Phase II trials of the first second-generation antisense cancer drug to be used in patients soon to be underway

Phase II trials of the first second-generation antisense cancer drug to be used in patients are soon to be underway in the wake of a successful Phase I study, which has demonstrated that the new drug blocks its target gene in exactly the way it is designed to do.

In the Phase I study the drug – OGX-011 – inhibited the production of clusterin, a protein that protects cell survival and is widely distributed in body tissue. Clusterin is implicated in a range of activities, including apoptosis (programmed cell death). When it is over-produced, as it is many major cancers, clusterin can stop cancer cells from dying and counters the effectiveness of chemotherapy, hormone treatment and radiotherapy.

Dr. Kim Chi, assistant professor of medicine at the University of British Columbia and medical oncologist at the BC Cancer Agency in Canada, told the EORTC-NCI-AACR[1] Symposium on Molecular Targets and Cancer Therapeutics in Geneva today (Wednesday 29 September) that the Phase I trial was unique in that the clinical research team was able to demonstrate that the target clusterin was inhibited by OGX-011 in patients’ cancers in a dose dependent way.

"This means that the drug is doing what it is supposed to be doing – something that we can’t always say about targeted therapeutics – and we were able to identify a biologically active dose," he said.

Antisense drugs work by inhibiting the production of a protein from a specifically targeted gene. As a second-generation antisense drug, OGX-011 is an advance on earlier ones in that the molecules have a longer tissue half life and are potentially more potent. Pre-clinical studies had shown that blocking the production of clusterin with OGX-011 impairs a cancer cell’s survival mechanism and enhances the effectiveness of standard chemotherapy, radiation and hormone therapy.

Twenty-five patients with localised prostate cancer that was to be removed by surgery were given escalating doses in the Phase I trial, which was coordinated by the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) and funded by the U.S. Department of Defense Army Medical Research and Material Command Prostate Cancer Research Program.

Two conventional prostate cancer hormone therapies, buserelin and flutamide, were given alongside OGX-011. Post surgery analysis of the patients’ prostate cancers showed that the higher the dose of OGX-011 given, the lower clusterin levels were within the cancer cells. At the highest dose given of 640mg the clusterin messenger RNA (mRNA) was down to a mean 8% level as compared to historical controls. The drug was well tolerated by patients.

Said Dr. Chi: "We designed the Phase I trial in such a way that we could identify the biologically active dose in the tumour tissue. Being able to identify the active dose in this way gives us confidence that the Phase II dose of the drug that we have selected is the appropriate one. The Phase II studies are of a more conventional design, looking at response rates from OGX-011 plus standard chemotherapy in patients with metastatic hormone refractory prostate, breast and lung cancer. Phase II breast and prostate studies will begin near the end of the year, and a Phase I lung cancer trial started this month. The trials will recruit around 40 to 50 patients each and accrual should be complete in around six to 12 months, with results soon after that.

"Of course, it is still early days, but we are optimistic. The drug worked well in animal models and we hope that we will be able to see benefits akin to some of the other targeted therapies now in use."