Safety Study of VAL-083 in Patients With Recurrent Malignant Glioma or Progressive Secondary Brain Tumor

• Evaluate tumor response in patients with recurrent malignant glioma or progressive secondary brain tumor [ Time Frame: Every 60 days ] [ Designated as safety issue: No ]
  Tumor assessment every other treatment cycle, as long as patient continues to demonstrate response or stable disease and tolerates therapy.
• Characterization of Cycle 1 plasma pharmacokinetics [ Time Frame: Cycle 1: 0, 0.25, 0.5, 1, 2, 4, 6 hrs and immediately prior to Cycle 1, Day 2 dosing ] [ Designated as safety issue: No ]
  Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).

• Evaluate tumor response in patients with recurrent malignant glioma [ Time Frame: Every 60 days ] [ Designated as safety issue: No ]
  Tumor assessment every other treatment cycle, as long as patient continues to demonstrate response or stable disease and tolerates therapy.
• Characterization of Cycle 1 plasma pharmacokinetics [ Time Frame: Cycle 1: 0, 0.25, 0.5, 1, 2, 4, 6 hrs and immediately prior to Cycle 1, Day 2 dosing ] [ Designated as safety issue: No ]
  Plasma will be analyzed to estimate appropriate PK parameters (Cmax, Tmax, AUC, elimination half-life, drug clearance, mean residence time, and volume of distribution).

The purpose of this Phase 1/2, open-label, single-arm study is to determine the safety and the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent malignant glioma or progressive secondary brain tumor. Pharmacokinetic (PK) properties will be explored and tumor responses to treatment will be evaluated.

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.

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 or progressive secondary brain tumor will be treated at the MTD (or other selected optimum Phase 2 dose) to measure tumor responses to treatment.

• Glioma
• Glioblastoma
• Glioblastoma Multiforme
• GBM
• Brain Cancer

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 progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy.
• 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.
• Patients with secondary brain tumors must be greater than or equal to 4 weeks from radiotherapy.
• 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.
• Recovered from all treatment-related toxicities to Grade 1 or less.
• Must have a predicted life expectancy of at least 12 weeks.

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.
• Prior treatment with prolifeprospan 20 with carmustine wafer (Gliadel wafer) within 60 days prior to first treatment (Day 0).
• Prior intracerebral agents.
• 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)
• Pregnant or breast feeding.