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

PRIMARY OBJECTIVES:

The primary objective of the study is to determine the 6-month progression free survival
probability of patients with recurrent, bevacizumab naïve glioblastoma multiforme treated
with ERC1671 in combination with GM-CSF and cyclophosphamide plus bevacizumab as compared
with patients receiving bevacizumab plus placebo controls.

SECONDARY OBJECTIVES:

1. To evaluate radiographic response, progression free survival and overall survival of
patients with recurrent malignant glioma treated with the ERC1671 regimen plus
bevacizumab

2. To evaluate safety and tolerability of ERC1671 plus bevacizumab among patients with
recurrent glioblastoma.

3. To characterize of the immune response to ERC1671 vaccination in adult patients with
relapsed glioblastoma. The patient's immune response evaluation will include cytotoxic T
lymphocytes (CTL) (cluster of differentiation 3+ (CD3+)/cluster of differentiation 8+
(CD8)+) and Treg (cluster of differentiation 3+/cluster of differentiation 4+
(CD4+)/cluster of differentiation 25+ )CD25+/cluster of differentiation 127low
(CD127low)) populations. Cytokine analyses should initially be limited to interferon
(IFN)-ɣ, tumor necrosis factor (TNF) and interleukin (IL)-6). Further immune studies
should include TGF-B2, IL-12, IL-10.

If this study demonstrates that the combination regimen of ERC1671 in combination with
bevacizumab is associated with encouraging anti-tumor activity among patients with recurrent
glioblastoma multiforme, further assessment of this regimen in a phase III study will be
considered.

OUTLINE: 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 250 µg/m² and cyclophosphamide dose is 50 mg/day. Bevacizumab is
administered as standard of care at 10 mg/kg.

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:

- Age ≥18 years of age.

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

- Karnofsky performance status (KPS) of ≥ 70%.

- Life expectancy > 12 weeks.

- First or second relapse of glioblastoma.

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

- 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.

- 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.

- 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 adverse events related to
their treatment is
- Systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone or
equivalent per day during the week prior to Day 1.

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

- hemoglobin (Hbg) > 9g/dL,

- leukocytes >1,500/microliter (mcL)

- absolute neutrophil count>1,000/mcL

- CD4 count > 450/mcL

- platelets>125,000/mcL

- total bilirubin within normal institutional limits

- aspartate aminotransferase (AST)(SGOT)/ Alanine aminotransferase(ALT)(SGPT)<2.5 X
institutional upper limit of normal

- serum creatinine < 1.5 mg/dl

- Signed informed consent approved by the Institutional Review Board;

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

Exclusion Criteria:

- Subjects unable to undergo an MRI with contrast.

- Presence of diffuse leptomeningeal disease

- History, presence, or suspicion of metastatic disease

- Administration of immunosuppressive drugs less than 2 weeks prior to first dose of
ERC1671, except dexamethasone for cerebral edema as detailed above;

- Prior receipt of bevacizumab or other VEGF- or VEGF receptor-targeted agents

- Known contraindication or hypersensitivity to any component of bevacizumab.

- 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.

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

- Evidence of bleeding diathesis or coagulopathy as documented by an elevated PT, PTT or
bleeding time

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

- Urine protein: creatinine ratio ≥ 1.0 at screening;

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

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

- 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 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

- Stroke, transient ischemic attack, unstable angina, myocardial infarction or
congestive heart failure (New York Heart Association Grade II or greater) within the
past 12 months. Unstable or severe inter-current medical conditions chronic renal
disease, or uncontrolled diabetes mellitus.

- Women who are pregnant or lactating. All female patients with reproductive potential
must have a negative pregnancy test prior to Day 1.

- Men refusing to exercise a reliable form of contraception.

- 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