VANCOUVER, British Columbia, MENLO PARK, Calif., and MIAMI, Nov. 17, 2014 /PRNewswire/ -- DelMar Pharmaceuticals, Inc. (OTCQB: DMPI) (“DelMar” and “DelMar Pharma”) today announced the presentation of new data supporting the development of VAL-083 (dianhydrogalactitol), which is currently undergoing clinical development in the United States as a potential new chemotherapy for the treatment of refractory glioblastoma multiforme (GBM), the most common and deadly form of human brain cancer.
The data were presented in two additional abstracts on Friday November 14, 2014 during the evening scientific session at the Society for NeuroOncology Annual Meeting. Overall, DelMar presented three abstracts at the meeting.
On Friday, DelMar announced the presentation of an abstract entitled In vivo efficacy of VAL-083 in the treatment of MGMT-positive glioblastoma multiforme (GBM), which highlighted the company’s research into the activity of VAL-083 in comparison to standard-of-care temozolomide in animal models of GBM.
The presentation can be viewed at: DELMAR INVIVO DATA PRESENTATION SNO2014
The second abstract entitled VAL-083 is a novel N7 alkylating agent that inhibits the growth of glioma stem and non-stem cultures, including temozolomide-resistant lines presented by DelMar’s collaborators from the University of California San Francisco (UCSF), provided further pre-clinical validation of VAL-083’s different and potentially superior activity compared to standard-of-care temozolomide.
The presentation can be viewed at: DELMAR INVITRO DATA PRESENTATION SNO2014
The third abstract entitled Phase I/II study of dianhydrogalactitol (VAL-083) in patients with recurrent malignant glioblastoma multiforme (GBM) provided an update on DelMar’s ongoing Phase I/II clinical trial with VAL-083 in the treatment of refractory glioblastoma.
The presentation can be viewed at: DELMAR CLINCAL PRESENTATION SNO2014
Overview of UCSF in vitro Research Findings
“Researchers from UCSF previously demonstrated that the response of both cancer stem cells (CSC) and paired non-CSC cultures isolated from glioblastoma patients to temozolomide, the current standard of care in the treatment of glioblastoma was dependent on the presence or absence of an enzyme called O6-methylguanine methyltransferase (MGMT),” said Jeffrey Bacha, president & CEO of DelMar Pharmaceuticals. “We collaborated with UCSF to investigate how the same cultures respond to VAL-083 alone or in combination with radiation, and how the response would compare to temozolomide.”
GBM is the most common and deadly form of human brain cancer. The standard of care for newly diagnosed GBM patients is surgical resection followed by temozolomide and radiation and subsequent maintenance therapy with temozolomide alone. Temozolomide is effective for a minority of patients that low expression of MGMT, a DNA repair enzyme that repairs the cytotoxic damage temozolomide causes to cancer cells. The majority of patients exhibit high expression of MGMT and are resistant to temozolomide.
“VAL-083 is a first-in-class alkylating agent that crosses the blood brain barrier and is currently in clinical trials for glioma patients with recurrent GBM. We hypothesized that the N7 alkylating agent, VAL-083, is not subject to MGMT mediated repair and might therefore be a more potent chemotherapeutic for the treatment of GBM,” said Joseph Costello, Professor of Neurological Surgery at UCSF.
Patient derived GBM cells were treated with increasing doses of temozolomide or VAL-083 and cell cycle analysis was performed four days after treatment. VAL-083 proved to be effective against temozolomide resistant cultures, even at single micromolar (uM) doses.
The activity of VAL-083 and temozolomide were compared by treating CSCs with a 5uM dose of VAL-083 or a 50uM dose of temozolomide in combination with a standard 2 gray (Gy) dose of radiation. CSCs were examined for cell viability four (4) days post treatment. The cultures studied were not sensitive to the combination of temozolomide and radiation but were sensitive to treatment with the combination of VAL-083 and radiation. Further, VAL-083 was shown to increase cancer cells sensitivity to radiation at doses below 2uM.
In summary, UCSF researchers demonstrated that:
- VAL-083 appears to cause cell cycle arrest and loss of cell viability at lower concentrations than temozolomide;
- Unlike temozolomide, VAL-083 is active against stem and non-stem cells and its activity affected by MGMT status. All cultures tested were sensitive to VAL-083 exposure; and
- For all cultures tested, a potential additive effect of VAL-083 with radiation therapy was observed, particularly at low concentrations of VAL-083.
“These in vitro results suggest that VAL-083 may provide greater killing of MGMT unmethylated tumor cells compared to the standard-of-care chemotherapy,” added Prof. Costello.
Mr. Bacha added, “While this program is progressing in clinical trials for GBM patients having failed approved therapies we continue believe in the importance of nonclinical research to differentiate VAL-083 not only for continued validation of its promise as a potential treatment for refractory GBM, but also to support its potential as an alternative front-line chemotherapy in the future.”
Overview of Clinical Data Presentation:
To date, 13 male and 10 female subjects with GBM have completed safety analysis at doses up to 40mg/m2 in DelMar’s VAL-083 clinical trial without encountering dose limiting toxicity (DLT). Seven additional subjects with CNS metastases were enrolled at lower doses; however, enrollment at doses above 5mg/m2 has been limited to GBM.
Historical studies sponsored by the US National Cancer Institutes (NCI) achieved promising results in newly diagnosed and recurrent GBM using a dosing regimen of 25 mg/m2/day for five days every five weeks. Historically, dose limiting hematologic toxic effects were noted on white blood cell (WBC) and platelet counts. For example, Egan etal. (1979) observed nadir of 2,100/mL (lymphopenia) and 88,000/mL (thrombocytopenia), respectively. In a separate study, a dose of 40mg/m2/day for five days resulted in a median platelet nadir of 31,000/mL and WBC nadir of 2,300/mL. In general, nadir occurred within three weeks and returned to normal within seven (7) days.
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