untitled h1
case 1317

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 therapy. Therefore, caution should be exercised before initiating bevacizumab therapy in these subjects. Monitoring of blood pressure is recommended during bevacizumab therapy. Optimal control of blood pressure according to standard public health guidelines is recommended for subjects on treatment with or without bevacizumab. Temporary interruption of bevacizumab therapy is recommended in subjects with hypertension requiring medical therapy until adequate control is achieved. If hypertension cannot be controlled with medical therapy, bevacizumab therapy should be permanently discontinued. Bevacizumab should be permanently discontinued in subjects who develop hypertensive crisis or hypertensive encephalopathy.  
Proteinuria: An increased incidence of proteinuria has been observed in subjects treated with bevacizumab compared with control arm subjects. In the bevacizumab‐containing treatment arms of clinical trials (across all indications), the incidence of proteinuria (reported as an adverse event) was up to 38% (metastatic CRC Study AVF2192g).67 The severity of proteinuria has ranged from asymptomatic and transient events detected on routine dipstick urinalysis to nephrotic syndrome; the majority of proteinuria events have been Grade 1.  
NCI‐CTC Grade 3 proteinuria was reported in up to 3% of bevacizumab‐treated subjects, and Grade 4 in up to 1.4% of bevacizumab‐treated subjects. The proteinuria seen in bevacizumab clinical trials was not associated with renal impairment and rarely required permanent discontinuation of bevacizumab therapy. Bevacizumab should be discontinued in subjects who develop Grade 4 proteinuria (nephrotic syndrome). Subjects with a history of hypertension may be at increased risk for the development of proteinuria when treated with bevacizumab. There is evidence from the dose‐finding, Phase II trials (AVF0780g, AVF0809s, and AVF0757g) suggesting that Grade 1 proteinuria may be related to bevacizumab dose. Proteinuria will be monitored by urinalysis, and urine protein: creatinine (UPC) ratio when necessary.  
Thromboembolic Events: Both venous and arterial thromboembolic (TE) events, ranging in severity from catheter‐associated phlebitis to fatal, have been reported in subjects treated with bevacizumab in the colorectal cancer trials, the recurrent glioblastoma trial and, to a lesser extent, in subjects treated with bevacizumab in NSCLC and breast cancer trials. Venous thromboembolic events (VTE) have also been observed in trials with bevacizumab and glioblastoma. To assess the overall risk of VTE associated with the use of bevacizumab, a systemic review and meta-analysis was performed and included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab.68 A total of 7,956 subjects with a variety of advanced solid tumors from 15 trials were identified. Among the subjects treated with bevacizumab, the rates of all-grade and highgrade VTE were 11.9% and 6.3, respectively. Subjects treated with bevacizumab had a significantly increased risk of VTE compared with controls (RR 1.31). Since TE events are very common in GBM independent of treatment,2 the relationship of thromboembolism to Page | 61  
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 in this population is uncertain. Based on a Phase II clinical trial of bevacizumab with or without irinotecan in recurrent GBM, the rates of arterial thromboembolism were 2.4%-2.5% and venous thromboembolism were 3.6%- 8.9%.60 The first incidence of VTE will therefore not constitute a DLT. An increased incidence of arterial thromboembolic events (ATE) was observed in subjects treated with bevacizumab compared with those receiving control treatments. ATE includes cerebrovascular accidents, myocardial infarction, transient ischemic attacks (TIAs), and other ATE. The analysis of pooled data of 1,745 subjects from five randomized trials using bevacizumab combined with chemotherapy showed an increased risk of ATE (3.8% in treatment arm vs. 1.7% in the control arm) but not VTE.69 Most ATE episodes described were myocardial or cerebrovascular events. Development of an ATE event was associated with a prior ATE event or age ≤ 65 years.  
Gastrointestinal perforation: Subjects may be at increased risk for the development of gastrointestinal perforation and fistula when treated with bevacizumab and steroids or chemotherapy. Bevacizumab should be permanently discontinued in subjects who develop gastrointestinal perforation. A causal association of intra‐abdominal inflammatory processes and gastrointestinal perforation to bevacizumab treatment has not been established.  
Nevertheless, caution should be exercised when treating subjects with intra‐abdominal inflammatory processes with bevacizumab. A meta-analysis of 17 randomized controlled trials demonstrated a significantly increased risk of gastrointestinal perforation in subjects treated with bevacizumab compared to control medication.70 The incidence was 0.9%, and the risks varied with tumor type, with colorectal cancer and renal cell cancer having the highest risk. In a Phase II clinical trial of bevacizumab with or without irinotecan for subjects with recurrent GBM, 2.1%-2.5% experienced a Grade 3 gastrointestinal perforation.59,60 Fistula: Bevacizumab use has been associated with serious cases of fistulae including events resulting in death. Fistulae in the GI tract are common (1%–10% incidence) in subjects with metastatic CRC, but uncommon (0.1%-1%) or rare (0.01%–0.1%) in other indications. In addition, fistulae that involve areas of the body other than the GI tract (e.g. tracheoesophageal, bronchopleural, urogenital, biliary) have been reported uncommonly (0.1%–1%) in subjects receiving bevacizumab in clinical studies and post-marketing reports. Events were reported at various time points during treatment, ranging from 1 week to > 1 year following initiation of bevacizumab, with most events occurring within the first 6 months of therapy.  
Wound healing complications: Wound healing complications such as wound dehiscence have been reported in subjects receiving bevacizumab. Most clinical trials with bevacizumab have required at least 28 days from any major surgery before starting treatment.71 In a retrospective analysis of randomized trials in metastatic colorectal cancer, for a subset of subjects who had Page | 62 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 surgeries 28-60 days before initiating bevacizumab, the incidence of wound complications were low (1.3%),72 indicating that the 28-day interval from colonic surgery might be appropriate. However, in the subset of subjects undergoing emergent surgery while on study, 13% of the subjects in the bevacizumab arm developed Grade 3 or Grade 4 postoperative wound complications compared to 3.4% of the subjects in the chemotherapy arm. Surgery in subjects currently receiving bevacizumab is not recommended. No definitive data are available to define a safe interval after bevacizumab exposure with respect to wound healing risk in subjects receiving elective surgery; however, the estimated half-life of bevacizumab is 21 days. Bevacizumab should be discontinued in subjects with severe wound healing complications. If subjects receiving treatment with bevacizumab require elective major surgery, it is recommended that bevacizumab be held for 4–8 weeks prior to the surgical procedure. Subjects undergoing a major surgical procedure should not begin or restart bevacizumab until 4 weeks after that procedure (in the case of high‐risk procedures such as liver resection, thoracotomy, or neurosurgery, it is recommended that bevacizumab be restarted no earlier than 4 weeks after surgery). In a Phase II clinical trial of bevacizumab with or without irinotecan in subjects with recurrent GBM, Grade 3 or higher wound-healing complications were reported in 1.3-2.4%.60 1132 subjects treated with bevacizumab in a pooled database from eight Phase I, Phase II, and Phase III clinical trials in multiple tumor types (Genentech 2005). The hemorrhagic events that have been observed in bevacizumab clinical studies were predominantly tumor‐associated hemorrhage (See below: Tumor-Associated Hemorrhage) and minor mucocutaneous hemorrhage. Tumor-Associated Hemorrhage: Major hemorrhage has been observed primarily in subjects with NSCLC. Life‐threatening and fatal hemoptysis was identified as a bevacizumab‐related adverse event in NSCLC trials. These events occurred suddenly and presented as major or massive hemoptysis. GI hemorrhages, including rectal bleeding and melena have been reported in subjects with CRC, and have been assessed as tumor associated hemorrhages. Grades 1-4 tumor‐associated hemorrhages were only very rarely seen in subjects with GBM (less than 4%).60 Two of the five subjects who developed intracranial hemorrhage were anticoagulated at the time of the hemorrhage; both hemorrhages were Grade 1.  
Mucocutaneous Hemorrhage: Across all bevacizumab clinical trials, mucocutaneous hemorrhage has been seen in 20%‐40% of subjects treated with bevacizumab (Genentech 2005). These were most commonly NCICTC Grade 1 epistaxis that lasted less than 5 minutes, resolved without medical intervention and did not require any changes in bevacizumab treatment regimen. There have also been less common events of minor mucocutaneous hemorrhage in other locations, such as gingival bleeding and vaginal bleeding. 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 Reversible Posterior Leukoencephalopathy Syndrome: There have been rare reports of bevacizumab‐treated subjects developing signs and symptoms that are consistent with RPLS, a rare neurologic disorder that can present with the following signs and symptoms (among others): seizures, headache, altered mental status, visual disturbance, or cortical blindness, with or without associated hypertension. Brain imaging is mandatory to confirm the diagnosis of RPLS. In subjects who develop RPLS, treatment of specific symptoms, including control of hypertension, is recommended along with discontinuation of bevacizumab. The safety of reinitiating bevacizumab therapy in subjects previously experiencing RPLS is not known. In a Phase II clinical trial of bevacizumab with or without irinotecan in subjects with recurrent GBM, only one patient (1.3%) experienced serious reversible posterior leukoencephalopathy syndrome.60 Congestive heart failure: In clinical trials CHF was observed in all cancer indications studied to date, but predominantly in subjects with metastatic breast cancer. In the Phase III clinical trial of metastatic breast cancer (AVF2119g), 7 (3%) bevacizumab‐treated subjects experienced CHF, compared with two (1%) control arm subjects.73 These events varied in severity from asymptomatic declines in left ventricular ejection fraction (LVEF) to symptomatic CHF requiring hospitalization and treatment. All the subjects treated with bevacizumab were previously treated with anthracyclines (doxorubicin cumulative dose of 240-360 mg/m2). Many of these subjects also had prior radiotherapy to the left chest wall. Most of these subjects showed improved symptoms and/or left ventricular function following appropriate medical therapy.73 No information is available on subjects with preexisting CHF of New York Heart Association (NYHA) Class II-IV at the time of initiating bevacizumab therapy, as these subjects were excluded from clinical trials.  
Adverse events in GBM studies from FDA labeling information: Bevacizumab is commercially available and FDA approved for subjects with recurrent glioblastoma. For further details, see the bevacizumab FDA labeling information available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125085s0169lbl.pdf. All adverse events were collected in 163 subjects enrolled in a non-comparative Phase II study who either received bevacizumab alone or bevacizumab plus irinotecan.60 All subjects received prior radiotherapy and temozolomide. Bevacizumab was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Bevacizumab was discontinued due to adverse events in 4.8% of subjects treated with bevacizumab alone. In subjects receiving bevacizumab alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to bevacizumab: one retroperitoneal hemorrhage and one neutropenic infection. In subjects receiving bevacizumab alone or bevacizumab plus irinotecan Page | 64 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 (N=163), the incidence of bevacizumab-related adverse events (Grade 1−4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3−5 events in these 163 subjects were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).
untitled h1
7.2 definitions 7.2.1 adverse events

An *Adverse Event (AE)* is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product. The causal relationship to study drug is determined by a physician and should be used to assess all adverse events (AE). The casual relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and the AE. Not related: There is not a reasonable causal relationship between study drug administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the specific occurrence of one or more AEs.)
untitled h1
7.2.2 serious adverse events

A S*erious Adverse Event (SAE)* is any untoward medical occurrence that at any dose:
results in death is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)
Page | 65  
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 requires inpatient hospitalization or causes prolongation of existing hospitalization results in persistent or significant disability/incapacity is a congenital anomaly/birth defect is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed in the definition above.). Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)
Potential drug induced liver injury (DILI) is also considered an important medical event.  
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study drug is an SAE.  
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI)
are not always serious by regulatory definition, these events must be handled as SAEs.  
Any component of a study endpoint that is considered related to study therapy (e.g.,
death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported as SAE
untitled h1
note

The following hospitalizations are not considered SAEs in BMS clinical studies:
a visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered an important medical or life-threatening event)
elective surgery, planned prior to signing consent admissions as per protocol for a planned medical/surgical procedure routine health assessment requiring admission for baseline/trending of health status
(e.g., routine colonoscopy)
medical/surgical admission other than to remedy ill health and planned prior to entry into the study. Appropriate documentation is required in these cases admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reason).  
Admission for administration of anti-cancer therapy in the absence of any other SAEs
untitled h1
potential drug induced liver injury

Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, Page | 66  
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 meeting the defined criteria, must be reported as SAEs. Potential drug induced liver injury is defined as:
ALT or AST elevation > 3 times upper limit of normal (ULN)
AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase)
AND
No other immediately apparent possible causes of AST/ALT elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
untitled h1
7.3 reporting procedures for all

All participating investigators will assess the occurrence of AEs throughout the subject's participation in the study starting with day 1 of treatment. Subjects will be followed for toxicity for 100 days after treatment has been discontinued or until death, whichever occurs first. The clinical course of each event will be followed until resolution, stabilization, or until it has been determined that the study treatment or participation is not the cause. The investigator is responsible for ensuring that all adverse events observed by the investigator or reported by the subject which occur after the subject has signed the informed consent are fully recorded in the subject's case report form, subject's medical records, and/or any other institutional requirement. Source documentation must be available to support all adverse events. A laboratory test abnormality considered clinically relevant (e.g., causing the subject to withdraw from the study), requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator, should be reported as an adverse event. The investigator will provide the following for all adverse events:
Description of the event Term that defines seriousness for the particular event, e.g., Hospitalization or Important Medical Event Date of onset and resolution Grade of toxicity Attribution of relatedness to each of the investigational agents, in this study nivolumab Action taken with each agent as a result of the event Page | 67  
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
untitled h1
outcome of event

In this study, descriptions and grading scales found in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 available at http://ctep.cancer.gov will be utilized for AE reporting. Investigative sites will report adverse events to their respective IRB according to the local IRB's policies and procedures in reporting adverse events.
untitled h1
7.4 reporting procedures for serious

Serious adverse events that occur beginning with the signing of the informed consent form, during treatment, or within 100 days of the last dose of treatment must be reported to the Principal Investigator. SAEs will be reported promptly to the Sponsor-Investigator Manmeet Ahluwalia M.D. or his designated study coordinator once the investigator determines that the event meets the protocol definitions of an SAE. Once an investigator becomes aware that an SAE has occurred in a study patient, the investigator must report the information to the Sponsor-Investigator Manmeet Ahluwalia M.D. or his designated study coordinator within 24 hours Investigative sites will report serious adverse events to their respective IRB according to the local IRB's policies and procedures in reporting serious adverse events.
untitled h1
7.4.1 bristol-myers squibb company serious

Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, must be collected, including those thought to be associated with protocol-specified procedures. All SAEs must be collected that occur within 100 days of discontinuation of dosing. All SAEs must be collected that occur during the screening period. If applicable, SAEs must be collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy). The investigator should report any SAE that occurs after these time periods that is believed to be related to study drug or protocol-specified procedure. 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 SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a Pregnancy Surveillance Form.  
SAE Email Address: Worldwide.Safety@BMS.com
untitled h1
sae facsimile number 609-818-3804

If only limited information is initially available, follow-up reports are required. (Note: Followup SAE reports should include the same investigator term(s) initially reported.)
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the same procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. For studies conducted under an Investigator IND in the US, any event that is both serious and unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) after the investigator's or institution's initial receipt of the information. BMS will be provided with a simultaneous copy of all adverse events filed with the FDA. SAEs should be reported on MedWatch Form 3500A, which can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. MedWatch SAE forms should be sent to the FDA at: MEDWATCH 5600 Fishers Lane Rockville, MD 20852-9787 Fax: 1-800-FDA-0178 (1-800-332-0178) http://www.accessdata.fda.gov/scripts/medwatch/ All SAEs should simultaneously be faxed or e-mailed to BMS at: Global Pharmacovigilance & Epidemiology Bristol-Myers Squibb Company Fax Number: 609-818-3804 Email: Worldwide.safety@bms.com Reporting Serious Adverse Events to the IRB/IEC: It is the Investigator's responsibility to report SAEs to the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) according to the requirements of the governing IRB/IEC. 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 | 69
untitled h1
worldwide.safety@bms.comaepbusinessprocess@bms.com 7.4.2 fda reporting

The Cleveland Clinic Principal Investigator, as holder of the IND, will be responsible for all communication with the FDA. In accordance with 21 CFR 312.32, the Cleveland Clinic Principal Investigator is responsible for notifying the FDA of SAEs that are serious, unexpected (not listed in the Investigator Brochure) and judged to be related (i.e., possible, probable, definite) to the study drug. Events meeting the following criteria need to be submitted to the FDA as Expedited IND Safety Reports.
untitled h1
7 calendar day ind safety

Any unexpected fatal or life-threatening suspected adverse event represents especially important safety information and, therefore, must be reported more rapidly to FDA (21 CFR 312.32(c)(2)). Any unexpected fatal or life-threatening suspected adverse event must be reported to FDA no later than 7 calendar days after the Cleveland Clinic Investigator's initial receipt of the information (21 CFR 312.32(c)(2)). Cleveland Clinic Principal Investigator will complete a Medwatch Form FDA 3500A and notify the FDA by telephone or facsimile transmission.
untitled h1
15 calendar day ind safety

The timeframe for submitting an IND safety report to FDA and all participating investigators is no later than 15 calendar days after the Cleveland Clinic Principal Investigator determines that the suspected adverse event or other information qualifies for reporting (21 CFR 312.32(c)(1)). This includes any serious, unexpected adverse events considered reasonably or possibly related to the investigational agent and that are not life-threatening or fatal. The Cleveland Clinic Principal Investigator will complete a Medwatch Form FDA 3500A and notify the FDA by telephone or facsimile transmission. If FDA requests any additional data or information, the Cleveland Clinic Principal Investigator must submit it to FDA as soon as possible, but no later than 15 calendar days after receiving the request (21 CFR 312.32(c)(1)(v)).
untitled h1
follow-up ind safety report

Any relevant additional information that the Cleveland Clinic Principal Investigator obtains that pertains to a previously submitted IND safety report must be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the information is available (21 CFR 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 312.32(d)(2)). The Cleveland Clinic Principal Investigator will maintain records of its efforts to obtain additional information.
untitled h1
reporting serious problems to fda

http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm Telephone: 1-800-332-1088 Fax: 301-796-9849 The fax cover sheet should note that this report will also be submitted formally in triplicate to the IND as an amendment per 21 CFR 312.32 (i.e. a formal paper submission to the Beltsville address).
untitled h1
ind annual reports

A summary of all IND safety reports submitting during the previous year will be reported to the FDA in the annual report by the Cleveland Clinic principal investigator, as holder of the IND.A copy will be sent to BMS.
untitled h1
saes and oncore - added

A copy of the SAE form(s) submitted to the sponsor-investigator is also uploaded into Oncore.  
7.5 Data Safety and Toxicity Committee It is the responsibility of each site PI to ensure that ALL SAEs occurring on this trial (internal or external) are reported to the Case Comprehensive Cancer Center's Data and Safety Toxicity Committee. This submission is simultaneous with their submission to the sponsor and/or other regulatory bodies. The sponsor-investigator is responsible for submitting an annual report to the DSTC as per CCCC Data and Safety Monitoring Plan.
untitled h1
7.6 data and safety monitoring

This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety Monitoring Plan in accordance with NCI guidelines.
untitled h1
8.0 pharmaceutical information

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 A list of the adverse events and potential risks associated with the investigational or commercial agents administered in this study can be found in Section 7.0.
untitled h1
nomenclature

| Research Name:   | BMS-936558   |
|------------------|--------------|
| Generic Name:    | Nivolumab    |
untitled h1
description of nivolumab

Nivolumab (also referred to as BMS-936558 or MDX1106) is a fully human monoclonal antibody (HuMAb; immunoglobulin G4 [IgG4]-S228P) that targets the programmed death-1 (PD-1) cluster of differentiation 279 (CD279) cell surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligands 1 (PD-L1) and 2 (PD-L2), results in the downregulation of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-antigens. The clinical study product is a sterile solution for parenteral administration.
untitled h1
drug substance chemistry

Nivolumab is a soluble protein consisting of 4 polypeptide chains, which include 2 identical heavy chains and 2 identical light chains. Nivolumab has a molecular weight of 146,221 daltons. It is a clear to opalescent, colorless to pale yellow liquid, which may contain light (few) particulates. The clinical study product is a sterile solution for parenteral administration. Drug Product Please refer to Investigational Brochure in Appendix. Container/Closure 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 Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial. Ten or five vials are provided in a carton.
untitled h1
storage and handling of pharmaceutical

Store at 2-8°C (36-46°F), protect from light, freezing, and shaking.  
If any temperature excursions are encountered during storage, please report these to BMS
for assessment via the Temperature Excursion Response Form.  
As with all injectable drugs, care should be taken when handling and preparing nivolumab.  
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents applying aseptic technique.  
Partially used vials should be disposed at the site following procedures for the disposal of anticancer drugs.  
After final drug reconciliation, unused nivolumab vials should be disposed at the site following procedures for the disposal of anticancer drugs.
untitled h1
use time/stability

Due to parameters surrounding the use time of Nivolumab, the time of preparation should be noted in the Pharmacy Source documents [accountability logs] or in study files as required for investigator sponsored research [FDA and GCP] The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be completed within 24 hours of preparation. If not used immediately, the infusion solution may be stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°- 46°F) and used within 4for up to 24 hours, and a maximum of 4 hours of the total 24 hours can be at room temperature (20°-25°C, 68°-77°F) and under room light. The maximum 4-hour period under room temperature and room light conditions for undiluted and diluted solutions of BMS-936558-01 injection in the IV bag should be inclusive of the includes the product administration period. 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
untitled h1
drug preparation and administration

1. Visually inspect the drug product solution for particulate matter and discoloration prior to administration. Discard if solution is cloudy, if there is pronounced discoloration (solution may have a pale-yellow color), or if there is foreign paticulate matter other than a few translucent-to-white, amorphous particles. Note: Mix by **gently** inverting several times. **Do not** *shake.*
2. Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense into an IV. bag. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. **Do not**
enter into each vial more than once. **Do not** administer study drug as an IV push or bolus injection 3. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose Injection solution. *It is acceptable to add nivolumab solution from the vials into an* appropriate pre-filled bag of diluent. Note: Nivolumab infusion concentration must be at or above the minimum allowable concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] Note: It is not recommended that so-called "channel" or tube systems are used to transport prepared infusions of nivolumab.  
4. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 5. At the end of the infusion period, flush the line with a sufficient quantity of approved diluents.
untitled h1
drug accountability

The investigator or designated study personnel are responsible for maintaining accurate dispensing records of the study drug. All study drugs must be accounted for, including study drug accidentally or deliberately destroyed. Under no circumstances will the investigator allow the investigational drug to be used other than as directed by the protocol. If appropriate, drug storage, drug dispensing, and drug accountability may be delegated to the pharmacy section of the investigative site.
untitled h1
drug destruction

At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and dated. Any discrepancies noted will be investigated, resolved, and documented prior to return or destruction of unused study drug. Drug destroyed on site will be documented in the study files."  
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
untitled h1
8.2 bevacizumab form

Bevacizumab is a clear to slightly opalescent, colorless to pale brown, sterile liquid concentrate for solution for intravenous (IV) infusion. Vials contain bevacizumab with phosphate, trehalose, polysorbate 20, and sterile water for injection (SWFI), USP. Vials contain no preservative and are suitable for single use only. This agent is commercially available and manufactured by Genentech.
untitled h1
administration

Bevacizumab is to be administered according to institutional standards. The dose of bevacizumab is 10 mg/kg IV for subjects on Arm A and 3 mg/kg for subjects on Arm B. Bevacizumab is administered on Days 1, 15 of each 4 week cycle. A window of +/- 3 day for bevacizumab dosing is acceptable but bevacizumab doses must be at least 12 days apart.
untitled h1
accountability

The investigator or designated study personnel are responsible for maintaining accurate dispensing records of bevacizumab which are to include start time of infusion, stop time of infusion, total volume.
untitled h1
9.0 study parameters and calendar

Screening studies and evaluations will be used to determine the eligibility of each subject for study inclusion. All evaluations must be completed < 14 days prior to administration of protocol therapy, except where otherwise noted.
untitled h1
9.1.2 treatment period

Enrolled subjects will randomize to Arm A (nivolumab + standard bevacizumab) and Arm B (nivolumab and low dose bevacizumab). Treatment is every 2 weeks and will continue until  
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 evidence of disease progression as determined by iRANO criteria, unacceptable toxicity, or death. In view of the Covid 19 crisis, all in person visits can be substituted for virtual visit. All nursing toxicity checks can be performed over the phone rather than in person. 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
untitled h1
9.2 study calendar

| Table 9.2.1 Study Calendar: Assessments prior to, during, and after therapy (Both Arms A and B):  Screening  w/in 28 days unless  otherwise indicated All Cycles - both odd  and even Day 1 Week 1, then  every 2 weeks (± 4  days) - unless  otherwise indicated Follow-up #1 - ᶻ Follow-up #2 - ᵃᵃ Survival - ᵇᵇ Informed Consent Xᵃ Inclusion/Exclusion  Xᵇ Criteria Medical History X Tumor Tissue Availability Xᵈ˒ ʰ MGMT Status Xᶜ Physical & Neurological  X (within 14 days) ˡ X (not required D1 Wk  X ˡ Exam 1) ˡ,  cc , cc Xᶠ Vital Signs Xᶠ Xᶠ Performance Status (KPS) Xᶢ Xᶰ , cc X Height and Weight Xᵉ Xᶰ X Adverse Event Assessment Xᶢ Continuously X Concomitant Medication  Collection & Review Xᶢ X X Steroid Documentation &  Xᶢ X XReview   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
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 | 77  
| CBC w/ differential                          | X ᶢ                                        | X ᵒ       | X   |
|----------------------------------------------|--------------------------------------------|-----------|-----|
| CMP                                          | X ᶢ                                        | X ᵒ       | X   |
| LDH                                          | X ᶢ                                        | X ᵒ       | X   |
| Magnesium                                    | X ᶢ                                        | X ᵒ       |     |
| Amylase                                      | X ᶢ                                        | X ᵒ       |     |
| Lipase                                       | X ᶢ                                        | X ᵒ       |     |
| TSH                                          | X ᶢ                                        | X ᵒ˒ᵖ     | X   |
| FT4                                          | X ᶢ                                        | X ᵒ˒ᵖ     |     |
| FT3                                          | X ᶢ                                        | X ᵒ˒ᵖ     |     |
| HBsAg, HCV                                   | X ᶢ                                        |           |     |
| Cytokine/chemokine/PBMC  Correlative Studies | X ᶢ˒ ʰ                                     | X ʰ˒ ᶸ    |     |
| Urinalysis - dipstick                        | X ᶢ                                        | X ʳ       |     |
| HCG - serum (WOCBP only)                     | X ᶢ                                        | X s       | X   |
| 12-Lead EKG                                  | X ᶢ                                        | X ᵗ       | X ᵗ |
| Tumor Assessments                            | X ᴵ                                        | X ʲ       | X ʸ |
| NANO scale                                   | X ᵛ                                        |           |     |
| Administer Study                             | Within 3 working days of                   |           |     |
| Treatment                                    | randomization:  Nivolumab and  Bevacizumab | Page | 78 |     |
| Case 1317                                    |                                            |           |     |  
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  
| administered every 2  weeks +/- 2days  X bb   |     |
|-----------------------------------------------|-----|
| Survival Status                               | X ʷ |  
a. Study allows for re-enrollment of a subject that has discontinued the study as a pre-treatment failure.  
b. Inclusion/Exclusion criteria should be assessed at screening and confirmed prior to randomization.  
c. If available d. Archival or fresh tissue taken at any point prior to study treatment. Up to 10 unstained slides of 5 microns thickness or block tissue will be required.  
e. Weight (Day 1 Wk 1, then every 4 weeks); height (only at baseline) f. BP, HR, temperature and respiratory rate g. Within 14 days prior to randomization h. See Appendix 8 i. Within 21 days of randomization j. Every 8 weeks (+/- 1 week)
k. Perform every 28 days on D1 of each cycle (+/- 4 days)
l. Includes cardiovascular, neurological and abdominal exams; D1 of each cycle m. Within 72 hours prior to first dose n. Day 1 of each cycle o. Complete prior to each dose through Wk 21, then every 4 weeks (Day 1 of each cycle). p. After C1D1 - TSH, FT3, FT4 are done every 8 weeks (+/- 1 week)
q. blank r. Dipstick within 72 hours prior to each bevacizumab dose. Subjects with 4+ (300-1000) proteinuria readings must undergo further assessment with a 24 hour urine collection prior to being dosed.  
s. Every 4 weeks (+/- 1 week)
t. As clinically indicated u. Obtain at week 4, week 8, and then at every MRI visit until progression v. Completed by study physician prior to dosing Wk 1 Day 1, and then with each MRI (must be done before MRI is reviewed with the subject)
w. Repeat labs at follow-up visit \#2 if study drug related toxicities persist x. May be obtained through a phone call or clinic visit y. Only for subjects who did not progress while on study therapy, including subjects who start subsequent anticancer therapy. Tumor assessments will not be collected for subjects who are lost to follow or withdraw consent.  
z. Subjects must be followed for at least 100 days after the last dose of study therapy. Follow-up visit
\#1 occurs approximately 35 days (+/- 1 week) after last dose or coinciding with the date of discontinuation so long as the date of discontinuation is greater than 35 days after last dose.  
aa. Follow-up visit \#2 occurs approximately 80 days (+/- 1 week) after F/U \#1 bb. +/- 2 days cc. In view of covid-19 crisis, virtual visits will be allowed and the need for physical exam as long as patient is asymptomatic will be waived.  
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
untitled h1
10.0 measurement of effect 10.1

Definitions of Tumor Response will be based on RANO criteria. There is an exploratory analysis using the iRANO criteria.65 Please refer to Appendix 2. 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
untitled h1
11.0 data reporting / regulatory

Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 (Adverse Events: List and Reporting Requirements).
untitled h1
11.1 data reporting

The OnCore™ Database will be utilized, as required by the Case Comprehensive Cancer Center, to provide data collection for both accrual entry and trial data management. OnCore™ is a Clinical Trials Management System housed on secure servers maintained at Case Western Reserve University. OnCore™. Access to data through OnCore™ is restricted by user accounts and assigned roles. Once logged into the OnCore™ system with a user ID and password, OnCore™ defines roles for each user which limits access to appropriate data. User information and password can be obtained by contacting the OnCore™ Administrator at OnCoreregistration@case.edu.  
OnCore™ is designed with the capability for study setup, activation, tracking, reporting, data monitoring and review, and eligibility verification. This study will utilize electronic Case Report Form completion in the OnCore™ database. A calendar of events and required forms are available in OnCore™.
untitled h1
11.2 regulatory considerations

The study will be conducted in compliance with ICH guidelines and with all applicable federal (including 21 CFR parts 56 & 50), state or local laws.
untitled h1
11.2.1 written informed consent

Provision of written informed consent must be obtained prior to any study-related procedures. The Principal Investigator will ensure that the subject is given full and adequate oral and written information about the nature, purpose, possible risks and benefits of the study as well as the subject's financial responsibility. Subjects must also be notified that they are free to discontinue from the study at any time. The subject should be given the opportunity to ask questions and be allowed time to consider the information provided. The original, signed written Informed Consent Form must be kept with the Research Chart in conformance with the institution's standard operating procedures. A copy of the signed written Informed Consent Form must be given to the subject. Additionally, documentation of the consenting process should be located in the research chart. 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
untitled h1
11.2.2 subject data protection

In accordance with the Health Information Portability and Accountability Act (HIPAA), a subject must sign an authorization to release medical information to the sponsor and/or allow the sponsor, a regulatory authority, or Institutional Review Board access to subject's medical information that includes all hospital records relevant to the study, including subjects' medical history.
untitled h1
11.2.3 retention of records

The Principal Investigator of The Case Comprehensive Cancer Center supervises the retention of all documentation of adverse events, records of study drug receipt and dispensation, and all IRB correspondence for as long as needed to comply with local, national and international regulations. No records will be destroyed until the Principal Investigator confirms destruction is permitted.
untitled h1
11.2.4 audits and inspections

Authorized representatives of the sponsor, a regulatory authority, an Independent Ethics Committee (IEC) or an Institutional Review Board (IRB) may visit the site to perform audits or inspections, including source data verification. The purpose of an audit or inspection is to systematically and independently examine all study-related activities and documents to determine whether these activities were conducted, and data were recorded, analysed, and accurately reported according to the protocol, Good Clinical Practice (GCP), guidelines of the International Conference on Harmonization (ICH), and any applicable regulatory requirements. For multi-center studies, participating sites must inform the sponsor-investigator of pending audits. 11.2.5 Data Safety and Monitoring Plan This protocol will adhere to the policies of the Case Comprehensive Cancer Center Data and Safety Monitoring Plan in accordance with NCI regulations.
untitled h1
12.0 statistical considerations statistical considerations

This section outlines the statistical analysis strategy and procedures for the study. If, after the study has begun, changes are made to primary and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the protocol has been finalized, along with an explanation as to when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory  
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 analyses will be clearly identified in the CSR. No separate Statistical Analysis Plan (SAP) for the primary, secondary and exploratory endpoints will be issued for this study. 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
untitled h1
12.1 statistical analysis plan summary

This section contains a brief summary of the statistical analyses for this trial. This trial includes randomization of accrual to two experimental treatment arms: nivolumab plus bevacizumab at standard dosing (Arm A); and nivolumab plus bevacizumab at reduced dosing (Arm B). The outcome of each treatment arm will be assessed separately relative to appropriate historical controls. The study consists of two arms to evaluate the efficacy and tolerability and safety profile of nivolumab in combination with reduced or standard dose bevacizumab in subjects with recurrent glioblastoma (in first recurrence). For this purpose, 90 eligible and evaluable subjects will be randomized in a 1:1 ratio to arm A (nivolumab plus standard bevacizumab) or arm B (nivolumab plus reduced dose bevacizumab). To facilitate robust data for assessing all objectives and generating future hypotheses, stratified randomization will be implemented in REDCap. The design will balance treatment assignments based on four stratification factors known to be prognostic for clinical outcomes. The stratification factors include: age (<=65 versus > 65), KPS (>=800 versus <800), Methylation Status (Not Methylated versus Methylated), Surgery Type (Biopsy Only, Partial Resection, Complete Resection/Near Complete Resection). The primary and secondary goals of the trial are to evaluate the safety and efficacy of the two therapies and to obtain a preliminary assessment of whether or not they differ with respect to outcome. The total sample size of 90 eligible and evaluable subjects randomized 1:1 to the two therapies is recommended to provide adequate statistical power to describe the efficacy and toxicity profiles of the two treatment arms. Using the BELOB trial, EORTC 26101 trial outcomes as historical benchmarks, the primary measure of efficacy for the current study will be the 12 month overall survival rate (OS12)47,48. OS-12 was approximately 45% in the BELOB and EORTC 26101 trials. The onesample log-rank test will be applied to outcomes observed for each arm individually to test the hypothesis that OS has been improved beyond the null 12-month survival rate of 45%. With N=45 subjects per arm, a one-sided test provides power=0.80 to detect survival rate of 58% at 12-months following treatment at the 0.10 significance level. Statistical calculations were implemented with PASS version 15.0.5.  
Although each treatment arm will be evaluated for efficacy independently they will also be compared in order to get a preliminary read on whether there is a signal that one may be Page | 84  
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 superior to the other. The sample size of N=45 subjects per treatment arm provides power=0.80 to detect a hazard ratio of 0.498 between the two study arms using a two-sided stratified logrank test. Statistical calculations were implemented with PASS version 15.0.5.  
With 45 subjects per arm the risk that a particular type and/or grade of adverse event will occur in a particular arm will be estimable using an exact 95% confidence interval that has a maximum half-width of 15%. For example, if 5 adverse events are observed (11%) the corresponding 95% confidence interval will be 4%-24%; if 20 are observed (44%) it will be 30%-60%. In addition, the likelihood of observing at least one adverse event of a particular type and/or grade is >90% even if the risk of such an event is only 5%. Although excessive toxicity is not expected, adverse events will be monitored continuously and the following table will be used as a guide for whether or not a formal review, possibly leading to early termination, should be considered.  
|              | Cumulative Likelihood of          |                         |     |     |     |     |
|--------------|-----------------------------------|-------------------------|-----|-----|-----|-----|
| Exceeding    | Consider Review if the Cumulative | the AE Threshold if the |     |     |     |     |
|              | No. Tx-Related Grade >3 AEs       | Risk of an Event is     |     |     |     |     |
| No. Subjects | Exceeds                           | 10%                     | 20% | 30% | 40% |     |
| 50%   1-10   | 4                                 | <1%                     | 3%  | 15% | 37% |     |
| 62%          |                                   |                         |     |     |     |     |
|              | 11-20                             | 7                       | <1% | 5%  | 27% | 62% |
| 88%          |                                   |                         |     |     |     |     |
|              | 21-30 10                          | <1%                     | 6%  | 36% | 76% | 96% |  
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
untitled h1
12.1.1 efficacy analysis

The primary and key secondary endpoints, primary analysis population, and statistical methods that will be employed for the efficacy analyses are discussed in detail in the following sections. The primary hypothesis of efficacy will be evaluated independently in each cohort.
untitled h1
12.1.2 safety analysis

Adverse events will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All subjects who receive any amount of nivolumab will be evaluable for toxicity. The All-Subjects-as-Treated population will be employed for safety analyses. Immune related adverse experiences are pre-specified as Events of Clinical Interest (Section 7.6.2).
untitled h1
12.2 statistical analysis plan

12.2.1 Responsibility for Analyses The statistical analysis of the data obtained from this study will be the responsibility of the study responsible biostatistician. This trial is being conducted as an open-label study, i.e., subjects, investigators, and SPONSOR personnel will be aware of subject treatment assignments after each subject is enrolled and treatment is assigned.
untitled h1
12.2.1 efficacy endpoints

All subjects within each arm that have been randomized will serve as the primary population for the analysis of the efficacy data in this study. Two supportive analyses of the primary and selected secondary efficacy endpoints will also be conducted. The first supportive analysis will include all subjects in the primary population for analysis who have a post baseline scan OR discontinue the trial due to progressive disease/drug related AE. The second analysis will be conducted using the intention to treat (ITT) population, defined as all randomized subjects.  
Subjects will be included in the arm to which they are randomized for the analysis of efficacy data. Efficacy endpoints that will be evaluated for are listed below, followed by the descriptions of the derivations of selected endpoints. The primary efficacy endpoint for both cohorts is OS-12, defined as the proportion of subjects in the analysis population who remain alive for at least twelve months following initiation of  
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 study therapy. Response for the primary analysis will be determined by the investigator assessment, and a confirmation assessment is required per RANO.74 Secondary efficacy endpoints include: (1) overall survival (OS); (2) ORR defined as the proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) using RANO criteria as well as duration of response, defined as time from first RANO response to disease progression in subjects who achieve a PR or better; (3) progressionfree survival (PFS), defined as the time from allocation to the first documented disease progression according to RANO or death due to any cause, whichever occurs first; and (4) progression-free survival at six months defined as the proportion of subjects in the analysis population who remain progression-free for at least six months following initiation of study therapy. Analyses of ORR, duration of response, and PFS will be conducted using RANO criteria, in which a confirmation assessment of disease progression must be obtained at least 4 weeks after the initial disease assessment indicating progressive disease. Nominal p –values may be computed for efficacy analyses as a measure of strength of association between the endpoint and the treatment effect rather than formal tests of hypotheses. Unless otherwise stated, all statistical tests will be conducted at α=0.05 (2-sided) level. Efficacy will be evaluated separately in each cohort. For PFS endpoint, Kaplan-Meier (KM) curves and median estimates from the KM curves will be provided as appropriate. Subjects without efficacy evaluation data or without survival data will be censored at Day 1. Participants without measurable disease will not be included in the analysis of ORR.
untitled h1
12.2.2 safety endpoints

All subjects who receive at least one dose of study treatment will be included in the safety data analysis. At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis of each specific parameter. To assess change from baseline, a baseline measurement is also required. Safety analyses will be performed in all treated subjects. Descriptive statistics of safety will be presented using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 by treatment group. All on-study AEs, treatment-related AEs, SAEs, and treatment-related SAEs will be tabulated using worst grade per NCI CTCAE v 4.03 criteria by system organ class and preferred term. On-study lab parameters including hematology, chemistry, liver function, and renal function will be summarized using worst grade NCI CTCAE v 4.03 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 Adverse experiences (specific terms as well as system organ class terms) and predefined limits of change in laboratory, and vital sign parameters that are not pre-specified as events of interest will be summarized with descriptive statistics (counts, percentage, mean, standard deviation, etc.). Continuous measures such as changes from baseline in laboratory, and vital signs parameters that are not pre-specified as events of interest will be summarized using descriptive statistics (mean, standard deviation, etc.) for baseline, on-treatment, and change from baseline values.  
12.2.3 Analysis of Demographics and Baseline Characteristics Baseline characteristics will be assessed by the use of tables and/or graphs for each cohort separately. No statistical hypothesis tests will be performed on these characteristics. The number and percentage of subjects screened, randomized, the primary reasons for screening failure, and the primary reason for discontinuation will be displayed. Demographic variables (e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be summarized by treatment either by descriptive statistics or categorical tables.  
12.2.4 Analysis of Immunocorrelative Data Longitudinal analyses of PBMC immune response kinetics and circulating cytokines to nivolumab and bevacizumab therapy will be presented graphically and descriptively at each time point. Changes in the magnitude of the response relative to pre-treatment after nivolumab plus bevacizumab therapy will be summarized descriptively. Changes in response between pre-treatment and prior to initiation of cycle 3 of nivolumab plus bevacizumab therapy will be assessed using the Wilcoxon signed-rank test.  
12.2.5 Power and Sample Size The primary and secondary goals of the trial are to evaluate the safety and efficacy of the two therapies and to obtain a preliminary assessment of whether or not they differ with respect to outcome. The total sample size of 90 eligible and evaluable subjects randomized 1:1 to the two therapies is recommended to provide good statistical power to describe the efficacy and toxicity profiles of the two treatment arms. Using the BELOB trial, EORTC 26101 trial outcomes as historical benchmarks, the primary measure of efficacy for the current study will be the 12 month overall survival rate (OS-12). OS-12 was approximately 45% in the BELOB and EORTC 26101 trials. The one-sample log-rank test will be applied to outcomes observed for each arm individually to test the hypothesis that OS has been improved beyond the null 12-month survival rate of  
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 | 88 45%. With N=45 subjects per arm, a one-sided test provides power=0.80 to detect survival rate of 58% at 12-months following treatment at the 0.10 significance level. Statistical calculations were implemented with PASS version 15.0.5. Although each treatment arm will be evaluated for efficacy independently they will also be compared in order to get a preliminary read on whether there is a signal that one may be superior to the other. The sample size of N=45 subjects per treatment arm provides power=0.80 to detect a hazard ratio of 0.498 between the two study arms using a two-sided stratified logrank test. Statistical calculations were implemented with PASS version 15.0.5.  
With 45 subjects per arm, the risk that a particular type and/or grade of adverse event will occur in a particular arm will be estimable using an exact 95% confidence interval that has a maximum half-width of 15%. For example, if 5 adverse events are observed (11%) the corresponding 95% confidence interval will be 4%-24%; if 20 are observed (44%) it will be 30%-60%. In addition, the likelihood of observing at least one adverse event of a particular type and/or grade is >90% even if the risk of such an event is only 5%. Although excessive toxicity is not expected, adverse events will be monitored continuously and the following table will be used as a guide for whether or not a formal review, possibly leading to early termination, should be considered. 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  
|              | Cumulative Likelihood of          |                         |     |     |     |     |
|--------------|-----------------------------------|-------------------------|-----|-----|-----|-----|
| Exceeding    | Consider Review if the Cumulative | the AE Threshold if the |     |     |     |     |
|              | No. Tx-Related Grade >3 AEs       | Risk of an Event is     |     |     |     |     |
| No. Subjects | Exceeds                           | 10%                     | 20% | 30% | 40% |     |
| 50%  1-10    | 4                                 | <1%                     | 3%  | 15% | 37% |     |
| 62%          |                                   |                         |     |     |     |     |
|              | 11-20                             | 7                       | <1% | 5%  | 27% | 62% |
| 88%          |                                   |                         |     |     |     |     |
|              | 21-30                             | 10                      | <1% | 6%  | 36% | 76% |
| 96%          |                                   |                         |     |     |     |     |  
As can be seen the likelihood is small (<1% to 6%) of instituting a formal review if the level of serious toxicity is low (<20%), moderate to high (15-76%) if significant toxicity is similar to the >26% grade 3/4 toxicity rate seen in subjects treated with single agent bevacizumab on the BELOB trial. or the 39% treatment related SAE rate seen in subjects treated with bevacizumab+lomustine in the EORTC 26101 trial*need to add reference no.*, and high (62-96%) if the risk of serious toxicity is >50%.  
13.0 Ethical Considerations
untitled h1
13.1 good clinical practice

This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonisation (ICH) and in accordance with the ethical principles underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). The study will be conducted in compliance with the protocol. The protocol and any amendments and the subject informed consent will receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study. All potential serious breaches must be reported to BMS immediately. A serious breach is a breach of the conditions and principles of GCP in connection with the study or the protocol, Page | 90  
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 which is likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of the study or the scientific value of the study. Personnel involved in conducting this study will be qualified by education, training, and experience to perform their respective tasks. This study will not use the services of study personnel where sanctions have been invoked or where there has been scientific misconduct or fraud (e.g., loss of medical licensure, debarment).
untitled h1
13.2 institutional review board/independent ethics

Before study initiation, the investigator must have a written and dated approval/favorable opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (e.g., advertisements), and any other written information to be provided to subjects. The investigator or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling information to be provided to subjects and any updates. The investigator or BMS should provide the IRB/IEC with reports, updates and other information (e.g., expedited safety reports, amendments, and administrative letters) according to regulatory requirements or institution procedures.
untitled h1
informed consent

Investigators must ensure that subjects are clearly and fully informed about the purpose, potential risks, and other critical issues regarding clinical studies in which they volunteer to participate. In situations where consent cannot be given to subjects, their legally acceptable representatives are clearly and fully informed about the purpose, potential risks, and other critical issues regarding clinical studies in which the subject volunteers to participate.  
BMS will provide the investigator with an appropriate (i.e., Global or Local) sample informed consent form which will include all elements required by ICH, GCP and applicable regulatory requirements. The sample informed consent form will adhere to the ethical principles that have their origin in the Declaration of Helsinki.  
Investigators must:
1) Provide a copy of the consent form and written information about the study in the language in which the subject is most proficient prior to clinical study participation. The language must be non-technical and easily understood.  
2) Allow time necessary for subject or subject's legally acceptable representative to inquire about the details of the study. 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 3) Obtain an informed consent signed and personally dated by the subject or the subject's legally acceptable representative and by the person who conducted the informed consent discussion.  
4) Obtain the IRB/IEC's written approval/favorable opinion of the written informed consent form and any other information to be provided to the subjects, prior to the beginning of the study, and after any revisions are completed for new information.  
5) If informed consent is initially given by a subject's legally acceptable representative or legal guardian, and the subject subsequently becomes capable of making and communicating his or her informed consent during the study, consent must additionally be obtained from the subject.  
6) Revise the informed consent whenever important new information becomes available that is relevant to the subject's consent. The investigator, or a person designated by the investigator, should fully inform the subject or the subject's legally acceptable representative or legal guardian, of all pertinent aspects of the study and of any new information relevant to the subject's willingness to continue participation in the study. This communication should be documented.  
The confidentiality of records that could identify subjects must be protected, respecting the privacy and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the US, the subjects' signed HIPAA Authorization. The consent form must also include a statement that BMS and regulatory authorities have direct access to subject records. Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may only be enrolled in the study with the consent of a legally acceptable representative. The subject must also be informed about the nature of the study to the extent compatible with his or her understanding, and should this subject become capable, he or she should personally sign and date the consent form as soon as possible. The explicit wish of a subject who is unable to give his or her written consent, but who is capable of forming an opinion and assessing information to refuse participation in or to be withdrawn from, the clinical study at any time should be considered by the investigator. The rights, safety, and well-being of the study subjects are the most important considerations and should prevail over interests of science and society. 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 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
untitled h1
14.0 references

1. Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66. 2. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. 3. Sampson JH, Aldape KD, Archer GE, et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro-oncology 2011;13:324-33. 4. Sampson JH, Heimberger AB, Archer GE, et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J Clin Oncol 2010;28:4722-9. 5. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clinical cancer research : an official journal of the American Association for Cancer Research 2005;11:5515-25. 6. Prins RM, Soto H, Konkankit V, et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin Cancer Res 2011;17:1603-15. 7. Yu JS, Liu G, Ying H, Yong WH, Black KL, Wheeler CJ. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T-cells in patients with malignant glioma. Cancer Res 2004;64:4973-9. 8. Hussain SF, Kong LY, Jordan J, et al. A novel small molecule inhibitor of signal transducers and activators of transcription 3 reverses immune tolerance in malignant glioma patients. Cancer research 2007;67:9630-6. 9. Heimberger AB, Bigner DD, Sampson JJ. Biological principles of brain tumor immunotherapy. In: Liau LM, Becker DP, Cloughesy T, Bigner DD, eds. Brain tumor immunotherapy. Totowa, N.J.: Humana Press; 2000. 10. Hussain SF, Yang D, Suki D, Aldape K, Grimm E, Heimberger AB. The role of human glioma-infiltrating microglia/macrophages in mediating antitumor immune responses. Neurooncology 2006;8:261-79.  
11. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007;13:84-8. 12. Heimberger AB, Abou-Ghazal M, Reina-Ortiz C, et al. Incidence and prognostic impact of FoxP3+ regulatory T cells in human gliomas. Clin Cancer Res 2008;14:5166-72. 13. Fecci PE, Ochiai H, Mitchell DA, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function. Clinical cancer research : an official journal of the American Association for Cancer Research 2007;13:2158-67.  
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 14. Grossman SA, Ye X, Lesser G, et al. Immunosuppression in patients with high-grade gliomas treated with radiation and temozolomide. Clin Cancer Res 2011;17:5473-80. 15. Lorgis V, Maura G, Coppa G, et al. Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. Journal of neurooncology 2012;107:351-8.  
16. de Groot JF, Fuller G, Kumar AJ, et al. Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neurooncology 2010;12:233-42.  
17. Keunen O, Johansson M, Oudin A, et al. Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma. Proc Natl Acad Sci U S A 2011;108:374954. 18. Piao Y, Liang J, Holmes L, et al. Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro-oncology 2012;14:1379-92. 19. Lu KV, Chang JP, Parachoniak CA, et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer cell 2012;22:21-35. 20. DeLay M, Jahangiri A, Carbonell WS, et al. Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2012;18:2930-42. 21. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 2013;73:2943-8. 22. Huang Y, Yuan J, Righi E, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A 2012;109:17561-6. 23. Griffioen AW. Anti-angiogenesis: making the tumor vulnerable to the immune system. Cancer immunology, immunotherapy : CII 2008;57:1553-8. 24. Johnson BF, Clay TM, Hobeika AC, Lyerly HK, Morse MA. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Expert opinion on biological therapy 2007;7:449-60. 25. Ohm JE, Carbone DP. VEGF as a mediator of tumor-associated immunodeficiency. Immunol Res 2001;23:263-72. 26. Gabrilovich D, Ishida T, Oyama T, et al. Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 1998;92:4150-66. 27. Gabrilovich DI, Chen HL, Girgis KR, et al. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 1996;2:1096-103. 28. Mulligan JK, Day TA, Gillespie MB, Rosenzweig SA, Young MR. Secretion of vascular endothelial growth factor by oral squamous cell carcinoma cells skews endothelial cells to suppress T-cell functions. Human immunology 2009;70:375-82.  
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 29. Ohm JE, Gabrilovich DI, Sempowski GD, et al. VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression. Blood 2003;101:4878-86. 30. Huang X, Raskovalova T, Lokshin A, et al. Combined antiangiogenic and immune therapy of prostate cancer. Angiogenesis 2005;8:13-23. 31. Miyazaki J, Tsuzuki Y, Matsuzaki K, et al. Combination therapy with tumor-lysate pulsed dendritic cells and antiangiogenic drug TNP-470 for mouse pancreatic cancer. Int J Cancer 2005;117:499-505. 32. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer research 2010;70:6171-80. 33. U.S. Department of Health and Human Services CfDE, and Research FaDa: FDA Project on Cancer Drug Aproval Endpoint Last updated April 20, 2007. 34. Li B, Lalani AS, Harding TC, et al. Vascular endothelial growth factor blockade reduces intratumoral regulatory T cells and enhances the efficacy of a GM-CSF-secreting cancer immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2006;12:6808-16. 35. Manning EA, Ullman JG, Leatherman JM, et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clinical cancer research : an official journal of the American Association for Cancer Research 2007;13:3951-9. 36. Hodi FS, Lawrence D, Lezcano C, et al. Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma. Cancer immunology research 2014;2:632-42. 37. Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist 2009;14:1131-8. 38. Piao Y, Liang J, Holmes L, Zurita A, al. e. Glioblastoma resistance to anti-VEGF therapy is associated with myeloid cell infiltration, stem cell accumulation, and a mesenchymal phenotype. Neuro-oncology 2012;14:1379-92. 39. Lu K, Chang J, Parachoniak C, Pandika M, Aghi M, al. e. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer cell 2012;22:21-35. 40. DeLay M, Jahangiri A, Carbonell WS, et al. Microarray analysis verifies two distinct phenotypes of glioblastomas resistant to antiangiogenic therapy. Clinical cancer research : an official journal of the American Association for Cancer Research 2012;18:2930-42. 41. Jain RK, Tong RT, Munn LL. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res 2007;67:2729-35. 42. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005;307:58-62. 43. Sorensen AG, Emblem KE, Polaskova P, et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 2012;72:402-7.  
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 44. Emblem KE, Mouridsen K, Bjornerud A, et al. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nature medicine 2013;19:1178-83. 45. Huang Y, Goel S, Duda D, Fukumura D, Jain R. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer research 2013;73:2943-8. 46. Lorgis V, Maura G, Coppa G, Hassani K, al. e. Relation between bevacizumab dose intensity and high-grade glioma survival: a retrospective study in two large cohorts. Journal of neuro-oncology 2012;107:351-8. 47. Taal W, Oosterkamp HM, Walenkamp AM, et al. Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): a randomised controlled phase 2 trial. Lancet Oncol 2014;15:94353. 48. Wick W, Brandes AA, Gorlia T, et al. EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma. ASCO Meeting Abstracts 2016;34:2001. 49. Presta LG, Chen H, O'Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997;57:4593-9. 50. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841-4. 51. Borgstrom P, Gold DP, Hillan KJ, Ferrara N. Importance of VEGF for breast cancer angiogenesis in vivo: implications from intravital microscopy of combination treatments with an anti-VEGF neutralizing monoclonal antibody and doxorubicin. Anticancer Res 1999;19:4203-14. 52. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest 2003;111:1287-95. 53. Shaheen RM, Ahmad SA, Liu W, et al. Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 2001;85:584-9. 54. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. 55. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2007;25:1539-44. 56. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. 57. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103-11.  
Page | 97  
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 58. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007;357:2666-76. 59. Kreisl TN, Kim L, Moore K, et al. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009;27:7405. 60. Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009;27:4733-40. 61. Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1999;17:2572-8. 62. Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. International journal of radiation oncology, biology, physics 2011;79:1487-95. 63. Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci U S A 2010;107:4275-80. 64. Emblem KE, Mouridsen K, Bjornerud A, et al. Vessel architectural imaging identifies cancer patient responders to anti-angiogenic therapy. Nat Med 2013.  
65. Okada H, Weller M, Huang R, et al. Immunotherapy response assessment in neurooncology: a report of the RANO working group. Lancet Oncol 2015;16:e534-42.  
66. Glusker P, Recht L, Lane B. Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 2006;354:980-2; discussion -2. 67. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2003;21:60-5. 68. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis. JAMA 2008;300:2277-85. 69. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst 2007;99:1232-9. 70. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol 2009;10:559-68. 71. Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nature reviews Clinical oncology 2009;6:465-77. 72. Scappaticci FA, Fehrenbacher L, Cartwright T, et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005;91:173-80.  
Page | 98  
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 73. Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2005;23:792-9. 74. Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010;28:1963-72.
untitled h1
15.0 appendices appendix 1 karnofsky

| Status                                                                              | Karnofsky                                       | Grade   | ECOG                                                                                  |
|-------------------------------------------------------------------------------------|-------------------------------------------------|---------|---------------------------------------------------------------------------------------|
| Normal, no complaints                                                               | 100                                             | 0       | Fully active, able to carry on all pre-disease  performance without restriction       |
| Able to carry on normal activities.                                                 | Restricted in physically strenuous activity but |         |                                                                                       |
| Minor signs or symptoms of disease                                                  | 90                                              | 1       | ambulatory and able to carry out work of a                                            |
| light or sedentary nature, e.g., light house work,                                  |                                                 |         |                                                                                       |
| Normal activity with effort                                                         | office work                                     |         |                                                                                       |
| 80                                                                                  |                                                 |         |                                                                                       |
| Care for self. Unable to carry on normal  activity or to do active work             | 70                                              | 2       | Ambulatory and capable of all self-care but                                           |
| unable to carry out any work activities. Up and about more than 50% of waking hours |                                                 |         |                                                                                       |
| Requires occasional assistance, but able  to care for most of his needs             | 60                                              |         |                                                                                       |
| Requires considerable assistance and  frequent medical care                         | 50                                              | 3       | Ambulatory and capable of all self-care but  unable to carry out any work activities. |
| Disabled. Requires special care and                                                 | Up and about more than 50% of waking hours      |         |                                                                                       |
| assistance                                                                          | 40                                              |         |                                                                                       |
| Severely disabled. Hospitalization                                                  |                                                 |         |                                                                                       |
| indicated though death non-imminent                                                 | 30                                              | 4       | Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair                                                                                       |
| Very sick. Hospitalization necessary.  Active supportive treatment necessary        | 20                                              |         |                                                                                       |
| Moribund                                                                            | 10                                              |         |                                                                                       |  
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 Dead 0 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
untitled h1
appendix 2 immunotherapy response assessment

Tumor response should be assessed every 8 weeks (+/- 1 week) for subjects treated with immunotherapy using modified RANO criteria65 as outlined below. Clinicians may repeat response assessment more frequently as clinically indicated.
untitled h1
anti-tumor effect definitions

Evaluable for toxicity. All subjects who receive at least one dose of immunotherapy treatment will be evaluable for toxicity from the time of their first treatment.  
Evaluable for objective response. Only those subjects who have measurable disease present at baseline (recommend obtaining within 14 days of cycle 1, day 1) scan and have received at least one dose of immunotherapy will be considered evaluable for response. These subjects will have their response classified according to the definitions stated below. (Note: Subjects who exhibit objective disease progression or die prior to the end of cycle 1 will also be considered evaluable.)
Measurable disease. For contrast-enhancing tumors, measurable disease is defined as the bidimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT or MRI scan, with a minimal diameter of 1 cm, and visible on 2 slices which are at least 5 mm apart with 0 mm skip. For non-contrast-enhancing tumors, measurable disease is defined as the T2 or FLAIR lesions with a minimal diameter of 1 cm, and visible on 2 slices which are at least 5 mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if necessary, requires a minimum thickness of 3 mm. If there are too many measurable lesions to measure at each evaluation, the investigator must choose the largest two to be followed. The remaining lesions will be considered non-measureable for the purpose of objective response determination. Unless progression is observed, objective response can only be determined when all measurable and non-measurable lesions are assessed.  
Non-measurable evaluable disease. Unidimensionally measurable lesions, masses with margins not clearly defined, and/or lesions with maximal diameter < 1cm. 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
untitled h1
response/progression categories

Complete response (CR). All of the following criteria must be met:
a) Complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered only stable disease.  
b) No new lesions. c) All measurable and non-measurable lesions must be assessed using the same techniques as baseline.  
d) Subjects must be on no steroids or on physiologic replacement doses only.  
e) For enhancing tumors: Stable or improved non-enhancing (T2/FLAIR) lesions f) Stable or improved clinically, for clinical signs and symptoms present at baseline and recorded to be disease related Subjects with residual non-measurable disease cannot have a complete response. The best response possible is stable disease.  
Partial response (PR). All of the following criteria must be met:  
a) Greater than or equal to 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable lesions sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be considered only stable disease.  
b) No progression of non-measurable disease. c) No new lesions. d) All measurable and non-measurable lesions must be assessed using the same techniques as baseline.  
e) The steroid dose at the time of the scan evaluation should be no greater than the dose at time of baseline scan.
f) For enhancing tumors: Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared to baseline scan.  
g) Stable or improved, for clinical signs and symptoms present at baseline and recorded to be disease related clinically.
Subjects with non-measurable disease cannot have a partial response. The best response possible is stable disease.  
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 | 102 Progressive disease (PD). Any of the following criterion must be met:  
a) > 25% increase in sum of the products of perpendicular diameters of measurable lesions
(over best response [smallest tumor size] or baseline if no decrease) on stable or increasing doses of corticosteroids b) Any new measurable lesion that when added to the change in initial tumor(s) exceeds a 25% increase in cross-sectional area.  
c) Clear clinical deterioration not attributable to other causes apart from the tumor (e.g.  
seizures, medication side effects, complications of therapy, cerebrovascular events, infection, etc.). The definition of clinical deterioration is left to the discretion of the investigator but it is recommended that a decline in the Karnofsky Performance Score (KPS) from 100 or 90 to 70 or less, a decline in KPS of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or less, for at least 7 days, be considered neurologic deterioration, unless attributable to co-morbid events or changes in corticosteroid dose.  
d) Failure to return for evaluation due to death or deteriorating condition
Classification of progressive disease may be deferred for up to three months for subjects with initial radiographic findings consistent with progressive disease (criteria a and b above) as detailed below. However, if follow-up imaging after three months confirms progression or if the patient experiences significant clinical decline at any time, the date of actual progression will be back-dated to the first date that the patient met criteria for progression and such subjects should discontinue further immunotherapy.  
Stable disease (SD). All of the following criteria must be met:
a) Does not qualify for CR, PR, or progression.  
b) All measurable and non-measurable sites must be assessed using the same techniques as baseline.  
c) Stable clinically.
Unknown response status. Progressive disease has not been documented and one or more measurable or non-measurable lesions have not been assessed.  
Algorithm for Treatment Decision Making for Subjects with Radiographic Progression 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
untitled h1
appendix 3 sample of drug

Nivolumab has a concentration of 10mg/mL and is provided in a 10mL vial. Ten or five vials are provided in a carton.
untitled h1
initial orders

Following submission and approval of the required regulatory documents, a supply of nivolumab may be ordered from by completing a Drug Request Form provided by BMS for this specific trial. The first request may take place upon screening of the first patient
*The initial order should be limited to 20 vials. Allow 5 business days for shipment of drug* from BMS receipt of the Drug Request Form. Drug is protocol specific, but not patient  
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 | 104 specific. All drug product will be shipped by courier in a temperature-controlled container. It is possible that sites may have more than one nivolumab clinical study ongoing at the same time. It is imperative that only drug product designated for this protocol number be used for this study.  
Pharmacy supplies not provided by BMS: Empty IV bags/containers, approved diluents, In-line filters and infusion tubing
untitled h1
re-supply

Drug re-supply request form should be submitted electronically business days before the expected delivery date. Deliveries will be made Tuesday through Friday.  
*When assessing need for resupply, institutions should keep in mind the number of vials* used per treatment dose, and that shipments may take 14 business days from receipt of request. Drug is not patient-specific. Be sure to check with your pharmacy regarding existing investigational stock to assure optimal use of drug on hand.
untitled h1
drug excursions

*Drug excursions should be reported immediately to BMS on the form provided with the* study-specific drug order form 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
untitled h1
please refer to the most

Store at 2-8°C (36-46°F), protect from light, freezing, and shaking.  
If any temperature excursions are encountered during storage, please report these to BMS
for assessment via the Temperature Excursion Response Form.  
As with all injectable drugs, care should be taken when handling and preparing nivolumab.  
Whenever possible, nivolumab should be prepared in a laminar flow hood or safety cabinet using standard precautions for the safe handling of intravenous agents applying aseptic technique.  
Partially used vials should be disposed at the site following procedures for the disposal of anticancer drugs.  
After final drug reconciliation, unused nivolumab vials should be disposed at the site following procedures for the disposal of anticancer drugs. For further information, please either discuss with your BMS CSR&O protocol manager or refer to your site IP Destruction policies and procedures Use Time/Stability: Please refer to section 3.2.3 of the current Investigator Brochure. Due to parameters surrounding the use time of Nivolumab, the time of preparation should be noted in the Pharmacy Source documents [accountability logs] or in study files as required for investigator sponsored research [FDA and GCP] The administration of BMS-936558-01 injection prepared for dosing nivolumab infusion must be completed within 24 hours of preparation. If not used immediately, the infusion solution may be stored up to 20 hours in a refrigerator at under refrigeration conditions (2°-°-8°C (, 36°- 46°F) and used within 4for up to 24 hours, and a maximum of 4 hours of the total 24 hours can be at room temperature (20°-25°C, 68°-77°F) and under room light. The maximum 4-hour period under room temperature and room light conditions for undiluted and diluted solutions of BMS-936558-01 injection in the IV bag should be inclusive of the includes the product administration period. 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
untitled h1
preparation and administration

6. Visually inspect the drug product solution for particulate matter and discoloration prior to administration. Discard if solution is cloudy, if there is pronounced discoloration (solution may have a pale-yellow color), or if there is foreign paticulate matter other than a few translucent-to-white, amorphous particles. Note: Mix by **gently** inverting several times. **Do not** *shake.*
7. Aseptically withdraw the required volume of nivolumab solution into a syringe, and dispense into an IV. bag. If multiple vials are needed for a subject, it is important to use a separate sterile syringe and needle for each vial to prevent problems such as dulling of needle tip, stopper coring, repeated friction of plunger against syringe barrel wall. **Do not**
enter into each vial more than once. **Do not** administer study drug as an IV push or bolus injection 8. Add the appropriate volume of 0.9% Sodium Chloride Injection solution or 5% Dextrose Injection solution. *It is acceptable to add nivolumab solution from the vials into an* appropriate pre-filled bag of diluent. Note: Nivolumab infusion concentration must be at or above the minimum allowable concentration of 0.35 mg/mL [IBV13 Addendum Section 3.2.2] Note: It is not recommended that so-called "channel" or tube systems are used to transport prepared infusions of nivolumab.  
9. Attach the IV bag containing the nivolumab solution to the infusion set and filter. 10. At the end of the infusion period, flush the line with a sufficient quantity of approved diluents. 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
untitled h1
appendix 4 adverse event reporting

All Serious Adverse Events (SAEs) that occur following the subject's written consent to participate in the study through 100 days of discontinuation of dosing must be reported to BMS Worldwide Safety.  
If the BMS safety address is not included in the protocol document (e.g.  
multicenter studies where events are reported centrally), the procedure for safety reporting must be reviewed/approved by the BMS Protocol Manager. Procedures for such reporting must be reviewed and approved by BMS prior to study activation.  
The BMS SAE form should be used to report SAEs. If the BMS form cannot be used, another acceptable form (i.e. CIOMS or Medwatch) must be reviewed and approved by BMS. The BMS protocol ID number must be included on whatever form is submitted by the Sponsor/Investigator.  
Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, are collected, including those thought to be associated with protocol-specified procedures. The investigator should report any SAE occurring after these time periods that is believed to be related to study drug or protocol-specified procedure.  
In accordance with local regulations, BMS will notify investigators of all reported SAEs that are suspected (related to the investigational product) and unexpected (i.e., not previously described in the IB). In the European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the form of an expedited safety report (ESR).  
o Other important findings which may be reported by the as an ESR include:
increased frequency of a clinically significant expected SAE, an SAE considered associated with study procedures that could modify the conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety finding from a nonclinical (e.g., animal) study, important safety recommendations from a study data monitoring committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons.  
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the IB. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will submit the ESR
to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the informed consent requires revision. The investigator should also comply with the IRB/IEC procedures for reporting any other safety information.
o In addition, suspected serious adverse reactions (whether expected or unexpected) shall be reported by BMS to the relevant competent health authorities in all concerned countries according to local regulations (either as expedited and/or in aggregate reports).
untitled h1
serious adverse event collection and

Following the subject's written consent to participate in the study, all SAEs, whether related or not related to study drug, must be collected, including those thought to be associated with protocol-specified procedures. All SAEs must be collected that occur within 100 days of discontinuation of dosing. All SAEs must be collected that occur during the screening period. If applicable, SAEs must be collected that relate to any protocol-specified procedure (e.g., a follow-up skin biopsy). The investigator should report any SAE that occurs after these time periods that is believed to be related to study drug or protocol-specified procedure. SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a Pregnancy Surveillance Form.  
SAE Email Address: Worldwide.Safety@BMS.com
untitled h1
sae facsimile number 609-818-3804

If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports should include the same investigator term(s) initially reported.) If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the same procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. For studies conducted under an Investigator IND in the US include the following: For studies conducted under an Investigator IND in the US, any event that is both serious and unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible and no later than 7 days (for a death or life-threatening event) or 15 days (for all Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 109 other SAEs) after the investigator's or institution's initial receipt of the information. BMS will be provided with a simultaneous copy of all adverse events filed with the FDA. SAEs should be reported on MedWatch Form 3500A, which can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. MedWatch SAE forms should be sent to the FDA at: MEDWATCH 5600 Fishers Lane Rockville, MD 20852-9787 Fax: 1-800-FDA-0178 (1-800-332-0178) http://www.accessdata.fda.gov/scripts/medwatch/ All SAEs should simultaneously be faxed or e-mailed to BMS at: Global Pharmacovigilance & Epidemiology Bristol-Myers Squibb Company Fax Number: 609-818-3804 Email: Worldwide.safety@bms.com An SAE report should be completed for any event where doubt exists regarding its seriousness.  
For studies with long-term follow-up periods in which safety data are being reported, include the timing of SAE collection in the protocol.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the conditions of the study (such as withdrawal of previous therapy or a complication of a study procedure), the relationship should be specified in the narrative section of the SAE Report Form.  
If only limited information is initially available, follow-up reports are required.  
(Note: Follow-up SAE reports should include the same investigator term(s)
initially reported.)
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes available, a follow-up SAE report should be sent within 24 hours to BMS using the same procedure used for transmitting the initial SAE report. All SAEs should be followed to resolution or stabilization. All SAEs should be followed to resolution or stabilization.
untitled h1
definitions

The protocol must include a definition for Serious Adverse Events (SAE)
untitled h1
serious adverse events

A S*erious Adverse Event (SAE)* is any untoward medical occurrence that at any dose: Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 110 results in death is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it were more severe)
requires inpatient hospitalization or causes prolongation of existing hospitalization (see **NOTE** below)
results in persistent or significant disability/incapacity is a congenital anomaly/birth defect is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.)
Potential drug induced liver injury (DILI) is also considered an important medical event.  
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic)
via the study drug is an SAE.  
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events must be handled as SAEs.  
NOTE: (PI- determines if this information should be included. This is provided as supplemental information that is included in BMS-sponsored trials) The following hospitalizations are not considered SAEs in BMS clinical studies:
a visit to the emergency room or other hospital department < 24 hours, that does not result in admission (unless considered an important medical or lifethreatening event)
elective surgery, planned prior to signing consent admissions as per protocol for a planned medical/surgical procedure routine health assessment requiring admission for baseline/trending of health status (e.g., routine colonoscopy)
Medical/surgical admission other than to remedy ill health and planned prior to entry into the study. Appropriate documentation is required in these cases  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 111  
Admission encountered for another life circumstance that carries no bearing on health status and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, family circumstances, administrative reason).
untitled h1
potential drug induced liver injury

Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined criteria, must be reported as SAEs Potential drug induced liver injury is defined as:
ALT or AST elevation > 3 times upper limit of normal (ULN)
AND
Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline phosphatase) AND
No other immediately apparent possible causes of AST/ALT elevation and hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the administration of other drug(s) known to be hepatotoxic.
untitled h1
adverse events

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of investigational product, whether or not considered related to the investigational product.  
The causal relationship to study drug is determined by a physician and should be used to assess all adverse events (AE). The casual relationship can be one of the following: Related: There is a reasonable causal relationship between study drug administration and the AE. Not related: There is not a reasonable causal relationship between study drug administration and the AE. The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 112 Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the specific occurrence of one or more AEs.)
untitled h1
nonserious adverse event

Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final study reports as specified in the agreement or, if a regulatory requirement [e.g. IND US trial] as part of an annual reporting requirement.  
Nonserious AE information should also be collected from the start of a placebo lead-in period or other observational period intended to establish a baseline status for the subjects.
A *nonserious adverse event* is an AE not classified as serious.
untitled h1
nonserious adverse event collection and

The collection of nonserious AE information should begin at initiation of study drug. All nonserious adverse events (not only those deemed to be treatment-related) should be collected continuously during the treatment period and for a minimum of 100 days following the last dose of study treatment. Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for nonserious AEs that cause interruption or discontinuation of study drug and for those present at the end of study treatment as appropriate.
untitled h1
laboratory test abnormalities

All laboratory test results captured as part of the study should be recorded following institutional procedures. Test results that constitute SAEs should be documented and reported as such. The following laboratory abnormalities should be documented and reported appropriately:
Any laboratory test result that is clinically significant or meets the definition of an SAE
Any laboratory abnormality that required the subject to have study drug discontinued or interrupted Any laboratory abnormality that required the subject to receive specific corrective therapy. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 113
untitled h1
pregnancy

If, following initiation of the investigational product, it is subsequently discovered that a study subject is pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 half-lives after product administration, the investigational product will be permanently discontinued in an appropriate manner (e.g., dose tapering if necessary for subject safety). The investigator must immediately notify Worldwide Safety @BMS of this event via the Pregnancy Surveillance Form in accordance with SAE reporting procedures. Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, where applicable, offspring information must be reported on the Pregnancy Surveillance Form [provided upon request from BMS] Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form.
untitled h1
overdose

An overdose is defined as the accidental or intentional administration of any dose of a product that is considered both excessive and medically important. All occurrences of overdose must be reported as an SAE.
untitled h1
other safety considerations

Any significant worsening noted during interim or final physical examinations, electrocardiograms, X-rays, and any other potential safety assessments, whether or not these procedures are required by the protocol, should also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 114  
| SE EPI Perf       | Ax 2D T2w                                  | 3D T1w  Postb   |           |                       |          |                 |
|-------------------|--------------------------------------------|-----------------|-----------|-----------------------|----------|-----------------|
| Sequence          | IR-GREd,e                                  | TSEc            | EPIf      | EPI                   | TSEc     | IR-GREd,e       |
| Plane             | Sagittal/Axial                             | Axial           | Axial     | Axial                 | Axial    | Axial/Sagi ttal |
| Mode              | 3D                                         | 2D              | 2D        | 2D                    | 2D       | 3D              |
| TR [ms]           | 2100g                                      | >6000           | >5000     | 2260                  | >2500    | 2100g           |
| TE [ms]           | Min                                        | 100-140         | Min       | 78                    | 80-120   | Min             |
| TI [ms]           | 1100h                                      | 2000 - 2500     | 1100h     |                       |          |                 |
| Flip Angle        | 10º-15º                                    | 90º/160º       | 90º/180º  | 90º/160º             | 10º-15º  |                 |
| Frequency         | 256                                        | 256            | 128       | 128                   | 256     | 256             |
| Phase             | 256                                        | 256            | 128       | 128                   | 256     | 256             |
| NEX               | 1                                         | 1              | 1        | 1                     | 1       | 1              |
| FOV               | 256mm                                      | 240mm           | 240mm     | 280                   | 240mm    | 256mm           |
| Slice Thickness   | 1mm                                        | 3mm             | 3mm       | 10mm                  | 3mm      | 1mm             |
| Gap/Spacing       | 0                                          | 0               | 0         | 0                     | 0        | 0               |
| Diffusion Options | b = 0, 500,  and 1000  s/mm2 3 directions |                 |           |                       |          |                 |
| Parallel Imaging  | Up to 2x                                   | Up to 2x        | Up to 2x  | Up to 2x              | Up to 2x |                 |
| Scan Time         | 4:53                                       | 3:39            | 3:20      | 1:36                  | 2:17     | 4:53            |
| (Approx)          | 3D T1w Pre                                 | Ax 2D FLAIR     | Ax 2D DWI | Contrast Injection  a |          |                 |
untitled h1
appendix 5 recommended mri sequences

A: Recommended 3T Protocola 0.1 mmol/kg or up to 20cc (single, full dose) of MR contrast.  
b Post-contrast 3D axial T1-weighted images should be collected with identical parameters to pre-contrast 3D axial T1weighted images c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba)
dIR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IR-SPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D fast field echo (3D Fast FE; Toshiba).  
e A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE or another IR-prepped 3D T1-weighted sequences and therefore should be avoided.  
f In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE [Siemens],
PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this acquisition scheme is can cause significant differences in ADC quantification and therefore should be used only if EPI is not an option.  
g For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5-15ms for similar contrast.  
h For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400-450ms for similar contrast. Acronyms:
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; DWI = diffusionweighted imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo planar imaging; MPRAGE =
magnetization prepared rapid gradient-echo; A/P = anterior to posterior; R/L = right to left; NEX = number of excitations or averages; FOV = field of view; IR-GRE = inversion-recovery gradient-recalled echo  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 115 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 116  
| Ax 2D T2w          | 3D T1w Postb                              |             |           |                      |                |
|--------------------|-------------------------------------------|-------------|-----------|----------------------|----------------|
| Sequence           | IR-GREd,e                                 | TSEc        | EPIf      | TSEc                 | IR-GREd,e      |
| Plane              | Sagittal/Axial                            | Axial       | Axial     | Axial                | Sagittal/Axial |
| Mode               | 3D                                        | 2D          | 2D        | 2D                   | 3D             |
| TR [ms]            | 2100g                                     | >6000       | >5000     | >3500                | 2100g          |
| TE [ms]            | Min                                       | 100-140     | Min       | 100-120              | Min            |
| TI [ms]            | 1100h                                     | 2000-2500   | 1100h     |                      |                |
| Flip Angle         | 10º-15º                                   | 90º/160º   | 90º/180º  | 90º/160º            | 10º-15º        |
| Frequency          | 172                                      | 256        | 128       | 256                 | 172           |
| Phase              | 172                                      | 256        | 128       | 256                 | 172           |
| NEX                | 1                                        | 1          | 1        | 1                   | 1             |
| FOV                | 256mm                                     | 240mm       | 240mm     | 240mm                | 256mm          |
| Slice Thickness    | 1.5mm                                    | 4mm        | 4mm      | 4mm                 | 1.5mm         |
| Gap/Spacing        | 0                                         | 0           | 0         | 0                    | 0              |
| Diffusion Optionsi | b = 0, 500, and  1000 s/mm2 3 directions |             |           |                      |                |
| Parallel Imaging   | No                                        | Up to 2x    | Up to 2x  | Up to 2x             | No             |
| Scan Time          | 5-10 min                                  | 4-5 min     | 3-5 min   | 3-5 min              | 5-10 min       |
| (Approx)           | 3D T1w Pre                                | Ax 2D FLAIR | Ax 2D DWI | a Contrast Injection |                |
untitled h1
b recommended 1.5t protocol

a 0.1 mmol/kg or up to 20cc (single, full dose) of MR contrast. b Post-contrast 2D axial T1-weighted images should be collected with identical parameters to pre-contrast 2D axial T1-weighted images c TSE = turbo spin echo (Siemens & Philips) is equivalent to FSE (fast spin echo; GE, Hitachi, Toshiba)
dIR-GRE = inversion-recovery gradient-recalled echo sequence is equivalent to MPRAGE = magnetization prepared rapid gradient-echo (Siemens & Hitachi) and the inversion recovery spoiled gradient-echo (IRSPGR or Fast SPGR with inversion activated or BRAVO; GE), 3D turbo field echo (TFE; Philips), or 3D
fast field echo (3D Fast FE; Toshiba).  
e A 3D acquisition without inversion preparation will result in different contrast compared with MPRAGE
or another IR-prepped 3D T1-weighted sequences and therefore should be avoided.  
f In the event of significant patient motion, a radial acquisition scheme may be used (e.g. BLADE
[Siemens], PROPELLER [GE], MultiVane [Philips], RADAR [Hitachi], or JET [Toshiba]); however, this acquisition scheme is can cause significant differences in ADC quantification and therefore should be used only if EPI is not an option.  
g For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TR = 5-15ms for similar contrast.  
h For Siemens and Hitachi scanners. GE, Philips, and Toshiba scanners should use a TI = 400-450ms for similar contrast.  
i Older model MR scanners that are not capable of >2 b-values should use b = 0 and 1000 s/mm2.  
Acronyms:
Ax = Axial; ADC = apparent diffusion coefficient. FLAIR = fluid attenuated inversion recovery; DWI =
diffusion-weighted imaging; 3D = three dimensional; TSE = turbo spin echo; EPI = echo planar imaging; MPRAGE = magnetization prepared rapid gradient-echo; A/P = anterior to posterior; R/L = right to left;  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 117 NEX = number of excitations or averages; FOV = field of view; IR-GRE = inversion-recovery gradientrecalled echo Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 118 Appendix 6 Hepatoxicity Article International Journal of Molecular Sciences Review Hepatotoxicity by Drugs: The Most CommonImplicated Agents Einar S. Björnsson Department of Internal Medicine, Division of Gastroenterology and Hepatology, The National University Hospital of Iceland and The Faculty of Medicine, The University of Iceland, 108 Reykjavik, Iceland; einarsb@landspitali.is; Tel.: +354543-6180; Fax: +354-543-4834 Academic Editors: Rolf Teschke and Raúl J. Andrade Received: 4 January 2016; Accepted: 1 February 2016; Published: 6 February 2016 Abstract: Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. Keywords: hepatotoxicity; drugs; drug-induced liver injury; idiosyncratic
untitled h1
1. introduction

Drug-induced liver injury (DILI) is a frequent differential diagnosis in patients with acute liver injury without obvious etiology. Apart from exclusion of competing etiologies, an important element in the diagnostic process is the information about the known and potential hepatotoxicity of the agent. However, data on hepatotoxicity is not always easily accessible. All drugs approved by regulatory authorities are accompanied by package inserts, called the "patient information" leaflet in Europe and "prescribing information" in the United States
[1,2]. Adverse liver reactions are often mentioned in these product labels (package inserts) as a part of the prescribing information. However, it is not always clear whether this is related to enzyme elevations in clinical trials and/or clinically apparent liver injury. Thus, from package inserts of prescribed medications the clinician can get the idea that adverse drug reactions are side effects of most drugs. It has recently been demonstrated that this information is insufficient and even misleading [3]. There was also a substantial discrepancy in the official package inserts and liver disease labeling between Europe and the United States [3]. The documentation of the hepatotoxicity of drugs in the medical literature is very variable. Some drugs have been convincingly documented to cause liver injury in numerous case reports and case series. Many such drugs have a known clinical signature (phenotype) of liver injury and causality has been further documented by instances of a positive rechallenge [4,5]. Examples are chlorpromazine, halothane, isoniazid and amoxicillin-clavulanate. In early DILI research, halothane and chlorpromazine were commonly reported causes of hepatotoxicity [6]. However, with some drugs, although marketed for many decades, only a single case report or very few reports of liver injury have been published. Case reports are often not well described and critical clinical information is frequently lacking [7]. A recent study found that reports of drug-induced liver diseases often did not provide the data needed to determine the causes of suspected adverse effects [7]. Although a case report has been published, it does not prove that the drug is hepatotoxic. Int. J. Mol. Sci. 2016, 17, 224; doi:10.3390/ijms17020224 www.mdpi.com/journal/ijms
untitled h1
int. j. mol. sci. 2016

A newly established website, LiverTox® [8], was an attempt to provide up-to-date, accurate, and easily accessible information on the diagnosis, causes, frequency and patterns of liver injury attributable to both prescription and nonprescription medications. In LiverTox® there is data on almost all medications marketed in the United States, both on those who have been reported to cause liver injury and those without reports of liver injury. Although in LiverTox® a thorough literature search has been undertaken and is provided, no attempt has been made to judge the quality of the published reports or the causality of the suspected liver injury reported.  
In a recently published paper, drugs in LiverTox® were classified into categories, using all reports in this website [9]. For drugs with rather few reports (<12), the Rousel Uclaf Causality Assessment Method (RUCAM) was used [10]. In this critical analysis, many of the published reports did not stand up to critical review and currently there is no convincing evidence for some drugs with reported hepatotoxicity to be hepatotoxic [9]. Although certain drugs have a distinct phenotype such as isoniazid, which generally leads to a hepatocellular pattern or chlorpromazine cholestatic liver damage, many drugs can lead to both hepatocellular and cholestatic injury. Listing all types of patterns that have been reported for all these drugs is unfortunately not possible in this paper.
untitled h1
2. categories of hepatotoxicity

In the creation of LiverTox, drugs were arbitrarily divided into four different categories of likelihood for causing liver injury based on reports in the published literature [8]. Category A with >50 published reports, B with >12 but less than 50, C with >4 but less than 12, and D with one to three cases. In the Hepatology paper, drugs were categorized based on these numbers and another category, T, was added for agents leading to hepatotoxicity mainly in higher-than-therapeutic doses [9]. The number of published cases was counted unless >100 cases were found. The analysis was based mainly on published case reports, but case series were used if a formal causality assessment had been undertaken. In the analysis of the hepatotoxicity of drugs found in LiverTox, fewer drugs than expected had documented hepatotoxicity. Among 671 drugs available for analysis, 353 (53%) had published convincing case reports of hepatotoxicity. Thus, overall, 47% of the drugs listed in LiverTox did not have evidence of hepatotoxicity. This is at odds with product labeling which very frequently lists liver injury as adverse reaction to drugs [3]. It has to be taken into consideration that 116/863 (13%) of marketed agents had be excluded from the analysis. New drugs approved within the last five years were not included as most instances of hepatotoxicity appear in the post-marketing phase [11]. Metals (iron, nickel, arsenic), illegal substances (cocaine, opium, heroin), and infrequently used and/or not available (not marketed currently) drugs were also excluded [9]. Herbal and dietary supplements listed in LiverTox were not included in the category analysis.  
Among the 671 drugs available for analysis, the proportions of the drugs in the different categories were: A, 48 (14%); B, 76 (22%); C, 96 (27%); and D, 126 (36%). A total of 318 (47%) drugs have not been implicated (category E). In general, drugs in categories A and B were more likely than those in C and D to have been marketed for a long time, and both were more likely to have at least one fatal case of liver injury and reported cases of positive rechallenge. There is little doubt that drugs with >50 or 100 published reports of DILI such as category A drugs are hepatotoxic. The same is probably true for the vast majority of drugs in category B. However, in categories C and D with one to 12 cases reported, it is still not clear whether these agents are really hepatoxic drugs.
untitled h1
3. category a

Although drugs in this category (n = 48) were supposed to have >50 case reports of liver injury associated with the use of these drugs, 81% of the drugs had >100 cases reported. Interestingly, overall, 92% of these drugs had documented positive rechallenge. In Table 1, the category A drugs are illustrated with the indication and/or class of drug. These agents in category A are the real potential
untitled h1
int. j. mol. sci. 2016

hepatotoxins and clinicians should be aware of that when evaluating the risk-benefit ratio of drug therapy. Treatment with these drugs should motivate physicians to guide patients about potential symptoms of liver injury when taking these drugs and about prompt discontinuation if these symptoms occur. All except one entity (estrogens-progestins) or 98% had at least one convincing case that was associated with fatal outcome. All of these drugs except telithromycin had been approved for marketing for more than 15 years and 63% for more than 35 years [9]. The most common types of drugs were antimicrobials among 33% of the drugs, followed by drugs acting on the central nervous system (12.5%), cardiovascular (12.5%), rheumatologic (12.5%), antineoplastic (10%), endocrine (6%) and other types of drugs (13%). Although antimicrobials were the most common agents among drugs, antimicrobials were also the most common agents in categories B (30%), C (19%) and D (27%). Antibiotics have been shown to be the dominating type of drug in both prospective and retrospective studies on DILI [12–16]. There is unfortunately not enough room to discuss many of these well-documented hepatotoxic agents. As mentioned in the abstract, azathioprine and infliximab have in one study been found to be associated with the highest risk of liver injury [9]. Both hepatocellular and cholestatic injury has been described due to azathioprine [8,9]. Despite the common problem of hepatotoxicity with azathioprine, there is a lack of studies with a significant number of well-characterized patients with this type of liver injury. Table 1. Drugs that, according to analysis of data in LiverTox [8], have been associated with more than 100 cases of drug-induced liver injury.  
| Drug Drug                        | Class/Indication        |
|----------------------------------|-------------------------|
| 1. Allopurinol                   | Gout prophylaxis        |
| 2. Amiodarone                    | Arrhythmia              |
| 3. Amoxicillin-clavulanate       | Antibiotic              |
| 4. Anabolic steroids             | Body building           |
| 5. Atorvastatin                  | Lipid lowering agent    |
| 6. Azathioprine/6-Mercaptopurine | Immunosuppressive agent |
| 7. Busulfan                      | Malignancy              |
| 8. Carbamazepine                 | Antiepileptic           |
| 9. Chlorpromazine                | Psychosis               |
| 10. Contraceptives               | Birth control           |
| 11. Dantrolene                   | Muscle relaxant         |
| 12. Diclofenac                   | NSAID                   |
| 13. Didanosine                   | Antimicrobial           |
| 14. Disulfiram                   | Substance abuse agent   |
| 15. Efavirenz                    | Antimicrobial           |  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 123  
| 16. Erythromycin                                                  | Antimicrobial           |
|-------------------------------------------------------------------|-------------------------|
| 17. Floxuridine                                                   | Antineoplastic          |
| 18. Flucloxacillin                                                | Antimicrobial           |
| 19. Flutamide                                                     | Antineoplastic          |
| 20. Gold salts                                                    | Immunosuppressive agent |
| 21. Halothane                                                     | Anaesthetic             |
| 22. Hydralazine                                                   | Antihypertensive        |
| 23. Ibuprofen                                                     | NSAID                   |
| 24. Infliximab                                                    | Immunosuppressive agent |
| 25. Interferon alpha/Peginterferon                                | Antimicrobial           |
| 26. Interferon beta                                               | Multiple Sclerosis      |
| 27. Isoniazid                                                     | Antituberculosis        |
| 28. Ketoconazole                                                  | Antifungal              |
| 29. Methotrexate                                                  | Immunosuppressive agent |
| 30. Methyldopa                                                    | Antihypertensive        |
| 31. Minocycline                                                   | Antibiotic              |
| 32. Nevirapine                                                    | Antimicrobial           |
| 33. Nimesulide                                                    | NSAID                   |
| 34. Nitrofurantoin                                                | Antibiotic              |
| Int. J. Mol. Sci. 2016, 17, 224 4 of 7  Table 1. Cont.  Drug Drug | Class/Indication        |
| 35. Phenytoin                                                     | Antiepileptic           |
|                                                                   |                         |  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 124  
| 36. Propylthiouracil              | Antithyroid          |
|-----------------------------------|----------------------|
| 37. Quinidine                     | Arrhythmia           |
| 38. Pyrazinamide                  | Antituberculosis     |
| 39. Rifampin                      | Antituberculosis     |
| 40. Simvastatin                   | Lipid lowering agent |
| 41. Sulfamethoxazole/Trimethoprim | Antibiotic           |
| 42. Sulfazalazine                 | Antibiotic           |
| 43. Sulfonamides                  | Antibiotic           |
| 44. Sulindac                      | NSAID                |
| 45. Telithromycin                 | Antibiotic           |
| 46. Thioguanine                   | Antineoplastic       |
| 47. Ticlopidine                   | Platelet inhibitor   |
| 48. Valproate                     | Antiepilepitic       |  
4. Category B As mentioned above, most of these drugs with >12 and up to 50 case reports of DILI published probably carry hepatotoxic potential. This seems particularly true for drugs with reports of documented rechallenge, which had been reported in at least one case in 38% of the drugs [9]. In comparison with category A drugs, which almost exclusively had been associated with fatality, approximately 50% of category B drugs had been associated with a fatal outcome. Thus, in drugs with less frequent reporting of liver injury in category B, only 38% had rechallenge reported vs. 92% in category A, which suggests that the "proof" of hepatotoxicity is not there for all these drugs. In category B, 13/76 (17%) drugs with >30 cases reported are shown in Table 2. Table 2. Drugs in category B (>12 and >40 cases) that, according to analysis of data in LiverTox [8],have been associated with >30 published case reports of drug induced liver injury.  
| Drug                   | Drug Class/Indication   |
|------------------------|-------------------------|
| Amodiaquine            | Antimicrobial           |
| Azithromycin           | Antimicrobial           |
| Chlorzoxazone          | Muscle relaxant         |
| Cyproterone            | Antineoplastic          |
| Heparin                | Anticoagulant           |
| Imatinib               | Antineoplastic          |
| Irinotecan             | Antineoplastic          |
| Levofloxacin/Ofloxacin | Antimicrobial           |
| Oxacillin              | Antimicrobial           |
| Phenobarbital          | Antiepileptic           |
| Stavudine              | Antimicrobial           |
| Tamoxifen              | Antineoplastic          |
| Terbinafine            | HIV                     |  
5. Categories C, D and E Overall, 222/353 (63%) of drugs in LiverTox® with hepatotoxicity fall into categories C and D. Compared with category D, with only one to three cases reported, category C (<12 and >4 case reports) drugs were more likely to have rechallenge reports, with 26% vs. 11%, and fatal cases of 23% and 7%, respectively.  
A positive rechallenge is usually defined with biochemical criteria, showing recurrence of liver test abnormalities upon readministration of the drug, due to either intentional or inadvertent re-exposure [4,5]. This is generally considered to be the gold standard of the diagnosis of drug-induced liver injury. A documented positive rechallenge provides more evidence of the hepatotoxicity of a Int. J. Mol. Sci. 2016, 17, 224 5 of 7 given drug. Given the frequency of case reports with drugs in categories A and B, there seems little doubt that drugs in these categories can lead to hepatotoxicity and little need to do a strict causality assessment of reports with these drugs. However, in category C, consisting of 4–11 case reports, the hepatotoxicity of some drugs can be put into question. To illustrate this, 16 drugs in this category only had case reports with a possible likelihood score according to RUCAM. None of these drugs had documented fatal liver reactions or rechallenge. Thus, it can be concluded that these drugs do not have a well-documented hepatotoxicity, although liver injury with their use cannot be excluded. The poorly documented exclusion of competing causes, as well as the use of other concomitant drugs, made a causality assessment difficult. This has been problematic in many reports of suspected hepatotoxicity with human immunodeficiency virus (HIV) drugs [17–19]. It is very important that observations of hepatotoxicity of new drugs should lead to well-documented case reports with detailed clinical and biochemical information. The analysis reported in the Hepatology paper revealed that many drugs labeled as hepatotoxic and with a single or few case reports suggesting hepatotoxicity did not fulfill causality criteria by use of the RUCAM instrument [9]. 6. Common Drugs Leading to Liver Injury in Drug-Induced Liver Injury (DILI) Studies As mentioned above, antibiotics have, in all prospective studies, been found to be the most common drugs leading to hepatotoxicity [12–16]. In the most recently published series from the DILIN cohort in the US, antimicrobials, including antibacterial agents and antituberculosis agents, were approximately 46% of all DILI cases [20]. Furthermore, among the top 10 drugs in the DILIN registry, all drugs except one (Diclofenac) are antibiotics [20]. Table 3 illustrates the five most common drugs associated with liver injury in at least three prospective studies.  
Interestingly, all of these drugs belong to category A. Table 3. The top five implicated drugs in three prospective studies on DILI, in Spain (Andrade et al. [12] 2005), liver injury in drug-induced liver Injury (DILI) study from the US (Chalasani et al. [13] 2013) and a prospective study from Iceland (Bjornsson et al. [14] 2015). Spanish Registry DILIN Study Icelandic Study Amoxicillin-clavulanate Amoxicillin-clavulanate Amoxicillin-clavulanate Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 127 Isoniazid Isoniazid Diclofenac  
RIP + INH + PIZ Nitrofurantoin Azathioprine  
Flutamide SMZ/TMP Infliximab  
Ibuprofen Minocycline Nitrofurantoin  
RIP + INH + PIZ: Rifampin, Isoniazid and Pyrazinamide; SMZ/TMPSulfamethoxazole/Trimethoprim. In India, anti-tuberculous drugs (58%), anti-epileptics (11%), olanzapine (5%), and dapsone (5%) were the most common causes [16]. A unified list of drugs associated with DILI was recently established [21]. Overall 385 individual drugs were identified; 319 drugs were identified in three DILI registries, i.e., from Spain, Sweden and the US. The 10 most frequently implicated drugs were: amoxicillinclavulanate, flucloxacillin, erythromycin, diclofenac, sulfamethoxazole/Trimethoprim, isoniazid, disulfiram, Ibuprofen and flutamide [12–14,21]. 7. Risk of DILI among Patients Using Potentially Hepatotoxic Drugs Previously, data on numbers needed to harm drug users in terms of liver injury has been limited. Several retrospective case control cohort studies using the General Practitioners Research Database (GPRD) were the first studies on this [22–24]. A risk of DILI greater than 100 per 100,000 users was found for chlorpromazine and isoniazid. Drugs with an intermediate risk were amoxicillin-clavulanic acid and cimetidine, with a risk of one per 10 per 100,000 users [24]. All other drugs were found to be less than 10 per 100,000 users.
untitled h1
int. j. mol. sci. 2016

The following drugs were most strongly associated with DILI: Chlorpromazine, amoxicillin-clavulanic acid, flucloxacillin, macrolides, tetracyclines, metoclopramide, chlorpheniramine, betahistine, sulfasalazine, azathioprine, diclofenac, and antiepileptics The highest crude incidence rates were one per 739 users (chlorpromazine), one per 1103 (azathioprine), one per 1000 (sulfasalazine), and one per 11,688 (amoxicillin-clavulanate). The limitations of this study were the retrospective design with a lack of complete data regarding diagnostic testing and a lack of data on over-the-counter drugs and herbal agents [24]. In a recent prospective study on DILI from Iceland, data on the use of drugs was available [9]. The risk of DILI among patients using potentially hepatotoxic drugs could therefore be calculated. Amoxicillin-clavulanate-induced liver injury was found in one of 2350 outpatient users, which was higher among those who were hospitalized already, one of 729. This might be due to a detection bias, with more routine testing of the liver in the hospital, but it cannot be excluded that sicker patients are more susceptible to liver injury from this drug. The incidence rates were higher than previously reported, with the highest being one of 133 users for azathioprine and one of 148 for infliximab. Acknowledgments: No specific grants were obtained for research work presented in this paper and no funds for publishing in open access. Conflicts of Interest: The author declares no conflict of interest. References 1. European Medicines Agency. Available online: http://www.ema.europa.eu (accessed on 1 May 2015). 2. Physician Desk Reference (PDR). Available online: http://www.pdr.net (accessed on 1 May 2015). 3. Bjornsson, E.S.; Jacobsen, E.I.; Einarsdottir, R.; Chalasani, N. Discrepancies in liver disease labeling in the package inserts of commonly prescribed medications. Gastroenterology 2015, 148, 269–273. [CrossRef]
untitled h1
[pubmed]

4. Andrade, R.J.; Robles, M.; Lucena, M.I. Rechallenge in drug-induced liver injury: The attractive hazard.  
Expert Opin. Drug Saf. 2009, 8, 709–714. [CrossRef] [PubMed] 5. Papay, J.I.; Clines, D.; Rafi, R.; Yuen, N.; Britt, S.D.; Walsh, J.S.; Hunt, C.M. Drug-induced liver injury following positive drug rechallenge. Regul. Toxicol. Pharmacol. 2009, 54, 84–90. [CrossRef] [PubMed] 6. Zimmerman, H.J. Drug-induced liver disease. In Diseases of the Liver, 8th ed.; Sciff, E.R., Sorrell, M.F., Maddrey, W.C., Eds.; Schiff's Lippincott-Raven Publishers: Philadelphia, PA, USA, 1999; pp. 973–1064. 7. Agarwal, V.K.; McHutchison, J.G.; Hoofnagle, J.H. Important elements for the diagnosis of drug-induced liver injury. Clin. Gastroenterol. Hepatol. 2010, 8, 463– 470. [CrossRef] [PubMed] 8. LiverTox. Available online: http://livertox.nlm.nih.gov (accessed on 1 May 2015). 9. Björnsson, E.S.; Hoofnagle, J.H. Categorization of drugs implicated in causing liver injury: Critical assessment based upon published case reports. Hepatology 2015. [CrossRef] [PubMed] 10. Danan, G.; Teschke, R. RUCAM in drug and herb induced liver injury: The update. Int. J. Mol. Sci. 2016, 17. [CrossRef] [PubMed] 11. Senior, J.R. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: Current status and challenges. Drug Saf. 2014, 37, S9–S17. [CrossRef] [PubMed] 12. Andrade, R.J.; Lucena, M.I.; Fernandez, M.C.; Pelaez, G.; Pachkoria, K.; García-Ruiz, E.; García-Muñoz, B.; González-Grande, R.; Pizarro, A.; Durán, J.A.; et al. Drug-induced liver injury: An analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005, 129, 512–521. [CrossRef]  
13. Chalasani, N.; Fontana, R.J.; Bonkovsky, H.L.; Watkins, P.B.; Davern, T.; Serrano, J.; Yang, H.; Rochon, J. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States.  
Gastroenterology 2008, 135, 1924–1934. [CrossRef] [PubMed] 14. Bjornsson, E.S.; Bergmann, O.M.; Bjornsson, H.K.; Kvaran, R.B.; Olafsson, S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013, 144, 1419–1425. [CrossRef] [PubMed]
15. Björnsson, E.; Olsson, R. Outcome and prognostic markers in severe druginduced liver disease. Hepatology 2005, 42, 481–489. [CrossRef] [PubMed]
untitled h1
int. j. mol. sci. 2016

16. Devarbhavi, H.; Dierkhising, R.; Kremers, W.K.; Sandeep, M.S.; Karanth, D.; Adarsh, C.K. Single-center experience with drug-induced liver injury from India: Causes, outcome, prognosis, and predictors of mortality. Am. J. Gastroenterol. 2010, 105, 2396–2404. [CrossRef] [PubMed] 17. Bräu, N.; Leaf, H.L.;Wieczorek, R.L.; Margolis, D.M. Severe hepatitis in three AIDS patients treated with indinavir. Lancet 1997, 349, 924–925. [CrossRef] 18. Vergis, E.; Paterson, D.L.; Singh, N. Indinavir-associated hepatitis in patients with advanced HIV infection. Int. J. STD AIDS 1998, 9, 53. [CrossRef] [PubMed] 19. Pavel, S.; Burty, C.; Alcaraz, I.; de la Tribonnière, X.; Baclet, V.; Ajana, F.; Mouton, Y. Severe liver toxicity in postexposure prophylaxis for HIV infection with a zidovudine, lamivudine and fosamprenavir/ritonavir regimen. AIDS 2007, 21, 268–269. [CrossRef] [PubMed] 20. Chalasani, N.; Bonkovsky, H.L.; Fontana, R.; Lee,W.; Stolz, A.; Talwalkar, J. Features and outcomes of 889 patients with drug-induced liver injury: The DILIN prospective study. Gastroenterology 2015, 148, 1340–1352. [CrossRef] [PubMed] 21. Suzuki, A.; Andrade, R.J.; Bjornsson, E.; Lucena, M.I.; Lee, W.M.; Yuen, N.A.; Hunt, C.M.; Freston, J.W. Unified list of drugs causing hepatotoxicity and the reporting frequency of liver events in the WHO vigibaset: International collaborative work. Drug Saf. 2010, 33, 503–522. [CrossRef] [PubMed] 22. Pérez Gutthann, S.; García Rodríguez, L.A. The increased risk of hospitalizations for acute liver injury in a population with exposure to multiple drugs. Epidemiology 1993, 4, 496–501. [CrossRef] [PubMed] 23. García Rodríguez, L.A.; Ruigómez, A.; Jick, H. A review of epidemiologic research on drug-induced acute liver injury using the general practice research data base in the United Kingdom. Pharmacotherapy 1997, 17, 721–728. [PubMed] 24. De Abajo, F.J.; Montero, D.; Madurga, M.; García Rodríguez, L.A. Acute and clinically relevant drug-induced liver injury: A population based case-control study. Br. J. Clin. Pharmacol. 2004, 58, 71–80. [CrossRef] [PubMed]
© 2016 by the author; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons by Attribution
(CC-BY) license ( http://creativecommons.org/licenses/by/4.0/ ).
untitled h1
appendix 7.0 ae management algorithms

Rule out non-inflammatory causes. If non-inflammatory cause is identified, treat accordingly and continue I-O therapy. Opiates/narcotics  
  
corticosteroids.  
Case 1317 Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018  
  
  
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids.
untitled h1
case 1317

10/24/2017 Protocol Version Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 133
untitled h1
pulmonary adverse event management algorithm

10/24/2017 Protocol Version Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 134
untitled h1
hepatic adverse event management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy. Consider imaging for 10/24/2017 Protocol Version Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018
untitled h1
endocrinopathy management algorithm

Case 1317 10/24/2017 Protocol Version Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 136
skin adverse event management algorithm
endocrinopathy management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.  
  
*Refer to NCI CTCAE v4 for term-specific grading criteria.  
^if SIS/TEN is suspected, withhold i-O therapy and refer patient for specialized care for assessment and treatment. If SIS or TEN is diagnosed, permanently discontinue I-O therapy.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018
neurological adverse event management algorithm
endocrinopathy management algorithm

Rule out non-inflammatory causes. If non-inflammatory cause, treat accordingly and continue I-O therapy.  
  
oce sustained clinical improvement is observed.  Lower bioavailability of oral corticosteroids should be taken into account when
switching to the equivalent dose of oral corticosteroids.  
Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 138
appendix 8 correlative studies
endocrinopathy management algorithm

Peripheral blood and tumor tissue-based assays: Blood and tumor specimens (when available) will be collected from each patient. Tissue: Up to ten unstained slides of 5 microns thickness or a block of tissue will be required to be sent if tissue is available. If the tissue is not available then Principal investigator permissions is required for enrollment. If the patient undergoes recent biopsy or resection then the more recent tissue is preferred. If the patient didn't undergo any recent surgery then the tissue from diagnosis can be used. Whole exome sequencing, transcriptome analysis, tumor mutational burden. Additional markers for immune function will be performed such as PDl- PD-1, PD-1L staining etc. The tissue will be sent to Manmeet Ahluwalia , Attn: Mary Mcgraw (Case 1317) ND4-52 Lab, Lerner Research Institute 9620 Carnegie Avenue, N Building, Cleveland, OH 44106 Collect 4-10ml green top tubes. Once the sample is collected it should be tubed to station 19, with a filled requisition (see Appendix 7). Blood will be sent to the lab of Dr. C. Marcela Diaz-Montero for analysis. Lerner Research 2111 E. 96th St. NE4-216 Cleveland, OH 44106 Attention: Pat Rayman Provide advance notice by calling the lab at 216-444-5589 or emailing Pat Rayman at raymanp@ccf.org. Methods:
Characterization of circulating immune cells: Frequencies of MDSCs, Tregs, CD8+ T
cells, CD4+T and additional circulating immune cells will be determined by flow cytometry in both unfractionated blood and in purified PBMCs. PBMCs will be isolated from whole blood using the standard ficoll separation assay. Expression of immunomodulatory factors (PD-1, PD-1L, Lag3, Tim3, OX40, 41BB) on circulating immune cells will be also performed by flow cytometry. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 139 Characterization of tumor immune infiltrate: Fresh tumor tissue will be digested to single cell suspension and analyzed by flow cytometry for frequencies of MDSCs, Tregs, CD8+ T cells, and CD4+T cells. Expression of immunomodulatory factors (such as but not limited to PD-1, PD-1L, Lag3, Tim3, OX40, 41BB) on tumor infiltrating immune cells will also be assayed by flow cytometry.  
Cytokine/Chemokine profile: Plasma will be isolated from whole blood and analyzed for levels of cytokines/chemokines involved in Th1 and Th2 responses. A multiplex system that measures 50+ analytes will be used. Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 140 Appendix 9 Laboratory Requisition CASE 1317: A Randomized Phase 2 Open Label Study of Nivolumab plus Standard Dose Bevacizumab versus Nivolumab plus Low Dose Bevacizumab in Recurrent Glioblastoma (GBM)  
  Consented: Y N
PLEASE DRAW:
(4) 10 ml Green top (Sodium Heparin) tubes Must fill tubes all the way Mix/Invert 5-7 times after Draw Send to Station 19 Attention Dr. Finke/Diaz Lab 444-5589 (20567)
(DO NOT REFRIGERATE)
Send this requisition with the sample Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 141
appendix 10 nano scale
endocrinopathy management algorithm

CA209-382 - A Randomized Phase 2 Open Label Study of Nivolumab plus standard dose Bevacizumab versus Nivolumab plus low dose Bevacizumab in Recurrent Glioblastoma (GBM) Patient ID: __________________ Date of Assessment: ______________ Protocol Version 10/24/2017 Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 142 Figure 1. Neurologic Assessment in Neuro-Oncology (NANO) Scale Scoring assessment is based on direct observation and testing performed during clinical evaluation and is not based on historical information or reported symptoms. Please check 1 answer per domain. Please check "Not assessed" if testing for that domain is not done. Please check "Not evaluable" if a given domain cannot be scored accurately due to pre-existing conditions, co-morbid events and/or concurrent medications.  
Date Assessment Performed (day/month/year):
Study time point (i.e. baseline, cycle 1, day 1, etc):
Assessment performed by (please print name):
appendix 10 nano scale
domains

Gait o Normal 1 □
2 □
Abnormal but walks without assistance Abnormal and requires assistance
(companion, cane, walker, etc.)
Unable to walk 3 □
→
Not assessed
□ Not evaluable Strength 0 1 Movement present but decreased against resistance Movement present but none against resistance  
| 2 □   |
|-------|
| 3 □   |
| →     |  
No movement Not assessed
□ Not evaluable
.  
Test each limb separately
.  
Recommend assess proximal (above knee or elbow)
and distal (below knee or elbow) major muscle groups
.  
.  
Score should reflect worst performing area Patients with baseline level 3 function in one major muscle group/limb can be scored based on assessment of other major muscle groups/limb  
| o   |
|-----|
| 1   |
| 2 □ |  
Ataxia (upper extremity)
Able to finger to nose touch without difficulty Able to finger to nose touch but difficult Unable to finger to nose touch
→
Not assessed Not evaluable 0  
| Sensation   |
|-------------|
| 0           |
| l 🙂        |
| 2 □         |  
Decreased but aware of sensory modality Unaware of sensory modality
→
Not assessed Not evaluable
appendix 10 nano scale
case 1317

10/24/2017 Protocol Version Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018 Page 143
. .  
Non-evaluable if strength is compromised  
| .   |
|-----|  
Trunk/lower extremities assessed by gait domain Particularly important for patients with brainstem and cerebellar tumors
.  
Score based on best response of at least 3 attempts
.  
Recommend evaluating major body areas separately (face, limbs and trunk)
. .  
| Score should reflect worst performing area           |
|------------------------------------------------------|
| Sensory modality includes but not limited to light   |
| touch, pinprick, temperature and proprioception      |
| Patients with baseline level 2 function in one major |
| body area can be scored based on assessment of       |
| other major body areas                               |  
Key Considerations Walking is ideally assessed by at least 10 steps Visual Fields o Normal 1 2 Inconsistent or equivocal partial hemianopsia
(>quadrantopsia)
Consistent or unequivocal partial hemianopsia
(
Complete hemianopsia Not assessed Not evaluable  
| 3    |
|------|
| □    |
| -    |  
Facial Strength 0 l □
Normal Mild/moderate weakness Severe facial weakness Not assessed Not evaluable  
| 2 □   |
|-------|
| -     |
| -     |  
Language  
| o   |
|-----|  
1 Normal Abnormal but easily conveys meaning to examiner Abnormal and difficulty conveying meaning to examiner Abnormal.  If verbal, unable to convey meaning to examiner. OR non-verbal (mute/global aphasia)
Not assessed Not evaluable 2 []
3
- 🙂
Level of Consciousness 0 Normal 1 2 □
3
□
Drowsy (easily arousable) Somnolent (difficult to arouse) Unarousable/coma Not assessed Not evaluable Behavior 0  
| 2 []   |
|--------|
| -      |  
1 Normal Mild/moderate alteration Severe alteration Not assessed Not evaluable 2 []  
10/24/2017 Protocol Version Protocol Amendment 1 05/03/2018 Protocol Amendment 2 05/21/2018
.  
.  
Patients who require corrective lenses should be evaluated while wearing corrective lenses Each eye should be evaluated and score should
reflect the worst performing eye
. .  
Particularly important for brainstem tumors Weakness includes nasolabial fold flattening, asymmetric smile and difficulty elevating eyebrows
.  
.  
Assess based on spoken speech. Non-verbal cues or writing should not be included. Level 1 : Includes word finding difficulty; few paraphasic errors/neologisms/word substitutions; but able to form sentences (full/broken)
Level 2: Includes inability to form sentences (<4 words per phrase/sentence); limited word output; fluent but "empty" speech.  
.  
.  
None
. .  
Particularly important for frontal lobe tumors Alteration includes but is not limited to apathy, disinhibition and confusion.  
Consider subclinical seizures for significant alteration
.