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

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ClinicalTrials.gov Identifier: NCT01903330
Recruitment Status : Recruiting
First Posted : July 19, 2013
Last Update Posted : January 25, 2018
Sponsor:
Collaborators:
University of California, Irvine
Epitopoietic Research Corporation
Information provided by (Responsible Party):
Daniela A. Bota, University of California, Irvine

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Glioblastoma Gliosarcoma 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 Phase 2

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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)
Study Start Date : March 2014
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019


Arm Intervention/treatment
Experimental: (ERC1671/GM-CSF/Cyclophosphamide)+bevacizumab

ERC1671 and 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 will be repeated every 28 days until progression of disease or intolerance.

Drug: ERC1671
Given intradermally
Other Name: Gliovac

Drug: GM-CSF
Given intradermally
Other Names:
  • Leukine®
  • sargramostim

Drug: Cyclophosphamide
Given PO. Drug class: Alkylating Agent; Antineoplastic Agent; Nitrogen Mustard.
Other Name: 2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate

Drug: Bevacizumab
Given IV. Drug class: Immunological Agent; Monoclonal Antibody.
Other Name: Avastin

Placebo Comparator: (Placebo Injection/Placebo Pill) +Bevacizumab

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 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)
Given PO

Drug: Injectable control (Sodium Chloride Injection United States Pharmacopeia (USP) (0.9%))
Given IV

Drug: Bevacizumab
Given IV. Drug class: Immunological Agent; Monoclonal Antibody.
Other Name: Avastin




Primary Outcome Measures :
  1. Safety [ Time Frame: 6 months ]
    Safety will be assessed by clinical laboratory tests, physical examinations, vital sign measurements and the incidence and severity of adverse events (AEs) (graded according to Common Toxicity Criteria for Adverse Effects (CTCAE) v 4.0.).


Secondary Outcome Measures :
  1. Efficacy [ Time Frame: 6 months ]
    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. Progression-free survival will be defined as the time from Day 1 to the date of progression or death due to any cause. Overall survival time will be measured from Day 1 until death.

  2. Immune Response [ Time Frame: 6 months ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 </= to 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.
  • 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 <ULN.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01903330


Locations
United States, California
University of California, Irvine Recruiting
Orange, California, United States, 92868
Contact: Chao Family Comprehensive Cancer Center University of California, Irvine Medical Center    877-827-8839    UCstudy@uci.edu   
Principal Investigator: Daniela A. Bota, MD, PhD         
Sponsors and Collaborators
Daniela A. Bota
University of California, Irvine
Epitopoietic Research Corporation
Investigators
Principal Investigator: Daniela A. Bota, MD, PhD University of California, Irvine

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Daniela A. Bota, Principal Investigator, University of California, Irvine
ClinicalTrials.gov Identifier: NCT01903330     History of Changes
Other Study ID Numbers: UCI 13-14 ERC1671-H02
UCI 13-14 ( Other Identifier: University of California, Irvine )
2013-9863 ( Other Identifier: University of California, Irvine )
First Posted: July 19, 2013    Key Record Dates
Last Update Posted: January 25, 2018
Last Verified: January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Daniela A. Bota, University of California, Irvine:
ERC1671
GM-CSF
Cyclophosphamide
Bevacizumab

Additional relevant MeSH terms:
Glioblastoma
Gliosarcoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Cyclophosphamide
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists