Genetically Engineered HSV-1 Phase 1 Study for the Treatment of Recurrent Malignant Glioma

M032 is a second-generation oncolytic herpes simplex virus (oHSV) that is conditionally
replication competent; that is, similar to G207, a first generation oHSV, it can replicate in
tumor cells, but not in normal cells, thus killing the tumor cells directly through this
process. Replication of M032 in the tumor itself 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 carries a therapeutic payload--acting as a gene therapy vector, too--and
causes the tumor cell to synthesize and secrete an immunity-stimulating protein called
Interleukin-12 (IL-12) before it is killed. This IL-12 is released and promotes an immune
response against surviving tumor cells, which increases the antitumor effect of the therapy.
The IL-12 that is expressed can also produce an anti-angiogenic effect, by interfering with
the production of new tumor blood vessels necessary to allow tumor growth. Anti-angiogenic
therapies potentially starve the tumor of necessary oxygen and nutrients. Thus, the M032 oHSV
produces three different potential mechanisms for antitumor effects. The virus has also been
genetically-engineered to minimize the production of any toxic effects for the patient
receiving the therapy.

Inclusion Criteria

- Patients must have histologically or cytologically confirmed glioblastoma multiforme,
anaplastic astrocytoma, or gliosarcoma.

- Prior therapy: Patients must have failed external beam radiotherapy >5,000 cGy
(centrigray)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 ≥19 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 <19 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 in diameter as determined by MRI.

- 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.

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.

- Prior history of encephalitis, multiple sclerosis, or other CNS infection.

- Required steroid increase within 2 weeks of scheduled M032 administration.

- 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.)