ERC1671/GM-CSF/Cyclophosphamide for the Treatment of Glioblastoma Multiforme

Inclusion Criteria:

-Patients must have histologically confirmed diagnosis of a recurrent/progressive WHO grade IV malignant gliomas (glioblastoma multiforme and gliosarcoma) and meet the following inclusion criteria:

1. Age ≥18 years of age.

2. Histologic diagnosis of glioblastoma or gliosarcoma (WHO Grade IV).

3. KPS of ≥ 70%.

4. Life expectancy > 12 weeks.

5. First or second relapse of glioblastoma.

6. Previous treatment for glioblastoma must include surgery (biopsy, partial resection,or full surgical resection), conventional radiation therapy and temozolomide (TMZ).

7. MRI record must be obtained showing the MRI was conducted at least 4 weeks after anysalvage surgery, and at least 12 weeks after radiation therapy, or at least 4 weeksafter radiation for a new lesion outside the prior primary radiation field unlessrelapse is confirmed by tumor biopsy or new lesion outside of radiation field, or ifthere are two MRIs confirming progressive disease per iRANO that are 8 weeks apart

8. If prior therapy with gamma knife or other focal high-dose radiation, must havesubsequent histologic documentation of local relapse, or relapse with new lesionoutside the irradiated field.

9. Resolution of all chemotherapy or radiation-related toxicities ≤ CTCAE Grade 1severity, except for alopecia and hematologic toxicity. Patients taking temozolomidecan start study treatment 23 days from the last temozolamide dose.For all otherchemotherapy drugs, study treatment can start as long as all adverse events relatedto their prior treatment are no higher than Grade 1.

10. Systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone orequivalent per day during the week prior to Day 1.

11. Pre-surgical Bi-dimensionally measurable disease (as per iRANO criteria)

12. Patients must have normal organ and marrow function as defined below:

• hemoglobin (Hbg) > 9g/dL,

• leukocytes >1,500/mcL

• absolute neutrophil count>1,000/mcL

• CD4 count > 450/mcL

• platelets>125,000/mcL

• Serum bilirubin = 1.5 × upper limit of normal (ULN) or = 3 x ULN if Gilbert'sdisease is documented AST(SGOT) and ALT(SGPT)<2.5 X institutional upper limitof normal

• serum creatinine < 1.5 mg/dl

13. Signed informed consent approved by the Institutional Review Board;

14. If sexually active, patients must agree to take contraceptive measures for theduration of the treatments.

Exclusion Criteria:

1. Subjects unable to undergo an MRI with contrast.

2. Presence of diffuse leptomeningeal disease

3. History, presence, or suspicion of metastatic disease

4. Administration of immunosuppressive drugs less than 2 weeks prior to first dose ofERC1671, except dexamethasone for cerebral edema as detailed above;

5. Prior receipt of bevacizumab, or bevacizumab biosimilars or other VEGF- or VEGFreceptor-targeted agents

6. Known contraindication or hypersensitivity to any component of bevacizumab.

7. Evidence of recent hemorrhage on screening MRI of the brain with the followingexceptions: presence of hemosiderin; resolving hemorrhagic changes related tosurgery; presence of punctate hemorrhage in the tumor.

8. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recentperipheral arterial thrombosis within 6 months prior to Day 1.

9. Evidence of bleeding diathesis or coagulopathy as documented by an elevated PT, PTTor bleeding time and clinically significant;

10. History of abdominal fistula, gastrointestinal perforation, or intra-abdominalabscess within 6 months prior to Day 1.

11. Urine protein: creatinine ratio ≥ 1.0 at screening;

12. Anticipation of need for major surgical procedure during the course of the study.

13. Serious non-healing wound, ulcer, or bone fracture.

14. Active infection requiring treatment, known immunosuppressive disease, activesystemic autoimmune diseases such as lupus, receipt of systemic immunosuppressivetherapy, human immunodeficiency virus (HIV) infection, Hepatitis B or Hepatitis C

15. Uncontrolled hypertension, blood pressure of > 150 mmHg systolic and > 100 mmHgdiastolic, or history of hypertensive encephalopathy. Subjects with any knownuncontrolled inter-current illness including ongoing or active infection,symptomatic congestive heart failure (NYHA Gr.2 or >), myocardial infarction,unstable angina pectoris , within the past 12 months

16. Stroke, transient ischemic attack, unstable angina, myocardial infarction orcongestive heart failure (New York Heart Association Grade II or greater) within thepast 6 months.Unstable or severe intercurrent medical conditions chronic renaldisease, or uncontrolled diabetes mellitus.

17. Women who are pregnant or lactating. All female patients with reproductive potentialmust have a negative pregnancy test prior to Day 1 and must use a reliable form ofcontraception during study participation.

18. Men refusing to exercise a reliable form of contraception.

19. History of any malignancy (other than glioblastoma) during the last three yearsexcept non-melanoma skin cancer, in situ cervical cancer, treated superficialbladder cancer or cured, early-stage prostate cancer in a patient with ProstateSurface Antigen (PSA) level <ULN.