This phase II clinical trial studies how well ERC1671 plus Granulocyte-macrophage colony-stimulating factor (GM-CSF) plus Cyclophosphamide with Bevacizumab works compared to Placebo Injection plus Placebo Pill with Bevacizumab in treating patients with recurrent/progressive, bevacizumab naïve glioblastoma multiforme and gliosarcoma (World Health Organization (WHO) grade IV malignant gliomas, GBM).

This is a blinded Phase II study of ERC1671 in combination with bevacizumab in patients with relapsed, bevacizumab naive glioblastoma. The patients who will be randomized (in a 1:1 ratio) to receive either ERC 1671 in combination with GM-CSF and cyclophosphamide or a placebo control, in combination with bevacizumab. The study will be double blinded.

ERC1671/GM-CSF will be intradermally administered, while cyclophosphamide is orally administered. GM-CSF dose is 500mcg fixed dose and cyclophosphamide dose is 50 mg/day. Bevacizumab or approved bevacizumab biosimilars are administered as standard of care at 10 mg/kg every 2 weeks.

The treatment cycles will be 28 days long.

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 any salvage surgery, and at least 12 weeks after radiation therapy, or at least 4 weeks after radiation for a new lesion outside the prior primary radiation field unless relapse is confirmed by tumor biopsy or new lesion outside of radiation field, or if there 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 have subsequent histologic documentation of local relapse, or relapse with new lesion outside the irradiated field.

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

10. Systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone or equivalent 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's disease is documented AST(SGOT) and ALT(SGPT)<2.5 X institutional upper limit of 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 the duration 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 of ERC1671, except dexamethasone for cerebral edema as detailed above;
5. Prior receipt of bevacizumab, or bevacizumab biosimilars or other VEGF- or VEGF receptor-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 following exceptions: presence of hemosiderin; resolving hemorrhagic changes related to surgery; presence of punctate hemorrhage in the tumor.
8. Significant vascular disease (e.g., aortic aneurysm, aortic dissection) or recent peripheral arterial thrombosis within 6 months prior to Day 1.
9. Evidence of bleeding diathesis or coagulopathy as documented by an elevated PT, PTT or bleeding time and clinically significant;
10. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 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, active systemic autoimmune diseases such as lupus, receipt of systemic immunosuppressive therapy, human immunodeficiency virus (HIV) infection, Hepatitis B or Hepatitis C
15. Uncontrolled hypertension, blood pressure of > 150 mmHg systolic and > 100 mmHg diastolic, or history of hypertensive encephalopathy. Subjects with any known uncontrolled 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 or congestive heart failure (New York Heart Association Grade II or greater) within the past 6 months.Unstable or severe intercurrent medical conditions chronic renal disease, or uncontrolled diabetes mellitus.
17. Women who are pregnant or lactating. All female patients with reproductive potential must have a negative pregnancy test prior to Day 1 and must use a reliable form of contraception 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 years except non-melanoma skin cancer, in situ cervical cancer, treated superficial bladder cancer or cured, early-stage prostate cancer in a patient with Prostate Surface Antigen (PSA) level \