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HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors

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ClinicalTrials.gov Identifier: NCT03911388
Recruitment Status : Recruiting
First Posted : April 11, 2019
Last Update Posted : July 8, 2021
Sponsor:
Information provided by (Responsible Party):
Gregory K. Friedman, MD, University of Alabama at Birmingham

Tracking Information
First Submitted Date  ICMJE April 9, 2019
First Posted Date  ICMJE April 11, 2019
Last Update Posted Date July 8, 2021
Actual Study Start Date  ICMJE September 12, 2019
Estimated Primary Completion Date September 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
Safety and Tolerability as Measured by Frequency of Grade 3 or Above Adverse Events [ Time Frame: Baseline to 15 years ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 10, 2019)
  • Immunologic Response [ Time Frame: Baseline to 24 months ]
    HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment.
  • Virologic Shedding [ Time Frame: Baseline to 15 years ]
    HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment.
  • Progression Free Survival [ Time Frame: Baseline to 24 months ]
    Time after G207 administration to clinical and radiographic disease progression will be evaluated.
  • Overall Survival [ Time Frame: Baseline to 60 months ]
    The overall survival for each patient receiving G207 will be calculated
  • Change in Performance (Ability to Perform Normal Activities) [ Time Frame: Baseline to 24 months ]
    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).
  • Quality of Life (optional) [ Time Frame: Baseline to 24 months ]
    Quality of life will be measured with questionnaires taken at baseline (before administration of G207) and at specified times thereafter.
Original Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2019)
  • Immunologic Response [ Time Frame: Baseline to 24 months ]
    HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment.
  • Virologic Shedding [ Time Frame: Baseline to 15 years ]
    HSV-1 antibody titers will be checked by ELISA prior to the administration of G207 and at regular intervals after treatment.
  • Progression Free Survival [ Time Frame: Baseline to 24 months ]
    Time after G207 administration to clinical and radiographic disease progression will be evaluated.
  • Overall Survival [ Time Frame: Baseline to 60 months ]
    The overall survival for each patient receiving G207 will be calculated
  • Change in Performance (Ability to Perform Normal Activities) [ Time Frame: Baseline to 24 months ]
    A performance score (0 [lowest] to 100 [highest]) will be recorded pre-treatment and measured serially at regular intervals after treatment.
  • Quality of Life (optional) [ Time Frame: Baseline to 24 months ]
    Quality of life will be measured with questionnaires taken at baseline (before administration of G207) and at specified times thereafter.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors
Official Title  ICMJE Phase 1 Trial of Engineered HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors
Brief Summary

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.

Funding Source- FDA OOPD

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
A traditional 3 + 3 design will be used with four patient cohorts.
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE Biological: G207
Single dose of 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 (which includes progressive leptomeningeal disease or any site of gross tumor progressing in the brain parenchyma) within 24 hours of virus inoculation.
Other Name: HSV G207
Study Arms  ICMJE Experimental: HSV G207
Single 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.
Intervention: Biological: G207
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 9, 2019)
15
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2024
Estimated Primary Completion Date September 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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: The patient must have received last dose ≥ 21 days prior.
  • 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).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 3 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kara Kachurak, CRNP (205) 638-9285 kkachurak@peds.uab.edu
Contact: Gregory K Friedman, M.D. (205) 638-9285 gfriedman@peds.uab.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03911388
Other Study ID Numbers  ICMJE UAB 18113
R01FD006368 ( U.S. FDA Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Gregory K. Friedman, MD, University of Alabama at Birmingham
Study Sponsor  ICMJE University of Alabama at Birmingham
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Gregory Friedman, M.D. University of Alabama at Birmingham
PRS Account University of Alabama at Birmingham
Verification Date July 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP