in tumor xenografts 
in vivo. 
 
1.3.2 Preclinical and Clinical Data 
 
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 
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and MCF-7 cell lines.49-51 The antitumor activity was enhanced with the combination of A4.6.1 
and chemotherapeutic agents compared to either agent alone. Furthermore, combined blockage 
of the VEGF pathway and other growth factor pathways (e.g., EGFR or PDGFR) has also 
demonstrated additive effects in vivo.52,53 Associated with the antitumor 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 uterine weight and 
endometrial proliferation as well as a decrease in ovarian weight and number of corpora lutea. 
Bevacizumab is teratogenic in rabbits, with increased frequency of fetal resorption as well as 
specific gross and skeletal fetal alterations. In juvenile Cynomolgus monkeys with open growth 
plates, bevacizumab induced epiphyseal dysplasia that 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. 
 
Bevacizumab has been studied in multiple Phase I, Phase II, and Phase III clinical trials and in 
multiple tumor types. The following discussion summarizes bevacizumab’s safety profile and 
presents some of the efficacy results pertinent to this particular trial. Clinical proof of principle 
for anti‐VEGF therapy with bevacizumab has been provided by the pivotal Phase III trial of 
bevacizumab (5 mg/kg every 2 weeks) in combination with bolus 
irinotecan/5‐fluorouracil/leucovorin (IFL) in subjects with untreated advanced colorectal 
cancer (AVF2107g).54 In that study, the addition of bevacizumab to IFL was associated with an 
increase in objective responses (45% vs. 35%) and significant prolongations of both time to 
progression (10.6 vs. 6.2 months) and overall survival (20.3 vs. 15.6 months) compared with 
IFL. 
 
Based on the survival advantage, bevacizumab was approved in 2004 in the United States for 
first‐line treatment in combination with IV 5-FU-based chemotherapy for subjects with 
metastatic colorectal cancer. Additional data from Phase III trials in metastatic CRC,55 non-
small cell lung cancer,56 renal cell carcinoma57 and metastatic breast cancer58 have also 
demonstrated clinical benefit from bevacizumab when added to chemotherapy. 
 
Single agent bevacizumab received accelerated FDA approval in 2009 for recurrent 
glioblastoma based on favorable results from two Phase II clinical trials.59,60 In these studies, 
six-month progression free survival (PFS6) for bevacizumab monotherapy ranged from 29% to 
42.6%. Compared to a historical PFS6 of 15% for recurrent GBM,61 these studies suggest that 
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Nonetheless, the optimal dosing schedule of bevacizumab for glioblastoma subjects remains 
unknown. Although a lower bevacizumab dose schedule has not been prospectively evaluated 
among recurrent glioblastoma subjects, a recent retrospective analysis of 219 subjects 
confirmed that lower dosing was associated with enhanced survival.15 In this study, subjects 
treated with < 10 mg/kg every other week of bevacizumab had a median OS of 9 months 
compared to only 5 months for those treated with standard 10 mg/kg biweekly (p=0.001). 
Similar improved survival benefit associated with lower bevacizumab dosing was confirmed in 
a validation cohort (n=109 subjects). The exact mechanism of improved survival is unclear but 
standard bevacizumab dosing can significantly decrease perfusion and tumor vasculature 
permeability, leading to intratumoral hypoxia which may in turn drive GBM invasion and 
infiltration.16-20 In contrast, lower doses of anti-angiogenic agents can normalize tumor 
vasculature leading to enhanced intratumoral immune cell infiltration.21,22  
 
In addition to these potential advantages, lower bevacizumab dosing is expected to decrease 
tumor vessel permeability62 which may lessen the cerebral edema that typically accompanies 
GBM recurrence. By decreasing cerebral edema, lower dosed bevacizumab may reduce the 
need for systemic corticosteroids such as dexamethasone which are routinely used to treat 
symptomatic cerebral edema but which may also abrogate anti-tumor immunoreactivity 
generated by PD-1 blockade. 
 
1.4 
Drug prohibited during the study  
 
Any concurrent drug or other investigational agents for treatment of GBM (i.e., chemotherapy, 
hormonal therapy, immunotherapy, radiation therapy) 
 
Medications contraindicated with bevacizumab treatment (refer to the package insert, summary 
of product characteristics (SmPC), or similar document) 
 
1.5 
Rationale  
 
Scientific Background 
 
The outcome for recurrent glioblastoma (GBM) remains dismal despite progress in surgical 
techniques, radiation and chemotherapies1,2. A number of single arm phase II studies using 
immunotherapy approaches in subjects with GBM provide support for considering an 
immunotherapy3-7 particularly a strategy designed to reverse the prominent cancer-mediated 
immune suppression8. T cells have access to antigens within the CNS, and the blood brain 
barrier does not form an absolute barrier to immune responses; the concept of “immunologic 

 
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privilege” in the CNS has been refuted9. Subjects with GBM have a variety of mechanisms that 
contribute to an overall state of immune suppression.  Primed CD8+ cytotoxic T cells gain 
CNS access, however, the cells are functionally impaired as evidenced by the lack of tumor 
eradication. Ex vivo studies demonstrate a lack of effector/activated T cells in the glioma 
microenvironment10.  Gliomas secrete factors such as prostaglandin E2 and TGF β that are 
capable of suppressing cytotoxic responses of T cells against tumor targets. Co-stimulatory 
inhibitory molecules like B7-H1 are expressed in malignant gliomas and can further inhibit 
immune responses11. T-regulatory cells, which suppress effector T-cell responses, are increased 
in the peripheral circulation and within the tumors of subjects with glioma12,13 and the subjects 
with more profound immunosuppression is associated with worse outcome14. 
Immune checkpoint blockade is a rapidly advancing therapeutic approach in the field of 
immuno-oncology and treatment with investigational agents targeting this mechanism has 
induced regressions in several types of cancer. Cytotoxic T-lymphocyte–associated antigen 
4(CTLA-4) and programmed death 1 (PD-1) receptor are two important cellular targets that 
play complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell 
exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation63.  
 
 
 
Nivolumab (BMS-936558; anti-PD-1 monoclonal antibody) is a fully human monoclonal 
immunoglobulin (Ig) G4 antibody that binds to the PD-1 cell surface membrane receptor, a 
negative regulatory molecule expressed by activated T and B lymphocytes. Inhibition of the 
interaction between PD-1 and its ligands promote immune responses and antigen-specific T 
cell responses to both foreign and self-antigens. PD-1 receptor blockade by nivolumab is a new 
approach for immunotherapy of tumors. Nivolumab monotherapy has demonstrated clinical 
activity across several tumor types, including advanced melanoma, NSCLC, and RCC. 
 
Increasing data suggests that VEGF inhibition can enhance the anti-tumor benefit of 
immunotherapies. First, VEGF is known to significantly contribute to the immunosuppressive 
ability of tumors.23-25 Specifically, VEGF can inhibit dendritic cell maturation and antigen 
presentation, induce apoptosis of CD8+ T cells, enhance Treg activity and diminish infiltration 
of T cells across tumor endothelium.26-29  Second, preclinical studies demonstrate that 
immunotherapeutics may be combined with VEGF inhibitors to generate enhanced anti-tumor 
benefit.22,24-35  Specifically, VEGF inhibition can diminish immunosuppressive features of 
tumors26-29,32,34,35 and enhance the anti-tumor activity of immunotherapies.30-32,34,35 Third, 
preclinical strategies to normalize tumor vasculature, including administration of ant-VEGF 
therapy, can shift tumor-associated macrophages from an M2 immune-inhibitory phenotype to 
an immune-stimulatory M1-phenotype, as well as increase tumor infiltrating CD8+ T cells and 

 
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enhance survival following whole tumor cell vaccination.22 Finally, data from a recently 
published phase I study among metastatic melanoma subjects revealed that administration of 
bevacizumab with ipilimumab, an inhibitor of the CTLA-4 immune checkpoint, led to 
improved overall survival as well as increased immune cell trafficking into tumor sites.36 
 
The rationale for evaluating two dose levels of bevacizumab in combination with standard 
nivolumab dosing is based on several factors. First, although a lower bevacizumab dose 
schedule has not been prospectively evaluated among recurrent glioblastoma subjects, a recent 
retrospective analysis of 219 subjects confirmed that lower dosing was associated with 
enhanced survival.15 In this study, subjects treated with < 10 mg/kg every other week of 
bevacizumab had a median OS of 9 months compared to only 5 months for those treated with 
standard 10 mg/kg biweekly (p=0.001). Similar improved survival benefit associated with 
lower bevacizumab dosing was confirmed in a validation cohort (n=109 subjects).  
 
Second, although standard bevacizumab dosing, administered as single agent therapy at 10 
mg/kg every 2 weeks, represents the approved schedule for recurrent GBM based on durable 
radiographic responses37 higher (standard) dosing has also been shown to significantly 
decrease perfusion and tumor vasculature permeability, leading to intratumoral hypoxia which 
may in turn drive GBM invasion and infiltration.16-20  In contrast, a lower dosing schedule has 
been shown to normalize rather than eradicate tumor vasculature, leading to improved blood 
flow, less hypoxia and enhanced delivery of co-administered anti-tumor agents in preclinical 
cancer models including GBM.41,42 Normalized vasculature has also been associated with 
enhanced survival among cancer subjects including those with GBM treated with anti-VEGF 
therapy.43,64  Furthermore, additional preclinical studies demonstrate that normalized tumor 
vasculature following reduced anti-VEGF therapy also leads to enhanced intratumoral immune 
cell infiltration.21,22  Finally, a recently published preclinical study evaluating lower versus 
higher doses of anti-VEGF therapy showed that only lower anti-VEGF therapy dosing led to 
enhanced immune infiltrate and improved survival following co-administration with an anti-
tumor immunotherapeutic.22  
 
In addition to these potential advantages, bevacizumab at either standard or reduced dosing, is 
expected to decrease tumor vessel permeability62 which may lessen the cerebral edema that 
typically accompanies GBM recurrence. By decreasing cerebral edema, bevacizumab may 
reduce the need for systemic corticosteroids such as dexamethasone which are routinely used 
to treat symptomatic cerebral edema but which may also abrogate anti-tumor immunoreactivity 
generated by PD-1 blockade. 
  
2.0  
Objectives 
 

 
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2.1  
Primary Objective  
 
 To evaluate the efficacy of nivolumab when administered with standard and reduced 
bevacizumab dosing among recurrent glioblastoma subjects as measured by the rate of 
overall survival at twelve months (OS-12). 
 
 
 
2.2 
Secondary Objective(s) 
 
 To evaluate the safety and tolerability of nivolumab in combination with 
bevacizumab administered according to standard and reduced dosage schedules for 
recurrent glioblastoma subjects.  
 To compare progression free survival (PFS) at 6 months of nivolumab when 
administered with standard and reduced bevacizumab dosing for recurrent glioblastoma 
subjects. 
 To compare the overall survival rate of nivolumab when administered with standard 
and reduced bevacizumab dosing for recurrent glioblastoma subjects. 
 To compare progression free survival (PFS) of when administered with standard and 
reduced bevacizumab dosing for recurrent glioblastoma subjects.  
 To compare the objective response rate (ORR) of nivolumab and bevacizumab 
administered according to standard and reduced dosage schedules for recurrent 
glioblastoma subjects. 
 
2.3 
Exploratory Objective(s) 
 
 To evaluate whether baseline values or subsequent changes in circulating immunologic 
parameters (including but not limited to the number of T, B and NK cells; the number 
of T cell subsets; soluble circulating cytokines) are associated with outcome; 
 To assess neurologic functioning in the treatment arms using the Neurologic 
Assessment in Neuro-Oncology (NANO)  
 To assess the perfusion and diffusion base imaging to correlate with changes and 
response to nivolumab when administered with standard and reduced bevacizumab 
dosing 
 To assess response using the immunotherapy response assessment in neuro-oncology 
criteria relative to survival. 
3.0 
Investigational Plan  

 
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3.1  
Study design and duration 
This is a randomized, open-label, phase 2 safety study of nivolumab and bevacizumab 
administered according to standard and reduced dosage schedules in adult (≥ 18 years) subjects 
with a first recurrence of glioblastoma (GBM). Subjects must have received previous treatment 
with radiotherapy and may have up to 2 recurrences. Subjects will undergo 1:1 randomization 
to receive treatment with either nivolumab (240 mg flat dosing IV every 2 weeks) and 
bevacizumab administered according to standard (10 mg/kg IV every 2 weeks; Arm A) and 
reduced (3 mg/kg IV every 2 weeks; Arm B) dosage schedules for recurrent glioblastoma 
subjects. The study will allow subjects that require decadron up to 4 mg/ day to participate in 
the study. 
 
All subjects will be followed for safety and tolerability, tumor progression and overall survival. 
Tumor progression or response endpoints will be assessed using the Radiologic Assessment in 
Neuro-Oncology criteria and an exploratory endpoint will evaluate the response endpoints 
using the Immunotherapy Radiologic Assessment in Neuro-Oncology criteria (iRANO)65 as 
described (Refer to Appendix 2). Treatment with study medication will continue until 
confirmed tumor progression, unacceptable toxicity, death, or other discontinuation criteria as 
specific in section 7.7, whichever comes first. A Data Safety Monitoring Committee (DMC) 
will meet regularly during the study to ensure that subject safety is carefully monitored.  
 
It is expected that enrollment and follow-up of randomized subjects (45 subjects in each arm) 
will take approximately 12months. The study design schematic is presented in Figure 4.1-1 
 
Figure 4.1-1: Study Design Schematic 
 
Randomization Phase  
          Treatment Phase                             Follow-up          
         
 
 
 
 
Screening:  
First 
recurrence of 
GBM after 
previous RT  
Treatment Arm A: 
Nivolumab 240mg 
+ Bevacizumab (10 
mg/kg) every 2 weeks 
(n = 45)  
 
 
Treatment until 
confirmed 
progression or 
study 
discontinuation for 
any other reason. 
Post treatment 
follow- up for 
safety, overall 
survival, and 

 
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3.2 
Number of Subjects 
 
This study consists of two arms to evaluate the anti-tumor activity of nivolumab and 
bevacizumab administered according to standard and low dosage schedules in subjects with 
recurrent glioblastoma (in first recurrence). For this purpose, approximately 90 subjects will be 
randomized at 1:1 ratio to arm A (nivolumab plus standard bevacizumab) or arm B (nivolumab 
plus low dose bevacizumab).  
 
Arm A (nivolumab plus standard bevacizumab)  
This arm will enroll 45 subjects in arm A. These subjects will receive nivolumab 240 mg and 
bevacizumab 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity.  
 
Arm B (nivolumab + low dose bevacizumab)  
This arm will enroll 45 subjects in arm B. These subjects will receive nivolumab 240 mg and 
bevacizumab 3mg/kg every 2 weeks until disease progression or unacceptable toxicity.   
 
 
 
 
 
3.3 
Study Phases  
 
This study will consist of 3 phases: screening, treatment, and follow-up. After confirmed 
progression or study discontinuation for any other reason, study treatment will be discontinued 
and subjects with enter the post-treatment follow-up phase to assess safety, progression, and 
overall survival.  
 
Screening Phase: 
1:1 
Randomiz
ation 
(n= 90) 
Treatment Arm B: 
Nivolumab 240 mg + 
Bevacizumab 3 mg/kg 
every 2 weeks   
(n = 45) 

 
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 Begins by establishing the subject’s initial eligibility and signing of the informed 
consent form (ICF). 
 Subject is enrolled using the OnCore™ Database. 
 
Treatment Phase: 
 The patient will be randomized and assigned to one of the two arms of treatment.  
 Within 3 working days from treatment assignment, the subject must receive the first 
dose of study medication: 
o Arm A (nivolumab + standard bevacizumab): Nivolumab 240 mg IV plus 
bevacizumab 10 mg/kg every two weeks.  
o Arm B (nivolumab + low dose bevacizumab): Nivolumab 240 mg IV combined 
with bevacizumab 3mg/kg IV every two weeks.  
 
For both treatment arms, nivolumab is to be administered first.  
The second infusion will be bevacizumab, and will start no sooner than 10 minutes 
after completion of the nivolumab infusion.    
 
 Adverse event assessments will be documented at each visit throughout the study. 
 All of the laboratory tests and vital signs will be collected prior to study drug dosing at 
the time points specified in Section 9.2.  
 Study drug dosing may be delayed for toxicity. See Section 6.6. 
 Treated subjects will be evaluated for response by the investigator and according to the 
iRANO criteria.65 Tumor assessments will be performed every 8 weeks + 1 week) until 
disease progression or treatment discontinuation, whichever occurs later. 
 Treated subjects will be evaluated for neurologic functioning by the investigator and 
according to the NANO scale. Assessments will be performed every 8 weeks (+ 1 
week) until disease progression or treatment discontinuation, whichever occurs later. 
 
This phase ends when the subject experiences a confirmed tumor progression, unacceptable 
toxicity, or other discontinuation criteria, whichever occurs first.  
 
 
 
 
 
Follow-Up Phase: 
 Begins when the decision to discontinue a subject from study therapy is made (no 
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 Subjects who discontinue treatment for reasons other than tumor progression will 
continue to have tumor assessments every 8 (+ 1 week) weeks until disease progression 
or, withdrawal of consent. All radiologically determined disease progression must be 
confirmed by an additional confirmatory MRI scan approximately 12 weeks following 
the initial assessment of radiological progression. Investigators may obtain additional 
follow-up MRI scans prior to 12 weeks as medically appropriate. 
 Subjects will be followed for drug-related toxicities until these toxicities resolve, return 
to baseline or are deemed irreversible. All adverse events will be documented for a 
minimum of 100 days after last dose. 
 After completion of the first two follow-up visits, subjects will be followed every 3 
months for survival. 
 
3.4  
Method of Assigning Subject Identification  
This protocol is a randomized study. After verifying each patient’s eligibility status and 
administering informed consent, the patient will be enrolled into the study by the study 
coordinator or research nurse to obtain the subject number. Every subject that signs the 
informed consent form must be assigned a subject number. The investigator or designee will 
register the subject for enrollment by following the enrollment procedures established by the 
principal investigator. If the subject withdraws or screen fails before starting treatment, the 
assigned subject number will not be re-issued. The following information is required for 
enrollment: 
 Date that informed consent was obtained 
 Date of birth 
 Gender at birth 
 
After enrollment, Enrolled subjects who have met all eligibility criteria will be ready to be 
randomized by the study coordinator. The following information is required for subject 
randomization: 
 Subject number 
 Date of birth 
 Methylation status 
 Surgery type (complete resection, near complete resection, or biopsy) 
 KPS- Karnofsky Performance Scale 
 
Subjects meeting all eligibility criteria will be randomized in a 1:1 ratio to either treatment arm 
A (nivolumab + standard bevacizumab) or arm B (nivolumab + low dose bevacizumab).  
 
 

 
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3.5   Review of Safety  
 
The subjects’ safety will be monitored on an ongoing basis. Safety meeting will be done every 
4-8 weeks depending on patient accrual. An independent Data Monitoring Committee (DMC) 
will provide safety reviews every six months. Decisions regarding safety will be made by the 
sponsor (Cleveland Clinic) in discussions with site investigators and BMS. In addition, a BMS 
medical safety team (MST) will routinely reviews safety signals across the entire nivolumab 
program and inform the team at Cleveland Clinic. The DMC will review all available data 
(safety and efficacy) and will recommend continuation, modification or termination of the 
study protocol based upon their review. 
 
4.0 
Patient Selection 
 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study.  Use the checklist to confirm a patient’s eligibility.  The 
checklist must be completed for each patient and must be signed and dated by the treating 
physician.   
 
Patient’s Initials _____________________________________________________________ 
 
Patient ID___________________________________________________________ 
 
Research Nurse /  
Study Coordinator Signature: ___________________________ Date __________ 
 
Treating Physician [Print] _______________________________________________ 
 
Treating Physician Signature:  ___________________________ Date __________ 
 
 
 
 
 
 
 
 
 

 
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4.1  Inclusion Criteria 
 
            Subjects must meet all of the following inclusion criteria to be eligible for enrollment: 
 
1.   Signed Written Informed Consent 
a) Written informed consent and HIPAA authorization obtained from the subject/legal       
representative prior to 
performing any protocol-related procedures, including screening evaluations 
b) Subjects must be willing and able to comply with scheduled visits, treatment 
schedule, laboratory testing, and other requirements of the study, including disease 
assessment by MRI.  
 
2.   Target Population 
a) Histologically confirmed diagnosis of supratentorial glioblastoma  
b) Age ≥ 18 years old  
c) Previous first line treatment with at least radiotherapy  
d) Documented first recurrence of GBM by diagnostic biopsy or contrast enhanced 
magnetic resonance imaging (MRI) performed within 21 days of randomization per 
RANO criteria. 
e) If first recurrence of GBM is documented by MRI, an interval of at least 12 weeks after 
the end of prior radiation therapy is required unless there is either:  
a. histopathologic confirmation of recurrent tumor, or 
b. new enhancement on MRI outside of the radiotherapy treatment field 
f) An interval of > 28 days and full recovery (i.e., no ongoing safety issues) from surgical 
resection prior to randomization. 
g) Karnofsky performance status of 70 or higher (Appendix 1) 
h) Life expectancy > 12 weeks 
i) Up to ten unstained slides of 5 microns thickness or a block of tissue will be required to 
be sent if tissue is available. If the tissue is not available then Principal investigator 
permissions is required prior to enrollment. 
 
3.   Age and Reproductive Status 
a) Men and women, age > 18 years old at the time of screening 
b) Women of childbearing potential (WOCBP, as defined in Section 5.4) must have a 
negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) within 1 day prior to the start of study drug 

 
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c) Women must not be breastfeeding 
d) WOCBP must use appropriate method(s) of contraception from the time of enrollment 
for the duration of treatment with study drug (s) plus 5 half-lives of study drug (s) plus 
6 months post treatment completion for a treatment arm A (nivolumab + standard dose 
bevacizumab)and treatment arm B (nivolumab + low dose bevacizumab).  
e) Men who are sexually active with WOCBP must use contraceptive method such as 
male condom with spermicide. Men receiving nivolumab and who are sexually active 
with WOCBP will be instructed to adhere to contraception for the duration of treatment 
with study drug (s) plus 5 half-lives of study drug (s) plus 90 days (duration of sperm 
turnover) for a total of 31 weeks post-treatment completion. 
f) Women who are not of childbearing potential (i.e., who are postmenopausal or 
surgically sterile as well as azoospermic men) do not require contraception. 
g) Azoospermic males and WOCBP who are continuously not heterosexually active are 
exempt from contraceptive requirements.  
 
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an unexpected 
pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active 
with WOCBP on the use of highly effective methods of contraception. Highly effective 
methods of contraception have a failure rate of < 1% per year when used consistently and 
correctly. 
 
At a minimum, subjects must agree to the use of two methods of contraception, with one 
method being highly effective and the other method being either highly effective or less 
effective as listed below: 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
 Male condoms with spermicide 
 Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants, and intrauterine devices (IUDs) such as Mirena® by 
WOCBP subjects or male subject’s WOCBP partner. 
 Nonhormonal IUDs, such as ParaGard 
 Tubal ligation 
 Vasectomy. 
 Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Subjects who choose complete abstinence 

 
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are not required to use a second method of contraception, but female subjects must continue to 
have pregnancy tests.  Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence.  
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
 Diaphragm with spermicide 
 Cervical cap with spermicide 
 Vaginal sponge 
 Male Condom without spermicide* 
 Progestin only pills by WOCBP subjects or male subject’s WOCBP partner 
 Female Condom* 
*A male and female condom must not be used together 
 
Women of Child Bearing Potential (WOCBP) 
 
A women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea 
in a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, women under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.* 
 
*Women treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
 
 1 week minimum for vaginal hormonal products (rings, creams, gels) 
 4 week minimum for transdermal products 
 8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study.  Use the checklist to confirm a patient’s eligibility.  The 

 
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checklist must be completed for each patient and must be signed and dated by the treating 
physician.  
 
Recovery from the toxic effects of prior therapy, with a minimum time of: 
 
 ≥ 28 days elapsed from the administration of any investigational agent 
 ≥ 28 days elapsed from the administration of any prior cytotoxic agents, except 
 ≥ 14 days from vincristine, ≥ 21 days from procarbazine, and ≥ 42 days from 
 nitrosureas 
 ≥ 14 days elapsed from administration of any non-cytotoxic agent (e.g., interferon, 
tamoxifen, thalidomide, cis-retinoic acid) 
 
 
4.   Physical and Laboratory Test Findings 
 
Screening/Baseline laboratory values must meet the following criteria (using CTCAE v5.0): 
 WBC  ≥ 2000/uL 
 Neutrophils  ≥  1500/uL 
 Platelets ≥ 100x103/uL 
 Hemoglobin  ≥  9.0 g/dL 
 Serum creatinine < 1.5 x ULN or creatinine clearance (CrCl) > 40 mL/min (using the 
Cockcroft-Gault formula) 
Female CrCl = (140 - age in years) x weight in kg x 0.85 /72 x serum creatinine in 
mg/dL 
Male CrCl = (140 - age in years) x weight in kg x 1.00/72 x serum creatinine in 
mg/dL 
 AST ≤ 3x ULN 
 ALT≤ 3x ULN 
 Pregnancy test (serum) 
 Bilirubin ≤ 1.5x ULN (except subjects with Gilbert Syndrome, who can have 
 total bilirubin < 3.0 mg/dL) 
 
4.2 
Exclusion Criteria 
Subjects with any of the following are ineligible for this research study: 
 
1.   Target Disease Exceptions 
a. More than one recurrence of GBM 

 
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b. Presence of extracranial metastatic, significant leptomeningeal disease or tumors 
primarily localized to the brainstem or spinal cord. 
 
2.   Medical History and Concurrent Diseases 
a. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, 
may increase the risk associated with study participation or study drug administration, 
impair the ability of the subject to receive protocol therapy, or interfere with the 
interpretation of study results. 
b. Subjects with active, known or suspected autoimmune disease. Subjects with 
vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune 
condition only requiring hormone replacement, psoriasis not requiring chronic and 
systemic immunosuppressive treatment, or conditions not expected to recur in the 
absence of an external trigger are permitted to enroll. Subjects have any other 
condition 
requiring 
systemic 
treatment 
with 
corticosteroids 
or 
other 
immunosuppressive agents within 14 days. Inhaled or topical steroids and adrenal 
replacement doses >10mg daily prednisone equivalent are permitted in absence of 
active autoimmune disease. 
c. Previous radiation therapy with anything other than standard radiation therapy (i.e., 
focally directed radiation) administered as first line therapy. 
d. Previous treatment with carmustine wafer except when administered as first line 
treatment and at least 6 months prior to randomization 
e. Previous bevacizumab or other VEGF or anti-angiogenic treatment  
f. Previous treatment with a PD-1, PD-L1 or CTLA-4 targeted therapy 
g. Evidence of > Grade 1 CNS hemorrhage on the baseline MRI scan 
h. Inadequately controlled hypertension (defined as systolic blood pressure ≥160 mmHg 
and /or diastolic blood pressure ≥100 mmHg) within 7 days of first study treatment 
i. Prior history of hypertensive crisis, hypertensive encephalopathy, reversible posterior 
leukoencephalopathy syndrome (RPLS); 
j. Prior history of gastrointestinal diverticulitis, perforation, or abscess; 
k. Clinically significant (i.e., active) cardiovascular disease, for example cerebrovascular 
accidents ≤ 6 months prior to study enrollment, myocardial infarction ≤  6 months prior 
to study enrollment, unstable angina, New York Heart Association (NYHA) Grade II or 
greater congestive heart failure (CHF), or serious cardiac arrhythmia uncontrolled by 
medication or potentially interfering with protocol treatment; 
l. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent 
arterial thrombosis) within 6 months prior to start of study treatment. Any previous 
venous thromboembolism ≥ NCI CTCAE Grade 3 within 3 months prior to start of 
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m. History of pulmonary hemorrhage/hemoptysis ≥ grade 2 (defined as ≥ 2.5 mL bright 
red blood per episode) within 1 month prior to randomization; 
n. History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of 
bleeding (i.e., in the absence of therapeutic anticoagulation); 
o. Current or recent (within 10 days of study enrollment) use of anticoagulants that, in the 
opinion of the investigator, would place the subject at significant risk for bleeding. 
Prophylactic use of anticoagulants is allowed; 
p. Surgical procedure (including open biopsy, surgical resection, wound revision, or any 
other major surgery involving entry into a body cavity) or significant traumatic injury 
within 28 days prior to first study treatment, or anticipation of need for major surgical 
procedure during the course of the study; 
q. Minor surgical procedure (e.g., stereotactic biopsy within 7 days of first study 
treatment; placement of a vascular access device within 2 days of first study treatment); 
r. History of intracranial abscess within 6 months prior to randomization; 
s. History of active gastrointestinal bleeding within 6 months prior to randomization; 
t. Serious, non-healing wound, active ulcer, or untreated bone fracture; 
u. Subjects unable (due to existent medical condition, e.g., pacemaker or ICD device) or 
unwilling to have a head contrast enhanced MRI 
 
 
 
 
3.   Physical and Laboratory Test Findings 
a. Positive test for hepatitis B virus surface antigen (HBV sAg) or detectable hepatitis C 
virus ribonucleic acid (HCV RNA) indicating acute or chronic infection 
b. Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS) 
 
4.   Allergies and Adverse Drug Reaction 
c. History of severe hypersensitivity reaction to any monoclonal antibody 
 
5.   Corticosteroid Use 
d. Subjects that require decadron > 4 mg/ day or equivalent of steroids  
 
4.3 
Inclusion of Women and Minorities  
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 
 

 
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4.4   Women of Child Bearing Potential (WOCBP) 
A women of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of amenorrhea 
in a woman over age 45 years in the absence of other biological or physiological causes. In 
addition, women under the age of 55 years must have a serum follicle stimulating hormone, 
(FSH) level > 40mIU/mL to confirm menopause.* 
 
*Women treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration 
of the washout period below are suggested guidelines and the investigators should use their 
judgment in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time 
during the washout period, the woman can be considered postmenopausal: 
 
 1 week minimum for vaginal hormonal products (rings, creams, gels) 
 4 week minimum for transdermal products 
 8 week minimum for oral products 
 
4.5 Concomitant Treatments 
4.5.1 Steroids  
This study allows subjects to receive systemic corticosteroid therapy consisting of 
dexamethasone up to 4 mg/day (or other dexamethasone-equivalent therapy) at entry.  
 
For subjects receiving study therapy, systemic corticosteroid at a dose higher than 4 mg/day or 
physiologic replacement doses of steroids are permitted for: 
a) treatment-related AEs; 
b) sequelae of underlying GBM treatment; or 
c) treatment of non-autoimmune conditions (such as prophylaxis for contrast dye allergy, 
delayed-type hypersensitivity reaction caused by contact allergen). 
 
Details regarding corticosteroid use prior to and during the study will be collected (name of 
medication, doses utilized, start and stop dates, frequency of use, route of administration). 
Information regarding concomitant corticosteroid use may be analyzed with regard to study 
outcome measures. Subjects should be maintained on as low a dose of corticosteroids 
administered for as short a time period as possible. If medically appropriate, subjects should be 
tapered off corticosteroids whenever possible.  

 
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Subjects requiring chronic treatment with corticosteroids should be treated with 
histamine-2-receptor antagonists or proton pump inhibitors as prophylaxis for potential 
gastrointestinal adverse reactions (ulceration, perforation, hemorrhage) unless otherwise 
contraindicated. 
 
4.5.2 Other Permitted Therapy  
Other concomitant medications such as anti-seizures medications and supportive care measures 
for treating depression, anxiety, and fatigue are permitted as the discretion of the treating 
physician. 
 
As there is potential for hepatic toxicity with nivolumab, drugs with a predisposition to 
hepatotoxicity should be used with caution in all study subjects (Appendix 6 – add the attached 
list as Appendix 6 before the Algorithms.  
 
Concomitant medications are recorded at baseline and throughout the treatment phase of the 
study in the appropriate section of the CRF. All medications (prescriptions or over the counter 
medications) continued at the start of the study or started during the study and different from 
the study drug must be documented in the concomitant therapy section of the CRF. 
 
4.5.3 Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study: 
 Any concurrent drug or other investigational agents for treatment of GBM (ie, 
chemotherapy, hormonal therapy, immunotherapy, radiation therapy) 
 Medications contraindicated with bevacizumab treatment (refer to the package insert, 
summary of product characteristics (SmPC), or similar document) 
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) 
are live attenuated vaccines, and are not allowed.  
Supportive care for disease-related symptoms may be offered to all subjects on the study. 
 
4.5.4 Other Restrictions and Precautions 
Study related MRI imaging of the brain will be performed based on schedule as defined in this 
protocol. Investigators may obtain additional follow-up MRI scans as medically indicated. It is 

 
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the local imaging facility’s responsibility to determine, based on subject attributes (e.g., allergy 
history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each subject. Subjects with renal insufficiency should be assessed as to whether or 
not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Specific to MRI, subjects with severe renal insufficiency (ie, estimated glomerular filtration 
rate (eGFR) < 30 mL/min/1.73m2) are at increased risk of nephrogenic systemic fibrosis. MRI 
contrast should not be given to this subject population. 
 
5.0 
Registration 
 
All subjects who have been consented are to be registered in the OnCore™ Database. 
Randomization will be completed per Taussig standard procedure. For those subjects who are 
consented, but not enrolled, the reason for exclusion must be recorded. 
 
All subjects will be registered through Cleveland Clinic and will be provided a study number 
by contacting the study coordinator listed on the cover page.  
 
The Advarra EDC™ and OnCore™ databases will be utilized, as required by the Case 
Comprehensive Cancer Center and Cleveland Clinic, to provide data collection for both accrual 
entry and trial data management. Advarra EDC and OnCore™ are Clinical Trials Management 
Systems housed on secure servers. Access to data through Advarra EDC and OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the Advarra EDC or 
OnCore™ system with a user ID and password, Advarra EDC™ and OnCore™ define roles 
for each user which limits access to appropriate data. Applications for user accounts can be 
obtained by contacting the OnCore™ Administrator at OnCore-registration@case.edu for 
OnCore™ access, and taussigoncore@ccf.org for Advarra EDC™ access. 
  
Advarra EDC™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification.  When properly utilized, Advarra 
EDC™ is 21 CFR 11 compliant.  This study will utilize electronic Case Report Form 
completion in the Advarra EDC™ database. A calendar of events and required forms are 
available in Advarra EDC™. 
 
6.0  
Treatment  
 
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following: 
 All products, active or placebo, being tested or used as a comparator in a clinical trial. 
 Study required pre-medication, and 

 
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 Other drugs administered as part of the study that are critical to claims of efficacy 
 (e.g., background therapy, rescue medications) 
 Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection 
 
 
6.1 
Investigational Products 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a 
reference in a clinical study, including products already with a marketing authorization but 
used or assembled (formulated or packaged) differently than the authorized form, or used for 
an unauthorized indication, or when used to gain further information about the authorized 
form. 
 
The investigational product should be stored in a secure area according to local regulations. It 
is the responsibility of the investigator to ensure that investigational product is only dispensed 
to study subjects. The investigational product must be dispensed only from official study sites 
by authorized personnel according to local regulations.  
 
In this protocol, the investigational products are BMS-936558 (nivolumab) and bevacizumab. 
Investigational product information is provided in Table 7.1-1. 
BMS is supplying the study drug BMS-936558 (nivolumab). Bevacizumab may be obtained by 
the investigational sites located in the USA as a local commercial product (which may be 
available as a different potency/package size than listed in Table 7.1-1) if local regulations 
allow and agreed to by BMS. 
 
 
Table 7.1-1 Investigational Product Description 
 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/Label 
Type 
Secondary 
Packaging 
(Qty)/Label 
Type 
Appearance 
Storage 
Conditions 
(per label) 
 
Nivolumab* 
(BMS-936558-01): 
Injection drug product 
is a sterile, non-
pyrogenic, single-use, 
 
100 
mg/vial  
(10 
mg/mL) 
 
10-mL Type 1 flint 
glass vials stoppered 
with butyl stoppers 
and sealed with 
aluminum seals / 
Open-label 
 
5 or 10 vials per 
carton / Open-
label 
 
 
 
Clear to 
opalescent 
colorless to pale 
yellow 
liquid. May 
contain 
 
2 to 8°C (36 
to 46°F). 
Protect from 
light and 
freezing 

 
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isotonic aqueous 
solution** 
 
particles 
 
Bevacizumab:  
Solution 
for infusion 
 
400 
mg/vial 
 
16mL per vial / 
Open-label 
 
1 vial per carton 
/ Open-label 
 
Clear to slightly 
opalescent, 
colorless to 
pale brown 
liquid 
 
2 to 8°C (36 
to 46°F). 
Protect from 
light and 
freezing. Do 
not shake.
 
* Note other names = MDX-1106, ONO-4538, anti-PD-1  
**Nivolumab may be labeled as BMS-936558-01 Solution for Injection 
 
6.2 Non-investigational Products 
Other medications used as support or escape medication for preventative, diagnostic, or 
therapeutic reasons, as components of the standard of care for a given diagnosis, may be 
considered as non-investigational products. 
 
In this protocol, non-investigational product(s) is/are: Not applicable for this study. 
6.3 Storage, Handling and Dispensing of Investigational Products 
The investigator should ensure that the study drug is stored in accordance with the 
environmental conditions (temperature, light, and humidity) as per product information and the 
Investigator Brochure and per local regulations. It is the responsibility of the investigator to 
ensure that investigational product is only dispensed to study subjects. The investigational 
product must be dispensed only from official study sites by authorized personnel according to 
local regulations. If concerns regarding the quality or appearance of the study drug arise, the 
study drug should not be dispensed and contact BMS immediately. 
Investigational product documentation will be maintained that includes all processes required 
to ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, and use of required 
processes (e.g., required diluents, administration sets).   
Infusion-related supplies (e.g., IV bags, in-line filters, 0.9% NaCl solution) will not be supplied 
by the sponsor and should be purchased locally if permitted by local regulations. 
 
For non-investigational product, if marketed product is utilized, it should be stored in 
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Please refer to the current version of the Investigator Brochure and/or shipment reference 
sheets for additional information on storage, handling, dispensing, and infusion information for 
nivolumab. 
 
6.3.1 Nivolumab (BMS-936558) 
Nivolumab is an injection drug product. This product is a sterile, non-pyrogenic, single-use, 
isotonic aqueous solution formulated at 10 mg/mL (100mg/vial). Vials should be stored at 2 to 
8 degrees C and should be protected from light and freezing. If stored in a glass front 
refrigerator, vials should be stored in the carton. Recommended safety measures for 
preparation and handling of nivolumab include laboratory coats and gloves. 
For additional details on prepared drug storage and use time of nivolumab under room 
temperature/light and refrigeration, please refer to the BMS-936558 (nivolumab) Investigator 
Brochure section for “Recommended Storage and Use Conditions”  
 
6.3.2 Bevacizumab 
Please refer to the package insert, summary of product characteristics (SmPC), or similar 
document for details regarding drug preparation, administration, and use time. 
 
6.4 Destruction or Return of Investigational Products 
For this study, the investigational products study drugs such as partially used study drug 
containers, vials and syringes may be destroyed on site.  
 
Any unused study drugs can only be destroyed after being inspected and to be reconciled by 
the site, and destroyed according to institution SOP.  Drug accountability and destruction logs 
to be sent to BMS  
 
On-site destruction is allowed provided the following minimal standards are met: 
 On-site disposal practices must not expose humans to risks from the drug. 
 On-site disposal practices and procedures are in agreement with applicable laws and 
 regulations, including any special requirements for controlled or hazardous substances. 
 Records are maintained that allow for traceability of each container, including the date 
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containers. The method of disposal, i.e., incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
 Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period. 
 
6.5 Study Drug Administration 
 
6.5.1 Dosing Schedule and Administration 
 
The dosing regimen and schedule for Arm A (nivolumab plus standard bevacizumab) and Arm 
B (nivolumab plus low dose bevacizumab) are detailed in Tables 6.5-1 and 6.5-2. 
 
Table 6.5.1-1: Dosing Schedule for Arm A: Nivolumab (BMS-936558) plus standard bevacizumab 
Every 2 week dosing 
Day 1, Week 1 
Day 1, Week 3 and every two weeks thereafter 
240 mg IV nivolumab + 
10 mg/kg IV bevacizumab 
240 mg IV nivolumab + 
10 mg/kg IV bevacizumab 
 
Table 6.5.1-2: Dosing Schedule for Arm B: Nivolumab (BMS-936558) plus low dose Bevacizumab 
Every 2 week dosing 
Day 1, Week 1 
Day 1, Week 3 and every two weeks thereafter 
240 mg IV nivolumab + 3 mg/kg IV bevacizumab 
240 mg IV nivolumab + 3 mg/kg IV bevacizumab 
 
Nivolumab will be given every two weeks at a dose of 240 mg. Nivolumab will be 
administered as a 30-minute IV infusion, using a volumetric pump with a 0.2/0.22 micron in-
line filter at the protocol-specified dose. The drug can be diluted with 0.9% normal saline for 
delivery but the total drug concentration cannot be below 0.35 mg/ml. The drug is not to be 
administered as an IV push or bolus injection. At the end of the infusion, flush the line with a 
sufficient quantity of normal saline. 
 
Bevacizumab will be given every two weeks with nivolumab as an IV infusion at a dose of 
10mg/kg for subjects in Arm A and at 3 mg/kg for subjects in Arm B. Nivolumab and 
bevacizumab will be prepared separately and administered in separate infusion bags including 
appropriate filtering. Nivolumab is to be administered first. The second infusion will be 
bevacizumab, and will start no sooner than 10 minutes after completion of the nivolumab 
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6.5.2 Dosing Calculation 
Each dose of nivolumab and bevacizumab will be administered every 2 weeks (+/- 3 days), but 
subjects may be dosed no less than 12 days from the previous dose of drug. Nivolumab will be 
dosed at a flat dose of 240 mg every 2 weeks. Bevacizumab will be dosed at 10 mg/kg for 
subjects on Arm A and at 3 mg/kg for subjects on Arm B. The dose of bevacizumab will be 
based on weight at screening and will be recalculated if there is a >10% change in body weight 
during the study or per institutional guidelines.   
 
6.5.3 Dosing Modifications 
Dosing modifications, including dose reductions or dose escalations, are not permitted.  
 
Dosing delay is allowed for toxicity management, as specified in section 6.6.  
 
6.5.4 Antiemetic Pre-medications 
Antiemetic pre-medications should not be routinely administered prior to dosing of drugs. See 
Section 6.8 for premedication recommendations following a nivolumab related infusion 
reaction. 
 
 
6.6 Dose Delay Criteria 
 
6.6.1 Dose Delay Criteria for Nivolumab 
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not the 
event is attributed to nivolumab). All study drugs must be delayed until treatment can resume.  
Nivolumab administration should be delayed for the following: 
Any Grade ≥ 2 non-skin, drug-related AE, with the following exceptions: 
 Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment 
delay 
 Any Grade 3 skin, drug-related AE 
 Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
lymphopenia, leukopenia, AST, ALT, total bilirubin, or asymptomatic amylase or 
lipase: 
o Grade 3 lymphopenia or leukopenia does not require dose delay. 

 
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o If a subject has a baseline AST, ALT, or total bilirubin that is within normal 
limits, delay dosing for drug-related Grade ≥ 2 toxicity. 
o If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity 
range, delay dosing for drug-related Grade ≥ 3 toxicity. 
 Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, warrants delaying the dose of study medication. 
 
6.6.2 Criteria to Delay or Discontinue Bevacizumab 
Guidance for when bevacizumab administration should be delayed or discontinued should be 
in accordance with the package insert or summary of product characteristics (SmPC).  
There are no reductions in the bevacizumab dose. Specific guidelines for bevacizumab dose 
management due to adverse events considered at least possibly related to bevacizumab are 
summarized in Table 8. If adverse events occur that require holding bevacizumab, the dose will 
remain the same once treatment resumes. Any toxicity associated or possibly associated with 
bevacizumab treatment should be managed according to standard medical practice, unless 
listed in Table 8 below. Bevacizumab has a terminal half-life of 2 to 3 weeks; therefore, its 
discontinuation results in slow elimination over several months. There is no available antidote 
for bevacizumab.  
Subjects should be assessed clinically for toxicity prior to, during, and after each infusion. If 
unmanageable toxicity occurs because of bevacizumab at any time during the study, treatment 
with bevacizumab should be discontinued.  
Adverse events requiring delays or permanent discontinuation of bevacizumab are listed in 
Table 8. 
Table 8 Bevacizumab Dose Management Due to Adverse Events 
 
Event 
Action to be Taken 
Hypertension 
No dose modifications for grade 1/2 events 
Grade 3 
If not controlled to ≤ 159/99 mmHg with medication, discontinue bevacizumab. 

 
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Grade 
4 
(including 
RPLS 
(confirmed 
by 
MRI) or hypertensive 
encephalopathy) 
Discontinue bevacizumab. 
Hemorrhage 
No dose modifications for grade 1 non-CNS events 
Grade ≥ 1 New CNS 
hemorrhage 
Discontinue bevacizumab. 
Grade > 1 non-CNS 
hemorrhage  
Discontinue bevacizumab.  
Venous Thrombosis 
No dose modifications for grade 1/2 events 
Grade 3/ Asymptomatic 
Grade 4 
Hold study drug treatment.  If the planned duration of full-dose anticoagulation is 
<2 weeks, study drug should be held until the full-dose anticoagulation period is over.  
If the planned duration of full-dose anticoagulation is ≥2 weeks, study drug may be 
resumed during the period of full-dose anticoagulation if the following criteria  is met: 
 
The participant must be therapeutically anti-coagulated with an approved 
anticoagulant agent according to standard prescribing guidelines. 
Symptomatic Grade 4 
Discontinue bevacizumab. 
Arterial Thromboembolic event 
(Angina, myocardial infarction, transient ischemic attack, cerebrovascular accident, and any other arterial 
thromboembolic event) 
 Any grade 
Discontinue bevacizumab. 
Congestive Heart Failure (Left ventricular systolic dysfunction) 
No dose modifications for grade 1/2 events 
Grade 3 
Hold bevacizumab until resolution to Grade ≤ 1. 
Grade 4 
Discontinue bevacizumab. 
Proteinuria 
No dose modifications for grade 1/2 events 
Grade 3 
 
Hold bevacizumab treatment until  Grade 2, as determined by 24 hr collection ≤ 3.5 g 
 

 
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Grade 4 (nephrotic 
syndrome) 
Discontinue bevacizumab 
GI Perforation 
Discontinue bevacizumab. 
Bowel Obstruction 
Grade 1 
 
Continue patient on study for partial obstruction NOT requiring medical intervention. 
Grade 2 
Hold bevacizumab for partial obstruction requiring medical intervention.  Patient may 
restart upon complete resolution. 
Grade 3/4 
Hold bevacizumab for complete obstruction.  If surgery is necessary, patient may 
restart bevacizumab after full recovery from surgery, and at investigator’s discretion. 
Wound dehiscence 
requiring medical or 
surgical therapy 
Discontinue bevacizumab. 
Infusion Related 
Reaction 
 
Grade 1/2 
Slow infusion to 50% or less or interrupt. When symptoms have completely resolved, 
the infusion may be continued at not 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. 
Grade 3/4 
Discontinue bevacizumab. 
Other Unspecified Bevacizumab-Related Adverse Events 
Grade 3 
Grade 4 
Hold bevacizumab until recovery to ≤ Grade 1 
Discontinue bevacizumab. 
 
 
6.6.3 Criteria to Resume Treatment 
Subjects may resume treatment with bevacizumab as summarized in Table 8. Subjects may 
resume treatment with nivolumab when the drug-related AE(s) resolve to Grade ≤1 or baseline 
value, with the following exceptions: 
 Subjects may resume treatment in the presence of Grade 2 fatigue  
 Subjects who have not experienced a Grade 3 drug-related skin AE may resume 
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 Subjects with baseline Grade 1 AST/ALT or total bilirubin who require dose delays for 
reasons other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment 
in the presence of Grade 2 AST/ALT OR total bilirubin 
 Subjects with combined Grade 2 AST/ALT AND total bilirubin values meeting 
discontinuation parameters should have treatment permanently discontinued 
 Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline 
before treatment is resumed 
 Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment 
If the criteria to resume treatment are met, the subject should restart treatment at the next 
scheduled time point per protocol. However, if the treatment is delayed past the next scheduled 
time point per protocol, the next scheduled time point will be delayed until dosing resumes. 
If treatment is delayed > 6 weeks, the subject must be permanently discontinued from study 
therapy, except as specified in discontinuation section 6.7. 
6.6.4 Management Algorithms 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and bevacizumab are considered 
immuno-oncology agents in this protocol. Early recognition and management of AEs 
associated with immuno-oncology agents may mitigate severe toxicity. Management 
algorithms have been developed to assist investigators in assessing and managing the following 
groups of AEs: 
 Gastrointestinal 
 Renal 
 Pulmonary 
 Hepatic 
 Endocrinopathies 
 Skin 
 Neurological. 

 
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While the nivolumab investigator brochure contains safety management algorithms for similar 
adverse events, the recommendations are to follow the nivolumab algorithms for immune-
oncology agents (I-O) in order to standardize the safety management. Therefore, the algorithms 
recommended for utilization in this protocol are included in Appendix 6. The guidance 
provided in these algorithms should not replace the Investigator’s medical judgment but should 
complement it. 
 
6.7 Discontinuation Criteria 
Subjects who require nivolumab discontinuation due to toxicity are permitted to continue to 
receive study treatment with bevacizumab alone. Conversely, subjects who require 
bevacizumab discontinuation due to toxicity are permitted to continue to receive study therapy 
with nivolumab alone. Treatment should be permanently discontinued for the following: 
 Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 severity within the re-treatment period 
OR requires systemic treatment  
 Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions 
for 
drug-related 
laboratory 
abnormalities, 
uveitis, 
pneumonitis, 
bronchospasm, diarrhea, colitis, neurologic adverse event, hypersensitivity reactions, 
and infusion reactions 
o Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, 
neurologic adverse event, hypersensitivity reaction, or infusion reaction of any 
duration requires discontinuation 
o Grade 3 drug-related laboratory abnormalities do not require treatment 
discontinuation except those noted below 
 Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding 
requires discontinuation 
 Any drug-related liver function test (LFT) abnormality that meets the 
following criteria require discontinuation:  
• 
AST or ALT > 8 x ULN 
 
• 
Total bilirubin > 5 x ULN 
• 
Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 

 
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 Any Grade 4 drug-related adverse event or laboratory abnormality, except for the 
following events which do not require discontinuation: 
 Isolated Grade 4 amylase or lipase abnormalities that are not associated with 
symptoms or clinical manifestations of pancreatitis and decrease to < Grade 4 
within 1 week of onset.  
 Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated 
with clinical sequellae and are corrected with supplementation/appropriate 
management within 72 hours of their onset 
 Any dosing interruption lasting > 6 weeks with the following exceptions: 
 Dosing interruptions to allow for prolonged steroid tapers to manage drug-
related adverse events are allowed. Prior to re-initiating treatment in a subject 
with a dosing interruption lasting > 6 weeks, the Investigator must be consulted. 
Tumor assessments should continue as per protocol even if dosing is interrupted 
 Dosing interruptions > 6 weeks that occur for non-drug-related reasons may be 
allowed if approved by the Investigator. Prior to re-initiating treatment in a 
subject with a dosing interruption lasting > 6 weeks, the Investigator must be 
consulted. Tumor assessments should continue as per protocol even if dosing is 
interrupted 
 Any adverse event, laboratory abnormality, or intercurrent illness which, in the 
judgment of the Investigator, presents a substantial clinical risk to the subject with 
continued nivolumab dosing 
6.8 Treatment of Nivolumab Related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, it is unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction 
were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritis, arthralgias, 
hypo- or hypertension, bronchospasm, or other symptoms.  
All Grade 3 or 4 infusion reactions should be reported as an SAE if criteria are met. Infusion 
reactions should be graded according to NCI CTCAE v5.0 guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate: 

 
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For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated) 
Remain at bedside and monitor subject until recovery from symptoms. The following 
prophylactic pre-medications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30 minutes before 
additional nivolumab administrations. 
For Grade 2 symptoms: (Moderate reaction requires therapy or infusion interruption but 
responds promptly to symptomatic treatment [e.g., antihistamines, non-steroidal anti-
inflammatory drugs, narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic 
medications indicated for 24 hours). 
Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000 mg 
(acetaminophen); remain at bedside and monitor subject until resolution of symptoms. 
Corticosteroid or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor subject closely. If symptoms recur 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 50 
mg IV, and remain at bedside and monitor the subject until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). The 
following 
prophylactic 
pre-medications 
are 
recommended 
for 
future 
infusions: 
diphenhydramine 50 mg (or equivalent) and/or paracetamol 325 to 1000 mg (acetaminophen) 
should be administered at least 30 minutes before additional nivolumab administrations. If 
necessary, corticosteroids (recommended dose: up to 25 mg of IV hydrocortisone or 
equivalent) may be used. 
For Grade 3 or Grade 4 symptoms: (Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae 
[eg, renal impairment, pulmonary infiltrates]). Grade 4: (life threatening; pressor or ventilatory 
support indicated).  
Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline, and 
treat the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 1:1,000 
solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution injected 

 
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slowly for IV administration, and/or diphenhydramine 50 mg IV with methylprednisolone 100 
mg IV (or equivalent), as needed. Subject should be monitored until the investigator is 
comfortable that the symptoms will not recur. Nivolumab will be permanently discontinued. 
Investigators should follow their institutional guidelines for the treatment of anaphylaxis. 
Remain at bedside and monitor subject until recovery from symptoms. In the case of late-
occurring hypersensitivity symptoms (e.g., appearance of a localized or generalized pruritis 
within 1 week after treatment), symptomatic treatment may be given (e.g., oral antihistamine, 
or corticosteroids). 

 
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6.9 Cerebral Edema 
Due to the immunologic nature of nivolumab, cerebral edema could theoretically result as a 
consequence of nivolumab administration due to immune infiltration of the brain. Symptoms 
related to cerebral edema may include headache or neurologic deficit that is either new or 
worsened. Subjects with any signs or symptoms of cerebral edema should be treated as 
clinically appropriate including initiation or increased systemic corticosteroid dosing, treatment 
with an osmotic diuretic or surgical decompression. Subsequent nivolumab dosing should be 
immediately interrupted if significant clinical symptoms attributable to cerebral edema 
develop. Treatment with additional nivolumab doses may only be re-initiated if clinically 
significant symptoms attributable to cerebral edema have resolved to grade ≤ 1 or pre-
treatment baseline. Subjects who develop CTCAE v5.0 grade 4 cerebral edema attributable to 
nivolumab administration should not receive further nivolumab doses but may continue study 
therapy bevacizumab. 
6.10   Treatment Beyond Initial Radiologic Assessment of Disease Progression 
Accumulating evidence indicates a minority of subjects treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD. Similarly, in the GBM patient population, 
it is well-known that a subset of subjects who receive standard of care including upfront 
radiation therapy and temozolomide will go on to demonstrate “pseudo-progression”. This 
phenomenon describes the transient increase in tumor enhancement on contrast MRI, which 
eventually returns to baseline without any change in therapy, unlike true tumor progression.  
 
As it can be challenging to distinguish disease progression from pseudo-progression, and to 
avoid premature discontinuation of study drug, subjects with radiographic evidence of 
progressive disease within six months of initiating study therapy and who are not experiencing 
significant neurologic decline, should remain on study pending radiographic confirmation of 
tumor progression on follow-up imaging obtained three months later as specified in the iRANO 
criteria.65 If radiographic confirmation is obtained on follow-up imaging, the date of tumor 
progression will be back-dated to the date of the scan that initially demonstrated progression. 
Thus, this protocol will allow for continuation of the study drug beyond initial demonstration 
of tumor progression pending confirmation of progression.   
 
 

 
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Subjects will be permitted to continue treatment beyond initial iRANO-defined PD as long as 
they meet the following criteria: 
 Investigator-assessed clinical benefit and  
 Subject is tolerating study drug and is not demonstrating significant neurologic decline 
felt to be attributable to underlying tumor growth. 
Subjects with confirmed progression on follow-up imaging three months later or who develop 
significant neurologic decline felt to be attributable to underlying tumor growth, will 
discontinue study medication and enter the follow up/survival phase of the study. If 
progression is confirmed then the date of disease progression will be the first date the subject 
met the criteria for progression.  
If radiologic progression cannot be differentiated from pseudoprogression, the investigator may 
recommend that patient undergo a surgical resection to assess histopathology. In this case, 
tumor biopsy samples (blocks or slides) must be submitted for central review by a 
neuropathologist to minimize any inter-observer variation in the histopathologic assessment of 
progression versus treatment-related changes. If tumor pathology confirms progression, then 
the subject will be discontinued from study medication per protocol discontinuation criteria, 
and the date of progression will be the day that it was first suspected. If tumor pathology 
reveals treatment-related changes and does not confirm disease progression, the subject may 
continue study medication. An MRI after the resection is required prior to treatment 
continuation. The subject will then continue all on-treatment tumor assessments as per the 
treatment schedule described in this protocol. 
 
6.10.1 Central Neuropathologic Review of Tumor Samples After Biopsy or Resection 
Representative tumor tissue samples will be reviewed locally for progression versus treatment-
associated changes. 
 
6.11  Blinding/Unblinding 
Not applicable. 
 
6.12 Treatment Compliance 
In this study, treatment compliance will be monitored by drug accountability as well as the 
subject’s medical record and eCRF 

 
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7.0 
Adverse Events and Potential Risks 
 
The following is a list of AEs (Section 7.1) and the reporting requirements associated with 
observed AEs (Sections 7.3 and 7.4).  
 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause.  
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the study 
period and is considered to be possibly related to the study treatment or study participation will 
be recorded and reported immediately. 
 
7.1      Adverse Events and Potential Risks 
 
7.1.1   Nivolumab  
 
CA209003 is an ongoing Phase 1 open label, multiple dose escalation study in 306 subjects 
with select previously treated advanced solid tumors, including melanoma, RCC, NSCLC, 
colorectal cancer, and hormone-refractory prostate cancer. Subjects received nivolumab at 
doses of 0.1, 0.3, 1, 3, or 10 mg/kg intravenously every 2 weeks, up to a maximum of 2 years 
of total therapy. As of 18-Mar-2013, a total of 306 melanoma subjects were treated with 
nivolumab in the dose range of 0.1 - 10 mg/kg. 
 
No maximal tolerated dose was identified in CA209003. The incidence, severity and 
relationship of AEs were generally similar across dose levels and tumor types. Nivolumab 
related AEs of any grade occurred in 75.2% of subjects. Of the 306 treated subjects, 303 
(99.0%) subjects have at least 1 reported AE regardless of causality. The most frequently 
reported AEs were fatigue (54.9%), decreased appetite (35.0%), diarrhea (34.3%), nausea 
(30.1%), and cough (29.4%). Treatment-related AEs were reported in 230 (75.2%) of the 306 
subjects. The most frequently reported treatment-related AEs were fatigue (28.1%), rash 
(14.7%), diarrhea (13.4%), and pruritus (10.5%). Most treatment-related AEs were low grade. 
Treatment-related high grade (Grade 3-4) AEs were reported in 52 (17.0%) of subjects. The 
most common treatment-related high grade AEs were fatigue (2.3%) and diarrhea (1%). 

 
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Drug-related SAEs occurred in 11.5% of subjects. Grade 3-4 drug-related SAEs reported in at 
least 2 subjects included: diarrhea (3 subjects, 1.0%), pneumonitis (3 subjects, 1.0%), 
pneumonia (2 subjects, 0.7%) and lipase increased (2 subjects, 0.7%). 
 
Select AE categories (events with a potential inflammatory mechanism requiring more frequent 
monitoring and/or unique intervention such as immunosuppressants and/or endocrine 
replacement therapy) include: GI AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, and 
endocrinopathies. In addition, select AEs include a category for infusion reactions. Each 
category is composed of a discrete set of preferred terms, including those of greatest clinical 
relevance. These select AEs are considered events of interest based on the mechanism of action 
and were previously referred to as immune-related AEs or immune-mediated AEs. 
The 10 mg/kg cohort had numerically greater frequency of high-grade select AEs including the 
subcategories of endocrinopathies, GI, pulmonary, and infusion reactions (Table 8.1.1-1). Most 
high grade events resolved following the treatment guidelines for the treatment of pulmonary 
events, GI events, hepatic events, renal events, and endocrine events, respectively. 
 
Treatment-related AEs leading to discontinuation were reported in 32 (10.5%) of the 306 
treated subjects on CA209003. The most frequent of these were pneumonitis (8 subjects; 2.6%) 
and colitis (3 subjects; 1.0%).There were 3 (1%) drug related deaths; each occurred after 
development of pneumonitis. 
 
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the BMS-936558 (nivolumab) IB. 
Table 8.1.1 -1 : Treatment-related Select Adverse Events by Treatment - All CTC Grades 
Reported in at Least 10 Treated Subjects in CA209003 
 

 
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Abbreviations: ALT: alanine aminotransferase, TSH: thyroid stimulating hormone 
Source: Preliminary data, MDX1106-03. Clinical data cut-off date: 18-Mar-2013 
 
 
 
 
7.1.2 
Bevacizumab: Adverse Event Profile  
In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety signals 
were identified: hypertension, proteinuria, thromboembolic events, and hemorrhage. 
Additional completed Phase II and Phase III studies of bevacizumab as well as spontaneous 
reports have further defined the safety profile of this agent. Bevacizumab‐associated adverse 
events identified in Phase III trials include congestive heart failure (CHF) primarily in 
metastatic breast cancer, gastrointestinal perforations, wound healing complications, and 
arterial thromboembolic events (ATE). 
 
Hypertension: An increased incidence of hypertension has been observed in subjects treated 
with bevacizumab. Grade 4 and 5 hypertensive events are rare. Clinical sequela of 
hypertension are rare but have included hypertensive crisis, hypertensive encephalopathy, and 

 
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reversible posterior leukoencephalopathy syndrome (RPLS).54,66 There is no information on the 
effect of bevacizumab in subjects with uncontrolled hypertension at the time of initiating 
bevacizumab therapy. Therefore, caution should be exercised before initiating bevacizumab 
therapy in these subjects. Monitoring of blood pressure is recommended during bevacizumab 
therapy. Optimal control of blood pressure according to standard public health guidelines is 
recommended for subjects on treatment with or without bevacizumab. Temporary interruption 
of bevacizumab therapy is recommended in subjects with hypertension requiring medical 
therapy until adequate control is achieved. If hypertension cannot be controlled with medical 
therapy, bevacizumab therapy should be permanently discontinued. Bevacizumab should be 
permanently discontinued in subjects who develop hypertensive crisis or hypertensive 
encephalopathy. 
 
Proteinuria: An increased incidence of proteinuria has been observed in subjects treated with 
bevacizumab compared with control arm subjects. In the bevacizumab‐containing treatment 
arms of clinical trials (across all indications), the incidence of proteinuria (reported as an 
adverse event) was up to 38% (metastatic CRC Study AVF2192g).67 The severity of 
proteinuria has ranged from asymptomatic and transient events detected on routine dipstick 
urinalysis to nephrotic syndrome; the majority of proteinuria events have been Grade 1. 
NCI‐CTC Grade 3 proteinuria was reported in up to 3% of bevacizumab‐treated subjects, and 
Grade 4 in up to 1.4% of bevacizumab‐treated subjects. The proteinuria seen in bevacizumab 
clinical trials was not associated with renal impairment and rarely required permanent 
discontinuation of bevacizumab therapy. 
 
Bevacizumab should be discontinued in subjects who develop Grade 4 proteinuria (nephrotic 
syndrome). Subjects with a history of hypertension may be at increased risk for the 
development of proteinuria when treated with bevacizumab. There is evidence from the 
dose‐finding, Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 
proteinuria may be related to bevacizumab dose. Proteinuria will be monitored by urinalysis, 
and urine protein: creatinine (UPC) ratio when necessary. 
 
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging in 
severity from catheter‐associated phlebitis to fatal, have been reported in subjects treated with 
bevacizumab in the colorectal cancer trials, the recurrent glioblastoma trial and, to a lesser 
extent, in subjects treated with bevacizumab in NSCLC and breast cancer trials. Venous 
thromboembolic events (VTE) have also been observed in trials with bevacizumab and 
glioblastoma. To assess the overall risk of VTE associated with the use of bevacizumab, a 
systemic review and meta-analysis was performed and included prospective randomized 
controlled trials in which standard antineoplastic therapy was used with and without 
bevacizumab.68 A total of 7,956 subjects with a variety of advanced solid tumors from 15 trials 

 
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were identified. Among the subjects treated with bevacizumab, the rates of all-grade and high-
grade VTE were 11.9% and 6.3, respectively. Subjects treated with bevacizumab had a 
significantly increased risk of VTE compared with controls (RR 1.31). Since TE events are 
very common in GBM independent of treatment,2 the relationship of thromboembolism to 
bevacizumab in this population is uncertain. Based on a Phase II clinical trial of bevacizumab 
with or without irinotecan in recurrent GBM, the rates of arterial thromboembolism were 
2.4%-2.5% and venous thromboembolism were 3.6%- 8.9%.60 The first incidence of VTE will 
therefore not constitute a DLT. 
 
An increased incidence of arterial thromboembolic events (ATE) was observed in subjects 
treated with bevacizumab compared with those receiving control treatments. ATE includes 
cerebrovascular accidents, myocardial infarction, transient ischemic attacks (TIAs), and other 
ATE. The analysis of pooled data of 1,745 subjects from five randomized trials using 
bevacizumab combined with chemotherapy showed an increased risk of ATE (3.8% in 
treatment arm vs. 1.7% in the control arm) but not VTE.69 Most ATE episodes described were 
myocardial or cerebrovascular events. Development of an ATE event was associated with a 
prior ATE event or age ≤ 65 years. 
 
Gastrointestinal perforation: Subjects may be at increased risk for the development of 
gastrointestinal perforation and fistula when treated with bevacizumab and steroids or 
chemotherapy. Bevacizumab should be permanently discontinued in subjects who develop 
gastrointestinal perforation. A causal association of intra‐abdominal inflammatory processes 
and gastrointestinal perforation to bevacizumab treatment has not been established. 
Nevertheless, caution should be exercised when treating subjects with intra‐abdominal 
inflammatory processes with bevacizumab. A meta-analysis of 17 randomized controlled trials 
demonstrated a significantly increased risk of gastrointestinal perforation in subjects treated 
with bevacizumab compared to control medication.70 The incidence was 0.9%, and the risks 
varied with tumor type, with colorectal cancer and renal cell cancer having the highest risk. In 
a Phase II clinical trial of bevacizumab with or without irinotecan for subjects with recurrent 
GBM, 2.1%-2.5% experienced a Grade 3 gastrointestinal perforation.59,60 
 
 
Fistula: Bevacizumab use has been associated with serious cases of fistulae including events 
resulting in death. Fistulae in the GI tract are common (1%–10% incidence) in subjects with 
metastatic CRC, but uncommon (0.1%-1%) or rare (0.01%–0.1%) in other indications. In 
addition, fistulae that involve areas of the body other than the GI tract (e.g. tracheoesophageal, 
bronchopleural, urogenital, biliary) have been reported uncommonly (0.1%–1%) in subjects 
receiving bevacizumab in clinical studies and post-marketing reports. Events were reported at 

 
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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. 
 
Wound healing complications: Wound healing complications such as wound dehiscence have 
been reported in subjects receiving bevacizumab. Most clinical trials with bevacizumab have 
required at least 28 days from any major surgery before starting treatment.71 In a retrospective 
analysis of randomized trials in metastatic colorectal cancer, for a subset of subjects who had 
surgeries 28-60 days before initiating bevacizumab, the incidence of wound complications 
were low (1.3%),72 indicating that the 28-day interval from colonic surgery might be 
appropriate. However, in the subset of subjects undergoing emergent surgery while on study, 
13% of the subjects in the bevacizumab arm developed Grade 3 or Grade 4 postoperative 
wound complications compared to 3.4% of the subjects in the chemotherapy arm. Surgery in 
subjects currently receiving bevacizumab is not recommended. No definitive data are available 
to define a safe interval after bevacizumab exposure with respect to wound healing risk in 
subjects receiving elective surgery; however, the estimated half-life of bevacizumab is 21 days. 
Bevacizumab should be discontinued in subjects with severe wound healing complications. If 
subjects receiving treatment with bevacizumab require elective major surgery, it is 
recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure. 
Subjects undergoing a major surgical procedure should not begin or 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 bevacizumab be restarted no earlier than 
4 weeks after surgery). In a Phase II clinical trial of bevacizumab with or without irinotecan in 
subjects with recurrent GBM, Grade 3 or higher wound-healing complications were reported in 
1.3-2.4%.60 
 
1132 subjects treated with bevacizumab in a pooled database from eight Phase I, Phase II, and 
Phase III clinical trials in multiple tumor types (Genentech 2005). The hemorrhagic events that 
have been observed in bevacizumab clinical studies were predominantly tumor‐associated 
hemorrhage (See below: Tumor-Associated Hemorrhage) and minor mucocutaneous 
hemorrhage. 
 
Tumor-Associated Hemorrhage: Major hemorrhage has been observed primarily in subjects 
with NSCLC. Life‐threatening and fatal hemoptysis was identified as a bevacizumab‐related 
adverse event in NSCLC trials. These events occurred suddenly and presented as major or 
massive hemoptysis. GI hemorrhages, including rectal bleeding and melena have been reported 
in subjects with CRC, and have been assessed as tumor associated hemorrhages. Grades 1-4 
tumor‐associated hemorrhages were only very rarely seen in subjects with GBM (less than 
4%).60 Two of the five subjects who developed intracranial hemorrhage were anticoagulated at 
the time of the hemorrhage; both hemorrhages were Grade 1. 

 
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Mucocutaneous Hemorrhage: Across all bevacizumab clinical trials, mucocutaneous 
hemorrhage has been seen in 20%‐40% of subjects treated with bevacizumab (Genentech 
2005). These were most commonly NCICTC 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. 
 
Reversible Posterior Leukoencephalopathy Syndrome: There have been rare reports of 
bevacizumab‐treated subjects developing signs and symptoms that are consistent with RPLS, a 
rare neurologic disorder that can present with the following signs and symptoms (among 
others): seizures, headache, altered mental status, visual disturbance, or cortical blindness, with 
or without associated hypertension. Brain imaging is mandatory to confirm the diagnosis of 
RPLS. In subjects who develop RPLS, treatment of specific symptoms, including control of 
hypertension, is recommended along with discontinuation of bevacizumab. The safety of 
reinitiating bevacizumab therapy in subjects previously experiencing RPLS is not known. In a 
Phase II clinical trial of bevacizumab with or without irinotecan in subjects with recurrent 
GBM, only one patient (1.3%) experienced serious reversible posterior leukoencephalopathy 
syndrome.60 
 
Congestive heart failure: In clinical trials CHF was observed in all cancer indications studied 
to date, but predominantly in subjects with metastatic breast cancer. In the Phase III clinical 
trial of metastatic breast cancer (AVF2119g), 7 (3%) bevacizumab‐treated subjects 
experienced CHF, compared with two (1%) control arm subjects.73 These events varied in 
severity from asymptomatic declines in left ventricular ejection fraction (LVEF) to 
symptomatic CHF requiring hospitalization and treatment. All the subjects treated with 
bevacizumab were previously treated with anthracyclines (doxorubicin cumulative dose of 
240-360 mg/m2). Many of these subjects also had prior radiotherapy to the left chest wall. 
Most of these subjects showed improved symptoms and/or left ventricular function following 
appropriate medical therapy.73 No information is available on subjects with preexisting CHF of 
New York Heart Association (NYHA) Class II-IV at the time of initiating bevacizumab 
therapy, as these subjects were excluded from clinical trials. 
 
Adverse events in GBM studies from FDA labeling information: Bevacizumab is 
commercially available and FDA approved for subjects with recurrent glioblastoma. For 
further 
details, 
see 
the 
bevacizumab 
FDA 
labeling 
information 
available 
at 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf. All adverse 
events were collected in 163 subjects enrolled in a non-comparative Phase II study who either 
received bevacizumab alone or bevacizumab plus irinotecan.60 All subjects received prior 

 
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radiotherapy and temozolomide. Bevacizumab was administered at 10 mg/kg every 2 weeks 
alone or in combination with irinotecan. Bevacizumab was discontinued due to adverse events 
in 4.8% of subjects treated with bevacizumab alone. 
 
In subjects receiving bevacizumab alone (N=84), the most frequently reported adverse events 
of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), 
epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was 
infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two 
deaths on study were possibly related to bevacizumab: one retroperitoneal hemorrhage and one 
neutropenic infection. In subjects receiving bevacizumab alone or bevacizumab plus irinotecan 
(N=163), the incidence of bevacizumab-related adverse events (Grade 1−4) were 
bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), 
venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing 
complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The 
incidence of Grade 3−5 events in these 163 subjects were bleeding/hemorrhage (2%), CNS 
hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial 
thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and 
gastrointestinal perforation (2%). 
 
7.2 Definitions  
 
7.2.1   Adverse Events  
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product and that does not necessarily have a causal relationship with this treatment.  
 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of investigational product, 
whether or not considered related to the investigational product.  
 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 

 
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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
 
7.2.2 Serious Adverse Events  
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may require 
intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed 
in the definition above.). Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization.)  
 Potential drug induced liver injury (DILI) is also considered an important medical 
event. 
 Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via 
the study drug is an SAE. 
 Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) 
are not always serious by regulatory definition, these events must be handled as SAEs. 
 Any component of a study endpoint that is considered related to study therapy (e.g., 
death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported) should be reported as SAE 
 
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
 a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 

 
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 routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
 medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases 
 admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (e.g., lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 Admission for administration of anti-cancer therapy in the absence of any other 
SAEs 
 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event.  All occurrences of potential DILIs, 
meeting the defined criteria, must be reported as SAEs. Potential drug induced liver injury is 
defined as: 
 ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
 Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase) 
AND 
 No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or 
acute liver disease, or the administration of other drug(s) known to be hepatotoxic. 
 
7.3 Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study starting with day 1 of treatment.  Subjects will be followed for 
toxicity for 100 days after treatment has been discontinued or until death, whichever occurs 
first.  The clinical course of each event will be followed until resolution, stabilization, or until 
it has been determined that the study treatment or participation is not the cause.   
 
The investigator is responsible for ensuring that all adverse events observed by the investigator 
or reported by the subject which occur after the subject has signed the informed consent are 
fully recorded in the subject’s case report form, subject’s medical records, and/or any other 

 
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institutional requirement. Source documentation must be available to support all adverse 
events.  
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event.   
 
The investigator will provide the following for all adverse events: 
 Description of the event 
 Term that defines seriousness for the particular event, e.g., Hospitalization or 
Important Medical Event 
 Date of onset and resolution 
 Grade of toxicity  
 Attribution of relatedness to each of the investigational agents, in this study 
nivolumab 
 Action taken with each agent as a result of the event 
 Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0 available at http://ctep.cancer.gov will be utilized for 
AE reporting.  
 
Investigative sites will report adverse events to their respective IRB according to the local 
IRB’s policies and procedures in reporting adverse events. 
 
7.4  
Reporting Procedures for Serious Adverse Events 
 
Serious adverse events that occur beginning with the signing of the informed consent form, 
during treatment, or within 100 days of the last dose of treatment must be reported to the 
Principal Investigator. 
 
SAEs will be reported promptly to the Sponsor-Investigator David Peereboom M.D. or his 
designated study coordinator once the investigator determines that the event meets the protocol 
definitions of an SAE.   
 
Once an investigator becomes aware that an SAE has occurred in a study patient, the 
investigator must report the information to the Sponsor-Investigator David Peereboom M.D. or 
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Investigative sites will report serious adverse events to their respective IRB according to the 
local IRB’s policies and procedures in reporting serious adverse events. 
 
 
 
7.4.1 Bristol-Myers Squibb Company Serious Adverse Event Reporting  
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur within 100 days of 
discontinuation of dosing.  
All SAEs must be collected that occur during the screening period. If applicable, SAEs must be 
collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy).  The 
investigator should report any SAE that occurs after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a 
Pregnancy Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
For studies conducted under an Investigator IND in the US, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will be provided 
with a simultaneous copy of all adverse events filed with the FDA.  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 

 
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MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
Reporting Serious Adverse Events to the IRB/IEC:  It is the Investigator’s responsibility to 
report SAEs to the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
according to the requirements of the governing IRB/IEC. 
 
 
Worldwide.Safety@bms.comaepbusinessprocess@bms.com 
 
7.4.2    FDA Reporting  
 
The Cleveland Clinic Principal Investigator, as holder of the IND, will be responsible for all 
communication with the FDA.  In accordance with 21 CFR 312.32, the Cleveland Clinic 
Principal Investigator is responsible for notifying the FDA of SAEs that are serious, 
unexpected (not listed in the Investigator Brochure) and judged to be related (i.e., possible, 
probable, definite) to the study drug.  Events meeting the following criteria need to be 
submitted to the FDA as Expedited IND Safety Reports.    
 
7 Calendar Day IND Safety Report 
Any unexpected fatal or life-threatening suspected adverse event represents especially 
important safety information and, therefore, must be reported more rapidly to FDA (21 CFR 
312.32(c)(2)).  Any unexpected fatal or life-threatening suspected adverse event must be 
reported to FDA no later than 7 calendar days after the Cleveland Clinic Investigator’s initial 
receipt of the information (21 CFR 312.32(c)(2)).  Cleveland Clinic Principal Investigator will 
complete a Medwatch Form FDA 3500A and notify the FDA by telephone or facsimile 
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15 Calendar Day IND Safety Report 
The timeframe for submitting an IND safety report to FDA and all participating investigators is 
no later than 15 calendar days after the Cleveland Clinic Principal Investigator determines that 
the suspected adverse event or other information qualifies for reporting (21 CFR 312.32(c)(1)).  
This includes any serious, unexpected adverse events considered reasonably or possibly related 
to the investigational agent and that are not life-threatening or fatal.  The Cleveland Clinic 
Principal Investigator will complete a Medwatch Form FDA 3500A and notify the FDA by 
telephone or facsimile transmission.  If FDA requests any additional data or information, the 
Cleveland Clinic Principal Investigator must submit it to FDA as soon as possible, but no later 
than 15 calendar days after receiving the request (21 CFR 312.32(c)(1)(v)).    
 
Follow-up IND Safety Report 
Any relevant additional information that the Cleveland Clinic Principal Investigator obtains 
that pertains to a previously submitted IND safety report must be submitted to FDA as a 
Follow-up IND Safety Report without delay, as soon as the information is available (21 CFR 
312.32(d)(2)).  The Cleveland Clinic Principal Investigator will maintain records of its efforts 
to obtain additional information. 
 
 
Reporting Serious Problems to FDA 
Medwatch Form FDA 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Telephone: 1-800-332-1088 
Fax: 301-796-9849 
 
The fax cover sheet should note that this report will also be submitted formally in triplicate to the IND as 
an amendment per 21 CFR 312.32 (i.e. a formal paper submission to the Beltsville address). 
 
IND Annual Reports 
A summary of all IND safety reports submitting during the previous year will be reported to 
the FDA in the annual report by the Cleveland Clinic principal investigator, as holder of the 
IND.A copy will be sent to BMS. 
 
SAEs and OnCore – added to OnCore™ Database 
 All SAEs will be entered into OnCore.   
 A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into 
Oncore. 

 
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7.5  
Data Safety and Toxicity Committee 
It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal 
or external) are reported to the Case Comprehensive Cancer Center’s Data and Safety Toxicity 
Committee. This submission is simultaneous with their submission to the sponsor and/or other 
regulatory bodies.  
 
The sponsor-investigator is responsible for submitting an annual report to the DSTC as per 
CCCC Data and Safety Monitoring Plan. 
 
7.6 
Data and Safety Monitoring Plan (DSMP) 
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI guidelines.  
 
8.0 
PHARMACEUTICAL INFORMATION  
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 7.0.  
 
8.1 Nivolumab 
Name of agent: Nivolumab 
 
Nomenclature 
 
Research Name: 
BMS-936558 
Generic Name: 
Nivolumab 
 
Description of Nivolumab 
Nivolumab (also referred to as BMS-936558 or MDX1106) is a fully human monoclonal 
antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 
(PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a 
negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to 
its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the down-
regulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands 
promotes immune responses and antigen-specific T-cell responses to both foreign antigens as 
well as self-antigens. The clinical study product is a sterile solution for parenteral 
administration. 
 

 
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Drug Substance Chemistry 
 
Nivolumab is a soluble protein consisting of 4 polypeptide chains, which 
include 2 identical heavy chains and 2 identical light chains. Nivolumab has a molecular 
weight of 146,221 daltons. It is a clear to opalescent, colorless to pale yellow liquid, which 
may contain light (few) particulates. The clinical study product is a sterile solution for 
parenteral administration. 
 
 
 
 
 
 
Drug Product 
Please refer to Investigational Brochure in Appendix. 
Container/Closure 
Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five vials 
are provided in a carton. 
 
Storage and Handling of Pharmaceutical Form 
 
 Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.    
 As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents applying aseptic 
technique.  
 Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs.  
 
Use Time/Stability 
 

 
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Due to parameters surrounding the use time of Nivolumab, the time of preparation should be 
noted in the Pharmacy Source documents [accountability logs] or in study files as required for 
investigator sponsored research [FDA and GCP] 
 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must 
be completed within 24 hours of preparation. If not used immediately, the infusion solution 
may be stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-
46°F) and used within 4for up to 24 hours, and a maximum of 4 hours of the total 24 hours can 
be at room temperature (20°-25°C, 68°-77°F) and under room light. The maximum 4-hour 
period under room temperature and room light conditions for undiluted and diluted solutions of 
BMS-936558-01 injection in the IV bag should be inclusive of the includes the product 
administration period. 
 
Drug Preparation and Administration: 
 
1. Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution 
may have a pale-yellow color), or if there is foreign paticulate matter other than a few 
translucent-to-white, amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
2. Aseptically withdraw the required volume of nivolumab solution into a syringe, and 
dispense into an IV. bag.  If multiple vials are needed for a subject, it is important to use a 
separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. Do not 
enter into each vial more than once.  Do not administer study drug as an IV push or bolus 
injection 
3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent. 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] 
Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab. 
4. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
5. At the end of the infusion period, flush the line with a sufficient quantity of approved 
diluents. 
 

 
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Drug Accountability 
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of the study drug.  All study drugs must be accounted for, including study 
drug accidentally or deliberately destroyed.  Under no circumstances will the investigator allow 
the investigational drug to be used other than as directed by the protocol.  If appropriate, drug 
storage, drug dispensing, and drug accountability may be delegated to the pharmacy section of 
the investigative site.   
 
 
 
 
Drug Destruction 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and 
dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug. Drug destroyed on site will be documented in the study files.” 
 
8.2 Bevacizumab 
 
Form 
Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid 
concentrate for solution for intravenous (IV) infusion. Vials contain bevacizumab with 
phosphate, trehalose, polysorbate 20, and sterile water for injection (SWFI), USP. Vials 
contain no preservative and are suitable for single use only. This agent is commercially 
available and manufactured by Genentech. 
Storage and Stability 
According to guidelines specified in the package insert. 
Preparation  
According to guidelines specified in the package insert. 
Administration   
Bevacizumab is to be administered according to institutional standards. 
The dose of bevacizumab is 10 mg/kg IV for subjects on Arm A and 3 mg/kg for subjects on 
Arm B. Bevacizumab is administered on Days 1, 15 of each 4 week cycle. A window of +/- 3 

 
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day for bevacizumab dosing is acceptable but bevacizumab doses must be at least 12 days 
apart. 
Accountability 
The investigator or designated study personnel are responsible for maintaining accurate 
dispensing records of bevacizumab which are to include start time of infusion, stop time of 
infusion, total volume.  
 
 
 
 
 
 
 
9.0  
STUDY PARAMETERS AND CALENDAR  
9.1      Study Parameters 
 
9.1.1   Screening Evaluation   
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion. All evaluations must be completed < 14 days prior to administration of 
protocol therapy, except where otherwise noted.  
 
9.1.2   Treatment Period 
Enrolled subjects will randomize to Arm A (nivolumab + standard bevacizumab) and Arm B 
(nivolumab and low dose bevacizumab). Treatment is every 2 weeks and will continue until 
evidence of disease progression as determined by iRANO criteria, unacceptable toxicity, or 
death.   
In view of the Covid 19 crisis, all in person visits can be substituted for virtual visit. All 
nursing toxicity checks can be performed over the phone rather than in person. 
 

 
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9.2 Study Calendar    
 
 
           Table 9.2.1 Study Calendar: Assessments prior to, during, and after therapy (Both Arms A and B): 
Screening 
w/in 28 days unless  
otherwise indicated 
All Cycles – both odd 
and even 
Day 1 Week 1, then 
every 2 weeks (± 4 
days) – unless 
otherwise indicated 
Follow‐up #1 ‐ ᶻ
Follow‐up #2 ‐ ᵃᵃ  
Survival ‐ ᵇᵇ 
Informed Consent 
Xᵃ 
 
Inclusion/Exclusion 
Criteria 
Xᵇ 
Medical History 
X 
Tumor Tissue Availability 
Xᵈ˒ ʰ 
MGMT Status 
Xᶜ 
Physical & Neurological 
Exam 
X   (within 14 days) ˡ 
X (not required D1 Wk 
1) ˡ, cc 
X ˡ 
Vital Signs 
Xᶠ 
Xᶠ, cc 
Xᶠ 
Performance Status (KPS) 
Xᶢ 
Xᶰ, cc 
X 
Height and Weight 
Xᵉ 
Xᶰ 
X 
Adverse Event Assessment 
Xᶢ 
Continuously 
X 
Concomitant Medication 
Collection & Review 
 
Xᶢ 
 
X 
 
X 
Steroid Documentation & 
Xᶢ 
X 
X 

 
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Review
 
 
  
CBC w/ differential 
X ᶢ 
X ᵒ 
X 
CMP 
X ᶢ 
X ᵒ 
X 
LDH 
X ᶢ 
X ᵒ 
X 
Magnesium 
X ᶢ 
X ᵒ 
Amylase 
X ᶢ 
X ᵒ 
Lipase 
X ᶢ 
X ᵒ 
TSH 
X ᶢ 
X ᵒ˒ᵖ 
X 
FT4 
X ᶢ 
X ᵒ˒ᵖ 
FT3 
X ᶢ 
X ᵒ˒ᵖ 
HBsAg, HCV 
X ᶢ 
Cytokine/chemokine/PBMC  
Correlative Studies 
 
X ᶢ˒ ʰ 
 
X ʰ˒ ᶸ 
Urinalysis – dipstick 
X ᶢ 
X ʳ 
HCG – serum (WOCBP only) 
X ᶢ 
X s  
X 
12‐Lead EKG 
X  ᶢ 
X ᵗ 
X ᵗ 
 
Tumor Assessments 
 
X ᴵ 
 
X j,dd 
 
X ʸ 
NANO scale 
 
X ᵛ 
 

 
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Administer Study 
Treatment 
Within 3 working days of 
randomization:  
Nivolumab and 
Bevacizumab 
administered every 2 
weeks +/‐ 2days  
X bb 
Survival Status 
X ʷ 
 
a. Study allows for re-enrollment of a subject that has discontinued the study as a pre-treatment 
failure. 
b. Inclusion/Exclusion criteria should be assessed at screening and confirmed prior to randomization. 
c. If available 
d. Archival or fresh tissue taken at any point prior to study treatment. Up to 10 unstained slides of 5 
microns thickness or block tissue will be required. 
e. Weight (Day 1 Wk 1, then every 4 weeks); height (only at baseline) 
f. 
BP, HR, temperature and respiratory rate 
g. Within 14 days prior to randomization 
h. See Appendix 8 
i. 
Within 21 days of randomization 
j. 
Every 8 weeks (+/- 1 week) 
k. Perform every 28 days on D1 of each cycle (+/- 4 days) 
l. 
Includes cardiovascular, neurological and abdominal exams; D1 of each cycle 
m. Within 72 hours prior to first dose 
n. Day 1 of each cycle 
o. Complete prior to each dose through Wk 21, then every 4 weeks (Day 1 of each cycle). 
p. After C1D1 – TSH, FT3, FT4 are done every 8 weeks (+/- 1 week) 
q. blank  
r. 
Dipstick within 72 hours prior to each bevacizumab dose. Subjects with 4+ (300-1000) proteinuria 
readings must undergo further assessment with a 24 hour urine collection prior to being dosed. 
s. Every 4 weeks (+/- 1 week) 
t. 
As clinically indicated 
u. Obtain at week 4, week 8, and then at every MRI visit until progression 
v. Completed by study physician prior to dosing Wk 1 Day 1, and then with each MRI (must be done 
before MRI is reviewed with the subject) 
w. Repeat labs at follow-up visit #2 if study drug related toxicities persist 
x. May be obtained through a phone call or clinic visit 
y. Only for subjects who did not progress while on study therapy, including subjects who start 
subsequent anticancer therapy. Tumor assessments will not be collected for subjects who are lost 
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z. Subjects must be followed for at least 100 days after the last dose of study therapy.  Follow-up visit 
#1 occurs approximately 35 days (+/- 1 week) after last dose or coinciding with the date of 
discontinuation so long as the date of discontinuation is greater than 35 days after last dose. 
aa. Follow-up visit #2 occurs approximately 80 days (+/- 1 week) after F/U #1 
bb. +/- 2 days 
cc. In view of covid-19 crisis, virtual visits will be allowed and the need for physical exam as long as 
patient is asymptomatic will be waived.  
 
dd. Patients who remain on study after 3 years , MRIs to be done every 12 weeks (+/- 1 week) 
 
Survival visits/calls = every 3 months from 
 
 
 
 
 
 
10.0 MEASUREMENT OF EFFECT  
  
10.1 RANO Criteria 
Definitions of Tumor Response will be based on RANO criteria. There is an exploratory 
analysis using the iRANO criteria.65 Please refer to Appendix 2. 

 
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11.0 
DATA REPORTING / REGULATORY CONSIDERATIONS  
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting  
The Advarra EDC™ and OnCore™ databases will be utilized, as required by the Case 
Comprehensive Cancer Center and Cleveland Clinic, to provide data collection for both accrual 
entry and trial data management. Advarra EDC and OnCore™ are Clinical Trials Management 
Systems housed on secure servers. Access to data through Advarra EDC and OnCore™ is 
restricted by user accounts and assigned roles. Once logged into the Advarra EDC or 
OnCore™ system with a user ID and password, Advarra EDC™ and OnCore™ define roles 
for each user which limits access to appropriate data. Applications for user accounts can be 
obtained by contacting the OnCore™ Administrator at OnCore-registration@case.edu for 
OnCore™ access, and taussigoncore@ccf.org for Advarra EDC™ access. 
  
Advarra EDC™ is designed with the capability for study setup, activation, tracking, reporting, 
data monitoring and review, and eligibility verification.  When properly utilized, Advarra 
EDC™ is 21 CFR 11 compliant.  This study will utilize electronic Case Report Form 
completion in the Advarra EDC™ database. A calendar of events and required forms are 
available in Advarra EDC™. 
 
11.2 
Regulatory Considerations 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
11.2.1 Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. 
The Principal Investigator will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, possible risks and benefits of the study as well 
as the subject’s financial responsibility. Subjects must also be notified that they are free to 
discontinue from the study at any time. The subject should be given the opportunity to ask 
questions and be allowed time to consider the information provided.  
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 

 
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Informed Consent Form must be given to the subject. Additionally, documentation of the 
consenting process should be located in the research chart. 
11.2.2 Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the sponsor and/or allow 
the sponsor, a regulatory authority, or Institutional Review Board access to subject’s medical 
information that includes all hospital records relevant to the study, including subjects’ medical 
history.  
 
11.2.3  Retention of records 
The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention 
of all documentation of adverse events, records of study drug receipt and dispensation, and all 
IRB correspondence for as long as needed to comply with local, national and international 
regulations. No records will be destroyed until the Principal Investigator confirms destruction 
is permitted.  
 
11.2.4  Audits and inspections  
Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or 
inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the 
International Conference on Harmonization (ICH), and any applicable regulatory requirements.  
For multi-center studies, participating sites must inform the sponsor-investigator of pending 
audits.  
 
11.2.5 Data Safety and Monitoring Plan  
This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and 
Safety Monitoring Plan in accordance with NCI regulations.  
 
 
12.0 STATISTICAL CONSIDERATIONS  
 
STATISTICAL CONSIDERATIONS 
 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 

 
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statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, along with an explanation as to when and why they 
occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory 
analyses will be clearly identified in the CSR. No separate Statistical Analysis Plan (SAP) for 
the primary, secondary and exploratory endpoints will be issued for this study. 

 
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12.1 Statistical Analysis Plan Summary 
 
This section contains a brief summary of the statistical analyses for this trial. This trial includes 
randomization of accrual to two experimental treatment arms: nivolumab plus bevacizumab at 
standard dosing (Arm A); and nivolumab plus bevacizumab at reduced dosing (Arm B). The 
outcome of each treatment arm will be assessed separately relative to appropriate historical 
controls.  
The study consists of two arms to evaluate the efficacy and tolerability and safety profile of 
nivolumab in combination with reduced or standard dose bevacizumab in subjects with 
recurrent glioblastoma (in first recurrence). For this purpose, 90 eligible and evaluable subjects 
will be randomized in a 1:1 ratio to arm A (nivolumab plus standard bevacizumab) or arm B 
(nivolumab plus reduced dose bevacizumab). To facilitate robust data for assessing all 
objectives and generating future hypotheses, stratified randomization will be implemented in 
REDCap. The design will balance treatment assignments based on four stratification factors 
known to be prognostic for clinical outcomes. The stratification factors include: age (<=65 
versus > 65), KPS (>=800 versus <800), Methylation Status (Not Methylated versus 
Methylated), Surgery Type (Biopsy Only, Partial Resection, Complete Resection/Near 
Complete Resection). 
 
 
The primary and secondary goals of the trial are to evaluate the safety and efficacy of the two 
therapies and to obtain a preliminary assessment of whether or not they differ with respect to 
outcome.  
 
The total sample size of 90 eligible and evaluable subjects randomized 1:1 to the two therapies 
is recommended to provide adequate statistical power to describe the efficacy and toxicity 
profiles of the two treatment arms.  
 
Using the BELOB trial, EORTC 26101 trial outcomes as historical benchmarks, the primary 
measure of efficacy for the current study will be the 12 month overall survival rate (OS-
12)47,48.  OS-12 was approximately 45% in the BELOB and EORTC 26101 trials. The one-
sample log-rank test will be applied to outcomes observed for each arm individually to test the 
hypothesis that OS has been improved beyond the null 12-month survival rate of 45%. With 
N=45 subjects per arm, a one-sided test provides power=0.80 to detect survival rate of 58% at 
12-months following treatment at the 0.10 significance level. Statistical calculations were 
implemented with PASS version 15.0.5. 

 
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 Although each treatment arm will be evaluated for efficacy independently they will also be 
compared in order to get a preliminary read on whether there is a signal that one may be 
superior to the other. The sample size of N=45 subjects per treatment arm provides power=0.80 
to detect a hazard ratio of 0.498 between the two study arms using a two-sided stratified log-
rank test. Statistical calculations were implemented with PASS version 15.0.5.  
With 45 subjects per arm the risk that a particular type and/or grade of adverse event will occur 
in a particular arm will be estimable using an exact 95% confidence interval that has a 
maximum half-width of 15%. For example, if 5 adverse events are observed (11%) the 
corresponding 95% confidence interval will be 4%-24%; if 20 are observed (44%) it will be 
30%-60%.  In addition, the likelihood of observing at least one adverse event of a particular 
type and/or grade is >90% even if the risk of such an event is only 5%.  Although excessive 
toxicity is not expected, adverse events will be monitored continuously and the following table 
will be used as a guide for whether or not a formal review, possibly leading to early 
termination, should be considered. 
 
                                                                                           Cumulative Likelihood of 
Exceeding  
                            Consider Review if the Cumulative                  the AE Threshold if the 
                               No. Tx-Related Grade >3 AEs                            Risk of an Event is  
   No. Subjects                           Exceeds                             10%      20%      30%     40%     
50% 
 
1-10    
  4    
<1%    
3%    
15%    37%   
 
62% 
 
11-20    
  7  
<1%    
5%    
27%     62%  
 
88% 
 
21-30   10  
<1%    6%   
36%   76%  96% 
 
 
 
 
 

 
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12.1.1 Efficacy Analysis 
The primary and key secondary endpoints, primary analysis population, and statistical methods 
that will be employed for the efficacy analyses are discussed in detail in the following sections.  
 
The primary hypothesis of efficacy will be evaluated independently in each cohort. 
 
12.1.2 Safety Analysis 
Adverse events will be graded according to Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. All subjects who receive any amount of nivolumab will be evaluable for 
toxicity. The All-Subjects-as-Treated population will be employed for safety analyses. Immune 
related adverse experiences are pre-specified as Events of Clinical Interest (Section 7.6.2).  
12.2 Statistical Analysis Plan 
 
12.2.1 Responsibility for Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
study responsible biostatistician. 
 
This trial is being conducted as an open-label study, i.e., subjects, investigators, and 
SPONSOR personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned. 
 
12.2.1 Efficacy Endpoints 
All subjects within each arm that have been randomized will serve as the primary population 
for the analysis of the efficacy data in this study. Two supportive analyses of the primary and 
selected secondary efficacy endpoints will also be conducted. The first supportive analysis will 
include all subjects in the primary population for analysis who have a post baseline scan OR 
discontinue the trial due to progressive disease/drug related AE. The second analysis will be 
conducted using the intention to treat (ITT) population, defined as all randomized subjects. 
Subjects will be included in the arm to which they are randomized for the analysis of efficacy 
data. 
 
Efficacy endpoints that will be evaluated for are listed below, followed by the descriptions of 
the derivations of selected endpoints. 
 

 
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The primary efficacy endpoint for both cohorts is OS-12, defined as the proportion of subjects 
in the analysis population who remain alive for at least twelve months following initiation of 
study therapy. Response for the primary analysis will be determined by the investigator 
assessment, and a confirmation assessment is required per RANO.74  
 
Secondary efficacy endpoints include: (1) overall survival (OS); (2) ORR defined as the 
proportion of subjects in the analysis population who have complete response (CR) or partial 
response (PR) using RANO criteria as well as duration of response, defined as time from first 
RANO response to disease progression in subjects who achieve a PR or better; (3) progression-
free survival (PFS), defined as the time from allocation to the first documented disease 
progression according to RANO or death due to any cause, whichever occurs first; and (4) 
progression-free survival at six months defined as the proportion of subjects in the analysis 
population who remain progression-free for at least six months following initiation of study 
therapy. Analyses of ORR, duration of response, and PFS will be conducted using RANO 
criteria, in which a confirmation assessment of disease progression must be obtained at least 4 
weeks after the initial disease assessment indicating progressive disease. 
 
Nominal p –values may be computed for efficacy analyses as a measure of strength of 
association between the endpoint and the treatment effect rather than formal tests of 
hypotheses. Unless otherwise stated, all statistical tests will be conducted at α=0.05 (2-sided) 
level. 
 
Efficacy will be evaluated separately in each cohort. For PFS endpoint, Kaplan-Meier (KM) 
curves and median estimates from the KM curves will be provided as appropriate. Subjects 
without efficacy evaluation data or without survival data will be censored at Day 1. 
Participants without measurable disease will not be included in the analysis of ORR. 
 
12.2.2 Safety Endpoints 
All subjects who receive at least one dose of study treatment will be included in the safety data 
analysis. At least one laboratory or vital sign measurement obtained subsequent to at least one 
dose of study treatment is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required. 
 
Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be 
presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03 by treatment group. All on-study AEs, treatment-related AEs, 
SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.03 
criteria by system organ class and preferred term. On-study lab parameters including 

 
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hematology, chemistry, liver function, and renal function will be summarized using worst 
grade NCI CTCAE v 4.03 criteria.  
 
Adverse experiences (specific terms as well as system organ class terms) and predefined limits 
of change in laboratory, and vital sign parameters that are not pre-specified as events of interest 
will be summarized with descriptive statistics (counts, percentage, mean, standard deviation, 
etc.). 
 
Continuous measures such as changes from baseline in laboratory, and vital signs parameters 
that are not pre-specified as events of interest will be summarized using descriptive statistics 
(mean, standard deviation, etc.) for baseline, on-treatment, and change from baseline values. 
 
12.2.3 Analysis of Demographics and Baseline Characteristics 
Baseline characteristics will be assessed by the use of tables and/or graphs for each cohort 
separately. No statistical hypothesis tests will be performed on these characteristics. The 
number and percentage of subjects screened, randomized, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed. Demographic variables 
(e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables. 
 
12.2.4 Analysis of Immunocorrelative Data 
Longitudinal analyses of PBMC immune response kinetics and circulating cytokines to 
nivolumab and bevacizumab therapy will be presented graphically and descriptively at each 
time point.  Changes in the magnitude of the response relative to pre-treatment after nivolumab 
plus bevacizumab therapy will be summarized descriptively.  Changes in response between 
pre-treatment and prior to initiation of cycle 3 of nivolumab plus bevacizumab therapy will be 
assessed using the Wilcoxon signed-rank test.  
 
12.2.5 Power and Sample Size 
The primary and secondary goals of the trial are to evaluate the safety and efficacy of the two 
therapies and to obtain a preliminary assessment of whether or not they differ with respect to 
outcome.  
 
The total sample size of 90 eligible and evaluable subjects randomized 1:1 to the two therapies 
is recommended to provide good statistical power to describe the efficacy and toxicity profiles 
of the two treatment arms.  
 

 
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Using the BELOB trial, EORTC 26101 trial outcomes as historical benchmarks, the primary 
measure of efficacy for the current study will be the 12 month overall survival rate (OS-12).  
OS-12 was approximately 45% in the BELOB and EORTC 26101 trials.  
 
The one-sample log-rank test will be applied to outcomes observed for each arm individually 
to test the hypothesis that OS has been improved beyond the null 12-month survival rate of 
45%. With N=45 subjects per arm, a one-sided test provides power=0.80 to detect survival rate 
of 58% at 12-months following treatment at the 0.10 significance level. Statistical calculations 
were implemented with PASS version 15.0.5. 
 
Although each treatment arm will be evaluated for efficacy independently they will also be 
compared in order to get a preliminary read on whether there is a signal that one may be 
superior to the other. The sample size of N=45 subjects per treatment arm provides power=0.80 
to detect a hazard ratio of 0.498 between the two study arms using a two-sided stratified log-
rank test. Statistical calculations were implemented with PASS version 15.0.5. 
 
 
With 45 subjects per arm, the risk that a particular type and/or grade of adverse event will 
occur in a particular arm will be estimable using an exact 95% confidence interval that has a 
maximum half-width of 15%. For example, if 5 adverse events are observed (11%) the 
corresponding 95% confidence interval will be 4%-24%; if 20 are observed (44%) it will be 
30%-60%.  In addition, the likelihood of observing at least one adverse event of a particular 
type and/or grade is >90% even if the risk of such an event is only 5%.  Although excessive 
toxicity is not expected, adverse events will be monitored continuously and the following table 
will be used as a guide for whether or not a formal review, possibly leading to early 
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                                                                                           Cumulative Likelihood of 
Exceeding  
                            Consider Review if the Cumulative                  the AE Threshold if the 
                               No. Tx-Related Grade >3 AEs                            Risk of an Event is  
   No. Subjects                           Exceeds                             10%      20%      30%     40%     
50% 
 
1-10    
  4    
<1%    
3%    
15%    37%   
 
62% 
 
11-20    
  7  
<1%    
5%    
27%     62%  
 
88% 
 
21-30   
10  
<1%    
6%   
36%   76% 
 
96% 
 
As can be seen the likelihood is small (<1% to 6%) of instituting a formal review if the level of 
serious toxicity is low (<20%), moderate to high (15-76%) if significant toxicity is similar to 
the >26% grade 3/4 toxicity rate seen in subjects treated with single agent bevacizumab on the 
BELOB trial. or the 39% treatment related SAE rate seen in subjects treated with 
bevacizumab+lomustine in the EORTC 26101 trialneed to add reference no., and high (62-96%) if the 
risk of serious toxicity is >50%. 
 
 
13.0 Ethical Considerations 
13.1 Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by 
the International Conference on Harmonisation (ICH) and in accordance with the ethical 
principles underlying European Union Directive 2001/20/EC and the United States Code of 
Federal Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any 
amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation 
of the study.  
 

 
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All potential serious breaches must be reported to BMS immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks. 
This study will not use the services of study personnel where sanctions have been invoked or 
where there has been scientific misconduct or fraud (e.g., loss of medical licensure, 
debarment). 
 
13.2 
Institutional Review Board/Independent Ethics Committee 
 
Before study initiation, the investigator must have a written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., 
advertisements), and any other written information to be provided to subjects.  
The investigator or BMS should also provide the IRB/IEC with a copy of the Investigator 
Brochure or product labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other 
information (e.g., expedited safety reports, amendments, and administrative letters) according 
to regulatory requirements or institution procedures. 
 
Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives 
are clearly and fully informed about the purpose, potential risks, and other critical issues 
regarding clinical studies in which the subject volunteers to participate.  
      BMS will provide the investigator with an appropriate (i.e., Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki. 
Investigators must: 
1) Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. 
The language must be non-technical and easily understood. 

 
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2) Allow time necessary for subject or subject's legally acceptable representative to 
inquire about the details of the study. 
3) Obtain an informed consent signed and personally dated by the subject or the subject's 
legally acceptable representative and by the person who conducted the informed 
consent discussion. 
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information. 
5) If informed consent is initially given by a subject’s legally acceptable representative or 
legal guardian, and the subject subsequently becomes capable of making and 
communicating his or her informed consent during the study, consent must additionally 
be obtained from the subject. 
6) Revise the informed consent whenever important new information becomes available 
that is relevant to the subject's consent. The investigator, or a person designated by the 
investigator, should fully inform the subject or the subject's legally acceptable 
representative or legal guardian, of all pertinent aspects of the study and of any new 
information relevant to the subject's willingness to continue participation in the study. 
This communication should be documented. 
 
The confidentiality of records that could identify subjects must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF 
and, in the US, the subjects’ signed HIPAA Authorization. 
 
The consent form must also include a statement that BMS and regulatory authorities have 
direct access to subject records. 
 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) 
may only be enrolled in the study with the consent of a legally acceptable representative. The 
subject must also be informed about the nature of the study to the extent compatible with his or 
her understanding, and should this subject become capable, he or she should personally sign 
and date the consent form as soon as possible. The explicit wish of a subject who is unable to 
give his or her written consent, but who is capable of forming an opinion and assessing 
information to refuse participation in or to be withdrawn from, the clinical study at any time 
should be considered by the investigator. 
 
The rights, safety, and well-being of the study subjects are the most important considerations 
and should prevail over interests of science and society. 
 

 
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28. 
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DeLay M, Jahangiri A, Carbonell WS, et al. Microarray analysis verifies two distinct 
phenotypes of glioblastomas resistant to antiangiogenic therapy. Clinical cancer research : an 
official journal of the American Association for Cancer Research 2012;18:2930-42. 
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a mathematical model. Cancer Res 2007;67:2729-35. 

 
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42. 
Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic 
therapy. Science 2005;307:58-62. 
43. 
Sorensen AG, Emblem KE, Polaskova P, et al. Increased survival of glioblastoma 
patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 
2012;72:402-7. 
44. 
Emblem KE, Mouridsen K, Bjornerud A, et al. Vessel architectural imaging identifies 
cancer patient responders to anti-angiogenic therapy. Nature medicine 2013;19:1178-83. 
45. 
Huang Y, Goel S, Duda D, Fukumura D, Jain R. Vascular normalization as an 
emerging strategy to enhance cancer immunotherapy. Cancer research 2013;73:2943-8. 
46. 
Lorgis V, Maura G, Coppa G, Hassani K, al. e. Relation between bevacizumab dose 
intensity and high-grade glioma survival: a retrospective study in two large cohorts. Journal of 
neuro-oncology 2012;107:351-8. 
47. 
Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or 
lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent 
glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 2014;15:943-
53. 
48. 
Wick W, Brandes AA, Gorlia T, et al. EORTC 26101 phase III trial exploring the 
combination of bevacizumab and lomustine in patients with first progression of a glioblastoma. 
ASCO Meeting Abstracts 2016;34:2001. 
49. 
Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial 
growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer 
Res 1997;57:4593-9. 
50. 
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced 
angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841-4. 
51. 
Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer 
angiogenesis in vivo: implications from intravital microscopy of combination treatments with 
an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 
1999;19:4203-14. 
52. 
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting 
both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin 
Invest 2003;111:1287-95. 
53. 
Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer 
carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br 
J Cancer 2001;85:584-9. 
54. 
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, 
fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. 
55. 
Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with 
oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic 
colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. Journal 

 
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of clinical oncology : official journal of the American Society of Clinical Oncology 
2007;25:1539-44. 
56. 
Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab 
for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. 
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Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for 
treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 
2007;370:2103-11. 
58. 
Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone 
for metastatic breast cancer. N Engl J Med 2007;357:2666-76. 
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by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology 2009;27:740-
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Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with 
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Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent 
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Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of 
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cancer patient responders to anti-angiogenic therapy. Nat Med 2013. 
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Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neuro-
oncology: a report of the RANO working group. Lancet Oncol 2015;16:e534-42. 
66. 
Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and 
bevacizumab. N Engl J Med 2006;354:980-2; discussion -2. 
67. 
Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing 
bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with 
metastatic colorectal cancer. Journal of clinical oncology : official journal of the American 
Society of Clinical Oncology 2003;21:60-5. 
68. 
Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with 
the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 
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69. 
Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in 
patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer 
Inst 2007;99:1232-9. 
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treated with bevacizumab: a meta-analysis. Lancet Oncol 2009;10:559-68. 
71. 
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pathway. Nature reviews Clinical oncology 2009;6:465-77. 
72. 
Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing 
complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 
2005;91:173-80. 
73. 
Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine 
compared with bevacizumab plus capecitabine in patients with previously treated metastatic 
breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology 2005;23:792-9. 
74. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 2010;28:1963-72. 
 
 
15.0 APPENDICES 
APPENDIX 1: KARNOFSKY AND ECOG PERFORMANCE STATUS 
SCALES 
Status 
Karnofsky 
Grade 
ECOG 
Normal, no complaints 
100 
0 
Fully active, able to carry on all pre-disease 
performance without restriction 
Able to carry on normal activities. 
Minor signs or symptoms of disease 
90 
1 
Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a 
light or sedentary nature, e.g., light house work, 
office work 
Normal activity with effort 
80 
Care for self. Unable to carry on normal 
activity or to do active work 
70 
2 
Ambulatory and capable of all self-care but 
unable to carry out any work activities. Up and 
about more than 50% of waking hours 
Requires occasional assistance, but able 
60 

 
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to care for most of his needs 
Requires considerable assistance and 
frequent medical care 
50 
3 
Ambulatory and capable of all self-care but 
unable to carry out any work activities. 
Up and about more than 50% of waking hours 
Disabled. Requires special care and 
assistance 
40 
Severely disabled. Hospitalization 
indicated though death non-imminent 
30 
4 
Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair 
Very sick. Hospitalization necessary. 
Active supportive treatment necessary 
20 
Moribund 
10 
Dead 
0 
 
 

 
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APPENDIX 2: IMMUNOTHERAPY RESPONSE ASSESSMENT IN 
NEURO-ONCOLOGY (IRANO) CRITERIA 
Tumor response should be assessed every 8 weeks (+/- 1 week) for subjects treated with 
immunotherapy using modified RANO criteria65  as outlined below. Clinicians may repeat 
response assessment more frequently as clinically indicated. 
 
Anti-Tumor Effect Definitions 
 
Evaluable for toxicity. All subjects who receive at least one dose of immunotherapy treatment 
will be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response. Only those subjects who have measurable disease present at 
baseline (recommend obtaining within 14 days of cycle 1, day 1) scan and have 
received at least one dose of immunotherapy will be considered evaluable for response. 
These subjects will have their response classified according to the definitions stated 
below. (Note: Subjects who exhibit objective disease progression or die prior to the end 
of cycle 1 will also be considered evaluable.) 
 
Measurable disease. For contrast-enhancing tumors, measurable disease is defined as the bi-
dimensionally, contrast-enhancing, measurable lesions with clearly defined margins by 
CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 slices which are at 
least 5 mm apart with 0 mm skip. For non-contrast-enhancing tumors, measurable 
disease is defined as the T2 or FLAIR lesions with a minimal diameter of 1 cm, and 
visible on 2 slices which are at least 5 mm apart with 0 mm skip. Measurement of 
tumor around a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 
mm. If there are too many measurable lesions to measure at each evaluation, the 
investigator must choose the largest two to be followed.  The remaining lesions will be 
considered non-measureable for the purpose of objective response determination.  
Unless progression is observed, objective response can only be determined when all 
measurable and non-measurable lesions are assessed. 
 
Non-measurable evaluable disease. Unidimensionally measurable lesions, masses with margins 
not clearly defined, and/or lesions with maximal diameter < 1cm.  
 
 
 

 
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Response/Progression Categories 
 
Complete response (CR). All of the following criteria must be met:   
a) Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks.  In the absence of a confirming scan 4 weeks later, this 
scan will be considered only stable disease. 
b) No new lesions. 
c) All measurable and non-measurable lesions must be assessed using the same techniques 
as baseline. 
d) Subjects must be on no steroids or on physiologic replacement doses only. 
e) For enhancing tumors: Stable or improved non-enhancing (T2/FLAIR) lesions 
f) Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related 
Subjects with residual non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
Partial response (PR).  All of the following criteria must be met: 
a) Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable lesions sustained for at least 4 weeks. In the 
absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease.  
 
b) No progression of non-measurable disease. 
c) No new lesions.  
d) All measurable and non-measurable lesions must be assessed using the same techniques 
as baseline.  
e) The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan. 
f) For enhancing tumors: Stable or improved non-enhancing (T2/FLAIR) lesions on same 
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g) Stable or improved, for clinical signs and symptoms present at baseline and recorded to 
be disease related clinically.  
Subjects with non-measurable disease cannot have a partial response. The best response 
possible is stable disease. 
Progressive disease (PD). Any of the following criterion must be met: 
a) > 25% increase in sum of the products of perpendicular diameters of measurable lesions 
(over best response [smallest tumor size] or baseline if no decrease) on stable or 
increasing doses of corticosteroids 
b) Any new measurable lesion that when added to the change in initial tumor(s) exceeds a 
25% increase in cross-sectional area. 
c) Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the Karnofsky Performance Score 
(KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a 
decline in KPS from any baseline to 50 or less, for at least 7 days, be considered 
neurologic deterioration, unless attributable to co-morbid events or changes in 
corticosteroid dose. 
d) Failure to return for evaluation due to death or deteriorating condition 
      Classification of progressive disease may be deferred for up to three months for 
subjects with initial radiographic findings consistent with progressive disease (criteria a 
and b above) as detailed below. However, if follow-up imaging after three months 
confirms progression or if the patient experiences significant clinical decline at any 
time, the date of actual progression will be back-dated to the first date that the patient 
met criteria for progression and such subjects should discontinue further 
immunotherapy. 
Stable disease (SD). All of the following criteria must be met: 
a) Does not qualify for CR, PR, or progression. 
b) All measurable and non-measurable sites must be assessed using the same techniques 
as baseline. 
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Unknown response status. Progressive disease has not been documented and one or more 
measurable or non-measurable lesions have not been assessed. 
 
Algorithm for Treatment Decision Making for Subjects with Radiographic Progression 
Figure 2. iRANO algorithm for treatment decision making for radiologic progression
Radiologic Progression
Significant clinical decline unrelated to co‐morbid event or concurrent medication?
Yes
Patient classified as PD
Discontinue current 
immunotherapy regimen
No
Duration on current immunotherapy regimen
Continue current  immunotherapy regimen for 3 months 
as long as no significant clinical decline unrelated to co‐morbid 
event or concurrent medication
> 6 months
≤ 6 months
Repeat imaging 3 months after initial imaging PD
CR, PR or SD
Confirms PD
Patient classified as PD 
with date of progression back‐dated to 
date of initial radiographic PD; 
Patient discontinues current 
immunotherapy regimen
Continue current 
immunotherapy regimen
 
APPENDIX 3: SAMPLE OF DRUG ORDERING AND PHARMACY 
REFERENCE MATERIAL 
 
Nivolumab (BMS-936558) Pharmacy Reference Material 
 Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial.  Ten or five 
vials are provided in a carton. 
 
Initial Orders  

 
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 Following submission and approval of the required regulatory documents, a supply of 
nivolumab may be ordered from by completing a Drug Request Form provided by BMS for 
this specific trial. The first request may take place upon screening of the first patient  
 The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug 
from BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient 
specific. All drug product will be shipped by courier in a temperature-controlled container. 
It is possible that sites may have more than one nivolumab clinical study ongoing at the 
same time. It is imperative that only drug product designated for this protocol number be 
used for this study. 
 Pharmacy supplies not provided by BMS:  Empty IV bags/containers, approved diluents,  
In-line filters and infusion tubing 
Re-Supply 
 Drug re-supply request form should be submitted electronically business days before the 
expected delivery date.  Deliveries will be made Tuesday through Friday. 
 When assessing need for resupply, institutions should keep in mind the number of vials 
used per treatment dose, and that shipments may take 14 business days from receipt of 
request. Drug is not patient-specific. Be sure to check with your pharmacy regarding 
existing investigational stock to assure optimal use of drug on hand. 
Drug Excursions 
 Drug  excursions should be reported immediately to BMS on the form provided with the 
study-specific drug order form 

 
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Please refer to the most recent version of the Investigator Brochure for additional 
information. 
 
Storage Conditions & Handling: 
 Store at 2-8°C (36-46°F), protect from light, freezing, and shaking. 
 If any temperature excursions are encountered during storage, please report these to BMS 
for assessment via the Temperature Excursion Response Form.    
 As with all injectable drugs, care should be taken when handling and preparing nivolumab. 
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet 
using standard precautions for the safe handling of intravenous agents applying aseptic 
technique.  
 Partially used vials should be disposed at the site following procedures for the disposal of 
anticancer drugs.  
 
After final drug reconciliation, unused nivolumab vials should be disposed at the site following 
procedures for the disposal of anticancer drugs. For further information, please either discuss 
with your BMS CSR&O protocol manager or refer to your site IP Destruction policies and 
procedures  
 
Use Time/Stability: Please refer to section 3.2.3 of the current Investigator Brochure. Due to 
parameters surrounding the use time of Nivolumab, the time of preparation should be noted in 
the Pharmacy Source documents [accountability logs] or in study files as required for 
investigator sponsored research [FDA and GCP] 
 
The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must 
be completed within 24 hours of preparation. If not used immediately, the infusion solution 
may be stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°-
46°F) and used within 4for up to 24 hours, and a maximum of 4 hours of the total 24 hours can 
be at room temperature (20°-25°C, 68°-77°F) and under room light. The maximum 4-hour 
period under room temperature and room light conditions for undiluted and diluted solutions of 
BMS-936558-01 injection in the IV bag should be inclusive of the includes the product 
administration period. 
 
 

 
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Preparation and Administration: 
 
6. Visually inspect the drug product solution for particulate matter and discoloration prior to 
administration.  Discard if solution is cloudy, if there is pronounced discoloration (solution 
may have a pale-yellow color), or if there is foreign paticulate matter other than a few 
translucent-to-white, amorphous particles. 
Note: Mix by gently inverting several times.  Do not shake. 
7. Aseptically withdraw the required volume of nivolumab solution into a syringe, and 
dispense into an IV. bag.  If multiple vials are needed for a subject, it is important to use a 
separate sterile syringe and needle for each vial to prevent problems such as dulling of 
needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. Do not 
enter into each vial more than once.  Do not administer study drug as an IV push or bolus 
injection 
8. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose 
Injection solution. It is acceptable to add nivolumab solution from the vials into an 
appropriate pre-filled bag of diluent. 
Note: Nivolumab infusion concentration must be at or above the minimum allowable 
concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] 
Note: It is not recommended that so-called “channel” or tube systems are used to transport 
prepared infusions of nivolumab. 
9. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 
10. At the end of the infusion period, flush the line with a sufficient quantity of approved 
diluents.

 
 
 
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APPENDIX 4: ADVERSE EVENT REPORTING 
 All Serious Adverse Events (SAEs) that occur following the subject’s written 
consent to participate in the study through 100 days of discontinuation of dosing 
must be reported to BMS Worldwide Safety. 
 If the BMS safety address is not included in the protocol document (e.g. 
multicenter studies where events are reported centrally), the procedure for safety 
reporting must be reviewed/approved by the BMS Protocol Manager.  Procedures 
for such reporting must be reviewed and approved by BMS prior to study 
activation. 
 The BMS SAE form should be used to report SAEs.  If the BMS form cannot be 
used, another acceptable form (i.e. CIOMS or Medwatch) must be reviewed and 
approved by BMS.  The BMS protocol ID number must be included on whatever 
form is submitted by the Sponsor/Investigator. 
 Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, are collected, including those thought 
to be associated with protocol-specified procedures. The investigator should 
report any SAE occurring after these time periods that is believed to be related to 
study drug or protocol-specified procedure.  
  
 In accordance with local regulations, BMS will notify investigators of all reported 
SAEs that are suspected (related to the investigational product) and unexpected 
(i.e., not previously described in the IB). In the European Union (EU), an event 
meeting these criteria is termed a Suspected, Unexpected Serious Adverse 
Reaction (SUSAR). Investigator notification of these events will be in the form of 
an expedited safety report (ESR).  
o Other important findings which may be reported by the as an ESR include: 
increased frequency of a clinically significant expected SAE, an SAE 
considered associated with study procedures that could modify the 
conduct of the study, lack of efficacy that poses significant hazard to study 
subjects, clinically significant safety finding from a nonclinical (e.g., 
animal) study, important safety recommendations from a study data 
monitoring committee, or sponsor decision to end or temporarily halt a 
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o Upon receiving an ESR from BMS, the investigator must review and 
retain the ESR with the IB. Where required by local regulations or when 
there is a central IRB/IEC for the study, the sponsor will submit the ESR 
to the appropriate IRB/IEC. The investigator and IRB/IEC will determine 
if the informed consent requires revision. The investigator should also 
comply with the IRB/IEC procedures for reporting any other safety 
information.  
o In addition, suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health 
authorities in all concerned countries according to local regulations (either 
as expedited and/or in aggregate reports). 
Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
within 100 days of discontinuation of dosing.  
All SAEs must be collected that occur during the screening period. If applicable, SAEs 
must be collected that relate to any protocol-specified procedure (e.g., a follow-up skin 
biopsy).  The investigator should report any SAE that occurs after these time periods that 
is believed to be related to study drug or protocol-specified procedure.  
SAEs, whether related or not related to study drug, and pregnancies must be reported to 
BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies 
on a Pregnancy Surveillance Form. 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
the BMS (or designee) using the same procedure used for transmitting the initial SAE 
report.  
All SAEs should be followed to resolution or stabilization. 
For studies conducted under an Investigator IND in the US include the following: 
For studies conducted under an Investigator IND in the US, any event that is both serious 
and unexpected must be reported to the Food and Drug Administration (FDA) as soon as 
possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all 

 
 
 
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other SAEs) after the investigator’s or institution’s initial receipt of the information. BMS 
will be provided with a simultaneous copy of all adverse events filed with the FDA.  
SAEs should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
 
An SAE report should be completed for any event where doubt exists regarding 
its seriousness.  
 
For studies with long-term follow-up periods in which safety data are being 
reported, include the timing of SAE collection in the protocol. 
 
If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of previous 
therapy or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to BMS using the same procedure used for transmitting the initial SAE 
report. All SAEs should be followed to resolution or stabilization.  All SAEs should 
be followed to resolution or stabilization. 
DEFINITIONS 
The protocol must include a definition for Serious Adverse Events (SAE)  
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  

 
 
 
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 results in death 
 is life-threatening (defined as an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe) 
 requires 
inpatient 
hospitalization 
or 
causes 
prolongation 
of 
existing 
hospitalization (see NOTE below) 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect  
 is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.)  
 Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
 Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) 
via the study drug is an SAE.  
 Although pregnancy, overdose, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs. 
NOTE: (PI- determines if this information should be included. This is provided as 
supplemental information that is included in BMS-sponsored trials) 
The following hospitalizations are not considered SAEs in BMS clinical studies:  
 a visit to the emergency room or other hospital department < 24 hours, that 
does not result in admission (unless considered an important medical or life-
threatening event) 
 elective surgery, planned prior to signing consent 
 admissions as per protocol for a planned medical/surgical procedure 
 routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 
 Medical/surgical admission other than to remedy ill health and planned prior 
to entry into the study. Appropriate documentation is required in these cases 

 
 
 
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 Admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative reason). 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities 
should occur prior to the reporting of a potential DILI event.  All occurrences of 
potential DILIs, meeting the defined criteria, must be reported as SAEs Potential drug 
induced liver injury is defined as: 
 ALT or AST elevation > 3 times upper limit of normal (ULN)  
AND 
 Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated 
serum alkaline phosphatase) 
AND 
 No other immediately apparent possible causes of AST/ALT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing 
chronic or acute liver disease, or the administration of other drug(s) known to 
be hepatotoxic. 
 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  

 
 
 
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Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects 
should not be questioned regarding the specific occurrence of one or more AEs.) 
NONSERIOUS ADVERSE EVENT 
 Nonserious Adverse Events are to be provided to BMS in aggregate via interim or 
final study reports as specified in the agreement or, if a regulatory requirement 
[e.g. IND US trial] as part of an annual reporting requirement.  
 Nonserious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status 
for the subjects.  
A nonserious adverse event is an AE not classified as serious.  
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. All 
nonserious adverse events (not only those deemed to be treatment-related) should be 
collected continuously during the treatment period and for a minimum of 100 days 
following the last dose of study treatment.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for nonserious AEs that cause 
interruption or discontinuation of study drug and for those present at the end of study 
treatment as appropriate.  
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported as such. 
The following laboratory abnormalities should be documented and reported 
appropriately: 
Any laboratory test result that is clinically significant or meets the definition of an 
SAE 
Any laboratory abnormality that required the subject to have study drug discontinued 
or interrupted 
Any laboratory abnormality that required the subject to receive specific corrective 
therapy.  
 
 
 

 
 
 
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Pregnancy 
 
If, following initiation of the investigational product, it is subsequently discovered that a 
study subject is pregnant or may have been pregnant at the time of investigational product 
exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued in an appropriate manner (e.g., 
dose tapering if necessary for subject safety).  
The investigator must immediately notify Worldwide Safety @BMS of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on the 
Pregnancy Surveillance Form [provided upon request from BMS] 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. All occurrences of 
overdose must be reported as an SAE. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or not 
these procedures are required by the protocol, should also be recorded as a nonserious or 
serious AE, as appropriate, and reported accordingly. 

 
 
 
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APPENDIX 5 Recommended MRI Sequences 
 
 
 
 
A: Recommended 3T Protocola 0.1 mmol/kg or up to 20cc (single, full dose) of MR contrast. 
b Post-contrast 3D axial T1-weighted images should be collected with identical parameters to pre-contrast 3D axial T1-
weighted images 
c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba) 
d IR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization prepared 
rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-SPGR or Fast SPGR 
with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; 
Toshiba). 
e A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE or another 
IR-prepped 3D T1-weighted sequences and therefore should be avoided. 
f In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE [Siemens], 
PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this acquisition scheme is 
can cause significant differences in ADC quantification and therefore should be used only if EPI is not an option. 
g For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5-15ms for similar contrast. 
h For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400-450ms for similar 
contrast. 
 
Acronyms: 
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; DWI = diffusion-
weighted imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo planar imaging; MPRAGE = 
magnetization prepared rapid gradient-echo; A/P = anterior to posterior; R/L = right to left; NEX = number of 
excitations or averages; FOV = field of view; IR-GRE = inversion-recovery gradient-recalled echo 
 
3D T1w Pre 
Ax 2D FLAIR 
Ax 2D DWI 
Contrast Injection a 
SE EPI Perf 
Ax 2D T2w 
3D T1w 
Postb 
Sequence 
IR-GREd,e 
TSEc 
EPIf 
EPI 
TSEc 
IR-GREd,e 
Plane 
Sagittal/Axial 
Axial 
Axial 
Axial 
Axial 
Axial/Sagi
ttal 
Mode 
3D 
2D 
2D 
2D 
2D 
3D 
TR [ms] 
2100g 
>6000 
>5000 
2260 
>2500 
2100g 
TE [ms] 
Min 
100-140 
Min 
78 
80-120 
Min 
TI [ms] 
1100h 
2000 - 2500 
 
 
 
1100h 
Flip Angle 
10º-15º 
90º/160º 
90º/180º 
 
90º/160º 
10º-15º 
Frequency 
256 
256 
128 
128 
256 
256 
Phase 
256 
256 
128 
128 
256 
256 
NEX 
1 
1 
1 
1 
1 
1 
FOV 
256mm 
240mm 
240mm 
280 
240mm 
256mm 
Slice Thickness 
1mm 
3mm 
3mm 
10mm 
3mm 
1mm 
Gap/Spacing 
0 
0 
0 
0 
0 
0 
Diffusion Options 
 
 
b = 0, 500, 
and 1000 
s/mm2 
3 directions 
 
 
 
Parallel Imaging 
Up to 2x 
Up to 2x 
Up to 2x 
 
Up to 2x 
Up to 2x 
Scan Time 
(Approx) 
4:53 
3:39 
3:20 
1:36 
2:17 
4:53 

 
 
 
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B: Recommended 1.5T Protocol  
 
 
3D T1w Pre 
Ax 2D FLAIR 
Ax 2D DWI 
Contrast Injection a 
Ax 2D T2w 
3D T1w Postb 
Sequence 
IR‐GREd,e 
TSEc  
EPIf 
TSEc 
IR‐GREd,e 
Plane 
Sagittal/Axial 
Axial 
Axial 
Axial 
Sagittal/Axial 
Mode 
3D 
2D 
2D 
2D 
3D 
TR [ms] 
2100g 
>6000 
>5000 
>3500 
2100g 
TE [ms] 
Min 
100‐140 
Min 
100‐120 
Min 
TI [ms] 
1100h 
2000‐2500 
 
 
1100h 
Flip Angle 
10º‐15º 
90º/160º 
90º/180º 
90º/160º 
10º‐15º 
Frequency 
172 
256 
128 
256 
172 
Phase 
172 
256 
128 
256 
172 
NEX 
1 
1 
1 
1 
1 
FOV 
256mm 
240mm 
240mm 
240mm 
256mm 
Slice Thickness 
1.5mm 
4mm 
4mm 
4mm 
1.5mm 
Gap/Spacing 
0 
0 
0 
0 
0 
Diffusion Optionsi 
 
 
b = 0, 500, and 
1000 s/mm2 
3 directions 
 
 
Parallel Imaging 
No 
Up to 2x 
Up to 2x 
Up to 2x 
No 
Scan Time 
(Approx) 
5‐10 min 
4‐5 min 
3‐5 min 
3‐5 min 
5‐10 min 
 
a 0.1 mmol/kg or up to 20cc (single, full dose) of MR contrast. 
b Post-contrast 2D axial T1-weighted images should be collected with identical parameters to pre-contrast 
2D axial T1-weighted images 
c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba) 
d IR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization 
prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-
SPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D 
fast field echo (3D Fast FE; Toshiba). 
e A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE 
or another IR-prepped 3D T1-weighted sequences and therefore should be avoided. 
f In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE 
[Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this 
acquisition scheme is can cause significant differences in ADC quantification and therefore should be used 
only if EPI is not an option. 
g For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5-15ms for 
similar contrast. 
h For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400-450ms for 
similar contrast. 
i Older model MR scanners that are not capable of >2 b-values should use b = 0 and 1000 s/mm2. 
 
Acronyms: 
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; DWI = 
diffusion-weighted imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo planar imaging; 
MPRAGE = magnetization prepared rapid gradient-echo; A/P = anterior to posterior; R/L = right to left; 

 
 
 
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NEX = number of excitations or averages; FOV = field of view; IR-GRE = inversion-recovery gradient-
recalled echo 
 
 

 
 
 
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Appendix 6   Hepatoxicity Article  
International Journal of Molecular Sciences 
Review 
Hepatotoxicity by Drugs: The Most CommonImplicated Agents 
Einar S. Björnsson 
Department of Internal Medicine, Division of Gastroenterology and Hepatology, 
The National University Hospital of Iceland and The Faculty of Medicine, The 
University of Iceland, 108 Reykjavik, Iceland; einarsb@landspitali.is; Tel.: +354-
543-6180; Fax: +354-543-4834 
Academic Editors: Rolf Teschke and Raúl J. Andrade 
Received: 4 January 2016; Accepted: 1 February 2016; Published: 6 February 2016 
Abstract: Idiosyncratic drug-induced liver injury (DILI) is an underreported and 
underestimated 
adverse 
drug 
reaction. 
Information 
on 
the 
documented 
hepatotoxicity of drugs has recently been made available by a website that can be 
accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to 
critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at 
least one case report of convincing reports of liver injury. Only 48 drugs had more 
than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly 
implicated agent leading to DILI in the prospective series. In a recent prospective 
study, liver injury due to amoxicillin-clavulanate was found to occur in 
approximately one out of 2300 users. Drugs with the highest risk of DILI in this 
study were azathioprine and infliximab. 
Keywords: hepatotoxicity; drugs; drug-induced liver injury; idiosyncratic 
1. Introduction 
Drug-induced liver injury (DILI) is a frequent differential diagnosis in patients with 
acute liver injury without obvious etiology. Apart from exclusion of competing 
etiologies, an important element in the diagnostic process is the information about 
the known and potential hepatotoxicity of the agent. 

 
 
 
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However, data on hepatotoxicity is not always easily accessible. All drugs approved 
by regulatory authorities are accompanied by package inserts, called the “patient 
information” leaflet in Europe and “prescribing information” in the United States 
[1,2]. Adverse liver reactions are often mentioned in these product labels (package 
inserts) as a part of the prescribing information. However, it is not always clear 
whether this is related to enzyme elevations in clinical trials and/or clinically 
apparent liver injury. Thus, from package inserts of prescribed medications the 
clinician can get the idea that adverse drug reactions are side effects of most drugs. 
It has recently been demonstrated that this information is insufficient and even 
misleading [3]. There was also a substantial discrepancy in the official package 
inserts and liver disease labeling between Europe and the United States [3]. The 
documentation of the hepatotoxicity of drugs in the medical literature is very 
variable.  
Some drugs have been convincingly documented to cause liver injury in numerous 
case reports and case series. Many such drugs have a known clinical signature 
(phenotype) of liver injury and causality has been further documented by instances 
of a positive rechallenge [4,5]. Examples are chlorpromazine, halothane, isoniazid 
and amoxicillin-clavulanate. In early DILI research, halothane and chlorpromazine 
were commonly reported causes of hepatotoxicity [6]. However, with some drugs, 
although marketed for many decades, only a single case report or very few reports 
of liver injury have been published. Case reports are often not well described and 
critical clinical information is frequently lacking [7]. A recent study found that 
reports of drug-induced liver diseases often did not provide the data needed to 
determine the causes of suspected adverse effects [7]. Although a case report has 
been published, it does not prove that the drug is hepatotoxic. 
Int. J. Mol. Sci. 2016, 17, 224; doi:10.3390/ijms17020224 
www.mdpi.com/journal/ijms 
Int. J. Mol. Sci. 2016, 17, 224 2 of 7 
A newly established website, LiverTox® [8], was an attempt to provide up-to-date, 
accurate, and easily accessible information on the diagnosis, causes, frequency and 
patterns of liver injury attributable to both prescription and nonprescription 
medications. In LiverTox® there is data on almost all medications marketed in the 
United States, both on those who have been reported to cause liver 

 
 
 
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injury and those without reports of liver injury. Although in LiverTox® a thorough 
literature search has been undertaken and is provided, no attempt has been made to 
judge the quality of the published reports or the causality of the suspected liver 
injury reported. 
In a recently published paper, drugs in LiverTox® were classified into categories, 
using all reports in this website [9]. For drugs with rather few reports (<12), the 
Rousel Uclaf Causality Assessment Method (RUCAM) was used [10]. In this critical 
analysis, many of the published reports did not stand up to critical review and 
currently there is no convincing evidence for some drugs with reported 
hepatotoxicity to be hepatotoxic [9]. Although certain drugs have a distinct 
phenotype such as isoniazid, which generally leads to a hepatocellular pattern or 
chlorpromazine cholestatic liver damage, many drugs can lead to both 
hepatocellular and cholestatic injury. Listing all types of patterns that have been 
reported for all these drugs is unfortunately not possible in this paper. 
2. Categories of Hepatotoxicity 
In the creation of LiverTox, drugs were arbitrarily divided into four different 
categories of likelihood for causing liver injury based on reports in the published 
literature [8]. Category A with >50 published reports, B with >12 but less than 50, C 
with >4 but less than 12, and D with one to three cases. In the Hepatology paper, 
drugs were categorized based on these numbers and another category, T, was added 
for agents leading to hepatotoxicity mainly in higher-than-therapeutic doses [9]. The 
number of published cases was counted unless >100 cases were found. The analysis 
was based mainly on published case reports, but case series were used if a formal 
causality assessment had been undertaken. In the analysis of the hepatotoxicity of 
drugs found in LiverTox, fewer drugs than expected had documented 
hepatotoxicity.  Among 671 drugs available for analysis, 353 (53%) had published 
convincing case reports of hepatotoxicity. Thus, overall, 47% of the drugs listed in 
LiverTox did not have evidence of hepatotoxicity. This is at odds with product 
labeling which very frequently lists liver injury as adverse reaction to drugs [3]. It 
has to be taken into consideration that 116/863 (13%) of marketed agents had be 
excluded from the analysis. New drugs approved within the last five years were not 
included as most instances of hepatotoxicity appear in the post-marketing phase 
[11]. Metals 

 
 
 
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(iron, nickel, arsenic), illegal substances (cocaine, opium, heroin), and infrequently 
used and/or not available (not marketed currently) drugs were also excluded [9]. 
Herbal and dietary supplements listed in LiverTox were not included in the 
category analysis. 
Among the 671 drugs available for analysis, the proportions of the drugs in the 
different categories were: A, 48 (14%); B, 76 (22%); C, 96 (27%); and D, 126 (36%). 
A total of 318 (47%) drugs have not been implicated (category E). 
In general, drugs in categories A and B were more likely than those in C and D to 
have been marketed for a long time, and both were more likely to have at least one 
fatal case of liver injury and reported cases of positive rechallenge. There is little 
doubt that drugs with >50 or 100 published reports of DILI such as category A 
drugs are hepatotoxic. The same is probably true for the vast majority of drugs in 
category B. However, in categories C and D with one to 12 cases reported, it is still 
not clear whether these agents are really hepatoxic drugs. 
3. Category A 
Although drugs in this category (n = 48) were supposed to have >50 case reports of 
liver injury associated with the use of these drugs, 81% of the drugs had >100 cases 
reported. Interestingly, overall, 92% of these drugs had documented positive 
rechallenge. In Table 1, the category A drugs are illustrated with the indication 
and/or class of drug. These agents in category A are the real potential 
Int. J. Mol. Sci. 2016, 17, 224 3 of 7 
hepatotoxins and clinicians should be aware of that when evaluating the risk-benefit 
ratio of drug therapy. Treatment with these drugs should motivate physicians to 
guide patients about potential symptoms of liver injury when taking these drugs and 
about prompt discontinuation if these symptoms occur. All except one entity 
(estrogens-progestins) or 98% had at least one convincing case that was associated 
with fatal outcome. All of these drugs except telithromycin had been approved for 
marketing for more than 15 years and 63% for more than 35 years [9]. The most 
common types of drugs were antimicrobials among 33% of the drugs, followed by 
drugs acting on the central nervous system (12.5%), cardiovascular (12.5%), 
rheumatologic (12.5%), antineoplastic (10%), endocrine (6%) and other types of 
drugs (13%). Although antimicrobials were the most common agents among drugs, 
antimicrobials were also the most common agents in categories B (30%), C (19%) 

 
 
 
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and D (27%). Antibiotics have been shown to be the dominating type of drug in both 
prospective and retrospective studies on DILI [12–16]. There is unfortunately not 
enough room to discuss many of these well-documented hepatotoxic agents. As 
mentioned in the abstract, azathioprine and infliximab have in one study been found 
to be associated with the highest risk of liver injury [9]. Both hepatocellular and 
cholestatic injury has been described due to azathioprine [8,9]. Despite the common 
problem of hepatotoxicity with azathioprine, there is a lack of studies with a 
significant number of well-characterized patients with this type of liver injury. 
Table 1. Drugs that, according to analysis of data in LiverTox [8], have been 
associated with more than 100 cases of drug-induced liver injury. 
Drug Drug                                                          Class/Indication 
1. Allopurinol                                                     Gout prophylaxis 
2. Amiodarone                                                    Arrhythmia 
3. Amoxicillin-clavulanate                                Antibiotic 
4. Anabolic steroids                                           Body building 
5. Atorvastatin                                                  Lipid lowering agent 
6. Azathioprine/6-Mercaptopurine                 Immunosuppressive agent 
7. Busulfan                                                        Malignancy 
8. Carbamazepine                                            Antiepileptic 
9. Chlorpromazine                                           Psychosis 
10. Contraceptives                                           Birth control 
11. Dantrolene                                                  Muscle relaxant 
12. Diclofenac                                                    NSAID 
13. Didanosine                                                  Antimicrobial 
14. Disulfiram                                                  Substance abuse agent 
15. Efavirenz                                                     Antimicrobial 

 
 
 
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16. Erythromycin                                            Antimicrobial 
17. Floxuridine                                                Antineoplastic 
18. Flucloxacillin                                             Antimicrobial 
19. Flutamide                                                  Antineoplastic 
20. Gold salts                                                   Immunosuppressive agent 
21. Halothane                                                  Anaesthetic 
22. Hydralazine                                              Antihypertensive 
23. Ibuprofen                                                  NSAID 
24. Infliximab                                                  Immunosuppressive agent 
25. Interferon alpha/Peginterferon               Antimicrobial 
26. Interferon beta                                         Multiple Sclerosis 
27. Isoniazid                                                   Antituberculosis 
28. Ketoconazole                                           Antifungal 
29. Methotrexate                                           Immunosuppressive agent 
30. Methyldopa                                            Antihypertensive 
31. Minocycline                                           Antibiotic 
32. Nevirapine                                            Antimicrobial 
33. Nimesulide                                            NSAID 
34. Nitrofurantoin                                     Antibiotic 
Int. J. Mol. Sci. 2016, 17, 224 4 of 7 
Table 1. Cont. 
Drug Drug                                                   Class/Indication 
35. Phenytoin                                              Antiepileptic 

 
 
 
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36. Propylthiouracil                                 Antithyroid 
37. Quinidine                                            Arrhythmia 
38. Pyrazinamide                                     Antituberculosis 
39. Rifampin                                             Antituberculosis 
40. Simvastatin                                         Lipid lowering agent 
41. Sulfamethoxazole/Trimethoprim     Antibiotic 
42. Sulfazalazine                                      Antibiotic 
43. Sulfonamides                                     Antibiotic 
44. Sulindac                                             NSAID 
45. Telithromycin                                   Antibiotic 
46. Thioguanine                                     Antineoplastic 
47. Ticlopidine                                       Platelet inhibitor 
48. Valproate                                         Antiepilepitic 
4. Category B 
As mentioned above, most of these drugs with >12 and up to 50 case reports of DILI 
published probably carry hepatotoxic potential. This seems particularly true for 
drugs with reports of documented rechallenge, which had been reported in at least 
one case in 38% of the drugs [9]. In comparison with category A drugs, which 
almost exclusively had been associated with fatality, approximately 50% of category 
B drugs had been associated with a fatal outcome. Thus, in drugs with less frequent 
reporting of liver injury in category B, only 38% had rechallenge reported vs. 92% 
in category A, which suggests that the “proof” of hepatotoxicity is not there for all 
these drugs. In category B, 13/76 (17%) drugs with >30 cases reported are shown in 
Table 2. 
Table 2. Drugs in category B (>12 and >40 cases) that, according to analysis of data 
in LiverTox [8],have been associated with >30 published case reports of drug 
induced liver injury. 

 
 
 
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Drug                                                             Drug Class/Indication 
Amodiaquine                                              Antimicrobial 
Azithromycin                                             Antimicrobial 
Chlorzoxazone                                           Muscle relaxant 
Cyproterone                                              Antineoplastic 
Heparin                                                     Anticoagulant 
Imatinib                                                     Antineoplastic 
Irinotecan                                                 Antineoplastic 
Levofloxacin/Ofloxacin                           Antimicrobial 
Oxacillin                                                   Antimicrobial 
Phenobarbital                                          Antiepileptic 
Stavudine                                                 Antimicrobial 
Tamoxifen                                               Antineoplastic 
Terbinafine                                              HIV 
5. Categories C, D and E 
Overall, 222/353 (63%) of drugs in LiverTox® with hepatotoxicity fall into 
categories C and D. Compared with category D, with only one to three cases 
reported, category C (<12 and >4 case reports) drugs were more likely to have 
rechallenge reports, with 26% vs. 11%, and fatal cases of 23% and 7%, respectively. 
A positive rechallenge is usually defined with biochemical criteria, showing 
recurrence of liver test abnormalities upon readministration of the drug, due to 
either intentional or inadvertent re-exposure [4,5]. This is generally considered to be 
the gold standard of the diagnosis of drug-induced liver injury. A documented 
positive rechallenge provides more evidence of the hepatotoxicity of a 
Int. J. Mol. Sci. 2016, 17, 224 5 of 7 

 
 
 
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given drug. Given the frequency of case reports with drugs in categories A and B, 
there seems little doubt that drugs in these categories can lead to hepatotoxicity and 
little need to do a strict causality assessment of reports with these drugs. 
However, in category C, consisting of 4–11 case reports, the hepatotoxicity of some 
drugs can be put into question. To illustrate this, 16 drugs in this category only had 
case reports with a possible likelihood score according to RUCAM. None of these 
drugs had documented fatal liver reactions or rechallenge. Thus, it can be concluded 
that these drugs do not have a well-documented hepatotoxicity, although liver injury 
with their use cannot be excluded. The poorly documented exclusion of competing 
causes, as well as the use of other concomitant drugs, made a causality assessment 
difficult. This has been problematic in many reports of suspected hepatotoxicity 
with human immunodeficiency virus (HIV) drugs [17–19]. It is very important that 
observations of hepatotoxicity of new drugs should lead to well-documented case 
reports with detailed clinical and biochemical information. 
The analysis reported in the Hepatology paper revealed that many drugs labeled as 
hepatotoxic and with a single or few case reports suggesting hepatotoxicity did not 
fulfill causality criteria by use of the RUCAM instrument [9]. 
6. Common Drugs Leading to Liver Injury in Drug-Induced Liver Injury (DILI) 
Studies 
As mentioned above, antibiotics have, in all prospective studies, been found to be the 
most common drugs leading to hepatotoxicity [12–16]. In the most recently 
published series from the DILIN cohort in the US, antimicrobials, including 
antibacterial agents and antituberculosis agents, were approximately 46% of all 
DILI cases [20]. Furthermore, among the top 10 drugs in the DILIN registry, all 
drugs except one (Diclofenac) are antibiotics [20]. Table 3 illustrates the five most 
common drugs associated with liver injury in at least three prospective studies. 
Interestingly, all of these drugs belong to category A. 
Table 3. The top five implicated drugs in three prospective studies on DILI, in Spain 
(Andrade et al. [12] 2005), liver injury in drug-induced liver Injury (DILI) study 
from the US (Chalasani et al. [13] 2013) and a prospective study from Iceland 
(Bjornsson et al. [14] 2015). 
Spanish Registry                 DILIN Study                       Icelandic Study 
Amoxicillin-clavulanate  Amoxicillin-clavulanate     Amoxicillin-clavulanate 

 
 
 
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Isoniazid                        Isoniazid                                          Diclofenac 
RIP + INH + PIZ          Nitrofurantoin                                Azathioprine 
Flutamide                      SMZ/TMP                                       Infliximab 
Ibuprofen                      Minocycline                                     Nitrofurantoin 
RIP + INH + PIZ: Rifampin, Isoniazid and Pyrazinamide; 
SMZ/TMPSulfamethoxazole/Trimethoprim. 
In India, anti-tuberculous drugs (58%), anti-epileptics (11%), olanzapine (5%), and 
dapsone (5%) were the most common causes [16]. A unified list of drugs associated 
with DILI was recently established [21]. Overall 385 individual drugs were 
identified; 319 drugs were identified in three DILI registries, i.e., from Spain, 
Sweden and the US. The 10 most frequently implicated drugs were: amoxicillin-
clavulanate, flucloxacillin, erythromycin, diclofenac, 
sulfamethoxazole/Trimethoprim, isoniazid, disulfiram, Ibuprofen and flutamide 
[12–14,21]. 
7. Risk of DILI among Patients Using Potentially Hepatotoxic Drugs 
Previously, data on numbers needed to harm drug users in terms of liver injury has 
been limited. Several retrospective case control cohort studies using the General 
Practitioners Research Database (GPRD) were the first studies on this [22–24]. 
A risk of DILI greater than 100 per 100,000 users was found for chlorpromazine 
and isoniazid. Drugs with an intermediate risk were amoxicillin-clavulanic acid and 
cimetidine, with a risk of one per 10 per 100,000 users [24]. All other drugs were 
found to be less than 10 per 100,000 users. 
Int. J. Mol. Sci. 2016, 17, 224 6 of 7 
The following drugs were most strongly associated with DILI: Chlorpromazine, 
amoxicillin-clavulanic 
acid, 
flucloxacillin, 
macrolides, 
tetracyclines, 
metoclopramide, 
chlorpheniramine, 
betahistine, 
sulfasalazine, 
azathioprine, 
diclofenac, and antiepileptics The highest crude incidence rates were one per 739 
users (chlorpromazine), one per 1103 (azathioprine), one per 1000 (sulfasalazine), 
and one per 11,688 (amoxicillin-clavulanate). The limitations of this study were the 
retrospective design with a lack of complete data regarding diagnostic testing and a 
lack of data on over-the-counter drugs and herbal agents [24]. In a recent 

 
 
 
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prospective study on DILI from Iceland, data on the use of drugs was available [9]. 
The risk of DILI among patients using potentially hepatotoxic drugs could therefore 
be calculated. Amoxicillin-clavulanate-induced liver injury was found in one of 2350 
outpatient users, which was higher among those who were hospitalized already, one 
of 729. This might be due to a detection bias, with more routine testing of the liver in 
the hospital, but it cannot be excluded that sicker patients are more susceptible to 
liver injury from this drug. The incidence rates were higher than previously 
reported, with the highest being one of 133 users for azathioprine and one of 148 for 
infliximab. 
Acknowledgments: No specific grants were obtained for research work presented in 
this paper and no funds for publishing in open access. 
Conflicts of Interest: The author declares no conflict of interest. 
References 
1. European Medicines Agency. Available online: http://www.ema.europa.eu 
(accessed on 1 May 2015). 
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3. Bjornsson, E.S.; Jacobsen, E.I.; Einarsdottir, R.; Chalasani, N. Discrepancies in 
liver disease labeling in the package inserts of commonly prescribed medications. 
Gastroenterology 2015, 148, 269–273. [CrossRef] 
[PubMed] 
4. Andrade, R.J.; Robles, M.; Lucena, M.I. Rechallenge in drug-induced liver 
injury: The attractive hazard. 
Expert Opin. Drug Saf. 2009, 8, 709–714. [CrossRef] [PubMed] 
5. Papay, J.I.; Clines, D.; Rafi, R.; Yuen, N.; Britt, S.D.; Walsh, J.S.; Hunt, C.M. 
Drug-induced liver injury following positive drug rechallenge. Regul. Toxicol. 
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6. Zimmerman, H.J. Drug-induced liver disease. In Diseases of the Liver, 8th ed.; 
Sciff, E.R., Sorrell, M.F., 

 
 
 
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Maddrey, W.C., Eds.; Schiff’s Lippincott-Raven Publishers: Philadelphia, PA, USA, 
1999; pp. 973–1064. 
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8. LiverTox. Available online: http://livertox.nlm.nih.gov (accessed on 1 May 2015). 
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liver injury: Critical assessment based upon published case reports. Hepatology 
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10. Danan, G.; Teschke, R. RUCAM in drug and herb induced liver injury: The 
update. Int. J. Mol. Sci. 2016, 17. [CrossRef] [PubMed] 
11. Senior, J.R. Evolution of the Food and Drug Administration approach to liver 
safety assessment for new drugs: Current status and challenges. Drug Saf. 2014, 37, 
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García-Ruiz, E.; García-Muñoz, B.; González-Grande, R.; Pizarro, A.; Durán, J.A.; 
et al. Drug-induced liver injury: An analysis of 461 incidences submitted to the 
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13. Chalasani, N.; Fontana, R.J.; Bonkovsky, H.L.; Watkins, P.B.; Davern, T.; 
Serrano, J.; Yang, H.; Rochon, J. Causes, clinical features, and outcomes from a 
prospective study of drug-induced liver injury in the United States. 
Gastroenterology 2008, 135, 1924–1934. [CrossRef] [PubMed] 
14. Bjornsson, E.S.; Bergmann, O.M.; Bjornsson, H.K.; Kvaran, R.B.; Olafsson, S. 
Incidence, presentation and outcomes in patients with drug-induced liver injury in 
the general population of Iceland. Gastroenterology 2013, 144, 1419–1425. 
[CrossRef] [PubMed] 
15. Björnsson, E.; Olsson, R. Outcome and prognostic markers in severe drug-
induced liver disease. Hepatology 2005, 42, 481–489. [CrossRef] [PubMed] 

 
 
 
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Int. J. Mol. Sci. 2016, 17, 224 7 of 7 
16. Devarbhavi, H.; Dierkhising, R.; Kremers, W.K.; Sandeep, M.S.; Karanth, D.; 
Adarsh, C.K. Single-center experience with drug-induced liver injury from India: 
Causes, outcome, prognosis, and predictors of mortality. Am. J. Gastroenterol. 
2010, 105, 2396–2404. [CrossRef] [PubMed] 
17. Bräu, N.; Leaf, H.L.;Wieczorek, R.L.; Margolis, D.M. Severe hepatitis in three 
AIDS patients treated with indinavir. Lancet 1997, 349, 924–925. [CrossRef] 
18. Vergis, E.; Paterson, D.L.; Singh, N. Indinavir-associated hepatitis in patients 
with advanced HIV infection. Int. J. STD AIDS 1998, 9, 53. [CrossRef] [PubMed] 
19. Pavel, S.; Burty, C.; Alcaraz, I.; de la Tribonnière, X.; Baclet, V.; Ajana, F.; 
Mouton, Y. Severe liver toxicity in postexposure prophylaxis for HIV infection with 
a zidovudine, lamivudine and fosamprenavir/ritonavir regimen. AIDS 2007, 21, 
268–269. [CrossRef] [PubMed] 
20. Chalasani, N.; Bonkovsky, H.L.; Fontana, R.; Lee,W.; Stolz, A.; Talwalkar, J. 
Features and outcomes of 889 patients with drug-induced liver injury: The DILIN 
prospective study. Gastroenterology 2015, 148, 1340–1352. [CrossRef] [PubMed] 
21. Suzuki, A.; Andrade, R.J.; Bjornsson, E.; Lucena, M.I.; Lee, W.M.; Yuen, N.A.; 
Hunt, C.M.; Freston, J.W. Unified list of drugs causing hepatotoxicity and the 
reporting frequency of liver events in the WHO vigibaset: International 
collaborative work. Drug Saf. 2010, 33, 503–522. [CrossRef] [PubMed] 
22. Pérez Gutthann, S.; García Rodríguez, L.A. The increased risk of 
hospitalizations for acute liver injury in a population with exposure to multiple 
drugs. Epidemiology 1993, 4, 496–501. [CrossRef] [PubMed] 
23. García Rodríguez, L.A.; Ruigómez, A.; Jick, H. A review of epidemiologic 
research on drug-induced acute liver injury using the general practice research data 
base in the United Kingdom. Pharmacotherapy 1997, 17, 721–728. [PubMed] 
24. De Abajo, F.J.; Montero, D.; Madurga, M.; García Rodríguez, L.A. Acute and 
clinically relevant drug-induced liver injury: A population based case-control study. 
Br. J. Clin. Pharmacol. 2004, 58, 71–80. [CrossRef] 
[PubMed] 

 
 
 
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© 2016 by the author; licensee MDPI, Basel, Switzerland. This article is an open 
access 
article distributed under the terms and conditions of the Creative Commons by 
Attribution 
(CC-BY) license (http://creativecommons.org/licenses/by/4.0/). 
 
Appendix 7.0 AE Management Algorithms 
 
 
 
 
 
 

 
 
 
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Appendix 8   Correlative Studies 
Peripheral blood and tumor tissue-based assays:  Blood and tumor specimens (when 
available) will be collected from each patient. 
 
Tissue: 
Up to ten unstained slides of 5 microns thickness or a block of tissue will be required to 
be sent if tissue is available. If the tissue is not available then Principal investigator 
permissions is required for enrollment. If the patient undergoes recent biopsy or resection 
then the more recent tissue is preferred. If the patient didn’t undergo any recent surgery 
then the tissue from diagnosis can be used. Whole exome sequencing, transcriptome 
analysis, tumor mutational burden. Additional markers for immune function will be 
performed such as PDl- PD-1, PD-1L  staining  etc.    
 
The tissue will be sent to  
David Peereboom M.D. 
Attn: Mary Mcgraw (Case 1317) 
ND4-52 Lab, 
Lerner Research Institute 
9620 Carnegie Avenue, N Building, Cleveland, OH 44106 
 
Collect 4-10ml green top tubes.  Once the sample is collected it should be tubed to station 
19, with a filled requisition (see Appendix 7). 
 
Blood will be sent to the lab of Dr. C. Marcela Diaz-Montero for analysis. 
Lerner Research 2111 E. 96th St. NE4-216 Cleveland, OH 44106 Attention: Pat Rayman  
Provide advance notice by calling the lab at 216-444-5589 or emailing Pat Rayman at 
raymanp@ccf.org.   
 
Methods: 
Characterization of circulating immune cells: Frequencies of MDSCs, Tregs, CD8+ T 
cells, CD4+T and additional circulating immune cells will be determined by flow 
cytometry in both unfractionated blood and in purified PBMCs.  PBMCs will be isolated 
from whole blood using the standard ficoll separation assay.  Expression of 
immunomodulatory factors (PD-1, PD-1L, Lag3, Tim3, OX40, 41BB) on circulating 
immune cells will be also performed by flow cytometry. 
 
Characterization of tumor immune infiltrate:  Fresh tumor tissue will be digested to 
single cell suspension and analyzed by flow cytometry for frequencies of MDSCs, Tregs, 

 
 
 
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CD8+ T cells, and CD4+T cells. Expression of immunomodulatory factors (such as but 
not limited to PD-1, PD-1L, Lag3, Tim3, OX40, 41BB) on tumor infiltrating immune 
cells will also be assayed by flow cytometry.  
 
Cytokine/Chemokine profile:  Plasma will be isolated from whole blood and analyzed 
for levels of cytokines/chemokines involved in Th1 and Th2 responses.  A multiplex 
system that measures 50+ analytes will be used. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Appendix 9 Laboratory Requisition  
 
CASE 1317: A Randomized Phase 2 Open Label Study of Nivolumab plus Standard 
Dose Bevacizumab versus Nivolumab plus Low Dose Bevacizumab in Recurrent 
Glioblastoma (GBM) 
 
Name_____________________________                                        
CCF#_________________________ 
 
Date________________ 
 
 
     MD__________________________ 
Collected by_____________________ 
     Time___________________ 
 
Case IRB  
 
Consented:    Y         N 
 
PLEASE DRAW: 
 
(4) 10 ml Green top (Sodium Heparin) tubes 
Must fill tubes all the way 
Mix/Invert 5-7 times after Draw 
Send to Station 19 
Attention Dr. Finke/Diaz Lab 444-5589 (20567) 
 
 (DO NOT REFRIGERATE) 
Send this requisition with the sample 
 
 
 

 
 
 
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Appendix 10 NANO Scale  
 
 
CA209-382 – A Randomized Phase 2 Open Label Study of Nivolumab plus standard 
dose Bevacizumab   versus Nivolumab plus low dose Bevacizumab in Recurrent 
Glioblastoma (GBM) 
 
Patient ID: __________________ 
 
Date of Assessment: ______________ 
 
 
 

 
 
 
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