Genetically Engineered HSV-1 Phase 1 Study for the Treatment of Recurrent Malignant Glioma
Condition: Recurrent Glioblastoma Multiforme; Progressive Glioblastoma Multiforme; Anaplastic Astrocytoma or Gliosarcoma
MeSH terms: Glioblastoma; Astrocytoma; Gliosarcoma; Recurrence
Intervention: M032 (NSC 733972)
Intervention description: A single dose of HSV-1 (M032) infused through catheters into region(s) of tumor defined by MRI
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Glioma; Virus; Oncolytic virus; Gene therapy; Immunotherapy; Brain Tumors

Summary:

      To determine the safety and tolerability of the maximum dose for laboratory engineered Herpes
      Simplex Virus-1 in patients who would not be eligible for surgical resection of recurrent
      glioma To determine the safety and tolerability of the maximum dose for laboratory engineered
      Herpes Simples Virus-1 in patients who would benefit from surgical resection of recurrent
      glioma
    

Eligibility criteria:

        Inclusion Criteria

          -  Patients must have histologically or cytologically confirmed glioblastoma multiforme,
             anaplastic astrocytoma, or gliosarcoma.

          -  Prior therapy: Patients must have failed external beam radiotherapy to the brain, and
             if eligible and tolerated, undergone appropriate treatment with temozolomide
             chemotherapy. All radiation and additional chemotherapies must have been completed at
             least 4 weeks prior to enrollment. Prior therapy with nitrosoureas must have been
             completed at least 6 weeks prior to enrollment.

          -  Age ≥18 years (age of majority for clinical trials in Alabama). Because no dosing or
             adverse event data are currently available on the use of M032 in patients <18 years of
             age, children are excluded from this study but will be eligible for future pediatric
             phase 1 single-agent 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/μl

               -  absolute neutrophil count: >1,500/μl

               -  platelets: >100,000/μl

               -  total bilirubin within normal institutional limits

               -  AST(SGOT)(aspartate aminotransferase)/ALT(SGPT)(alanine aminotransferase): <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
                  above institutional normal.

          -  Residual lesion must be ≥1.0 cm 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 effects of M032 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 M032. Because it is currently
             unknown if M032 can be transmitted by sexual contact, a barrier method of birth
             control must be employed and for six (6) months following the administration of the
             study drug. Should a woman become pregnant while participating in this study, she
             should inform her treating physician immediately. For two weeks after receiving M032,
             subjects should avoid intimate contact with pregnant women, infants and young children
             and individuals with decreased immunity (ability to fight infection). Subjects should
             also refrain from donating blood during the trial

          -  Ability to understand and the willingness to sign a written informed consent document.

          -  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
             M032 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.

        Exclusion Criteria

          -  Patients who have had chemotherapy, cytotoxic therapy, immunotherapy within 4 weeks
             prior to entering the study (6 weeks for nitrosoureas), surgical resection within 4
             weeks prior to entering the study, or have received experimental viral therapy or gene
             therapy at any time (e.g., adenovirus, retrovirus or herpes virus protocol). However,
             this does not preclude re-treatment with M032 at a later date.

          -  Patients 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.

          -  History of allergic reactions attributed to compounds of similar biologic composition
             to M032 or to IL-12.

          -  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. Also, since M032 is a local treatment, patients whose tumors have
             bilateral extension through the corpus callosum, those with actively growing
             multifocal disease by MRI, and/or CSF dissemination/ leptomeningeal disease, are
             ineligible.

          -  Prior history of encephalitis, multiple sclerosis, or other CNS infection.

          -  Required steroid increase within 2 weeks of scheduled M032 administration. When
             possible, the patient should be on a dexamethasone equivalent dose of ≤ 2mg daily at
             the time of treatment.

          -  Active oral herpes lesion.

          -  Concurrent therapy with any drug active against HSV (acyclovir, valacyclovir,
             penciclovir, famciclovir, gancyclovir, foscarnet, cidofovir).

          -  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.

          -  Excluded patient groups

               -  Pregnant women are excluded from this study because M032 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 M032, breastfeeding women will not be
                  included in the study.

               -  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.

          -  Patients with known history of allergic reaction to IV contrast material that is not
             amenable to pre-treatment by University of Alabama at Birmingham protocol.

          -  Patients with pacemakers, ferro-magnetic aneurysm clips, metal infusion pumps, metal
             or shrapnel fragments or certain types of stents.

          -  Receipt of Gliadel Therapy.

          -  (Receipt of Bevacizumab (Avastin) therapy within 4 weeks of scheduled M032
             administration. (Receipt of Bevacizumab (Avastin) greater than 4 weeks of scheduled
             M032 administration does not exclude patient.)

          -  Any other reason the investigator deems subject is unfit for participation in the
             study.