DelMar Pharmaceuticals (DMPI) (“DelMar” and “the Company”), a biopharmaceutical company focused on the development of new cancer therapies, today announced the presentation of a poster at the American Association for Cancer Research (AACR) Special Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment, being held October 1-4, 2017 in Pittsburgh, PA. 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.