Safety and Effectiveness Study of G207, a Tumor-Killing Virus, in Patients With Recurrent Brain Cancer
Safety and Effectiveness Study of G207, a Tumor-Killing Virus, in Patients With Recurrent Brain Cancer
This clinical trial will study the safety and effectiveness of an engineered herpes virus,
 G207, administered directly into the brain of patients with recurrent brain cancer. G207 has
 been modified from the herpes virus that causes cold sores (called herpes simplex virus type
 1 or HSV-1). G207 has been designed so that it should kill tumor cells, but not harm normal
 brain cells. G207 has been shown to be safe in animal testing completed to date and in
 previous studies in patients with brain tumors.

 This is a phase Ib/II study. In the phase Ib portion of the study, patients will receive G207
 at a dose that is higher than tested in previous human studies. Patients will initially
 receive 15% of the assigned dose injected directly into the brain tumor. Approximately two
 days later, as much of the tumor as possible will be surgically removed, and more G207 will
 be injected into the brain tumor bed. Patients will be monitored, and medical tests will be
 done at specific study timepoints.

 The phase II portion will begin only if there are no safety concerns in the phase Ib portion.
 The goals of the phase II portion of the study are to determine the safety of G207 and to
 study patient survival at six months after G207 dosing. In the phase II portion of the study,
 patients will receive a single dose of G207 at the highest dose determined to be safe in the
 phase Ib portion of the study. The tumor will be removed, and G207 will be injected into any
 remaining tumor tissue in the brain tumor bed. Patients will be closely monitored, medical
 tests will be performed at specific study visits, and survival will be evaluated.
Protocol NG1-003 is an open-label, phase Ib/II study of the safety and efficacy of G207, a
 genetically engineered herpes simplex type-1 virus. Up to 21 patients will be enrolled in the
 phase Ib portion and will receive doses of G207 that are higher than tested in the previous
 trials. The highest G207 dose tested in a previous phase I trial (NG1-001) was 3E9 plaque
 forming units (pfu). G207 was generally well tolerated and safe in NG1-001, and there was no
 dose-limiting toxicity. Patients' deaths were due to progressive cancer disease except for
 one (due to radiation necrosis), and two patients remain alive today.

 Patients in the phase Ib portion of NG1-003 will receive G207 in divided doses. Initially,
 15% of the assigned dose will be injected into the tumor. Two days later, the tumor will be
 removed, and the assigned dose of G207 will be injected into the tumor bed at the time of
 resection. The assigned doses are as follows: 1E9, 3E9, and 1E10 pfu. Patient status will be
 followed by MRI, Karnofsky performance, neurologic examination and the presence of G207 virus
 in the body, in addition to other medical tests done at specific study visits.

 The phase II portion of protocol NG1-003 is a two-stage study. The phase II portion will
 begin only if there are no safety concerns in the phase Ib portion. The goals are to
 determine the safety of G207 and survival at six months. Enrollment of up to 14 patients is
 planned for stage one. Additional patients will be enrolled (up to 30 additional patients and
 44 overall) in stage II if at least 6 of the 14 patients in stage 1 survive 6 months or
 longer. Participants in phase II will receive a single dose of G207 at the highest dose
 determined to be safe from phase Ib. G207 will be injected into the tumor bed at the time of
 resection. Again, patient status will be followed as previously described and survival will
 be evaluated.
Main Inclusion Criteria:

 -  Age 19 years and older

 -  Phase Ib: Histologically confirmed recurrent glioblastoma multiforme or gliosarcoma
 (recurrent anaplastic astrocytoma also included in phase Ib) that is progressive
 despite previous radio- or chemotherapy

 -  Phase II: Histologically confirmed recurrent glioblastoma multiforme or gliosarcoma
 that is progressive despite previous radio- or chemotherapy

 -  Enhancing brain tumor measures at least 1.0 cm in diameter and evaluable by MRI within
 14 days of G207 administration (and proposed area of study drug inoculation appears to
 be resectable en bloc--for phase Ib only)

 -  Steroid regimen stable for at least 1 week prior to G207 inoculation

 -  Karnofsky Performance Status 70% or greater

 -  Failed external beam radiotherapy of at least 5000 cGy 4 weeks or longer prior to G207
 administration

 -  Candidate for brain tumor resection

 -  Females: negative urine pregnancy test within 24 hours prior to G207 administration

 -  Willing to use effective barrier birth control

 -  Able to give informed consent

 Main Exclusion Criteria:

 -  Multiple (more than one) intracranial malignant glioma lesions

 -  Documented extracranial metastases

 -  Laboratory test values (CBC, platelets, clinical chemistry, liver and renal function
 tests) outside protocol specified limits

 -  Chemotherapy, cytotoxic or immunotherapy within 6 weeks of G207 administration

 -  Any contraindication for undergoing MRI such as pacemakers, infusion pumps, aneurysm
 clips, metal prosthesis, former welders etc.

 -  Surgical resection within 4 weeks of G207 administration

 -  Pregnant or nursing females

 -  History of any of the following: HIV seropositive (historical or known); other
 investigational agents or vaccinations within 30 days; encephalitis, multiple
 sclerosis or other CNS infection; prior gene transfer therapy or prior therapy with a
 cytolytic virus of any type

 -  Any of the following concurrent conditions: evidence of active herpes infection;
 requires antiviral therapy for HSV at baseline; previous history or current diagnosis
 of other cancer except curative cervical cancer in situ or basal or squamous cell
 carcinoma of the skin; active uncontrolled infection, granulocytopenia, any unstable
 or severe medical condition that precludes surgery; alcohol or other substance abuse