Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma

Recurrent glial tumors of the brain continue to be one of the most challenging malignancies
to treat. Median survival for patients with recurrent disease is approximately 6 months for
glioblastoma multiforme. Bevacizumab is used for treatment of recurrent disease; however
patients who fail bevacizumab do not have many treatment options.

Metastases to the brain are the most common intracranial tumors in adults and occur ten
times more frequently than primary brain tumors. It is estimated that 8 - 10% of cancer
patients may develop symptomatic metastatic tumors in the brain. Systemic therapy is rarely
used for primary treatment of brain metastases because many tumors that metastasize to the
brain are not chemosensitive or have been already heavily pretreated with potentially
effective agents, and poor penetration through the blood brain barrier is an additional
concern.

Dianhydrogalactitol (DAG) rapidly penetrates both the cerebrospinal fluid (CSF) and the
blood-brain barrier and accumulates in brain tissue. Clinical study of DAG in patients with
GBM or with progressive secondary brain tumors is warranted. Patients with secondary brain
metastases were allowed to enroll into the current protocol in Cohorts 2 and 3; however,
enrollment ceased with Amendment 5 and will not be continued beyond Cohort 3.

This study will utilize a standard 3 + 3 dose escalation design, until the MTD or the
maximum specified dose has been reached. In Phase 2, additional patients with GBM will be
treated at the MTD (or other selected optimum Phase 2 dose) to measure tumor responses to
treatment.

Inclusion Criteria:

- Patients must be greater than or equal to 18 years old.

- Histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma
(glioblastoma), now recurrent; or Cohorts 2 and 3 only: progressive secondary brain
tumor, has failed standard brain radiotherapy, and has brain tumor progression after
at least one line of systemic therapy. Patients with progressive secondary brain
tumors will not be enrolled under this protocol following the completion of Cohort 3.

- If GBM, previously treated for GBM with surgery and/or radiation, if appropriate, and
must have failed both bevacizumab (Avastin) and temozolomide (Temodar), unless either
or both are contraindicated.

- If GBM, greater than or equal to 12 weeks from radiotherapy, or 4 weeks if a new
lesion, relative to the pre-radiation MRI, develops that is outside the primary
radiation field.

- Cohorts 2 & 3 only: Patients with secondary brain tumors must be greater than or
equal to 4 weeks from radiotherapy. Patients with progressive secondary brain tumors
will not be enrolled under this protocol following the completion of Cohort 3.

- At least 4 weeks from last chemotherapy or bevacizumab (Avastin) therapy (6 weeks for
nitrosourea or mitomycin C), or for chemotherapy regimes given continuously or on a
weekly basis with limited potential for delayed toxicity, at least 2 weeks from last
dose.

- At least 21 days or 5 half-lives (whichever is shorter) since prior investigational
anti-cancer drugs. A minimum of 10 days between termination of the investigational
drug and administration of DAG is required

- Recovered from all treatment-related toxicities to Grade 1 or less.

- Must have a Karnofsky performance status of > 50 with a predicted life expectancy of
at least 12 weeks.

- Must have known MGMT methylation and IDH1 mutation status to be screened for study
entry.

Exclusion Criteria:

- 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 Medical Monitor.

- Evidence of leptomeningeal spread of disease.

- Evidence of recent hemorrhage on baseline MRI of the brain.

- Concurrent severe, intercurrent illness.

- History of severe cardiac disease.

- Significant vascular disease.

- History of stroke or transient ischemic attack within 6 months prior to beginning
treatment.

- Concomitant medications that are known inducers of CYP.

- Concomitant medications that are strong inhibitors of cytochrome P450 and CYP3A up to
14 days before Cycle 1 Day 1 (pimozide, diltiazem, erythromycin, clarithromycin, and
quinidine, and amiodarone up to 90 days before)

- Known to be HIV positive or to have an AIDS-related illness.

- Pregnant or breast feeding.