Clinical Trials /

HSV G207 With a Single Radiation Dose in Children With Recurrent High-Grade Glioma

NCT04482933

Description:

This study is a clinical trial to assess the efficacy and confirm the safety of intratumoral inoculation of G207 (an experimental virus therapy) combined with a single 5 Gy dose of radiation in recurrent/progressive pediatric high-grade gliomas

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: HSV G207 With a Single Radiation Dose in Children With Recurrent High-Grade Glioma
  • Official Title: Phase II Clinical Trial of HSV G207 With a Single 5 Gy Radiation Dose in Children With Recurrent High-Grade Glioma

Clinical Trial IDs

  • ORG STUDY ID: XUAB 2045
  • NCT ID: NCT04482933

Conditions

  • Neoplasms
  • High Grade Glioma
  • Glioblastoma Multiforme
  • Malignant Glioma of Brain
  • Anaplastic Astrocytoma of Brain
  • High-grade Glioma
  • Anaplastic Glioma
  • Giant Cell Glioblastoma

Interventions

DrugSynonymsArms
Biological G207Experimental: HSV G207Experimental: HSV G207

Purpose

This study is a clinical trial to assess the efficacy and confirm the safety of intratumoral inoculation of G207 (an experimental virus therapy) combined with a single 5 Gy dose of radiation in recurrent/progressive pediatric high-grade gliomas

Detailed Description

      Outcomes for children with recurrent or progressive high-grade glioma (brain tumor) are very
      poor, and there are a lack of effective salvage therapies once a patient fails standard
      treatments. Novel innovative treatments are greatly needed.

      G207 is an oncolytic herpes simplex virus-1 (HSV) that has been successfully engineered to
      introduce mutations in the virus that enable it to selectively replicate in and kill cancer
      cells, but not normal cells. Replication of G207 in the tumor not only kills the infected
      tumor cells, but causes the tumor cell to act as a factory to produce new virus. These virus
      particles are released as the tumor cell dies, and can then proceed to infect other tumor
      cells in the vicinity, and continue the process of tumor kill. In addition to this direct
      oncolytic activity, the virus engenders an anti-tumor immune response; the virus is
      immunogenic and produces a debris field which exposes cancer cell antigens to immune cells,
      which can target other cancer cells. Thus, the oncolytic effect of the virus and the immune
      response that the virus stimulates provide a dual attack against cancer cells. In preclinical
      studies, a single 5 Gy dose of radiation within 24 hours of virus inoculation to the tumor
      increased virus replication and tumor cell killing. Radiation may also enhance the immune
      response against the tumor.

      The University of Alabama at Birmingham has conducted three phase I trials of G207 injected
      into the recurrent tumor alone or combined with a single dose of radiation in adults with
      recurrent high-grade gliomas. In these trials, high doses (up to 3 x 10^9 plaque-forming
      units) of virus were safely injected directly into the tumor or surrounding brain tissue
      without serious toxicities. Radiographic and neuropathologic evidence of an antitumor
      response was seen in some patients. Preclinical laboratory studies have demonstrated that a
      variety of aggressive pediatric brain tumor types are sensitive to G207.

      A Phase I study of intratumoral G207 alone or combined with a 5 Gy dose of radiation in
      children ages 3-18 with biopsy-confirmed recurrent/progressive supratentorial brain tumors
      recently completed the highest planned dose level (UAB1472; NCT02457845). The study used a 3
      + 3 design with 4 dose cohorts.12 Patients underwent stereotactic placement of up to 4
      intratumoral catheters. The following day they received a single controlled-rate infusion of
      G207 (1 x 10^7 or 1 x 10^8 pfu) over 6 hours. Cohorts 3 and 4 received a 5 Gy radiation
      fraction to the gross tumor volume within 24 hours of G207. Twelve subjects with progressive
      high-grade glioma received G207. Twenty adverse events, all grade 1, were attributed to G207.
      G207 was determined to be safe and tolerable in children and a recommended Phase 2 was
      established (1 x10^8 followed by 5 Gy radiation to the tumor).

      This study is a phase II, open-label, single arm clinical trial of G207 alone or combined
      with a single low dose of radiation in children with recurrent or progressive high grade
      glioma. The primary objective is to assess the efficacy. The secondary objective is to
      confirm the safety and tolerability of G207 and to survey for virologic shedding following
      G207.

      Subjects will receive G207 at 1 x 10^8 plaque-forming units (pfu), intratumorally via
      controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject
      will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus
      inoculation.
    

Trial Arms

NameTypeDescriptionInterventions
Experimental: HSV G207ExperimentalAll subjects will receive G207 at 1 x 10^8 plaque-forming units (pfu), intratumorally via controlled rate infusion through up to 4 silastic catheters over a 6 hour period. The subject will then receive a single 5 Gy dose of radiation to the tumor within 24 hours of virus inoculation.
  • Biological G207

Eligibility Criteria

        Inclusion Criteria:

        Patients meeting the following inclusion criteria will be eligible for the study:

          -  Age ≥ 3 years of age and ≤ 21 years of age at the time of study enrollment

          -  Patients must have a pathologically proven malignant high-grade glioma (including
             glioblastoma multiforme, giant cell glioblastoma, anaplastic astrocytoma, midline
             diffuse glioma) which is progressive or recurrent despite standard care including
             surgery, radiotherapy, and/or chemotherapy

          -  Lesion must be ≥ 1.0 cm and ≤ 4.0 cm in longest dimension and surgically accessible as
             determined by MRI. Larger tumors may be surgically debulked and treated if ≤ 4.0 cm
             after debulking

          -  Multifocal disease on the unilateral side is eligible if at least one catheter can be
             placed in all multifocal areas

          -  Performance score ≥ 60% (Karnofsky for children ≥16 years old; modified Lansky for
             children < 16 years old)

          -  Patients with neurological deficits should have deficits that are stable for ≥ 1 week
             prior to enrollment. A baseline detailed neurological exam should clearly document the
             neurological status of the patient at the time of enrollment on the study

          -  Prior therapy: patients must have recovered from acute treatment related toxicities of
             all prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy,
             biologic therapy, or virotherapy prior to entering this study

          -  Myelosuppressive chemotherapy: patients must have received their last dose at least 3
             weeks prior and demonstrated count recovery as defined below

          -  Investigational/Biologic agents: patients must have recovered from any acute
             toxicities potentially related to the agent and received the last dose ≥ 7 days prior
             to entering this study (this period must be extended beyond the time during which
             adverse events are known to occur for agents with known adverse events ≥ 7 days). For
             viral therapy or cellular therapy, patients must have received therapy ≥ 3 months
             prior to study entry and have recovered from all acute toxicities potentially related
             to the agent.

          -  Monoclonal antibodies: patient must have received last dose ≥ 28 days prior

          -  Radiation: Patients must have received their last fraction of radiation (≥ 54 Gy) ≥ 3
             months prior to study entry. Patients must have received local palliative radiation ≥
             28 days prior to study entry

          -  Patient must have adequate organ and marrow function as defined by the following:
             Hemoglobin ≥8 g/dL (may receive blood transfusions); absolute neutrophil count ≥ 1.0 x
             10^9 cells/L; platelet count ≥ 100 x 10^9 cells/L (transfusion independent defined as
             not receiving platelets transfusions ≥ 7 days prior to enrollment); alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the
             institutional upper limit of normal for age; creatinine within normal institutional
             limits OR creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine
             levels above institutional normal

          -  Written informed consent in accordance with institutional and FDA guidelines must be
             obtained from patient or legal guardian

        Exclusion Criteria:

        Patients with the following conditions will be excluded from participation in the study:

          -  Primary cerebellar, brainstem or spinal tumors

          -  Metastatic disease or gliomatosis cerebri

          -  Acute infection or medical condition precluding surgery

          -  Pregnant or lactating

          -  Diagnosis of encephalitis or central nervous system (CNS) infection < 3 months prior,
             or receiving ongoing treatment for encephalitis, CNS infection or multiple sclerosis

          -  Tumor involvement which would require ventricular, cerebellar or brainstem inoculation
             or would require access through a ventricle in order to deliver treatment

          -  Required steroid increase within 1 week prior to G207 inoculation or patients
             requiring >4 mg of dexamethasone daily

          -  Known HIV seropositivity

          -  Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir,
             penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir) or any immunosuppressive
             drug therapy (except dexamethasone or prednisone).

          -  Other current malignancy

          -  Concurrent anticancer or investigational drug
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy (overall survival)
Time Frame:Baseline to 24 months
Safety Issue:
Description:The overall survival for each patient receiving G207 will be calculated by estimating the 1-year and 2-year overall survival.

Secondary Outcome Measures

Measure:Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Time Frame:Baseline to 15 years
Safety Issue:
Description:All events with a Grade 3 or above toxicity (defined by the CTCAE v5.0) will be tabulated by event and by relationship to G207.
Measure:Virologic Shedding
Time Frame:Baseline to 15 years
Safety Issue:
Description:Virologic shedding will be assessed from saliva, conjunctiva and blood by polymerase chain reaction (PCR)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of Alabama at Birmingham

Trial Keywords

  • Brain Tumor, Recurrent
  • glioma
  • oncolytic virotherapy
  • immunotherapy
  • immunovirotherapy
  • neoplasm
  • progressive
  • virus
  • HSV
  • herpes virus
  • herpes simplex virus
  • oncolytic virus

Last Updated

January 29, 2021