Study of VAL-083 in Patients With MGMT Unmethylated, Bevacizumab-naive Recurrent Glioblastoma

Recurrent glioblastoma (GBM) is characterized by a dismal prognosis, with a median overall
survival of 6-9 months. While a standard of care is established for the initial treatment of
GBM - radiation with concurrent and adjuvant temozolomide chemotherapy - management of
recurrent disease remains suboptimal. Treatment options include repeat surgery,
re-irradiation, or chemotherapy (including experimental targeted therapies, biologic agents,
and immunotherapies). Only a minority of patients has response to these treatments, and the
resultant benefits in progression-free and overall survival are on the order of weeks to
months.

Prognosis and response to therapy are known to be better in patients with a methylated MGMT
promoter gene. Epigenetic silencing of MGMT by promoter methylation is an important factor in
predicting outcome for patients with GBM treated with temozolomide. Approximately 66% of GBM
tumors are MGMT unmethylated (high expression of MGMT), which through a MGMT repair
mechanism, confers resistance to temozolomide, the standard chemotherapy treatment of GBM.

VAL-083, Dianhydrogalactitol (DAG), unlike temozolomide, is demonstrated to be active
independent of MGMT resistance mechanisms, in vitro. Thus, it may provide a treatment option
for those patients that are considered likely to be poor responders to temozolomide.

This is a non-comparative, single arm, biomarker-driven study with VAL-083. Forty-eight (48)
eligible patients will receive VAL-083 at 40 mg/m2 IV on days 1, 2, and 3, for up to 12,
21-day treatment cycles or until they fulfill one of the criteria for study discontinuation
(disease progression, death, intolerable toxicities, investigator's judgment, or withdrawal
of consent). Disease status will be evaluated with clinical and MRI evaluation every other
21-day cycle, while the patient is receiving VAL-083 treatment, and then approximately every
42 ± 7 days while remaining on study. Symptom burden will be evaluated using the MD Anderson
Symptom Inventory-Brain Tumor (MDASI-BT) completed by patients at baseline and at the time of
each imaging evaluation.

Interval medical histories, targeted physical exams, neurologic evaluations, complete blood
counts, and other laboratory and safety assessments will be performed approximately every
21-days. Blood samples will be taken at Cycle 1 Day 1 pre-dose, 15 ± 5 min, 30 ± 5 min, 60 ±
10 min, 120 ± 10 min, 240 ± 15 min, and 360 ± 15 min after the end of the of iv infusion with
VAL-083 to determine the PK profile and dose-exposure relationship of VAL-083.

Toxicity will be evaluated and documented using the NCI CTCAE version 4.

This study will take approximately 32 months to enroll.

Inclusion Criteria:

- Patient must willingly provide written consent after being informed of the procedure
to be followed, the experimental nature of the therapy, alternatives, potential
benefits, side effects, risks, and discomforts.

- Patients must be ≥ 18 years old.

- Patients must have histologically confirmed initial diagnosis of primary intracranial
World Health Organization (WHO) Grade IV malignant glioma (glioblastoma, GBM), now
recurrent. Patients with recurrent disease whose initial diagnostic pathology
confirmed glioblastoma will not need re-biopsy. Alternately, patients with prior
intracranial low-grade glioma or anaplastic glioma will be eligible, if histologic
assessment demonstrates transformation to GBM (first diagnosis of secondary GBM).

- Patients must have radiographic evidence of recurrent/progressive GBM after prior
therapy (biopsy or resection and chemoradiation); 1st recurrence of GBM only, per
Response Assessment in Neuro-Oncology Criteria (RANO) criteria. Histologically
documented transformation from a lower grade gliomas will be considered first
recurrence.

- Patients must have confirmed GBM MGMT status (tumor must be MGMT promoter
unmethylated) by central laboratory Clinical Laboratory Improvement Amendments (CLIA)
certified testing at MD Anderson, prior to registration. If initial MGMT testing
obtained at an outside institution, MGMT status must be centrally retested at MD
Anderson.

- Patients must have Karnofsky Performance Status (KPS) > 60% (i.e., 70, 80, 90 or 100).

- Patients must have been previously treated for GBM with radiation with concurrent and
adjuvant temozolomide chemotherapy.

- Adequate recovery from all recent surgery is required. At least 21-days must have
elapsed from the time of any major surgery, including craniotomy/tumor resection.
Patients must have recovered from all surgery-related toxicities to Grade 1 or less.

- Patients must ≥ 12 weeks from radiotherapy, to minimize the potential for magnetic
resonance imaging (MRI) changes related to treatment (pseudo progression) that might
be misdiagnosed as true progression of disease, unless the patient fulfills criteria
for early progressive disease by RANO.

- Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at
least 2 weeks must have elapsed from the time of treatment, and the patient must have
subsequent histologic documentation of recurrence, unless the recurrence is a new
lesion outside the irradiated field.

- Patients having prior therapy with Laser Induced Thermal Therapy (LITT) is allowed,
but at least 21 days must have elapsed from last LITT, with recovery from all
LITT-related toxicities to Grade 1 or less and subsequent histologic documentation of
recurrence

- Patients must be at least 4 weeks from last dose of chemotherapy.

- Patients must be at least 4 weeks or 5 half-lives (whichever is shorter) from the last
dose of prior investigational anti-cancer drugs.

- Patients must have recovered from all treatment-related toxicities to Grade 1 or less.

- If receiving corticosteroids, patients must be on a stable or decreasing dose of
corticosteroids for ≥ 5 days prior to baseline MRI.

- Patients must have a predicted life expectancy of at least 12 weeks.

- Patients must have adequate bone marrow and organ function.

- Patients must be willing and able to comply with scheduled visits, treatment plan, and
laboratory tests and accessible for follow-up.

- If the patient has been using the Optune™ device, it will be discontinued before
initiating treatment with either study medication, and per inclusion criterion listed
above, the patient must have recovered from all treatment-related toxicities to Grade
1 or less.

- Pregnancy restrictions - Women of childbearing potential must have a negative B-HCG
documented within 7 days prior to registration

Exclusion Criteria:

- Within 12 weeks of chemoradiation unless the patient fulfills criteria for early
progressive disease by RANO

- Receipt of investigational agents within 5 half-lives of last dose of investigational
agent

- Concurrent use of other investigational agents or Optune™ device

- Prior therapy with lomustine

- Prior therapy with bevacizumab

- Current history of neoplasm other than the entry diagnosis. Patients with previous
cancers treated and cured with local therapy alone may be considered with approval of
the PI

- Evidence of leptomeningeal spread of disease

- Need for urgent palliative intervention (e.g., impending herniation)

- Severe, intercurrent illness including, but not limited to unstable systemic disease,
including ongoing or active infection, uncontrolled hypertension, serious cardiac
arrhythmia requiring medication, or psychiatric illness/social situations that would
limit compliance with study requirements

- Patients with a known sensitivity to any of the products to be administered during
treatment

- Patients unable to undergo MRI of the brain

- Women who are pregnant or lactating. Women of childbearing potential must have a
negative serum or urine pregnancy test performed within 7 days prior to start of
treatment. Women of childbearing potential or men with partners of childbearing
potential must use effective birth control measures during treatment.