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

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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A Randomized, Double-blinded, Placebo-controlled Study of (ERC1671/GM-CSF/Cyclophosphamide)+Bevacizumab vs. (Placebo Injection/Placebo Pill) +Bevacizumab in the Treatment of Recurrent/Progressive, Bevacizumab naïve Glioblastoma Multiforme and Glioasarcoma Patients (WHO Grade IV Malignant Gliomas, GBM)

Conditions
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Glioblastoma, Gliosarcoma

Intervention / Treatment
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* Drug: ERC1671
* Drug: GM-CSF
* Drug: Cyclophosphamide
* Drug: Oral Control (Sucrose pill)
* Drug: Injectable control (Sodium Chloride Injection United States Pharmacopeia (USP) (0.9%))
* Drug: Bevacizumab/Bevacizumab Biosimilar


Participation Criteria
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Eligibility Criteria
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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). 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 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 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 all adverse events related to their prior treatment are no higher than Grade 1. Systemic corticosteroid therapy must be at a dose of ≤ 4 mg of dexamethasone or equivalent per day during the week prior to Day 1. Pre-surgical Bi-dimensionally measurable disease (as per iRANO criteria) 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 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 bevacizumab biosimilars 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 and clinically significant; 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 6 months.Unstable or severe intercurrent 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 and must use a reliable form of contraception during study participation. 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 <ULN.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: (ERC1671/GM-CSF/Cyclophosphamide)+bevacizumab/bevacizumab biosimilar<br>ERC1671 and 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 will be repeated every 28 days until progression of disease or intolerance. | Drug: ERC1671<br>* Given intradermally<br>* Other names: Gliovac;Drug: GM-CSF<br>* Given intradermally<br>* Other names: sargramostim;Drug: Cyclophosphamide<br>* Given PO. Drug class: Alkylating Agent; Antineoplastic Agent; Nitrogen Mustard.<br>* Other names: 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate;Drug: Bevacizumab/Bevacizumab Biosimilar<br>* Given IV. Drug class: Immunological Agent; Monoclonal Antibody.<br>* Other names: ZIRABEV;|
| Placebo Comparator: (Placebo Injection/Placebo Pill) +Bevacizumab/bevacizumab biosimilar<br>The control group will have the same study schedule except that the patients will be receiving the Oral Control on the Cyclophosphamide treatment days and the Injectable control on the GM-CSF + ERC1671 treatment days. The control group will receive bevacizumab or approved bevacizumab biosimilar just as the active treatment group above. The treatment will be repeated every 28 days until progression of disease or intolerance. | Drug: Oral Control (Sucrose pill)<br>* Given PO<br>Drug: Injectable control (Sodium Chloride Injection United States Pharmacopeia (USP) (0.9%))<br>* Given IV<br>Drug: Bevacizumab/Bevacizumab Biosimilar<br>* Given IV. Drug class: Immunological Agent; Monoclonal Antibody.<br>* Other names: ZIRABEV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival at 12 months of patients with recurrent, bevacizumab naïve glioblastoma treated with ERC1671 in combination with GM-CSF and cyclophosphamide plus bevacizumab as compared with patients receiving bevacizumab plus placebo controls. | To evaluate overall survival in patients with with recurrent, bevacizumab naïve glioblastoma treated with ERC1671 in combination with GM-CSF and cyclophosphamide plus bevacizumab as compared with patients receiving bevacizumab plus placebo controls. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Progression-Free Survival | Progression-free survival will be defined as the time from Day 1 to the date of progression or death due to any cause. | 12 months | 
| Immune Response | The patient's immune response evaluation will include cytotoxic T lymphocytes (CTL) (CD3+/cluster of differentiation (CD)8+) and Treg (CD3+/CD4+/cluster of differentiation 25+ (CD25+)/CD127low) populations where CD refers to cluster of differentiation. Cytokine analyses should initially be limited to IFN-ɣ, TNF and IL-6. Further immune studies should include transforming growth factor (TGF)-B2, IL-12, IL-10. | 12 months | 
| Percentage of Grade 3-5 Adverse Events | Toxicity and adverse events are based on the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0. Safety will also be assessed by clinical laboratory tests, physical examinations, vital sign measurements and the incidence and severity of adverse events (AEs). | 12 months | 
| Rate of Radiographic Response as assessed using MacDonald Criteria or IRANO | Patients will be followed both clinically and radiographically every 6 weeks for evidence of tumor progression. Tumor response will be assessed using the MacDonald Criteria or iRANO, Immunotherapy Response Assessment in Neuro-Oncology. iRANO/MacDonald CRITERIA: Complete response (CR): Disappearance of all enhancing tumor on contrast enhanced MRI scan. Partial response (PR): Greater than or equal to a 50% reduction in the size (sum of products of the largest diameter, SPD) for all enhancing lesions. Stable Disease (SD): SPD <50% decrease to <25% increase, does not qualify for CR, PR, or progression. Progressive Disease (PD): Greater than or equal to a 25% increase in SPD. Unable to Assess (UA): Some target lesions cannot be evaluated because of technical factors. | 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GM-CSF, ERC1671, Cyclophosphamide, Bevacizumab