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

Overview

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 (closed to accrual) 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 and young adults, ages 3 to 21 years, 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.

Interventions

• 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.

Primary outcome measures

• Safety and Tolerability as Measured by Frequency of Grade 3 or Above Adverse Events [Time frame: Baseline to 15 years]

Secondary outcome measures (6)

• Immunologic Response [Time frame: 24 months]
• Virologic Shedding [Time frame: Up to 15 years]
• Progression Free Survival [Time frame: Up to 15 years]
• Overall Survival [Time frame: Up to 15 years]
• Change in Performance Score (Ability to Perform Normal Activities) [Time frame: Baseline to 15 years]
• Quality of Life (optional) [Time frame: Up to 12 months]

Eligibility criteria

Inclusion criteria

• Age ≥ 36 months and < 22 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.
• A review of the MRI scan will be necessary to determine if the tumor location and size are such that the patient may be included in the study. The MRI scan must be reviewed and approved by the site neurosurgeon and/or study radiologist for enrollment. The following guidelines must be met: Lesion must be ≤ 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. Tumor measurements should be confirmed on the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) form or the institutional MRI report
• Patients must have fully recovered from acute treatment-related toxicities of all prior chemotherapy, immunotherapy or radiotherapy prior to the date of G207 administration. All washout intervals below are measured relative to the date of G207 administration.
• Myelosuppressive chemotherapy: patients must have received their last dose at least 3 weeks prior (or at least 6 weeks if nitrosurea) to G207 administration.
• Monoclonal antibodies: patient must have received the last dose ≥ 21 days prior to G207 administration
• Investigational/Biologic agents: patients must have recovered from any acute toxicities potentially related to the agent and received last dose ≥ 7 days prior to G207 administration (this period must be extended beyond the time during which adverse events are known to occur for agents with known adverse events ≥>= 7 days).
• Viral therapy: Patients must have received viral therapy ≥ 3 months prior to G207 administration and must have recovered from all acute toxicities potentially related to the agent
• Radiation: Patients must have received their last fraction of craniospinal radiation (>24 Gy) or total body irradiation ≥ 3 months prior to G207 administration. Patients must have received focal radiation to symptomatic metastatic sites or local palliative radiation ≥ 28 days prior to G207 administration.
• Autologous bone marrow transplant: Patients must be ≥ 3 months since transplant prior to G207 administration.
• Absolute neutrophil count > 1000/mm3
• Platelets ≥ 100,000/mm\^3
• 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 m\^2 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
• Written informed consent in accordance with institutional and Food and Drug Administration (FDA) guidelines must be obtained from patient or legal guardian

Exclusion criteria

• Acute infection, granulocytopenia or medical condition precluding surgery
• Pregnant or lactating females
• Diagnosis of encephalitis or central nervous system (CNS) infection ≤ 3 months prior
• Receiving ongoing treatment for encephalitis, CNS infection or multiple sclerosis
• Tumor involvement which would require ventricular or brainstem inoculation or would require access through a ventricle in order to deliver treatment
• Patient requires an escalation in ongoing systemic corticosteroid therapy within 7 days prior to G207 inoculation or requires ongoing systemic corticosteroid therapy at a dose > 2 mg/day of dexamethasone (or equivalent) at the time of inoculation. For this study, 'systemic corticosteroids' include oral, intravenous, or intramuscular formulations. A single, non-consecutive dose does not constitute exclusion. Physiologic corticosteroid replacement therapy (e.g., hydrocortisone for adrenal insufficiency) is not considered immunosuppressive and does not constitute exclusion
• Known human immunodeficiency virus (HIV) seropositivity
• Concurrent therapy with any drug active against herpes simplex virus (HSV) (acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir) or any immunosuppressive drug therapy (except dexamethasone or prednisone)
• Patients with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen for this trial
• Concurrent anticancer or investigational drug

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 3 centers

• University of Alabama at Birmingham Cancer Center — Birmingham
• Siteman Cancer Center at Washington University — St Louis
• MD Anderson Cancer Center — Houston

Identifiers

NCT: NCT03911388 · 2023-0688 · R01FD006368 · NCI-2021-00011

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗