Trial of C134 in Patients With Recurrent GBM

Prior treatment

• Patients who have had chemotherapy, cytotoxic therapy, immunotherapy or gene therapy within 6 weeks prior to entering the study, surgical resection within 4 weeks prior to entering the study, or have received experimental viral therapy at any time (e.g., adenovirus, retrovirus or herpesvirus \* protocol). Also, those who have not recovered from adverse events due to therapeutic interventions administered more than 4 weeks earlier.
• Patients may not be receiving any other investigational agents.
• Prior history of encephalitis, multiple sclerosis, or other CNS infection.
• Required steroid increase within 2 weeks of scheduled IRS1-chimeric HSV1 administration.
• Concurrent therapy with any drug active against HSV (acyclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, foscarnet, cidofovir).
• Required steroid increase within 2 weeks of scheduled C134 administration. When possible, the patient should be on a dexamethasone equivalent dose of ≤2mg daily at the time of treatment.
• Received Bevacizumab (Avastin) therapy within 4 weeks of scheduled C134 administration.
• Excluded patient groups
  • Pregnant women are excluded from this study because IRS1-chimeric HSV1 is a viral oncolytic therapy with unknown potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IRS1-chimeric HSV1, breastfeeding should be discontinued if the mother is treated with IRS1-chimeric HSVl.
  • Because patients with immune deficiency will be unable to mount the anticipated immune response underlying this therapeutic rationale, HIV-seropositive patients are excluded from this study. Other treatment studies for this disease that are less dependent on the patients' immune response are more appropriate for HIV-seropositive patients.

Other illness

• History of allergic reactions attributed to compound of similar biologic composition to IRS1-chimeric HSVl.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or any other medical condition that precludes surgery . Also, psychiatric illness/social situations that would limit compliance with study requirements.
• Known history of allergic reaction to IV contrast material that is not amenable to pre-treatment by UAB protocol.

Other

• Tumor involvement which would require ventricular, brainstem, basal ganglia, or posterior fossa inoculation or would require access through a ventricle in order to deliver treatment.
• Active oral herpes lesion.
• Have a pacemaker, ferro-magnetic aneurysm clips, metal infusion pumps, metal or shrapnel fragments, or certain types of stents.

• Patients must have histologically or cytologically confirmed recurrent/progressive glioblastoma multiforme, anaplastic astrocytoma, or gliosarcoma.
• Prior therapy. Patients must have failed external beam radiotherapy to the brain at least 4 weeks prior to enrollment.
• Age 18 years or older, because no dosing or adverse event data are currently available on the use of IRSl-chimeric HSVl in patients below 18 years of age, children are excluded from this study but will be eligible for future pediatric phase 1 single-agent trials. Note: 18 is the age of majority in the state of Alabama for participation in clinical trials.
• Karnofsky Performance Status ≥70%
• Life expectancy of greater than 4 weeks.
• Patients must have normal organ and marrow function as defined below:
  • leukocytes ≥3,000/uL
  • absolute neutrophil count ≥1,500/uL
  • platelets ≥100,000/uL
  • total bilirubin within normal institutional limits
  • AST(SGOT)/ ALT(SGPT) ≤2.5 X institutional upper limit of normal
  • Creatinine within normal institutional limits OR Creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels
• Residual lesion must be ≥1.0 and \< 5.5 cm in diameter without bilateral extension through the corpus callosum as determined by MRI as this is a locally delivered treatment. These parameters will be re-evaluated on imaging done on the day of catheter implantation and if the lesion no longer meets the criteria, the patient will not undergo catheter implantation or treatment with C134.
• The effects of IRS1-chimeric HSV1 on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the first six months after receiving IRS1-chimeric HSVl. Because it is currently unknown if IRS1-chimeric HSV1 can be transmitted by sexual contact, a barrier method of birth control should be employed. Should a woman become pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document (Informed consent document in Appendix E).
• Females of childbearing potential must not be pregnant; this will be confirmed by a negative serum pregnancy test within 14 days prior to starting study treatment.
• Steroid use is allowed as long as dose has not increased within 2 weeks of scheduled C134 administration whenever possible, the patient should be on a steroid dose that is equivalent to a dexamethasone dose of ≤2mg daily at the time of treatment.