A new drug designed to inhibit an enzyme that plays a crucial role in cell division and growth has shown signs of anticancer activity with manageable side effects in patients with liver cancer and up to three lines of previous unsuccessful treatment, according to a new study published by Reig et al in the European Journal of Cancer.
The findings were also presented at the 34th European Organisation for Research and Treatment of Cancer (EORTC)–National Cancer Institute (NCI)–American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics (Abstract 3LBA).
“Primary liver cancer is the sixth most common cancer and among the leading causes of cancer-related deaths worldwide. Although new treatments options are becoming available, the overall prognosis for advanced liver cancer remains poor. I wanted to find new treatments for this cancer,” said Maria Reig, PhD, Associate Professor of Medicine, Director of the Hepatic Oncology Unit, and Director of the Barcelona Clinic Liver Cancer Unit at the Hospital Clinic of Barcelona at Barcelona University, as well as Head of the Liver Oncology Group at CIBER.
NMS-01940153E
NMS-01940153E has been designed to be a very potent and selective inhibitor of monopolar spindle 1 (MPS1) kinase, which is overexpressed in several cancers including liver cancer. MPS1 plays a critical role in regulating the processes involved in cell division and growth, and leads to cancer if these processes malfunction.
“Preclinical work demonstrated that NMS-01940153E was highly effective in preventing the proliferation of cancer cells, both on its own and in combination with other anticancer drugs. It seems more potent than other kinase inhibitors in liver cancer cells, and so we are testing it as a single agent in a phase I clinical trial in [patients with] liver cancer,” said Dr. Reig.
Study Methods and Results
In a trial called MPS-153-001, NMS-01940153E was given intravenously to 12 patients with liver cancer on days 1, 8, and 15 every 4 weeks—and also at increasing doses starting at 100 mg/m2 per week. The patients had all received previous treatments with up to three other anticancer drugs that eventually failed to halt their cancer.
Ten patients eventually discontinued treatment, seven due to disease progression. In the 11 patients who could be evaluated to see if the drug was making an impact on the cancer, tumors shrank by at least 30% in 2 patients for 2.5 and 9.3 months, respectively. Both discontinued treatment after their cancer started to grow again at 6.5 and 11.1 months, respectively. Two further patients had long-lasting stable disease and are still receiving the treatment after 11 and 18 cycles.
“At the 100 mg/m2/[week] dose, one of six patients who could be evaluated had a partial response to the study drug. At the 135 mg/m2/[week] dose, one of five [patients] had a partial response. Since each patient had three prior failures with standard treatments, the responses to NMS-01940153E are a strong sign that this new mechanism might be valuable in liver cancer, especially for patients whose cancer has already failed to respond to standard options,” Dr. Reig highlighted.
“Neutropenia was the main adverse side effect, but it was always quickly reversible and mostly managed carefully with observation and dose reductions by the treating physicians,” Dr. Reig continued.
When the doses were increased, two patients experienced neutropenia with either sepsis or a urinary tract infection at a dose of 135 mg/m2/wk—side effects that were serious enough to halt the increase in dosage. Other side effects included chromaturia, thrombocytopenia, anemia, weakness, diarrhea, and reaction at the site of the injection. There were no drug-related deaths.
Conclusion
“Drugs to prevent cancer cells dividing and proliferating have not shown much benefit in the clinic for patients with liver cancer so far. Liver cancer is one of the most fatal diseases; the percentage of people with advanced disease who are still alive 5 years after diagnosis is measured in months rather than years. Therefore, new and more effective treatments are needed urgently. The results from this small study are encouraging and the phase II trial should give us more information about the safety and efficacy of NMS-01940153E,” said Ruth Plummer, MD, PhD, Professor of Experimental Cancer Medicine at Newcastle University and Chair of the 34th EORTC–NCI–AACR Symposium on Molecular Targets and Cancer Therapeutics, who was not involved in the study.
“NMS-01940153E represents a new type of treatment, working in a very different way from the current options for treating liver cancer; therefore, it offers potential to help patients in the future,” Dr. Reig concluded. “This is a small study, so the results will need to be shown in larger studies. The strength of the study is that the effect of NMS-01940153E appears to be realistic, due to the history of prior treatment failures of these patients and the early pattern of response we observed. Therefore, these results suggest that NMS-01940153E should continue to be studied in liver cancer.”
NMS-01940153E is currently being evaluated in a phase II clinical trial in patients with liver cancer that cannot be treated with surgery and whose cancer has failed to respond to the existing standard treatments.
Disclosure: For full disclosures of the study authors, visit ejcancer.com.
