Clinical Trials /

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

NCT01903330

Description:

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).

Related Conditions:
  • Glioblastoma
  • Gliosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ERC1671/GM-CSF/Cyclophosphamide for the Treatment of Glioblastoma Multiforme
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: UCI 13-14 ERC1671-H02
  • SECONDARY ID: UCI 13-14
  • SECONDARY ID: 2013-9863
  • NCT ID: NCT01903330

Conditions

  • Glioblastoma
  • Gliosarcoma

Interventions

DrugSynonymsArms
ERC1671Gliovac(ERC1671/GM-CSF/Cyclophosphamide)+bevacizumab
GM-CSFLeukine®, sargramostim(ERC1671/GM-CSF/Cyclophosphamide)+bevacizumab
Cyclophosphamide2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate(ERC1671/GM-CSF/Cyclophosphamide)+bevacizumab
Oral Control (Sucrose pill)(Placebo Injection/Placebo Pill) +Bevacizumab
Injectable control (Sodium Chloride Injection United States Pharmacopeia (USP) (0.9%))(Placebo Injection/Placebo Pill) +Bevacizumab
BevacizumabAvastin(ERC1671/GM-CSF/Cyclophosphamide)+bevacizumab

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
(ERC1671/GM-CSF/Cyclophosphamide)+bevacizumabExperimentalERC1671 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.
  • ERC1671
  • GM-CSF
  • Cyclophosphamide
  • Bevacizumab
(Placebo Injection/Placebo Pill) +BevacizumabPlacebo ComparatorThe 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.
  • Oral Control (Sucrose pill)
  • Injectable control (Sodium Chloride Injection United States Pharmacopeia (USP) (0.9%))
  • Bevacizumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety
Time Frame:6 months
Safety Issue:
Description: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

Measure:Efficacy
Time Frame:6 months
Safety Issue:
Description: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.
Measure:Immune Response
Time Frame:6 months
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daniela A. Bota

Trial Keywords

  • ERC1671
  • GM-CSF
  • Cyclophosphamide
  • Bevacizumab

Last Updated

December 28, 2016