On October 3, 2017 DelMar Pharmaceuticals (Nasdaq: DMPI) (“DelMar” and “the Company”), a biopharmaceutical company focused on the development of new cancer therapies, reported the presentation of a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment, being held October 1-4, 2017 in Pittsburgh, PA (Press release, DelMar Pharmaceuticals, OCT 3, 2017, View Source [SID1234520751]). The poster entitled “Distinct mechanism of action of DNA damaging agent dianhydrogalactitol (VAL-083) suggests combination therapy with PARP inhibitors,” and focuses on the unique mechanism of action of the Company’s lead agent, VAL-083.
Data presented in the Company’s poster demonstrates how its lead asset VAL-083 targets the DNA of cancer cells in a mechanistically different fashion than platinum (Pt)-based chemotherapeutic agents or PARP Inhibitors, and how these differences position VAL-083 as a potential new therapeutic option in the treatment of ovarian cancer.
Platinum-based chemotherapy is the standard-of-care in the treatment of advanced ovarian cancer. Treatment with platinum-based chemotherapy often leads to initial efficacy but subsequent emergence of multiple resistance mechanisms that limit the long-term utility of these agents (cisplatin and carboplatin).
Dysfunctional p53 tumor-suppressor protein, seen in a majority of advanced ovarian cancers, is a primary resistance mechanism that diminishes the therapeutic cytotoxicity of many DNA targeting drugs, particularly Pt-agents. In addition, deficiencies in the mismatch repair (MMR) pathway are correlated with platinum resistance.
DelMar’s data demonstrates that VAL-083 can overcome platinum resistance because its cytotoxic activity is independent of both the MMR pathway and the p53 status of a cancer cell.
Recently, PARP inhibitors have been shown to offer benefit as maintenance therapy in platinum-sensitive ovarian cancer, demonstrating improvements in progression free survival. However, an overall survival benefit has not been reported and recent literature cites PARP inhibitor-resistance as an emerging unmet need in the treatment of ovarian cancer.
Defects in the non-homologous end joining (NHEJ) pathway have been implicated in tumor resistance to PARP inhibitors. DelMar’s data indicates that VAL-083’s activity remains unaffected by defects in the NHEJ repair pathway and provides a mechanistic rationale for VAL-083 to overcome PARP inhibitor-resistance in the treatment of cancer.
DelMar’s poster also provides preclinical data demonstrating that VAL-083 displays synergy and/or super-additivity when combined with Pt-based agents (cisplatin and oxaliplatin) and PARP inhibitors (olaparib, veliparib and talazoparib). This supports a rationale for combination therapy with VAL-083 in front-line (platinum agents + VAL-083) or recurrent (PARP inhibitors +VAL-083) disease.
With a significant body of emerging preclinical evidence and historic clinical data suggesting reversal of platinum resistance by VAL-083, DelMar has recently obtained an Investigational New Drug Application (IND) allowance from the U.S. Food and Drug Administration (FDA) to initiate the REPROVe phase 1/ 2 trial of this agent in patients with recurrent platinum resistant ovarian cancer.
About the VAL-083 REPROVe Trial
On September 18th, 2017, DelMar announced that the FDA had accepted the Company’s IND for an open label multi-center Phase 1/2 Study of VAL-083 in Patients with Recurrent Platinum Resistant Ovarian Cancer (VAL-083 REPROVe Trial).
The Phase 1 portion of the trial is planned to enroll approximately 24 patients with Pt-resistant ovarian cancer to evaluate the response to treatment with VAL-083. Ovarian cancer patients enrolled in the trial will have been previously treated with at least two lines of Pt-based chemotherapy and up to two other cytotoxic regimens, and whose cancer has recurred within six months of prior Pt-based chemotherapy.
The primary efficacy of the trial will be overall response rate (ORR) based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria. RECIST is a set of published rules that define when tumors in cancer patients improve (“respond”), stay the same (“stabilize”), or worsen (“progress”) during treatment.
DelMar plans to request a meeting with FDA following completion of the Phase 1 portion of the REPROVe trial. If successful, data from this trial would lead to a confirmatory Phase 2 study of approximately 60 patients, which if successful, and subject to feedback from the FDA may position DelMar to potentially file an application for accelerated approval or to advance to a pivotal Phase 3 trial.
Further details regarding the VAL-083 REPROVe Ovarian Cancer trial can be found on clinicaltrials.gov: View Source
About VAL-083
VAL-083 (dianhydrogalactitol) is a “first-in-class”, DNA-targeting agent that introduces interstrand DNA cross-links at the N7-position of guanine leading to DNA double-strand breaks and cancer cell death. VAL-083 has demonstrated clinical activity against a range of cancers including GBM in historical clinical trials sponsored by the U.S. National Cancer Institutes (NCI).
VAL-083 has been granted an orphan drug designation by the U.S. FDA Office of Orphan Products for the treatment of glioma, medulloblastoma and ovarian cancer, and in Europe for the treatment of malignant gliomas. VAL-083 is currently being studied in multiple clinical trials as a potential new treatment for glioblastoma multiforme (GBM), the most common and aggressive form of brain cancer.
DelMar has demonstrated that VAL-083’s mechanism of action is distinct from multiple chemotherapies widely used in the treatment of cancer and that this unique mechanism may offer opportunities to overcome treatment resistance thereby offering new treatment options to cancer patients. Further details regarding these studies can be found at View Source