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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  
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: Manmeet Ahluwalia, MD Case Comprehensive Cancer Center  
Cleveland Clinic  
Taussig Cancer Center  
9500 Euclid Avenue Cleveland, OH 44195 (216) 445-6145  
ahluwam@ccf.org  
CO-PI: David A. Reardon, M.D. Center for Neuro-Oncology Dana-Farber Cancer Institute 450 Brookline Avenue, D2134 Boston, MA 02215-5450 Telephone: 617-632-4750 david_reardon@dfci.harvard.edu  
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| Protocol Version                                                                                                                   | 10/24/2017   |
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| Protocol Amendment 1 05/03/2018  Protocol Amendment 2 05/21/2018  Protocol Amendment 3 01/06/2020  Protocol Amendment 4 03/20/2020 |              |  
| STATISTICIAN:      | Brian Hobbs Ph.D.                                                                                         |
|--------------------|-----------------------------------------------------------------------------------------------------------|
|                    | Cleveland Clinic  9500 Euclid Avenue, CA-60  Cleveland, OH 44195  (216) 444-3738                          |
|                    | hobbsb@ccf.org                                                                                            |
| STUDY COORDINATOR: | Marci Ciolfi                                                                                              |
|                    | Case Comprehensive Cancer Center  Cleveland Clinic  9500 Euclid Avenue  Cleveland, OH 195  (216) 445-3407 |
|                    | ciolfim@ccf.org                                                                                           |
| SPONSOR:           | Case Comprehensive Cancer Center                                                                          |
| SUPPORT/FUNDING:   | Cleveland Clinic/Bristol Myers Squibb                                                                     |
| SUPPLIED AGENT:    | Nivolumab                                                                                                 |
| IND #:             | 137535                                                                                                    |
| OTHER AGENT:       | Bevacizumab                                                                                               |  
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summary of changes

10/24/2017  
Table 9.2-1  
10/24/2017  
Page 39 6.5.1 11  
05/03/2018 Page 41  
Section 6.5.1  
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| 10/05/2017               | Initial IRB approval 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                                                                                                             |
| Table  9.2-1             |                                                                                                                                                                                                       |                                                                                                                                             |
| 10/24/2017               | Page 28                                                                                                                                                                                               | Corrected nivolumab monotherapy to state nivolumab + standand  bevacizumab Corrected nivolumab to state nivolumab plus standard bevacizumab |
| 6.5.1 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                                                                                                                        |
| section                  | Exclusion Criteria 1 updated to "more than one recurrences of GBM"                                                                                                                                    |                                                                                                                                             |
| 4.2                      |                                                                                                                                                                                                       |                                                                                                                                             |
| 05/03/2018               | Page 36                                                                                                                                                                                               | Typo of sequelae corrected                                                                                                                  |
| 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                                                                                                           |  
| Protocol  Date                    | Section                                                  | Change 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 68 Table  9.2-1                                     | 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 70 Table  9.2-2                                     |                                                                                                                                                                                                                                                                                                                                                                                 |                            |
| 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                        | Page 71 Table 9.2-3                                      | Deletion of Oxygen saturation by pulse oximetry. Pulse oximetry at  rest and after exertion Statistical Section of the protocol amended  Section 12.1 Amended Section 12.2.5 Amended                                                                                                                                                                                            |                            |
| 05/03/2018                        | Pages 75-81                                              | 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  115                                                |                                                                                                                                                                                                                                                                                                                                                                                 |                            |
| 05/03/2018                        | Page  118                                                | Appendix 9 NANO Scale added                                                                                                                                                                                                                                                                                                                                                     |                            |
| 05/03/2018                        | CTCAE version updated to CTCAE v 5.0 throughout protocol |                                                                                                                                                                                                                                                                                                                                                                                 |                            |
| Pages                             |                                                          |                                                                                                                                                                                                                                                                                                                                                                                 |                            |
| 05/03/2018                        | 7,26,27                                                  | First or second recurrence amended to state only first recurrence                                                                                                                                                                                                                                                                                                               |                            |
| ,31,74                            |                                                          |                                                                                                                                                                                                                                                                                                                                                                                 |                            |
| 05/03/2018                        | Page 34                                                  | Exclusion criteria amended to >                                                                                                                                                                                                                                                                                                                                                 | NCI CTCAE Grade 3 within 6 |
| 4.2                               | 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                                                                                                                                                                                                                                                                                                                                                                         |                            |
| Cover  page and  Protocol  footer |                                                          |                                                                                                                                                                                                                                                                                                                                                                                 |                            |
| 01/06/2020                        | Updated to include Amendment number and version date     | Page | 4                                                                                                                                                                                                                                                                                                                                                                        |                            |  
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| Protocol  Date   | Section                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Change                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| 01/06/2020       | All  Protocol                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Patients amended to Subjects throughout protocol  Deleted "may have up to 2 recurrences" amended to state "Subjects  must have received previous treatment with radiotherapy and one  recurrence"                                                                                                                                                                                                                                                                                                                                                                                                             |
| 01/06/202        | Study  Design 3.2  Number  of  Subjects                                                                                                                                                                                                                                                                                                                                                                                                                                             | Arm B (nivolumab + reduced dose bevacizumab) amended to Arm B  (nivolumab + low dose bevacizumab)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
| 01/06/2020       | 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       | 3.3 Study  Phases 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                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
| 01/06/2020       | 3.4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | 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       | 4.1                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |  
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| Protocol  Date                                     | Section                                                                                                                                                                                                                                                                                                      | Change                                                                                                                                                                                                                       |             |    |     |         |          |    |           |
|----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|----|-----|---------|----------|----|-----------|
| 01/06/2020                                         | 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                                         | 4.2                                                                                                                                                                                                                                                                                                          | 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                                         | The dose of bevacizumab will be based on with at study entry                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                              |             |    |     |         |          |    |           |
| 6.5.2                                              | 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 SponsorInvestigator 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 |                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                              |             |    |     |         |          |    |           |
| 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                                                                                                                                                                                                                                                                                                          | Updated protocol where is states reduced dose bevacizumab to low                                                                                                                                                             |             |    |     |         |          |    |           |
| Protocol                                           | dose bevacizumab for consistency                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                              |             |    |     |         |          |    |           |
| 01/06/2020 Table                                   | of                                                                                                                                                                                                                                                                                                           |                                                                                                                                                                                                                              |             |    |     |         |          |    |           |
| Contents                                           | Corrected numbering of section 12.0                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                              |             |    |     |         |          |    |           |
| 6.5.1                                              | Page | 6                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                              |             |    |     |         |          |    |           |  
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| Protocol  Date   | Section                                                                                                                                                                                                                                                                      | Change   |
|------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------|
| 03/20/2020       | Cover  page and  Protocol  footer Updated to include Amendment number and version date 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  9.1.2 Section                                                                                                                                                                                                                                                       |          |
| 03/20/2020       | 9.2 Study  Calendar cc superscript added to Physical & Neurological exam, vital signs,  Performance Status (KPS) Section                                                                                                                                                     |          |
| 03/20/2020       | 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                                                                             |          |  
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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 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 Page | 8 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 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 Page | 9  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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
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investigational product(s) dose and mode

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)
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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. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020
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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.  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 Page | 11 |
| Case 1317                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |  
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| 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 Tlymphocyte–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 Page | 12   |
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| 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  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 Page | 13   |
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| hypoxia and enhanced delivery of co-administered antitumor 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 antiVEGF 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  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 Page | 14 |
| Case 1317              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |  
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| 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  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
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5.0 registration

6.0 TREATMENT 6.1 Investigational Product  
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| 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                   |
| 4.5.2 | Other Permitted Therapy                  |
| 4.5.3 | Prohibited and/or Restricted Treatment   |  
| 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 |                                                                       |
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8.0 pharmaceutical information 8.1 nivolumab

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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  
Page | 18 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
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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
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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
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14. references 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  
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1.0 introduction 1.1 background of

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. Tregulatory 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 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 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 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 Page | 21 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).
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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).
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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 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 Page | 22  
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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)
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pharmacokinetics and absorption distribution metabolism

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 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 Page | 23  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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, 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.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 Thus a flat dose of 240 mg every 2 weeks is recommended for investigation in this study
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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.
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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, heparinbinding 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.
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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 SKLMS-1 leiomyosarcoma, G55 glioblastoma multiforme, A673 rhabdomyosarcoma, Calu-6, 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.  
Page | 25  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 nonsmall 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 bevacizumab has significant clinical activity in this patient population. 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 Page | 26  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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1.4 drug prohibited during the

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)
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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 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 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 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 Page | 28  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 antitumor 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).
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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.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 To compare the objective response rate (ORR) of nivolumab and bevacizumab administered according to standard and reduced dosage schedules for recurrent glioblastoma subjects.
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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.
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3.0 investigational plan

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 Page | 30  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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
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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  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020  
$\text{Pa}_{\text{fe}}$.
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.
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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:
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.  
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Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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follow-up phase

Begins when the decision to discontinue a subject from study therapy is made (no further treatment with study therapy).  
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.
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3.4 method of assigning subject

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  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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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.
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patient's initials

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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.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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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 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.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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:
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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 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.
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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
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women of child bearing potential

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
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Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 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)
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4. physical and laboratory test

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  
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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:
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1. target disease exceptions

a. More than one recurrence of GBM b. Presence of extracranial metastatic, significant leptomeningeal disease or tumors primarily localized to the brainstem or spinal cord.
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2. medical history and concurrent

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 Page | 39  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 study treatment; 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
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3. physical and laboratory test

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
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4.3 inclusion of women and

Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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

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
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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.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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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.
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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.
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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 the local imaging facility's responsibility to determine, based on subject attributes (e.g., allergy Page | 42  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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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 Forte 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. Forte EDC and OnCore™ are Clinical Trials Management Systems housed on secure servers. Access to data through Forte EDC and OnCore™ is restricted by user accounts and assigned roles. Once logged into the Forte EDC or OnCore™ system with a user ID and password, Forte EDC™ and OnCore™ define roles for each user which limits access to appropriate data. User information and password can be obtained by contacting the OnCore™ Administrator at OnCore-registration@case.edu for OnCore™ access, and taussigoncore@ccf.org for Forte EDC™ access. Forte EDC™ is designed with the capability for study setup, activation, tracking, reporting, data monitoring and review, and eligibility verification. When properly utilized, Forte EDC™ is 21 CFR 11 compliant. This study will utilize electronic Case Report Form completion in the Forte EDC™ database. A calendar of events and required forms are available in Forte EDC™.
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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 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 Page | 43  
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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.  
| Primary  Packaging                  |                                         |                                                                                                               |                           |                                                                               |                                                           |
|-------------------------------------|-----------------------------------------|---------------------------------------------------------------------------------------------------------------|---------------------------|-------------------------------------------------------------------------------|-----------------------------------------------------------|
| (Volume)/Label  Type                | Secondary  Packaging  (Qty)/Label  Type |                                                                                                               |                           |                                                                               |                                                           |
| Product                             |                                         |                                                                                                               |                           |                                                                               |                                                           |
| Description and                     | Potency                                 |                                                                                                               |                           |                                                                               |                                                           |
| Dosage Form                         | Storage                                 |                                                                                                               |                           |                                                                               |                                                           |
| Appearance                          | Conditions  (per label)                 |                                                                                                               |                           |                                                                               |                                                           |
| Nivolumab* (BMS-936558-01): Injection drug product  is a sterile, nonpyrogenic, single-use,  isotonic aqueous  solution**                                     | 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 / Openlabel                           | Clear to  opalescent colorless to pale  yellow liquid. May  contain particles | 2 to 8°C (36  to 46°F).  Protect from light and  freezing |
| Bevacizumab:  Solution for infusion | 400                                     | 16mL per vial /                                                                                               | 1 vial per carton         | Clear to slightly                                                             |                                                           |
| mg/vial                             | Open-label                              | / Open-label                                                                                                  | opalescent,  colorless to | 2 to 8°C (36  to 46°F).  Protect fromPage | 44                                |                                                           |
| Case 1317                           |                                         |                                                                                                               |                           |                                                                               |                                                           |  
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| pale brown   | light and                |
|--------------|--------------------------|
| liquid       | 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
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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.
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6.3 storage handling and dispensing

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 accordance with the package insert, summary of product characteristics (SmPC), or similar. 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. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020
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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"
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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.
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6.4 destruction or return of

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 disposed of, quantity disposed, and identification of the person disposing the 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.
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6.5 study drug administration

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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.  
| 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 + 240 mg IV nivolumab + 10 mg/kg IV bevacizumab 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 inline 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 infusion.
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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.
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6.5.3 dosing modifications

Dosing modifications, including dose reductions or dose escalations, are not permitted. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 Page | 47
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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.
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6.6 dose delay criteria 6.6.1

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. 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.
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6.6.2 criteria to delay or

Guidance for when bevacizumab administration should be delayed or discontinued should be in accordance with the package insert or summary of product characteristics (SmPC).  
Page | 48 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.  
| 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. 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  Discontinue bevacizumab. hemorrhage Grade > 1 non-CNS  Discontinue bevacizumab.  hemorrhage  Venous Thrombosis No dose modifications for grade 1/2 events |                      |  
Table 8 Bevacizumab Dose Management Due to Adverse Events  
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| Grade 3/ Asymptomatic                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Hold study drug treatment.                                                                                                                                                                                                                                                                                                                                                                                           | If the planned duration of full-dose anticoagulation is   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------|
| Grade 4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | <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 Grade 4 (nephrotic  Discontinue bevacizumab syndrome) 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  ReactionPage | 50 |                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                           |  
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| 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 Hold bevacizumab until recovery to ≤ Grade 1 Grade 4 Discontinue bevacizumab. |                                                                                                                                                                                                                                                                                                                     |
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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 treatment in the presence of Grade 2 skin toxicity 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.  
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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.
While the nivolumab investigator brochure contains safety management algorithms for similar adverse events, the recommendations are to follow the nivolumab algorithms for immuneoncology 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.
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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,
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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
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 drugrelated 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
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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
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6.8 treatment of nivolumab related

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:
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 antiinflammatory 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) Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 Page | 54 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 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 lateoccurring 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). Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020
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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 pretreatment 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.
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6.10 treatment beyond initial radiologic

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. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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.
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6.10.1 central neuropathologic review of

Representative tumor tissue samples will be reviewed locally for progression versus treatmentassociated changes.
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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 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020
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7.0 adverse events and potential

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
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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%). 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%). Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020 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 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Protocol Amendment 3 01/06/2020 Protocol Amendment 4 03/20/2020  
| Preferred Term                                                                 | 0.1 mg/kg   | 0.3 mg/kg   | 10 mg/kg   | Total   |         |       |         |       |         |         |          |         |
|--------------------------------------------------------------------------------|-------------|-------------|------------|---------|---------|-------|---------|-------|---------|---------|----------|---------|
| 1 mg/kg                                                                        | 3 mg/kg     |             |            |         |         |       |         |       |         |         |          |         |
| n=18                                                                           | n=54        | n=131       | N=306      |         |         |       |         |       |         |         |          |         |
| n=17                                                                           | n=86        |             |            |         |         |       |         |       |         |         |          |         |
| Any                                                                            | Grade       | Grade       | Grade      | Any     | Grade   | Any   | Grade   | Grade |         |         |          |         |
| Grade                                                                          | 3.4         | Grade       | 3.4        | Grade   | 3-4     | Grade | 3-4     | Grade | 3       | Grade   | 34       |         |
| Any Select AE                                                                  | 8 (47)      | 1 (5.9)     | 9 (50)     | o       | 42 (49) | 3 (4) | 23 (43) | 2 (4) | 58 (44) | 13 (10) | 140 (46) | 19 (6)  |
| 4 (24)                                                                         | 2 (11)      | 3 (1)       |            |         |         |       |         |       |         |         |          |         |
| Any                                                                            | o           | 0           | 9 (11)     | o       | 4 (7)   | o     | 10 (8)  | 3 (2) | 29 (10) |         |          |         |
| Endocrinopathies                                                               |             |             |            |         |         |       |         |       |         |         |          |         |
| Endocrinopathies                                                               | 3 (18)      | 0           | 2 (11)     | 0       | 9 (11)  | 4 (7) | 0       | 8 (6) | 2 (2)   | 26 (9)  | 2 (1)    |         |
| Thyroid                                                                        |             |             |            |         |         |       |         |       |         |         |          |         |
| Blood TSH                                                                      | 2 (12)      | 0           | 1 (6)      | 0       | 2 (2)   | 0     | 2 (4)   | 0     | 4 (3)   | 1 (1)   | 1 (4)    | 1 (0.3) |
| increased                                                                      |             |             |            |         |         |       |         |       |         |         |          |         |
| Hypothyroidism                                                                 | 3 (2)       | 1 (4)       | 1 (0.3)    |         |         |       |         |       |         |         |          |         |
| 1 (6)                                                                          | 0           | 1 (6)       | 0          | s (6)   | 0       | 1 (2) | 0       | 1 (1) |         |         |          |         |
| Any Skin AEs                                                                   | 3 (18)      | o           | 5 (28)     | o       | 27 (31) | o     | 12 (22) | o     | 28 (21) | 1 (1)   | 75 (25)  | 1 (0.3) |
| Rash                                                                           | 3 (18)      | 0           | 3 (17)     | 0       | 20 (23) | 0     | 5 (9)   | 0     | 14 (11) | 45 (15) | 0        |         |
| 0                                                                              |             |             |            |         |         |       |         |       |         |         |          |         |
| Prunitus                                                                       | 0           | 0           | 1 (6)      | 0       | 15 (17) | 0     | 3 (6)   | 0     | 13 (10) | 1 (1)   | 32 (11)  | 1 (0.3) |
| Any GI AE                                                                      | 1 (6)       | o           | 2 (11)     | o       | 19 (22) | o     | 7 (13)  | o     | 14 (11) | 3 (2)   | 43 (14)  | 3 (1)   |
| Diarrhea                                                                       | 2(11)       | 19 (22)     | 6 (11)     | 13 (10) | 41 (13) | 3 (1) |         |       |         |         |          |         |
| 1 (6)                                                                          | 0           | 0           | 0          | 0       | 3 (2)   |       |         |       |         |         |          |         |
| Any hepatic AE                                                                 | 0           | 0           | 2 (11)     | 0       | 8 (9)   | 0     | 3 (6)   | 2 (4) | 5 (4)   | 2 (2)   | 18 (6)   | 4 (1)   |
| ALT increased                                                                  | 0           | 0           | 1 (6)      | o       | 6 (1)   | 0     | 1 (2)   | 0     | 3 (2)   | 1 (1)   | 1 (4)    | 1 (0.3) |
| Any Pulmonary AE                                                               | 1 (6)       | o           | 1 (6)      | o       | 6 (7)   | 3 (4) | 2 (4)   | o     | 7 (5)   | 3 (2)   | 17 (6)   | 6 (2)   |
| Pneumonitis                                                                    | 1 (6)       | 0           | 1 (6)      | 0       | 4 (5)   | 2 (2) | 1 (2)   | 0     | 6 (5)   | 2 (2)   | 12 (4)   | 4 (1)   |
| Other Select AE                                                                | o           | o           | 1 (6)      | o       | 3 (4)   | o     | 3 (6)   | o     | 8 (6)   | 2 (2)   | 15 (5)   | 2 (1)   |
| Infusion-related                                                               | 0           | 0           | 1 (6)      | 0       | 3 (4)   | 0     | 3 (6)   | 0     | 5 (4)   | 0       | 12 (4)   | 0       |
| reaction                                                                       |             |             |            |         |         |       |         |       |         |         |          |         |
| Abbreviations: ALT: alanine aminotransferase, TSH: thyroid stimulating hormone |             |             |            |         |         |       |         |       |         |         |          |         |
| Source: Preliminary data, MDX1106-03. Clinical data cut-off date: 18-Mar-2013  |             |             |            |         |         |       |         |       |         |         |          |         |  
Source: Preliminary data, MDX1106-03. Clinical data cut-off date: 18-Mar-2013
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7.1.2 bevacizumab adverse event profile

In the initial Phase I and II clinical trials, four potential bevacizumab-associated safety signals identified: hypertension, proteinuria, thromboembolic events, and hemorrhage.  
were 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 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 Page | 60