Proposed Pivotal Phase III Clinical Trial in bevacizumab-failed glioblastoma multiforme (GBM) to enroll 180 patients with target completion in well under two years
Two separate collaborator-supported Phase II studies designed to position VAL-083 as a new chemotherapeutic for the treatment of GBM Patients with unmethylated MGMT will be conducted in parallel with Phase III
VANCOUVER, British Columbia and MENLO PARK, Calif., Nov. 21, 2016 /PRNewswire/ — DelMar Pharmaceuticals, Inc. (NASDAQ: DMPI) (“DelMar” and the “Company”), a biopharmaceutical company focused on the development and commercialization of new cancer therapies, today summarized the Company’s presentations at the CNS Anticancer Drug Discovery and Development Conference and Society for NeuroOncology Annual meeting, which was held November 16-20, 2016 in Scottsdale, Arizona.
During the conference, DelMar’s chairman and CEO, Jeffrey Bacha, delivered an oral address during CNS Anticancer Drug Discovery and Development sessions. Mr. Bacha described DelMar’s research and recent clinical trial results and how these data position VAL-083 as a potential solution for newly diagnosed GBM patients whose cancer exhibits features, such as a high expression of MGMT, implicated in resistance to currently approved chemotherapy.
“It was an honor to be invited to share and discuss our research with leaders in the global neuro-oncology community,” stated Mr. Bacha. “Overcoming the unique challenges in treating brain tumors requires cooperation among experts across a range of medical and scientific disciplines. We look forward to continuing to advance VAL-083 as a potential new chemotherapy in collaboration with leading cancer centers and researchers.”
DelMar also provided an overview of three upcoming clinical trials with VAL-083 for the treatment of chemo-resistant GBM. A copy of the company’s poster presentation entitled ‘Clinical Trials of VAL-083 in Patients with Chemo-Resistant Glioblastoma’ can be viewed at http://www.delmarpharma.com/scientific-publications.html. The planned trials include:
1. A pivotal, randomized multi-center Phase 3 study measuring survival outcomes compared to a “physicians’ choice” control for the treatment of bevacizumab-failed GBM. A summary of the proposed clinical trial design includes:
•Approximately 180 patients with histologically confirmed recurrent GBM who have failed both standard chemo-radiation and bevacizumab will be randomized in a 2:1 fashion to receive either VAL-083 or a commonly used salvage chemotherapy;
•The proposed study is projected to be enrolled at approximately 25 centers;
•The proposed primary endpoint is overall survival (OS);
•The proposed statistical design between the two arms of the study is 90% power, and is proposed to include an interim analysis at 50% events for futility with O’Brien-Fleming superiority boundary and non-binding, gamma (-5) futility boundary; and
•The estimated length of the proposed study is less than two years from initiation.
The proposed trial design is subject to feedback from the FDA and other regulatory authorities. DelMar plans to submit the protocol to the FDA in coming weeks.
2. An open label, single-arm, biomarker-driven, Phase 2 study of VAL-083 in patients with MGMT-unmethylated, bevacizumab-naïve recurrent GBM (clinicaltrials.gov identifier: NCT02717962)
•This single arm, biomarker-driven study will enroll 48 patients to determine if treatment of MGMT-unmethylated recurrent glioblastoma with VAL-083 improves overall survival (OS), compared to historical reference control;
•The lomustine arm of the recently published EORTC26101 trial will serve as the reference control; and
•The study is initially being enrolled at the University of Texas MD Anderson Cancer Center as a single center trial, but may be expanded to include additional centers.
This trial is being conducted in collaboration with the University of Texas MD Anderson Cancer Center (“MDACC”). The MDACC Institutional Review Board (IRB) has approved the protocol for this Phase II Study, and DelMar has completed a formal site initiation visit. DelMar and MDACC anticipate commencing enrollment and initiating patient treatment in the coming weeks.
3. An open label, single-arm, biomarker-driven, Phase 2 study of VAL-083 and radiation therapy patients in newly diagnosed MGMT-unmethylated GBM
•This single-arm trial will enroll up to 30 newly diagnosed (temozolomide-naïve) GBM patients to examine whether VAL-083 is active in patients with newly diagnosed GBM with MGMT-unmethylated compared to historical control;
•If successful, data from the trial will serve as a lead-in to a global randomized Phase II/III clinical trial of VAL-083 in newly diagnosed GBM patients with MGMT-unmethylated;
•Progression free survival (PFS) will serve as the primary endpoint to assess VAL-083 treatment activity;
•The study will also confirm the safety and tolerability of VAL-083 in combination with a standard-of-care radiation regimen; and
•The study will initially be enrolled at the Sun-Yat Sen University (Guangzhou, China) as a single center trial, but may be expanded to include additional centers.
This trial is being conducted in collaboration with Guangxi Wuzhou Pharmaceutical (Group) Co. Under the terms of the company’s collaboration agreement Guangxi Wuzhou Pharmaceuticals is providing drug product and funding for the trial. The Sun-Yat Sen University Clinical Review Committee has approved the protocol and DelMar is completing the final remaining regulatory steps required for initiation of the trial and expects to begin enrollment in early 2017.
In a separate poster presentation, DelMar provided additional non-clinical data regarding VAL-083’s unique anti-cancer mechanism and potential combination therapies. DelMar’s poster presentation, entitled ‘Molecular Mechanisms of Dianhydrogalactitol (VAL-083) in Overcoming GBM Chemo-resistance’ can be viewed on the company’s website here.
In summary, DelMar’s data indicates that:
•The mechanism of action of VAL-083 is distinct from other alkylating agents used in the treatment of CNS tumors;
•VAL-083 induces irreparable DNA double strand breaks, irreversible S/G2-phase arrest and activation of the homologous recombination DNA repair pathway;
•VAL-083’s cytotoxic activity is MGMT-independent and able to overcome TMZ-resistance in GBM cancer stem cells and non-stem cells in vitro;
•VAL-083 potentiates radiation in GBM cancer stem cells in vitro;
•VAL-083’s activity appears independent of p53; and
•VAL-083 displays synergy with a number of agents used in the treatment of GBM and other CNS tumors, including temozolomide, topoisomerase inhibitors, and platinum-based chemotherapy.
“These data are particularly valuable because they demonstrate the potential to combine VAL-083 with topoisomerase inhibitors, which are regularly used in the treatment of recurrent GBM,” added Mr. Bacha. “Topoisomerase inhibitors such as irinotecan and etoposide have a relatively narrow therapeutic window and require cells to be in the ‘S-phase’ of the cell cycle for activity. Because VAL-083 causes cell-cycle arrest in the S-phase these data suggest an opportunity to combine VAL-083 with a lower and better tolerated dose of a topoisomerase inhibitor while maintaining or improving efficacy.”
About Glioblastoma Multiforme (GBM)
Glioblastoma multiforme (GBM) is the most common and most malignant form of brain cancer. Approximately 15,000 people are diagnosed with GBM each year in the U.S., with similar incidence in Europe. Standard of care is surgery, followed by either radiation therapy, or radiation therapy combined with temozolomide. Approximately 60 percent of GBM patients treated with temozolomide experience tumor progression within one year. More than half of glioblastoma patients will fail the currently approved therapies and face a very poor prognosis.
VAL-083 is a “first-in-class,” small-molecule chemotherapeutic. In more than 40 Phase I and II clinical studies sponsored by the U.S. National Cancer Institute, VAL-083 demonstrated clinical activity against a range of cancers including lung, brain, cervical, ovarian tumors and leukemia both as a single-agent and in combination with other treatments.
DelMar’s research has demonstrated that VAL-083 is active against GBM cell lines that are resistant to standard-of-care chemotherapy due to features such as high expression of MGMT, in vitro.
DelMar presented data from its Phase I/II clinical trial in refractory GBM at the 2016 American Association of Clinical Oncology (ASCO) Annual meeting demonstrating that the median survival of 22 patients receiving an assumed therapeutic dose of VAL-083 (≥20mg/m2) was 8.35 months following Avastin™ (bevacizumab) failure compared to published literature where survival of approximately two to five months has been reported.
VAL-083 has received an orphan drug designation in Europe for the treatment of malignant gliomas and the U.S. FDA Office of Orphan Products has granted an orphan designation to VAL-083 for the treatment of glioma, medulloblastoma and ovarian cancer.
DelMar believes that data from its upcoming clinical trials, if successful, will form the basis of a new paradigm in the treatment for all GBM patients who fail, or whose tumors exhibit features that make them unlikely to respond to currently available chemotherapy.
Further details can be found here.
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