Clinical Trials /

HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors

NCT03911388

Description:

This study is a clinical trial to determine the safety of inoculating G207 (an experimental virus therapy) into a recurrent or refractory cerebellar brain tumor. The safety of combining G207 with a single low dose of radiation, designed to enhance virus replication, tumor cell killing, and an anti-tumor immune response, will also be tested.

Related Conditions:
  • Anaplastic Astrocytoma
  • Atypical Teratoid/Rhabdoid Tumor
  • Conventional Glioblastoma Multiforme
  • Ependymoma
  • Germ Cell Tumor
  • Giant Cell Glioblastoma
  • Medulloblastoma
  • Primitive Neuroectodermal Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors
  • Official Title: Phase 1 Trial of Engineered HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors

Clinical Trial IDs

  • ORG STUDY ID: UAB 18113
  • NCT ID: NCT03911388

Conditions

  • Neoplasms, Brain
  • Glioblastoma Multiforme
  • Glioblastoma of Cerebellum
  • Neoplasms
  • Astrocytoma
  • Astrocytoma, Cerebellar
  • Neuroectodermal Tumors
  • Neuroectodermal Tumors, Primitive
  • Cerebellar PNET, Childhood
  • Cerebellar Neoplasms
  • Cerebellar Neoplasms, Primary
  • Cerebellar Neoplasm, Malignant
  • Cerebellar Neoplasm Malignant Primary
  • Neoplasm Metastases
  • Neoplasm Malignant
  • Neoplasms, Neuroepithelial
  • Neoplasms, Germ Cell and Embryonal
  • Neoplasms by Histologic Type
  • Neoplasms, Glandular and Epithelial
  • Neoplasms, Nerve Tissue
  • Central Nervous System Neoplasms, Primary
  • Central Nervous System Neoplasms, Malignant
  • Nervous System Neoplasms
  • Neoplasms by Site
  • Brain Diseases
  • Central Nervous System Diseases
  • Nervous System Diseases
  • Medulloblastoma Recurrent
  • HSV
  • Virus
  • Pediatric Brain Tumor
  • Nervous System Cancer
  • Primitive Neuroectodermal Tumor (PNET) of Cerebellum

Interventions

DrugSynonymsArms
G207HSV G207HSV G207

Purpose

This study is a clinical trial to determine the safety of inoculating G207 (an experimental virus therapy) into a recurrent or refractory cerebellar brain tumor. The safety of combining G207 with a single low dose of radiation, designed to enhance virus replication, tumor cell killing, and an anti-tumor immune response, will also be tested.

Detailed Description

      Outcomes for children with recurrent or progressive cerebellar malignant brain tumors are
      very poor, and there are a lack of effective salvage therapies once a patient fails standard
      treatments. 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 "one-two punch" at attacking 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.

      The safety of G207 has been demonstrated in 3 phase I clinical trials involving adults with
      supratentorial high-grade gliomas adults at the University of Alabama (UAB) and in an ongoing
      phase I clinical trial involving children with recurrent supratentorial brain tumors at
      Children's of Alabama. In the adult 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 anti-tumor responses have
      been seen. Preclinical laboratory studies have demonstrated that a variety of aggressive
      pediatric brain tumor types are sensitive to G207.

      This study is a phase I, open-label, single institution clinical trial of G207 alone or
      combined with a single low dose of radiation in children with recurrent or progressive
      cerebellar brain tumors.The primary goal is to determine safety. The secondary aims are to
      obtain preliminary information on the effectiveness of and immune response to G207. A
      traditional 3 + 3 design will be used with four patient cohorts. The first cohort will
      receive G207 alone, and the next cohorts will receive G207 at one of three doses followed by
      a 5 Gy dose of radiation to active areas of tumor.
    

Trial Arms

NameTypeDescriptionInterventions
HSV G207ExperimentalSingle dose of HSV-1 (G207) infused through catheters into region(s) of tumor. If G207 is safe in the first cohort of patients, subsequent patients will receive a single dose of G207 infused through catheters into region(s) of tumor followed by a 5 Gy dose of radiation to the tumor given with 24 hours of virus inoculation.
  • G207

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 36 months and < 19 years

          -  Pathologically proven malignant cerebellar brain tumor (including medulloblastoma,
             glioblastoma multiforme, giant cell glioblastoma, anaplastic astrocytoma, primitive
             neuroectodermal tumor, ependymoma, atypical teratoid/rhabdoid tumor, germ cell tumor,
             or other high-grade malignant tumor) which is progressive or recurrent despite
             standard care including surgery, radiotherapy, and/or chemotherapy. A pathologically
             proven secondary malignant cerebellar tumor without curative treatment options is
             eligible.

          -  Lesion must be ≥ 1.0 cm ≤ 3.0 cm in diameter and surgically accessible as determined
             by MRI. Larger tumors may be surgically debulked and treated if ≤ 3.0 cm after
             debulking

          -  Patients must have fully recovered from acute treatment related toxicities of all
             prior chemotherapy, immunotherapy or radiotherapy prior to entering this study.

          -  Myelosuppressive chemotherapy: patients must have received their last dose at least 3
             weeks prior (or at least 6 weeks if nitrosurea)

          -  Investigational/Biologic agents: patients must have recovered from any acute
             toxicities potentially related to the agent and received 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, patients must have received viral therapy ≥ 3 months prior to study entry and
             have recovered from all acute toxicities potentially related to the agent.

          -  Monoclonal antibodies: For bevacizumab, the patient must have received last dose ≥ 28
             days prior. At least 3 half-lives must have elapsed prior to study entry for other
             monoclonal antibodies.

          -  Radiation: Patients must have received their last fraction of craniospinal radiation
             (>24 Gy) or total body irradiation ≥ 3 months prior to study entry. Patients must have
             received focal radiation to symptomatic metastatic sites or local palliative radiation
             ≥ 28 days prior to study entry.

          -  Autologous bone marrow transplant: Patients must be ≥ 3 months since transplant prior
             to study entry.

          -  Normal hematological, renal and liver function (absolute neutrophil count > 1000/mm3,
             platelets > 100,000/mm3, prothrombin time (PT) or partial thromboplastin time (PTT) <
             1.3 x control, creatinine within normal institutional limits OR creatinine clearance
             >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal,
             total bilirubin < 1.5 mg/dl, transaminases < 3 times above the upper limits of the
             institutional norm)

          -  Patients < 16 years, Modified Lansky performance score ≥ 60; patients ≥ 16 years,
             Karnofsky performance score ≥ 60

          -  Patient life expectancy must be at least 8 weeks

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

        Exclusion Criteria:

          -  Any treatment outside the allowable guidelines outlined in section 5.1.

          -  Acute infection, granulocytopenia or medical condition precluding surgery

          -  Pregnant or lactating females

          -  Prior history of encephalitis, multiple sclerosis, or other central nervous system
             infection

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

          -  Required steroid increase within 1 week prior to injection

          -  Known HIV seropositivity

          -  Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir,
             penciclovir, famciclovir, gancyclovir, foscarnet, cidofovir) or any immunosuppressive
             drug therapy (except dexamethasone or prednisone).
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and Tolerability as Measured by Frequency of Grade 3 or Above Adverse Events
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.

Secondary Outcome Measures

Measure:Immunologic Response
Time Frame:Baseline to 24 months
Safety Issue:
Description:HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment.
Measure:Virologic Shedding
Time Frame:Baseline to 15 years
Safety Issue:
Description:HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment.
Measure:Progression Free Survival
Time Frame:Baseline to 24 months
Safety Issue:
Description:Time after G207 administration to clinical and radiographic disease progression will be evaluated.
Measure:Overall Survival
Time Frame:Baseline to 60 months
Safety Issue:
Description:The overall survival for each patient receiving G207 will be calculated
Measure:Change in Performance (Ability to Perform Normal Activities)
Time Frame:Baseline to 24 months
Safety Issue:
Description:A modified Lansky score (for children under 16 years of age) or Karnofsky score (for children 16 and older) will be recorded pre-treatment and measured serially at regular intervals after treatment. The score is a standard performance score that measures overall function of the child with a scale range from 0 (lowest, poorest performance score) to 100 (highest, best performance).
Measure:Quality of Life (optional)
Time Frame:Baseline to 24 months
Safety Issue:
Description:Quality of life will be measured with questionnaires taken at baseline (before administration of G207) and at specified times thereafter.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Alabama at Birmingham

Trial Keywords

  • Brain Tumor, Recurrent
  • Glioma
  • Glioblastoma Multiforme
  • Gliosarcoma
  • Medulloblastoma
  • Anaplastic Astrocytoma
  • Oligodendroglioma
  • Rhabdoid Tumor
  • Ependymoma
  • Germ Cell Tumor
  • Choroid Plexus Carcinoma
  • Cerebral Primitive Neuroectodermal Tumor
  • Giant Cell Glioblastoma
  • Atypical teratoid/rhabdoid tumor
  • Secondary Malignant Cerebellar Tumor
  • Embryonal Tumor
  • Neoplasms
  • Oncolytic Virus Therapy
  • Virotherapy, Oncolytic
  • Immunotherapy
  • Central Nervous System Agents
  • Antineoplastic Agents
  • Pediatric
  • Pediatrics
  • Oncolytic
  • Virus
  • HSV
  • Herpes Virus
  • G207
  • Oncolytic Herpes Virus

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