Clinical trial NCT03911388: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
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
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
Lead sponsor: M.D. Anderson Cancer Center
Sponsor class: OTHER
Collaborators: name: Cannonball Kids' Cancer Foundation
name: Treovir, Inc
First posted: 2019-04-11
Enrollment: 24
Sex: ALL
Minimum age (years): 3
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: A traditional 3 + 3 design will be used with four patient cohorts.
Primary purpose: TREATMENT

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 (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.

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.
* 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.
* Diffuse, widespread, abnormal tumor pattern involving 3 or more lobes of the brain
* Acute infection, granulocytopenia or medical condition precluding surgery
* Pregnant or lactating females
* Diagnosis of encephalitis or CNS infection \< 3 months prior, or 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
* Required steroid increase within 1 week prior to G207 inoculation or patients requiring \>2 mg of dexamethasone daily
* 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).
* Other current malignancy
* Concurrent anticancer or investigational drug

Primary outcomes:
measure: Safety and Tolerability as Measured by Frequency of Grade 3 or Above Adverse Events
timeFrame: Baseline to 15 years
Secondary outcomes:
measure: Immunologic Response
timeFrame: Baseline to 24 months
measure: Virologic Shedding
timeFrame: Baseline to 15 years
measure: Progression Free Survival
timeFrame: Baseline to 24 months
measure: Overall Survival
timeFrame: Baseline to 60 months
measure: Change in Performance (Ability to Perform Normal Activities)
timeFrame: Baseline to 24 months
measure: Quality of Life (optional)
timeFrame: Baseline to 24 months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's of Alabama
state: Alabama
city: Saint Louis
country: United States
facility: St. Louis Children's Hospital
state: Missouri
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
Study officials:
affiliation: M.D. Anderson Cancer Center
name: Gregory Friedman, MD
role: PRINCIPAL_INVESTIGATOR
References: