Open-label, Single Arm, Safety and Tolerability Dose-escalation Study of DAG in Patients with Recurrent Malignant Glioma
DelMar's ongoing clinical trial is a Phase 1/2 an open-label, single arm dose- escalation study designed to evaluate the safety, tolerability, pharmacokinetics and anti-cancer activity of VAL-083 in patients with GBM. To be eligible for our clinical trial, patients must have been 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 contra-indicated.
Response to treatment with VAL-083 is measured prior to each treatment cycle. An initial phase of the study involves dose escalation cohorts until a maximum tolerated dose ("MTD") is established in the context of modern care. The goal of our Phase 1/2 clinical trial is to determine a modernized dosing regimen for advancement into a registration directed clinical trial.
We have presented interim data at peer-reviewed scientific meetings, including most recently at the annual meetings of the American Association of Cancer Research ("AACR") in April 2015, and the Society for Neuro-Oncology (SNO) annual meeting in November 2014, as well as and previously during the year at the annual meetings of AACR and the American Society of Clinical Oncology ("ASCO") earlier in the year. We anticipate presenting additional data at upcoming scientific meetings during 2015.More information about our clinical trial and a list of participating
The prognosis for recurrent GBM is poor, with a median survival of 4 to 6 months and less than a 5% survival rate at 5 years.1,2 Front-line systemic therapy is temozolomide. However, chemo-resistance due to the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), which may be present in GBM tumors, has been implicated in poor outcomes in patients with GBM.3
VAL-083 (Dianhydrogalactitol, DAG) is a structurally unique, "first-in-class", small-molecule chemotherapeutic, which means that the molecular structure of VAL-083 is not an analogue or derivative of other small molecule chemotherapeutics approved for the treatment of cancer. Research suggests that VAL-083 crosses the blood-brain barrier and accumulates in brain tumor tissue. VAL-083 has a distinct mechanism of action: bifunctional N7 DNA alkylation, which is shown to be different from other pharmaceutical treatments approved to treat GBM such as Temodar™ (temozolomide/TMZ), Avastin™ (bevacizumab) and BCNU (carmustine)4,5. This unique mechanism has been demonstrated to overcome chemo-resistance to MGMT in vitro6. VAL-083 demonstrates activity in a wide range of cancer cell lines, including pediatric and adult GBM cell lines and GBM cancer stem cells7. Notably, prior human clinical studies conducted by the U.S. National Cancer Institute ("NCI") in the late 1970's and early 1980's suggested that VAL-083 had anti-tumor activity in brain tumors, including glioblastoma multiforme (GBM). 8-11
This is an open-label, single-arm Phase 1-2 dose-escalation clinical trial in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a standard 3 + 3 dose escalation design, until the maximum tolerated dose (MTD) or the maximum specified dose has been reached. In Phase 2, additional patients with recurrent GBM will be treated at the MTD (or other selected optimum Phase 2 dose) to measure tumor responses to treatment. Patients receive VAL-083 intravenously on days 1, 2, and 3 of a 21 day cycle. GBM patients have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab (Avastinaacute™) and temozolomide (Temodar™), unless either of these therapies is not appropriate for the patient.
Results to date have been presented at scientific conferences, most recently at the Society for NeuroOncology Annual Meeting in November 2013.
- Patients must be 18 years of age or older.
- Histologically confirmed initial diagnosis of primary WHO Grade IV malignant glioma (glioblastoma), now recurrent.
- 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.
- 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.
- At least 4 weeks from last chemotherapy or bevacizumab (Avastin) therapy (6 weeks for nitrosourea or mitomycin C), or for chemotherapy regimens 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 VAL-083 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.
- 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.