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|---|  
| NCI Protocol #:                                                                                                                                               |                                                                                                                                          |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------|
| DF/HCC Protocol #: 17-037                                                                                                                                     |                                                                                                                                          |
| Protocol Version Date: September 25, 2018                                                                                                                     |                                                                                                                                          |
| 8.                                                                                                                                                            | PHARMACEUTICAL INFORMATION                                                                                                               |
| 8.1                                                                                                                                                           | Bavituximab                                                                                                                              |
| 8.2                                                                                                                                                           | TEMOZOLOMIDE .                                                                                                                           |
| 9.                                                                                                                                                            | BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ..........................................33                                                 |
| 9.1                                                                                                                                                           | Biomarker Studies                                                                                                                        |
| 9.2                                                                                                                                                           | Laboratory Correlative Studies                                                                                                           |
| STUDY CALENDAR ......................................................................................................................36                       |                                                                                                                                          |
| 10.                                                                                                                                                           |                                                                                                                                          |
| 11.                                                                                                                                                           | MENT OF EFFECT.................................................................................................................41        |
| 11.1                                                                                                                                                          | Antitumor Effect - Solid Tumors ....................................................................................41                   |
| 12.                                                                                                                                                           | DATA REPORTING / REGULATORY REQUIREMENTS ................................................45                                              |
| 12.1                                                                                                                                                          | DATA Reporting .......................................................................................................................45 |
| 12.2                                                                                                                                                          | Data Safety Monitoring                                                                                                                   |
| 13.                                                                                                                                                           | STATISTICAL CONSIDERATIONS                                                                                                               |
| 13.1                                                                                                                                                          | Study Design/Endpoints..................................................................................................46               |
| 13.2                                                                                                                                                          | Sample Size, Accrual Rate and Study Duration ........................................................46                                  |
| 13.3                                                                                                                                                          | Analysis of Primary Endpoints ......................................................................................47                   |
| 13.4                                                                                                                                                          | Analysis of Secondary Endpoints .................................................................................47                      |
| 13.5                                                                                                                                                          | Reporting and Exclusions ..............................................................................................47                |
| 14.                                                                                                                                                           | PUBLICATION PLAN ............................................................................................................488         |
| REFERENCES ................................................................................................................................................49 |                                                                                                                                          |
| APPENDIX A                                                                                                                                                    | PERFORMANCE STATUS CRITERIA ..........................................................532                                                |
| DRUG DIARY                                                                                                                                                    |                                                                                                                                          |
| APPENDIX B                                                                                                                                                    |                                                                                                                                          |
| APPENDIX C                                                                                                                                                    | INFORMATION ON POSSIBLE DRUG INTERACTIONS ...................58                                                                          |  
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facilitated by m1 macrophages, mature dendritic cells, and activated t lymphocytes). This process occurs via fc-mediated signaling and direct cell killing (antibody-dependent cellular cytotoxicity). In essence, expression of PS on the external surface of the cell acts as an immunosuppressive signal in normal cell death and immune phagocytic clearance. Tumor PS exposure in the microenvironment is immunosuppressive in malignant transformation and progression. Thus bavituximab has been shown to overcome immune suppression and stimulate antitumor immunity in nonclinical models (DeRose 2011; Yin 2013).
- !"#%&'()+-.
nonclinical experience

Data suggest that PS is primarily responsible for expansion of MDSCs and M2-like tumorassociated macrophages (TAMs) in tumors, and that bavituximab could reverse this process and reactivate antitumor immunity. Treatment of tumor-bearing mice with docetaxel in combination with 2aG4 (a PS-targeting antibody and the murine precursor to bavituximab), has been shown to potently suppress the growth and progression of prostate tumors and increase the presence of M1-like TAMs and mature dendritic cells in the tumor microenvironment (Yin 2013).  
The tumor and tumor vasculature localization of PS-targeting antibodies is followed by tumor immunity enhancing effects, tumor vessel damage, tumor vascularity reduction, tumor necrosis, and tumor growth retardation in multiple models (Ran 2005). The synergistic antitumor activity of antibodies targeting PS in combination with cytotoxic chemotherapy has been demonstrated in animal models, including but not limited to the Pan02 pancreatic adenocarcinoma cell line with gemcitabine and the MDA MB 435 cell line with docetaxel (Beck 2006, Huang 2005).  
In toxicology studies, no target organs of toxicity were identified in rats (up to 20 mg/kg) and monkeys (up to 10 mg/kg) receiving weekly doses for 8 weeks of bavituximab, and minimal histological findings in heart and lung were noted when administered to monkeys at 100 mg/kg. Detailed information about comprehensive nonclinical safety, immunology, and pharmacokinetics (PK) is provided in the current Investigator's Brochure for bavituximab.
- !"#%&'()+-.
clinical experience

Bavituximab has been evaluated by Oncologie in clinical studies in over 800 patients (as of July 216), most of whom were treated with combination therapy. These clinical trials have included patients with a number of tumor types, including breast, lung, pancreatic and hepatocellular carcinoma, and in chronic HCV. A dose of 3 mg/kg bavituximab given intravenously (IV) was determined and selected for further clinical study based on Phase 1 single-agent and combination therapy studies.  
In a Phase II, multicenter, breast cancer trial (PPHM 0702), bavituximab (3 mg/kg), given weekly until progression, was combined with paclitaxel (100 mg/m2) and carboplatin (area under the concentration-time curve = 2), given on Days 1, 8 and 15 of planned 4-week cycles for up to 6 cycles, to 46 patients with metastatic disease, unrestricted by hormone or HER2 status. Objective response per Response Evaluation Criteria in Solid Tumors (RECIST) occurred in 34 of 46 patients (73.9%) with a median duration of response (DOR) of 3.7 months (95%
confidence interval [CI]: 3.1, 5.8) and median PFS of 6.9 months (95% CI: 5.6, 7.7) (Jain 2010).  
The most common Grade 4 treatment-emergent adverse event (TEAE) was neutropenia (12 patients, 26.1%), and the most common Grade 3 TEAEs were leukopenia (11 patients, 23.9%),
nutropenia (9 patients, 19.6%), and anemia (5 patients, 10.9%).  
In a Phase II, multicenter, lung cancer trial (PPHM 0704), bavituximab (3 mg/kg), given weekly until progression, was combined with docetaxel (35 mg/m2), given on Days 1, 8, and 15 of planned 4-week cycles for up to 6 cycles, to 46 patients with MBC (with any hormone or HER2 status). Objective response occurred in 28 of 46 patients (60.9%) with median DOR of 6.1 months (95% CI: 5.7, 7.5) and median PFS of 7.4 (95% CI: 6.1, 9.1) months (Tabagari 2010). Of the most common TEAEs reported, only fatigue, headache, back pain, and hypertension were Grade ≥ 3. In another Phase II, multicenter trial in patients with advanced nonsquamous non– small-cell lung cancer patients were randomized 1:1:1 to docetaxel 75 mg/m 2 every 21 days for up to 6 cycles combined with weekly, blinded infusions of placebo, bavituximab 1 mg/kg, or bavituximab 3 mg/kg until disease progression or unacceptable toxicity (Gerber 2016). Efficacy end points in the bavituximab 3 mg/kg group (n = 41) and in the placebo/bavituximab 1 mg/kg group (n = 80), respectively, were as follows: ORR, 17.1% (95% confidence interval [CI], 5.6%-
2.6%) and ORR, 11.3% (95% CI, 4.3%-18.2%); median progression-free survival 4.5 and 3.3 months (hazard ratio [HR], 0.74 [95% CI, 0.45-1.21]; P = .24); median overall survival 11.7 and 7.3 months (HR, 0.66 [95% CI, 0.40-1.10]; P = .11). Toxicities were manageable and similar btween arms.  
In a single-center, investigator sponsored study, breast cancer patients received bavituximab 3 mg/kg weekly in combination with paclitaxel (80 mg/m2) given on Days 1, 8, and 15 in 4-week cles to 14 patients with HER2-negative MBC. Treatment resulted in an ORR of 85% (2 patients had complete responses) and a median PFS of 7.3 months (95% CI: 2.8, 10.8) (Chalasani 2015). Bone pain, fatigue, headache, and neutropenia were the most common AEs. Infusion-related reactions were the most common AE related to bavituximab. A Phase II, single institution study of bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC) was also conducted.  Patients received 3 mg/kg IV weekly of bavituximab and 40 mg PO BID of sorafenib until radiologic progression.  Secondary endpoints included overall survival, disease specific survival, 4 month progression free survival, safety, and response rate.  
The study accrued 38 patients.  Median OS was 6.2 months.  Two patients achieved partial response and four month PFS was 61%. There were no grade 4 or 5 adverse events recorded.  
Most common all grade events were diarrhea (32%), fatigue (26%), and anorexia (24%) (Yopp 2015).  These results demonstrated that bavituximab and sorafenib were well tolerated in patients with advanced HCC. Overall, results from Phase I and Phase II studies have demonstrated a clinically meaningful treatment effect of bavituximab, and results were consistent among the studies. The overall sfety profile of bavituximab was acceptable, and the safety data were consistent with those observed in other clinical studies. Combination therapy did not substantially increase the risks of side effects. Thus the potential additional benefits of combination therapy are likely to outweigh the risk of AEs experienced during bavituximab treatment. Refer to the Investigator's Brochure for additional details.  
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GBM is considered a relatively low mutational load tumor so we hypothesis that radiation will increase antigen presentation and improve outcomes when combined with bavituximab in newly diagnosed GBM. The underlying mechanisms for this improved response can be measured using blood and MRI markers of immune status, vascular biology, and the tumor microenvironment. Based on this hypothesis, we propose evaluating the following correlative markers:
1. Correlate baseline and change in circulating immune cell biomarkers and cells within the resected tumors (i.e. from blood as well as histological samples) with radiographic response
(RR), progression free survival (PFS), and overall survival (OS). 2. Determine if changes in MRI parameters (specifically changes in perfusion, vascular permeability, or tissue cellularity/metabolism) will shed light on the mechanism of action of bavituximab in GBM.  
3. Determine if changes in MRI parameters (specifically changes in perfusion, vascular permeability, or tissue cellularity/metabolism) will help distinguish responders from nonresponders early in the course of bavituximab therapy.  
4. Determine if changes in MRI parameters (specifically changes in perfusion, vascular permeability, or tissue cellularity/metabolism) will help distinguish a positive inflammatory response from active tumor.  
5. Determine changes in PS exosomes and serum B2GP1 during treatment with bavituximab. Blood will be analyzed for circulating immune cells to help distinguish inflammation from active tumor by tracking T cell receptor (TCR) repertoire and its correlation with TCRs that expand in the tumor. In addition, myeloid cells will be analyzed to detect changes with therapy.  
Tumor tissue will be analyzed for myeloid cells and T cells using single cell RNA-seq (fresh tissue) or population RNA-seq (fixed tissue), which will provide information about changes in myeloid cells with treatment as well as TCRs present in infiltrating T cells. If patient requires further surgery, tissue will be analyzed again for changes in myeloid cells and TCRs with therapy. This will allow for pre- and post-therapy comparison.
- !"#%&'()+-.
preliminary data mri

We have conducted several clinical trials that incorporate advanced imaging to shed light on tumor response to treatment (Batchelor 2013, Gerstner 2016, Gerstner 2015). Most relevant to this proposal, we have looked at MRI changes in newly diagnosed GBM patients receiving standard radiation and temozolomide with or without cediranib, a tyrosine kinase inhibitor of VEGF receptors (Batchelor 2015). These data demonstrate our ability to analyze complex imaging datasets but, more importantly shed light on how anti-angiogenic therapy might be helping during chemoradiation. We found that increased tumor perfusion was associated with improved survival with cediranib therapy suggesting a vascular normalization effect in a subset of patients leading to improved delivery of chemotherapy and oxygen needed for radiation to be effective. In our patients treated with standard chemoradiation, we did not see this change in perfusion. Therefore, our MRI techniques were able to shed light on the physiological impact the drug was having on GBM. Both of these datasets will be available to compare to data derived from this proposal so we will be able to determine how immunotherapy impacts tumor differently from standard therapy or anti-angiogenic therapy. Furthermore, there is a complex interaction between tumor vasculature and the immune system and our MRI, which captures vessel size and permeability as well as perfusion and blood volume, will be able to shed light on this complexity by measuring structural and functional changes in tumor vasculature longitudinally.  
Vessel architectural imaging (VAI), derived from the MR perfusion acquisition, can distinguish between responders and non-responders treated with immunotherapy by measuring changes in tissue oxygenation status (SO2). Patients with metastatic melanoma to the brain treated with stereotactic radiosurgery +/- ipilumimab experienced changes in vascular structure and function.  
Shorter surviving patients experienced worsening in SO2 relative to healthy tissue suggesting that the immunotherapy was not effectively modulating vasculature or ultimately killing the tumor itself (Digenes 2016). Hypoxia is a negative prognostic marker in cancer so a decrease in the tissue oxygenation status (i.e. decrease in SO2) suggests that the tumor is actively growing - a fact supported by the shorter survival in these patients. The improvement in SO2 suggests vascular remodeling in response to therapy. These findings are similar to our experience in glioblastoma where a decrease in SO2 compared to healthy tissue was associated with shorter survival. We will include monitoring of tissue oxygenation, perfusion, and vascular permeability in this clinical trial to help assess tumor response.
- !"#%&'()+-.
immunomitoring

The Hacohen lab has analyzed myeloid cells in both blood and tumor tissue in depth using flow cytometry and single cell RNA sequencing (scRNA-seq). For example, they can identify 6 types of dendritic cells and 4 types of monocytes using scRNA-seq, allowing an unbiased analysis of the myeloid compartment. In addition, both myeloid and T cells can be seen by scRNA-seq of tumors pre- and post immune therapy. They have also analyzed TCR repertoire using scRNA-seq and identified enriched clones expressing a specific pair of TCRα/β□ in patient tumors. For FFPE samples, the Hacohen lab has published methods to analyze the T cell responses using bulk RNA-seq (Rooney 2015).
- !"#%&'()+-.
3. participant selection 3.1 eligibility

3.1.1
Participants must have histologically confirmed newly diagnosed glioblastoma or glioblastoma variant (ex. gliosarcoma), including documentation of unmutated isocitrate dehydrogenase (IDH) by immunohistochemistry  or sequencing.  
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3.1.9 Able to undergo an MRI scan and receive gadolinium-based contrast.  
3.1.10 1 cm3 of available tissue for N=5 patients for correlative tissue studies (Section 9.2.2).  
Patients can enroll regardless of their tissue availability being checked beforehand but at least 5 patients will need to have sufficient tissue by study accrual completion. Tissue availability will be checked after patients are successfully enrolled.  
3.1.11 Ability to understand and the willingness to sign a written informed consent document.
- !"#%&'()+-.
3.2 exclusion criteria

3.2.1 Participants who are receiving any other investigational agents.  
3.2.2 History of allergic reactions attributed to compounds of similar chemical or biologic composition to bavituximab.  
3.2.3 Participants receiving any medications or substances that are moderate and/or potent enzyme inducers or inhibitors which may have an effect on the metabolism of bavituximab.  As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications ned to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product (Appendix C for partial list).  
3.2.4 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.  
3.2.5 Pregnant women are excluded from this study because bavituximab is an immunotherapy agent with the potential for teratogenic or abortifacient effects.  Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with bavituximab breastfeeding should be discontinued if the mother is treated with bavituximab.  These potential risks may also apply to other agents used in this study.  
3.2.6  
HV-positive participants on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with bavituximab.  In addition, these participants are at increased risk of lethal infections when treated with marrowsuppressive therapy.
3.2.7  
Participants with other active malignancy in the past 3 years excluding in situ tumors.
3.2.8  
Participants must meet the following windows from procedures (there is no window required for port placement since there is no anticipated impact on wound healing with bvituximab):
- Major surgery (ex. craniotomy) within 3 weeks of initiation of treatment.  
- Brain biopsy within 2 weeks 3.2.9  
Participants with active bleeding disorder/coagulopathy.
3.2.10 Participants with active chronic or acute hepatitis C or B infection.
- !"#%&'()+-.
3.3 inclusion of women and

Both men and women of all races and ethnic groups are eligible for this trial.
- !"#%&'()+-.
4. registration procedures 4.1 general

Institutions will register eligible participants in the Clinical Trials Management System (CTMS)
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not registered to the protocol before protocol therapy begins will be considered ineligible and registration will be denied.  
An investigator will confirm eligibility criteria and a member of the study team will complete the protocol-specific eligibility checklist. Following registration, participants may begin protocol therapy. Issues that would cause treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant does not receive protocol therapy following registration, the participant's registration on the study must be canceled. Registration cancellations must be made in OnCore as soon as possible.
- !"#%&'()+-.
4.2 registration process for df/hcc

DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol Registration (SOP \#: REGIST-101) must be followed.  
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will resume at next scheduled time.  
Infusion Reactions: Administer standard hypersensitivity reaction medications per institution guidelines. In addition, all patients should be pre-medicated as outlined in Section 5.  
Clinically mild reactions (eg, generalized rash or itching, hives) are treated as soon as possible with Benadryl® (diphenhydramine hydrochloride) 25 to 50 mg, orally or IV at the investigator's discretion. The period of observation is extended beyond 3 hours, as necessary, until symptoms and signs have resolved or stabilized. Patients who have experienced a clinically mild reaction may continue to have study drug administered.  
Clinically moderate reactions (eg, hypotension, shortness of breath, presyncope, facial edema) are treated immediately and supportive care measures instituted as medically indicated (eg, IV fluids, corticosteroids, vasopressors, oxygen, bronchodilators, diphenhydramine, and acetaminophen). Vital signs are monitored at 10-minute intervals until they have normalized. The period of observation is extended beyond 3 hours, if ncessary, until symptoms and signs have resolved. In the event of a clinically moderate reaction, the patient should receive no further treatment with study drug. For grade 3-4 reactions, halt infusion and discuss with principle investigator if rechallenge is reasonable or if the patient should go off treatment.
- !"#%&'()+-.
5.3.2 other agent(s)

Temozolomide will be taken per standard of care. Guidelines provided below on dosing/schedule.
- !"#%&'()+-.
temozolomide during concomitant radiation therapy

Temozolomide will be administered continuously from day 1 of radiotherapy to the last day of radiotherapy at a daily oral dose of 75 mg/m² for a maximum of 42 days. The drug will be administered orally 1-3 hours before each session of radiotherapy during weekdays (Monday through Friday). During weekends without radiotherapy (Saturday and Sunday), the drug will be taken in the morning. The dose will be determined using actual body surface area (BSA) as calculated in square meters at the beginning of the concomitant treatment. Patients will be instructed to swallow the capsules whole, in rapid succession, without chewing them. If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the next scheduled dose. The capsules should be taken on an empty stomach, therefore a minimum of 2 hours after eating and with no food consumption for at least 1 hour after temozolomide administration. Although, nightly administration just before bedtime has been reported to improve tolerance, the low daily dose administered during radiation is very well tolerated and administration in the morning before radiation dosing is required for this protocol.  
Administration of the higher dosing regimen during the adjuvant phase of the protocol should be performed using the nightly administration.  
Antiemetic prophylaxis is usually not required for the continuous daily dosing schedule (during radiation). However, prophylaxis with a 5-HT3 antagonist is recommended 30-60 minutes prior to administration of the first few temozolomide doses. Most patients report optimal nausea control with the use of a 5-HT3 antagonist. Routine use of antiemetics is recommended during the adjuvant phase of treatment. Additionally, pneumocystis carinii prophylaxis is at the discretion of the Investigator during the radiation phase.
- !"#%&'()+-.
post-radiation temozolomide dosing

As part of this protocol, patients will receive up to 2 cycles of adjuvant temozolomide at a dose of 150-200 mg/m2 days 1-5 of a 28-day cycle. Patients will be treated for up to 6 months of post- RT temozolomide (Stupp 2005). If patients experience grade 3 or higher toxicity attributable to the temozolomide that does not resolve to a grade 2 or less within 60 days of the last temozolomide dose, temozolomide should be discontinued. If the toxicity returns to a grade 2 or less within 30 days of the last dose, temozolomide can be dose reduced to 150mg/m2. The active period of this clinical trial will be approximately 18 weeks as long as there are no delays or missed doses that need to be made up.  
As part of this protocol, temozolomide will be administered orally once per day for 5 consecutive dys (days 1-5) of a 28-day cycle. The starting dose for the first cycle will be 150 mg/m 2 /day, with a single dose escalation to 200 mg/m²/day in subsequent cycles if no treatment-related adverse events > Grade 2 are noted. Patients can be increased to 200 mg/m2 at any time during the maintenance phase if deemed clinically appropriate by the treating physician.  
The start of the cycle 2 will be scheduled 28 days ± 7 days after the last day of radiotherapy. The start of the subsequent cycles (Cycles 3-4) will be scheduled in 28 days ± 7 days) after the first daily dose of temozolomide of the preceding cycle.  
The dose will be determined using the BSA per institutional standard.  
Patients will be instructed to fast at least 2 hours before and 1 hour after temozolomide administration. Water is allowed during the fast period. Patients will be instructed to swallow the capsules whole, in rapid succession, without chewing them. Treatment can be given at night if patient prefers. If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed before the next scheduled dose.  
If a patient misses the dose of temozolomide, it made be made up within 8 hours, otherwise the dose should be delayed until the next time it is due. Missed doses can be added on to the end of the 5 day dosing (i.e. taken on day 6) during the maintenance phase (i.e. 5/28 day cycles).  
Antiemetic prophylaxis with a 5-HT3 antagonist is recommended and should be administered 30 to 60 minutes before temozolomide administration. Temozolomide should be stored at room temperature.  
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Dose reductions of temozolomide during the adjuvant period should be made according to the prescribing information, as summarized below. No dose reductions will be made during the chemoradiation phase. If an adverse event related to temozolomide occurs during chemoradiation, dosing will be held and missed doses will not be made up.  
| Table: Temozolomide Dose Levels for Cycles 3 and 4   |                  |                                   |
|------------------------------------------------------|------------------|-----------------------------------|
| Dose Level                                           | Dose (mg/m2/day) | Remarks                           |
| -l                                                   | 100              | Reduction for prior toxicity      |
| (                                                    | 150              | Dose during Cycle 1               |
| +1                                                   | 200              | Dose during Cycle 2 in absence of |
| toxicity                                             |                  |                                   |  
AE's attributed to bavituximab will be managed with maximal supportive care but since temozolomide is the more likely culprit for toxicity, a decrease in temozolomide should be tried prior to stopping bavituximab.  
If a patient develops a blood clot, low molecular weight heparin can be used. The bavituximab does not need to be held but may be held at the treating physician's discretion.
- !"#%&'()+-.
7. adverse events list and

Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The following list of reported and/or potential AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine whether the event requires expedited reporting in addition to routine reporting.  
7.1
- !"#%&'()+-.
expected toxicities

7.1.1  
Adverse Events List(s)  
$$7.1.1.1$$
$$\mathrm{{\boldsymbol{b}}a v i t u x i m a l}$$  
Adverse Event List(s) for bavituximab Table 24:  
| and Chemotherapy by Preferred Term and Dose Level for all Oncology Studies Safety Population   |             |             |             |
|------------------------------------------------------------------------------------------------|-------------|-------------|-------------|
| Preferred Terr                                                                                 | 14 (17.7%)  | 174 (30.5%) | 188 (29.0%) |
| 21 (26.6%)                                                                                     | 167 (29.3%) | 188 (29.0%) |             |
| 21 (26.6%)                                                                                     | 162 (28.4%) | 183 (28.2%) |             |
| 15 (19.0%)                                                                                     | 166 (29.1%) | 181 (27.9%) |             |
| .18 (22.8%)                                                                                    | 149 (26.1%) | 167 (25.7%) |             |
| 14 (17.7%)                                                                                     | 145 (25.4%) | 159 (24.5%) |             |
| 13 (16.5%)                                                                                     | 121 (21.2%) | 134 (20.6%) |             |
| 17 (21.5%)                                                                                     | 103 (18.1%) | 120 (18.5%) |             |
| Dyson                                                                                          | 1 (13.9%)   | 106 (18.6%) | 17 (18.0%)  |
| 13 (16.5%)                                                                                     | 101 (17.7%) | 14 (17.6%)  |             |
| 9 (11.4%)                                                                                      | 103 (18.1%) | 12 (17.3%)  |             |
| 12 (15.2%)                                                                                     | 95 (16.7%)  | 107 (16.5%) |             |
| 12 (15.2%)                                                                                     | 85 (14.9%)  | 97 (14.9%)  |             |
| 5 (6.3%)                                                                                       | 84 (14.7%)  | 89 (13.7%)  |             |
| .16 (20.3%)                                                                                    | 6 (11,6%)   | 82 (12.6%)  |             |
| 8 (10.1%)                                                                                      | 71 (12.5%)  | 79 (12.2%)  |             |
| 8 (10.1%)                                                                                      | 70 (12.3%)  | 78 (12.0%)  |             |
| 8 (10.1%)                                                                                      | 61 (10.7%)  | 69 (10.6%)  |             |
| 8 (10.1%)                                                                                      | 61 (10.7%)  | 69 (10.6%)  |             |
| 12 (15.2%)                                                                                     | 48 (8.4%)   | 60 (9.2%)   |             |
| 4 (5.1%)                                                                                       | 55 (9.6%)   | 59 (9.1%)   |             |  
7.1.1.2 Adverse Event List(s) for Other Agent(s)
Please see package insert for adverse events for temozolomide.
- !"#%&'()+-.
7.2 adverse event characteristics

.  
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm .  
.
- !"#%&'()+-.
for expedited reporting purposes only

AEs for the agent(s) that are listed above should be reported only if the adverse event varies in nature, intensity or frequency from the expected toxicity information which is provided.  
Other AEs for the protocol that do not require expedited reporting are outlined in the nxt section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions.  
.  
Attribution of the AE:  
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of bavituximab.  An unexpected adverse event is one that is not already described in the Investigator Brochure.  Such reports are to be telephoned or faxed to the FDA and Oncologie within 7 calendar days of first learning of the event.  Each telephone call or fax transmission (see fax number below) should be directed to the FDA new drug review division in the Center for Drug Evaluation and Research or in the product review division for the Center for Biologics Evaluation and Research, whichever is responsible for the review of the IND.  
15 Calendar-Day Written Report:
The Investigator-Investigator is also required to notify the FDA and all participating investigators, in a written IND Safety Report, of any serious, unexpected AE that is considered possibly related to the use of bavituximab.  An unexpected adverse event is one that is not already described in the Investigator Brochure.  
Written IND Safety Reports should include an Analysis of Similar Events in accordance with regulation 21 CFR § 312.32.  All safety reports previously filed with the IND concerning similar events should be analyzed.  The new report should contain comments on the significance of the nw event in light of the previous, similar reports.  
Written IND safety reports with Analysis of Similar Events are to be submitted to the FDA, Oncologie Drug Safety, and all participating investigators within 15 calendar days of first learning of the event.  The FDA prefers these reports on a MedWatch 3500A Form but alternative formats are acceptable (e.g. summary letter).  
FDA fax number for IND Safety Reports:
- !"#%&'()+-.
l (800) fda - 0178

All written IND Safety Reports submitted to the FDA by the Investigator must also be emailed to: Oncologie Drug Safety  
| North America          |                                   |
|------------------------|-----------------------------------|
| Hagop Youssoufian, MD  | hagop@oncologie.international     |
| Safety Reporting Email |                                   |
| Fax                    | oncologiesafety@medassessment.com |  
For questions related to safety reporting, contact:
Oncologie Drug Safety (c/o MedAssessment)
Tel:
1-781-434-5010
- !"#%&'()+-.
b. ind annual reports

In accordance with the regulation 21 CFR § 312.32, the Investigator- Sponsor shall within 60  
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disposal of the chemotherapeutic agent in a self-contained and protective environment.
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8.1.6

Availability
Oncologie will supply drug and provide a request form for shipping.  Drug will supplied free of charge.
- !"#%&'()+-.
8.1.7 preparation

A pharmacist or designee at the study site will prepare bavituximab to be administered by study personnel to patients in accordance with the scheme. Infusion preparation and administration are to be performed as follows:
Using aseptic technique, withdraw the calculated dose volume of bavituximab from the vials using a sterile non-siliconized needle and syringe and inject contents of syringe into the normal saline container.  Thoroughly mix the infusion container by gentle manual rotation.  Avoid shaking or vigorous agitation during preparation and prior to administration. The IV normal saline container admixed with IP may contain a small amount of intrinsic, translucent to white proteinaceous particles.  Administer through a low protein binding 0.2-micrometer in-line filter (placed as proximal to the patient as practical).
- !"#%&'()+-.
8.1.8 administration do not administer

Pre-medication is no longer required prior to bavituximab administration as the steroids may interfere with drug efficacy and there have been limited reactions in patients so far.  
If pre-medication is warranted, one possible regimen is 250 mg hydrocortisone IV and 25-50 mg diphenhydramine IV administered ideally 30 minutes prior to infusion; regimen, dosages, and timing can be adjusted at the investigator's discretion. Patients receiving premedication for other therapy do not require additional corticosteroids on days when both are administered. Patients who tolerate bavituximab without reaction may not need pre-medication with subsequent doses and pre-medication use can be decided in conjunction with patient, nursing, treating physician.  
Affix the infusion line and prime it with infusate before starting the infusion.  
The first IV infusion must be administered over approximately 90 (±10) minutes. Patients should be watch for 180 minutes after the start of the first infusion. If the first IV infusion is tolerated, subsequent infusions may be administered over 60 minutes with no postinfusion observation as long as no hypersensitivity reactions occur.  
Flush the main infusion line with normal saline after infusion.  
NOTE: Bavituximab should only be administered in settings in which emergency
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resting state MRI. There will be 2 injections of gadolinium based contrast agent for a total 0.2 mol/kg (less than the FDA limit of 0.3 mmol/kg). Patients will be required to have an eGFR>60 mL/min/1.73 m2 within 30 days prior to the MRI. Total scan time is approximately 50 minutes and data will be processed by Dr. Gerstner's group at the Martinos Center to extract information about tumor vascular structure and function, connectivity, as well as cell density and metabolism as outlined in Section 2.5 and per our standard analytical techniques (Batchelor 2013, Gerstner 2016). Quantitative markers to be evaluated as exploratory markers of response include cerebral blood flow/volume, relative tissue oxygenation saturation, apparent diffusion coefficient, intracellular volume fraction, ktrans, and metabolites (ex. Cr, NAA). We anticipate others arising as the field of physiological imaging for brain tumors is rapidly evolving with novel analysis approaches continually being proposed. These novel markers would be extracted from existing data.
- !"#%&'()+-.
9.2 laboratory correlative studies 9.2.1.1

Blood will be analyzed for circulating immune cells to help distinguish inflammation from active tumor by tracking T cell receptor (TCR) repertoire and its correlation with TCRs that expand in the tumor. In addition, myeloid cells will be analyzed to detect changes with therapy.  
We will perform a flow cytometry analysis of myeloid cells, focusing on the number of (myeloid derived suppressor cells (MDSCs). We will use flow cytometry to analyze myeloid cells (HLA-
DR+, CD3-, CD19-, CD56) cells, including CD14+ and CD16+ monocytes, DC subtypes
(CLEC9A/CD141; CD1C+; CLEC9A-CD1C-), and MDSCs (CD33+CD11b+Lin-HLADR-,
CD14+CD11b+Lin-HLADR- and CD15+CD11b+Lin-HLADR-) This will quantify the absolute nmber and frequencies of these cell types pre and post therapy.  In addition, we will track TCR
repertoire using standard next generation sequencing approaches (amplify TCRbeta from blood and analyze repertoire). A prior study in vaccinated glioblastoma patients demonstrated coordinate changes in TCR repertoire in tumor and blood in association with durable responses.  
(Hsu 2016)
- !"#%&'()+-.
9.2.1.2 collection of specimen(s)

Blood will be collected prior to start of treatment, at the end of chemoradiation (week 6 of chemoradiation), first week after radiation, and then monthly for the subsequent 2 months during bavituximab + monthly temozolomide treatment.
- !"#%&'()+-.
9.2.1.3 handling of specimens(s)

At appropriate time points, 50 cc of fresh whole blood will be collected in K2 EDTA 10 ml Blood Collection Tubes, delivered immediately after collection at room temperature (no ice) to Dr. Curry's laboratory (3rd Floor Simches Research Building , Room CPZN 3) for isolation and storage of peripheral blood mononuclear cells (PBMC's). Label subject ID, date and time of collection. Site will be responsible for all of the supplies, inclusive of packaging and shipping materials and shipping charges. Contact Leland Richardson
(LRICHARDSON7@mgh.harvard.edu) to arrange delivery (or phone 732-600-6514) Monday through Friday 8:00m - 4:00 pm.
- !"#%&'()+-.
9.2.1.4

Shipping of Specimen(s)
Dr. Curry's lab will arrange shipping to Dr. Hacohen's laboratory (Broad Institute, 7 Cambridge Center, Cambridge MA).  
9.2.1.5 Site(s) Performing Correlative Study Dr. Nir Hacohen's lab in conjunction with Dr. William Curry's lab will be responsible for analyzing the tissue and blood.
- !"#%&'()+-.
9.2.2 tumor tissue

For a subset of tumor samples (N=5 initially that will be identified once patients have consented to treatment and determined to have sufficient tissue), we will isolate myeloid cells (using a Linantibody cocktail to exclude all lymphocytes- CD56, CD2, CD3, CD19 and CD20) and use single cell RNA-seq (scRNA-seq) to characterize the types and activation status of these cells, as well as capture the paired TCR repertoire from T cells. If fresh tissue is not available, we will isolate RNA from fixed tissue and perform bulk sequencing of TCRs for the T cell repertoire, and mRNA for gene expression, from which we will infer myeloid cell populations and TCR
repertoire. Fresh or fixed tissue will be obtained from pathology from the original surgery for analysis. Currently, pre-surgical patients are consented under DFHCC Protocol 10-417 to contribute fresh tissue as part of a tissue bank and we will petition this bank for fresh tissue. For patients requiring repeat resection while on study treatment, we will obtain fresh frozen tissue for analyze and comparison to the initial tumor tissue. Ideally we will obtain ~1cm 3 of tissue but if that amount of tissue is not available, Dr. Curry will review with Pathology what is available and determine if sufficient for the planned analyses.
- !"#%&'()+-.
9.2.2.1 collection of specimen(s)

Fresh frozen tissue or fixed if fresh is not available will be obtained at the time of diagnostic surgery or repeat surgery.
- !"#%&'()+-.
9.2.2.2 handling of specimens(s)

At the time of surgery, after confirmation that adequate specimen has been obtained for pathology review, fresh tumors will be collected and the presence of malignant cells will be confirmed in frozen sections on adjacent, representative pieces of tissue. Fresh tumor tissue will be delivered to Dr.  Hacohen's laboratory minced with a scalpel and enzymatically dissociated using a gentle papain-based brain tumor dissociation kit (Miltenyi Biotec). From these cells, we  
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| C w/diff, plts                                                                               | x   | x   | x   | x   | x   | x   | X   | X   |
|----------------------------------------------------------------------------------------------|-----|-----|-----|-----|-----|-----|-----|-----|
| Serum chemistry®                                                                             | X   | x   | X   |     |     |     |     |     |
| PT/INR/aPTT                                                                                  | X   |     |     |     |     |     |     |     |
| EG (as indicated)                                                                            | X   |     |     |     |     |     |     |     |
| Adverse event evaluation                                                                     | x   | X   | x   | X   |     |     |     |     |
| Tumor measurements via                                                                       | x   | x   |     |     |     |     |     |     |
| MRI b                                                                                        |     |     |     |     |     |     |     |     |
| B-HCG °                                                                                      | x   |     |     |     |     |     |     |     |
| Tissue d, k                                                                                  | x   |     |     |     |     |     |     |     |
| Correlative Blood Draws f                                                                    | x   | x   |     |     |     |     |     |     |
| a- Serum chemistry panel should include albumin, alkaline phosphatase, total bilirubin, BUN, |     |     |     |     |     |     |     |     |  
chloride, creatinine, glucose, potassium, total protein, AST/SGOT, ALT/SGPT, sodium. b- MRI to be done at the Martinos Center for Biomedical Imaging c - Serum Pregnancy Test (for women of childbearing potential)
d - Assessment to determine if there is sufficient tissue for correlative studies. Tissue may be sent as a batch later to minimize shipping requirements. Tissue is not required for registration. e- This column included in case patient goes off study during cycle 1. This visit can occur within 2 weeks of the participant coming off study.  
f - See section 9.2. Blood will be drawn prior to start of chemoradiation and during week 6 of chemoradiation.  
g- First bavituximab infusion should happen after the 4th radiation treatment and before the 6 th treatment.  
h- See Appendix B for the required drug diary. i - if ECG is clinically indicated, the QTc-B rather than QTc-F should be used to look for abnormalities J - Radiation dose not have to be done at a DFHCC site but should be considered to allow for ease of dosing bavituximab during radiation K - MGMT status will be collected but is not required for registration l - if it is determined that a patient will not be coming in for bavituximab on a specific day (ex.  
due to treatment hold or scheduling conflicts), then the patient does not need to return to clinic solely for the physical exam, weight, KPS, and vital sign assessments as theses were intended to be done prior to the infusion as a safety check.
- !"#%&'()+-.
cycle 2 post-radiation - bavituximab

| Wk              |    |    |                 |    |    |
|-----------------|----|----|-----------------|----|----|
| Wk              | W  | Wk | Off Treatment 6 |    |    |
| l               | 2  | 3  | 4               |    |    |
| Bavituximab     | x  | x  | x               | x  |    |
| Concurrent meds | x  | x  |                 |    |    |
| Physical exam 8 | x  | x  | x               |    |    |
| Vital signs 1   | x  | x  | x               | x  | x  |  
Labs should be drawn up to 3 days prior to bavituximab dosing.  
| Weight 2                                                                                     | x   | x   |    |
|----------------------------------------------------------------------------------------------|-----|-----|----|
| Performance status 2                                                                         | X   | x   | x  |
| CBC w/diff, plts                                                                             | X   | x   |    |
| Serum chemistry®                                                                             | X   | x   |    |
| Adverse event evaluation                                                                     | X   | x   | x  |
| Tumor measurements via                                                                       | x   | x   |    |
| MRI b                                                                                        |     |     |    |
| Correlative Blood draws f                                                                    | X   |     |    |
| a- Serum chemistry panel should include albumin, alkaline phosphatase, total bilirubin, BUN, |     |     |    |  
chloride, creatinine, glucose, potassium, total protein, AST/SGOT, ALT/SGPT, sodium.  
b- MRI to be done at the Martinos Center for Biomedical Imaging. This should be done at any time during the 4-5 weeks after completion of radiation but within 1 week of starting post-RT
temozolomide.  
e- This column included in case patient goes off study during cycle 2. This visit can occur within 2 weeks of the participant coming off study.  
f - See section 9.2 g - if it is determined that a patient will not be coming in for bavituximab on a specific day (ex.  
due to treatment hold or scheduling conflicts), then the patient does not need to return to clinic solely for the physical exam, weight, KPS, and vital sign assessments as theses were intended to be done prior to the infusion as a safety check.  
| Follow-up f              |    |    |    |               |    |
|--------------------------|----|----|----|---------------|----|
| Wk                       | W  | Wk | W  | EOT/Off Study |    |
| l                        | 2  | 3  | 4  |               |    |
| Bavituximab              | x  | x  | x  | x             |    |
| Temozolomide             | x  |    |    |               |    |
| Drug diary for           | x  |    |    |               |    |
| temozolomide 11          |    |    |    |               |    |
| Concurrent meds          | x  |    |    |               |    |
| Physical exam k          | x  | x  | x  |               |    |
| Vital signs*             | x  | x  | x  | x             | x  |
| Height                   |    |    |    |               |    |
| Weight k                 | x  | x  |    |               |    |
| Performance status 5     | x  | x  | x  |               |    |
| CBC w/diff, plts'        | x  | x  | x  |               |    |
| Serum chemistry'         | X  | x  |    |               |    |
| EKG/coag panel (as       |    |    |    |               |    |
| indicated)               |    |    |    |               |    |
| Adverse event evaluation | x  | x  |    |               |    |
| Tumor measurements via   | x  |    |    |               |    |
| MRI                      |    |    |    |               |    |
- !"#%&'()+-.
cycle 3 monthly temozolomide +

2 Correlative Blood draws f X
a- Serum chemistry panel should include albumin, alkaline phosphatase, total bilirubin, BUN,
chloride, creatinine, glucose, potassium, total protein, AST/SGOT, ALT/SGPT, sodium.  
b- EOT MRI to be done at the Martinos Center for Biomedical Imaging if possible e- EOT = end of treatment. For patients removed from the study for one of the criteria in Section 5.5 during cycle 3 or 4 or has completed treatment after cycle 4, this information should be collected within 28 days of the last bavituximab dose.  Follow-up of AE resolution to </= grade l or baseline may be beyond 28 days.  
f - See section 9.2 g- Temozolomide is administered for 5 consecutive days during week 1 of the cycle h - See Appendix B for the required drug diary.  
i - Participants will be followed for progression via MRI or clinic assessment per standard of care which is typically every 8 weeks as well as overall survival for up to 3 years. MRIs will be collected for central review. If MRI is not performed at Martinos, it should be sent to the study PI on a DVD or contact Dr. Gerstner for electronic transfer instructions. j - CBC with diff should align with standard of care assessments on day 21± 3 days and day 28 ± 3 days of each cycle.  
K - if it is determined that a patient will not be coming in for bavituximab on a specific day (ex.  
due to treatment hold or scheduling conflicts), then the patient does not need to return to clinic solely for the physical exam, weight, KPS, and vital sign assessments as theses were intended to be done prior to the infusion as a safety check.  
| Cycle 4: Monthly temozolomide + bavituximab therapy                                          |    |    |    |             |    |
|----------------------------------------------------------------------------------------------|----|----|----|-------------|----|
| Wk                                                                                           | W  | Wk | W  | Follow-up 3 |    |
| EOT/Off Study A                                                                              |    |    |    |             |    |
| 2                                                                                            |    |    |    |             |    |
| l                                                                                            | 3  | 4  |    |             |    |
| Bavituximab                                                                                  | x  | x  | x  | x           |    |
| Temozolomide'                                                                                | x  |    |    |             |    |
| Drug diary for                                                                               | x  |    |    |             |    |
| tmozolomide'                                                                                 | x  |    |    |             |    |
| Concurrent meds                                                                              | x  |    |    |             |    |
| Physical exam'                                                                               | x  | x  |    |             |    |
| Vital signs k                                                                                | x  | x  | x  | x           | x  |
| Height                                                                                       |    |    |    |             |    |
| Weight                                                                                       | x  | x  |    |             |    |
| x                                                                                            | x  | x  |    |             |    |
| Performance status                                                                           |    |    |    |             |    |
| C w/diff, plts'                                                                              | x  | x  | x  |             |    |
| Serum chemistry a                                                                            | x  | x  |    |             |    |
| EKG/coag panel (as                                                                           |    |    |    |             |    |
| indicated)                                                                                   |    |    |    |             |    |
| Adverse event evaluation                                                                     | x  | x  |    |             |    |
| Tumor measurements via                                                                       | x  |    |    |             |    |
| x                                                                                            | x  |    |    |             |    |
| MRI b                                                                                        |    |    |    |             |    |
| Correlative Blood draws f                                                                    |    |    |    |             |    |
| a- Serum chemistry panel should include albumin, alkaline phosphatase, total bilirubin, BUN, |    |    |    |             |    |  
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Correlative Blood draws f X
a- Serum chemistry panel should include albumin, alkaline phosphatase, total bilirubin, BUN,
chloride, creatinine, glucose, potassium, total protein, AST/SGOT, ALT/SGPT, sodium. b- If possible, MRI to be done at the Martinos Center for Biomedical Imaging. The MRI scan should be performed at any time during the 4 th week of every other cycle, starting with Cycle 6, to align with standard of care timepoints. If MRI during the study duration is not performed at Martinos, it should be sent to the study PI on a DVD or contact Dr. Gerstner for electronic transfer instructions.  
e- EOT = end of treatment. For patients removed from the study for one of the criteria in Section 5.5 during cycle 5 or beyond, this information should be collected within 28 days of the last bavituximab dose.  Follow-up of AE resolution to </= grade 1 or baseline may be beyond 28 days.  
f - See section 9.2 i - Participants will be followed for progression via MRI or clinic assessment per standard of care which is typically every 8 weeks as well as overall survival for up to 3 years. MRIs will be collected for central review.  
k - Weekly bavituximab infusion until progression or as outlined in Section 5.5.  
l - if it is determined that a patient will not be coming in for bavituximab on a specific day (ex.  
due to treatment hold or scheduling conflicts), then the patient does not need to return to clinic solely for the physical exam, weight, KPS, and vital sign assessments as theses were intended to be done prior to the infusion as a safety check.
- !"#%&'()+-.
1. measurement of effect 1.1

For the purposes of this study, patients should be reevaluated for response every 8 weeks following completion of chemoradiation.
- !"#%&'()+-.
11.1.1 definitions

Evaluable for Target Disease response.  Only those participants who have measurable disease present at baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for target disease response.  These participants will have their response classified according to the definitions stated below.  
(Note:  Participants who exhibit objective disease progression prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response.  Participants who have lesions present at baseline that are evaluable but do not meet the definitions of measurable disease, have received at least one cycle of therapy, and have had their disease re-evaluated will be considered evaluable for non-target disease.  The response assessment is based on the presence, absence, or unequivocal progression of the lesions.
- !"#%&'()+-.
11.1.2 disease parameters

Measurable disease.  Measurable disease is defined as bidimensionally contrast enhancing lesions with clearly defined margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, visible on two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip.  All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters).  
Non-measurable disease. All other lesions (or sites of disease), including small lesions
(longest diameter <10 mm), are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non-measurable.  
'Cystic lesions' thought to represent cystic metastases can be considered as measurable lesions, if they meet the definition of measurability described above. However, if noncystic lesions are present in the same participant, these are preferred for selection as target lesions.
- !"#%&'()+-.
11.1.3 methods for evaluation of

All measurements should be taken and recorded in metric notation using a ruler, calipers, or a digital measurement tool.  All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 4 weeks before the beginning of the treatment.  
The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up.
- !"#%&'()+-.
1.1.4 response criteria

Response and progression will be evaluated in this study using the Response Assessment in Neuro-Oncology Criteria (RANO) and incorporating the updated iRANO criteria proposed specifically for brain tumors treated with immunotherapy as it allows for early inflammation- related changes and potential for delayed responses.
- !"#%&'()+-.
11.1.4.1

Evaluation of Target Lesions Complete Response (CR): Complete disappearance of all enhancing tumor determined by two consecutive MRI scans not less than 4 weeks apart and no corticosteroid usage with a stable or improved neurologic examination for a minimum of 4 weeks.  
Partial Response (PR): Greater than or equal to 50% reduction in tumor size of all measurable lesions on a stable or decreasing dose of corticosteroids, with a stable or improving neurologic examination for a minimum of 4 weeks.  
Progressive Disease (PD): Progressive neurologic abnormalities not explained by causes unrelated to tumor progression (example: anti-epileptic drug or corticosteroid toxicity, electrolyte abnormalities, hyperglycemia, etc.) or a greater than 25%
increase in the volume of the tumor by MRI scan. If neurologic status deteriorates on a stable or increasing dose of corticosteroids, or if new lesions appear on serial MRI
scans, this will also be considered PD.  
iRANO recommends confirmation of disease progression on follow-up imaging 3 months after initial radiographic progression if there is no new or substantially worsened neurological deficits that are not due to comorbid events or concurrent medication, and it is 6 months or less from starting immunotherapy. This includes if there is appearance of new lesions that could represent a transient inflammatory response. If progression is subsequently confirmed, the progression date should be the date the new lesion or concern for progression occurred.  
Stable Disease (SD): A patient whose clinical status and MRI measurements do not meet the criteria for CR, PR or PD. Unknown (UN): Assessment of target lesions cannot be made due to insufficient or unevaluable data. In this case, a concise explanation must be given.  
Note : If tumor response data is missing for target lesions, the overall assessment must be UN unless there is new disease that would result in an overall assessment of PD. However, if there is missing or unevaluable data for non-target lesions, but data is available for all target lesions, the overall response for that time point will be assigned based on the sum LD of all target lesions. Additionally, the assessment of CR cannot be made if there is missing or unevaluable data for non-target lesions. In this case, the overall assessment would be PR.  
11.1.4.2 Evaluation of Non-Target Lesions
- !"#%&'()+-.
na 11.1.4.3 evaluation of new

The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning technique, imaging modality, or findings thought to represent something other than tumor (for example, some 'new' bone lesions may be simply healing or flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an anatomical location that was not scanned at baseline is considered new and will indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up evaluation will clarify if it truly represents new disease and if PD is confirmed, progression should be declared using the date of the initial scan on which the lesion was discovered.  
11.1.4.4 Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
- !"#%&'()+-.
11.1.5 duration of response

Duration of overall response:  The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).  
Duration of overall complete response: The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented, or death due to any cause. Participants without events reported are censored at the last disease evaluation.  
Duration of stable disease:  Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest measurements recorded since the treatment started, including the baseline measurements.
- !"#%&'()+-.
11.1.6 progression-free survival

Overall Survival: Overall Survival (OS) is defined as the time from start of treatment to death due to any cause, or censored at date last known alive.  
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from start of treatment to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.  
Time to Progression: Time to Progression (TTP) is defined as the time from start of treatment to progression, or censored at date of last disease evaluation for those without progression reported.
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1.1.7 response review

Response will be determined by the treating physician but all MRIs scans will be collected for later, central review of response by Dr. Gerstner and her team members.  
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13.5.1 evaluation of toxicity

All participants will be monitored for 90 days from completion of radiation in order to assess for any AEs related to radiation and bavituximab regardless of duration of bavituximab.  
Otherwise, all participants will be evaluable for toxicity from the time of their first treatment until 30 days after the last dose of bavituximab.
- !"#%&'()+-.
13.5.2 evaluation of the primary

Intent to treat analysis will be used for the primary endpoint.
- !"#%&'()+-.
14. publication plan

The results should be made public within 24 months of reaching the end of the study. The end of the study is the time point at which the last data items are to be reported, or after the outcome data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors. A full report of the outcomes should be made public no later than three
(3) years after the end of the study.  
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Protocol Version Date: September 25, 2018 Digernes I, Saxhaug C, Geier O, Reitan E, Waldeland E, Hole K, Jacobsen K, Helland A, Emblem K. Immunotherapy revised; Ipilimumab potentiates the vascular response to stereotactic radiosurgery in patients with brain metastases. AACR 2016: abstract 1471.  
Denekamp J. Angiogenesis, neovascular proliferation and vascular pathophysiology as targets for cancer therapy. Br J Radiol. 1993;66(783):181-96. DeRose P, Thorpe PE, Gerber DE. Development of bavituximab, a vascular targeting agent with immune-modulating properties, for lung cancer treatment. Immunotherapy. 2011;3(8):933-44. Emblem KE, Farrar CT, Gerstner ER, Batchelor TT, Borra RJ, Rosen BR, Sorensen AG, Jain RK (2014) Vessel caliber--a potential MRI biomarker of tumour response in clinical trials. Nature reviews Clinical oncology 11: 566-584 Gerber DE, Spigel DR, Giorgadze D, Shtivelband M, Ponomarova OV, Shan JS, Menander KB,
Belani CP. Docetaxel Combined With Bavituximab in Previously Treated, Advanced Nonsquamous Non-Small-Cell Lung Cancer. Clin Lung Cancer. 2016 May;17(3):169-76. Gerstner E, Zhang Z, Fink J, Muzi M, Hanna L, Greco E, Prah M, Schmainda K, Mintz A,
Kostakoglu L, Eikman EA, Ellingson BM, Ratai EM, Sorensen AG, Barboriak D, Mankoff DA.  
ACRIN 6684: Assessment of tumor hypoxia in newly diagnosed GBM using 18F-FMISO PET
and MRI. Clin Cancer Res. 2016 Oct 15;22(20):5079-5086.  
Gerstner ER, Ye X, Duda DG, Levine MA, Mikkelsen T, Kaley TJ, Olson JJ, Nabors BL,
Ahluwalia MS, Wen PY, Jain RK, Batchelor TT, Grossman S (2015) A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Neuro Oncol 17: 1386-1392 Gilbert MR, Sulman EP, Mehta MP (2014) Bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370: 2048-2049 Gilbert MR, Wang M, Aldape KD, Stupp R, Hegi ME, Jaeckle KA, Armstrong TS, Wefel JS,
Won M, Blumenthal DT, Mahajan A, Schultz CJ, Erridge S, Baumert B, Hopkins KI, Tzuk-
Shina T, Brown PD, Chakravarti A, Curran WJ, Jr., Mehta MP (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31: 40854091. He J, Yin Y, Luster TA, Watkins L, Thorpe PE (2009) Antiphosphatidylserine antibody combined with irradiation damages tumor blood vessels and induces tumor immunity in a rat model of glioblastoma. Clin Cancer Res. Nov 15;15(22):6871-80. Huang X, Bennet M, Thorpe PE. A monoclonal antibody that binds anionic phospholipids on tumor blood vessels enhances the antitumor effect of docetaxel on human breast tumors in mice.  
Cancer Res 2005; 65:4408-4416. Hsu MS, Sedighim S, Wang T, Antonios JP, Everson RG, Tucker AM, Du L, Emerson R, Yusko Protocol Version Date: September 25, 2018.  
E, Sanders C, Robins HS, Yong WH, Davidson TB, Li G, Liau LM, Prins RM (2016) TCR
Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination. Cancer Immunol Res 4: 412-418.  
Jain M, Raizada N, Kuttan R, et al. Phase II study of bavituximab plus paclitaxel and carboplatin in locally advanced or metastatic breast cancer; interim results. J Clin Oncol 2010; 28(15s)
Abstract 1062.  
Lee EQ, Kaley TJ, Duda DG, Schiff D, Lassman AB, Wong ET, Mikkelsen T, Purow BW,
Muzikansky A, Ancukiewicz M, Huse JT, Ramkissoon S, Drappatz J, Norden AD, Beroukhim R, Weiss SE, Alexander BM, McCluskey CS, Gerard M, Smith KH, Jain RK, Batchelor TT,
Ligon KL, Wen PY (2015) A Multicenter, Phase II, Randomized, Noncomparative Clinical Trial of Radiation and Temozolomide with or without Vandetanib in Newly Diagnosed Glioblastoma Patients. Clin Cancer Res 21: 3610-3618 Li W, Graeber MB (2012) The molecular profile of microglia under the influence of glioma.  
Neuro Oncol 14: 958-978 Nida Hussain HD, Subrahmanya Vallabhapurapu, Zhengtao Chu, Victor Blanco and Xiaoyang Qi (2015) ATPS-35 RADIATION TREATMENT INCREASES PHOSPHATIDYLSERINE
EXTERNALIZATION ON GLIOBLASTOMA CELLS - INDICATES POTENTIAL TARGET
FOR THERAPY. Neuro Oncol 17 (suppl 5): v25-v26 Ran S, He J, Huang X, Soares M, et al. Anti-tumor effects of a monoclonal antibody directed against anionic phospholipids on the surface of tumor blood vessels in mice. Clin Cancer Res 2005; 11:1551-1162.  
Okada H, Weller M, Huang R, Finocchiaro G, Gilbert MR, Wick W, Ellingson BM, Hashimoto N, Pollack IF, Brandes AA, Franceschi E, Herold-Mende C, Nayak L, Panigrahy A, Pope WB,
Prins R, Sampson JH, Wen PY, Reardon DA (2015) Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. The Lancet Oncology 16: e534-542 Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N (2015) Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160: 48-61. 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.  
Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, Wang M, Wen PY, Ivy P, Batchelor TT, Jain RK (2012) Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 72: 402-407 Tabagari D, Nemsadze G, Janjalia M, et al. Phase II study of bavituximab plus docetaxel in locally advanced or metastatic breast cancer. J Clin Oncol 2010; 28(15s) Abstract 1042.  
Winter PM, Pearce J, Chu Z, McPherson CM, Takigiku R, Lee JH, Qi X. Imaging of brain Protocol Version Date: September 25, 2018 tumors with paramagnetic vesicles targeted to phosphatidylserine. J Magn Reson Imaging. 2015 Apr;41(4):1079-87.  
Wojton J, Chu Z, Mathsyaraja H, Meisen WH, Denton N, Kwon CH, Chow LM, Palascak M,
Franco R, Bourdeau T, Thornton S, Ostrowski MC, Kaur B, Qi X (2013) Systemic delivery of SapC-DOPS has antiangiogenic and antitumor effects against glioblastoma. Mol Ther. 2013 Aug;21(8):1517-25. Wojton J, Meisen WH, Jacob NK, Thorne AH, Hardcastle J, Denton N, Chu Z, Dmitrieva N,
Marsh R, Van Meir EG, Kwon CH, Chakravarti A, Qi X, Kaur B (2014) SapC-DOPS-induced lysosomal cell death synergizes with TMZ in glioblastoma. Oncotarget. 2014 Oct 30;5(20):97039.  
Yin Y, Huang X, Lynn KD, Thorpe PE (2013) Phosphatidylserine-targeting antibody induces Ml macrophage polarization and promotes myeloid-derived suppressor cell differentiation. Cancer Immunol Res 1: 256-268 Yin Y, Huang X, Barbero G, et al. Phosphatidylserine-targeting antibody reactivates tumor immunity and destroys tumor vasculature in mice. American Association of Cancer Research Meeting 2013; Poster \#1244.  
Yopp, AC, Singal, AG, Yull, EA, Udit, NV, Kallinteris, NL, Shan, J, Beg, S, Mansour, JC, Zhu, H. A phase II study of bavituximab and sorafenib in advanced hepatocellular carcinoma (HCC).  
J Clin Oncol 2015; Abstract 4109.  
Zhang L, Habib AA, Zhao D. Phosphatidylserine-targeted liposome for enhanced gliomaselective imaging. Oncotarget. 2016 Jun 21;7(25):38693-38706.  
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| Protocol Version Date: September 25, 2018   |             |
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| 24                                          |             |
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Participant Signature or Initials Date
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