Validation for VAL-083

VANCOUVER, British Columbia & MENLO PARK, Calif.—As the 2015 meeting of the American Association for Cancer Research (AACR) wraps up, DelMar Pharmaceuticals Inc. is capping off its presence at the event by presenting promising data on VAL-083 (dianhydrogalactitol), its lead product candidate, for the treatment of platinum drug-resistant non-small cell lung cancer (NSCLC) and as a potential combination therapy option for those patients.

The compound in question is a first-in-class bi-functional alkylating agent that mediates inter-strand DNA crosslinks at N⁷ of guanine. It had already demonstrated activity against lung cancer in both preclinical and clinical trials, and has been approved for the treatment of lung cancer in China.

The study these data resulted from sought to determine the role of p53 status in the activity of VAL-083, how VAL-083 activity compared to that of cisplatin and oxaliplatin and the combination of VAL-083 with cisplatin or oxaliplatin.

The p53 gene is known to be pivotal in protecting the body from cancer, in part by triggering apoptosis if cells become damaged or cancerous and in part because the p53 pathway plays a key role in the activity of a number of chemotherapy drugs. This gene is frequently mutated in NSCLC, however, and such mutations correlate with chemotherapy resistance and poor patient outcomes in this cancer type. In isogenic models with or without p53 knockout, loss of p53 led to increased resistance to cisplatin and oxaliplatin by three- and six-fold, respectively, with only two-fold increase in resistance to VAL-083.

In DelMar's study, it was found that VAL-083's mechanism of action is distinct from platinum-based chemotherapy, which is the current standard of care for NSCLC. Compared to cisplatin or oxaliplatin, VAL-083 maintains a high level of anti-cancer activity in NSCLC cell lines with p53 mutations, supporting VAL-083's potential as a treatment option for platinum drug-resistant patients. When VAL-083 is combined with either of those drugs, it demonstrated superadditivity/synergy against NSCLC cell lines, including those that had proved resistant to tyrosine kinase inhibitors.

"VAL-083's novel cytotoxic mechanism is distinct from other alkylating agents used in the treatment of cancer, and the data from this study show the promise of VAL-083 not only in drug-resistance NSCLC, but also as a standalone agent and potential in combination therapy," Jeffrey Bacha, president and CEO of DelMar, commented on the results. "As a next step, we plan to initiate a clinical study of VAL-083 in relapsed or refractory NSCLC patients to further explore the potential of VAL-083 to become a key component of modern lung cancer therapy."

And this isn't the only indication in which DelMar is advancing VAL-083. The compound has also demonstrated safety and efficacy in treating several other cancers, including brain, cervical, ovarian cancers and leukemia, in more than three dozen Phase 1 and 2 clinical studies sponsored by the National Cancer Institute.

Specifically, within brain cancer, DelMar is investigating VAL-083's potential in treating refractory glioblastoma multiforme (GBM). DelMar's presentations at AACR also included updated clinical data on the maximum tolerated dose (MTD) with respect to its Phase 1/2 study of VAL-083 in patients with refractory GBM. The study is focused on determining the MTD of VAL-083 using an optimized dosing scheme, and once the MTD is identified, enrollment will be expanded by up to an additional 14 patients. To date, at the highest dose, 50mg/m2/day, one patient was observed with Grade 4 thrombocytopenia, with three other patients in the cohort experiencing Grade 3 thrombocytopenia, though the symptoms resolved rapidly and spontaneously without concomitant treatment. In other dosing cohorts, treatment-related toxicities have been mild to moderate.

"While we have only observed one patient with Grade 4 thrombocytopenia, which is defined as dose-limiting toxicity (DLT), in the cohort to date, the strong trend suggested by multiple observations of Grade 3 thrombocytopenia confirm that we have reached the end of the dose-escalation phase of our clinical trial," noted Bacha. "Through our optimized dosing regimen, we have successfully achieved our goal of delivering higher doses of VAL-083 than prior promising NCI-sponsored clinical trials with VAL-083 in GBM. We are pleased to achieve this milestone with VAL-083 as a potential new therapy for GBM patients who fail, or are unlikely to respond to, current standard of care."

The study consists of 37 patients enrolled across eight dose cohorts, in which they receive VAL-083 on days 1, 2 and 3 of a 21-day cycle, with tumor response assessed according to RANO criteria prior to every other 21-day cycle. Tumor regression was seen after therapy in more than 40 percent of treated patients, with stabilization seen in a further 20 to 30 percent. Previous clinical studies have shown VAL-083 to have a statistically significant impact on median survival in high-grade glioma brain tumors when combined with radiation versus radiation alone, with results that match or surpass those of other chemotherapeutics approved for GBM treatment. Compared to other chemotherapies for GBM, VAL-083 has a different mechanism of action, particularly in that it does not seem to be affected by MGMT, a DNA repair enzyme that causes resistance to Temodar.