Medical journals highlight evidence that patients with elevated levels of PLK1 in their tumors exhibit poorer prognosis and survival rates. We have conducted TKM-PLK1 clinical trials with patients who have Hepatocellular Carcinoma (HCC), Gastrointestinal Neuroendocrine Tumors (GI-NET), and Adrenocortical Carcinoma (ACC) . More information on HCC, GI-NET, and ACC follows below.
Inhibition of PLK1 expression prevents the tumor cell from completing cell division, resulting in cell cycle arrest and death of the cancer cell. By using an RNAi approach and exploiting its naturally occurring mechanism of action, Arbutus can potentially overcome the limitations of other approaches and effectively silence PLK1.
We completed a Phase I/II clinical trial with TKM-PLK1 focused on patients with HCC. Arbutus intends to explore partnership opportunities to enable further study of TKM-PLK1 in HCC. This clinical study was an open-label, multi-center, study in patients with advanced HCC conducted in the US, Asia, and Canada. The trial was designed to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of the product. TKM-PLK1 was administered weekly with each four-week cycle consisting of three once-weekly doses followed by a rest week. The study included a total of 43 subjects (12 subjects in the dose escalation arm, followed by 31 subjects in the expansion cohort). The HCC efficacy endpoint of the study was tumor response rate. Some of the topline results from this study include:
Based on the encouraging results from the dose escalation portion and expansion cohort from our Phase I TKM-PLK1 clinical trial, we expanded into a Phase I/II clinical trial with TKM-PLK1, targeting two therapeutic indications: advanced GI-NET and ACC. This multi-center, single arm, open label study was designed to measure efficacy using Response Evaluation Criteria in Solid Tumors (RECIST) and tumor biomarkers for GI-NET patients, as well as to evaluate the safety, tolerability and pharmacokinetics of TKM-PLK1. TKM-PLK1 is administered weekly with each four-week cycle consisting of three once-weekly doses followed by a rest week.
The TKM-PLK1 Phase I/II study evaluated the safely, tolerability, and anti-tumor activity of TKM-PLK1 in a population of 63 subjects with advanced solid tumors, including 15 subjects with GI-NET, and 10 subjects with ACC. We provided an update on the Phase I/II GI-NET clinical study in October 2015 at the NANETS conference. The results from this study provide evidence of anti-tumor activity based on a decrease in tumor size from baseline for 50% of subjects, including a partial response (PR) (RECIST 1.1) reduction in tumor size of 61% in one of the subjects. Stable disease with duration of at least 4 cycles was observed for 77% of GI-NET subjects, with a maximum duration of response of 14 cycles. Therapy with TKM-PLK1 was received for up to 14 months and was generally well tolerated by the majority of subjects. The TKM-PLK1 GI-NET/ACC trial has concluded. In addition, a PR was achieved in one subject with ACC with almost complete resolution of target tumor observed on subsequent resection of tumor.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the third most common cause of cancer-related death worldwide. HCC is overwhelmingly related to chronic liver disease, particularly hepatitis B and hepatitis C. Patients with HCC usually are asymptomatic until later stages. The prognosis of HCC generally is very poor, with a median survival of six to 20 months and less than 5% of symptomatic patients surviving more than two years. 350,000 to one million cases of HCC occur every year worldwide. (source: www.clinicalkey.com)
Neuroendocrine tumors (NETs) refer to a group of unusual and complex cancers that affect neuroendocrine cells, with those arising in the gastrointestinal tract referred to as GI-NET. A Surveillance Epidemiology and End Results (SEER) database analysis demonstrates a dramatic five-fold increase in the incidence of neuroendocrine tumors from 1973 to 2004, and it is predicted to continue to rise at a faster rate than other malignant tumors.
Each year an estimated 8,000 people in the United States are diagnosed with a neuroendocrine tumor that starts in the gastrointestinal tract, which includes the stomach, intestine, appendix, colon, or rectum. There is a poor prognosis for advanced metastatic NETs, with survival rates for GI-NET ranging from five to 56 months. (source: American Cancer Society,www.neuroendocrinetumor.com)
Adrenocortical Carcinoma is a rare cancer that forms in the outer layer of tissue of the adrenal gland (a small organ on top of each kidney that makes steroid hormones, adrenaline, and noradrenaline to control heart rate, blood pressure, and other body functions). Adult adrenocortical carcinoma tumors are aggressive with a very poor prognosis. Between 60% - 70% of patients at the time of diagnosis are found to have stage III or IV disease. These patients have a survival rate of 40% or less, with a known recurrence rate between 70% - 90%. As adrenocortical carcinomas are so rare, there has only been limited prospective evaluation of treatment strategies. Very few, if any, universally accepted treatment standards have been identified. (source: American Cancer Society)