Ovarian

Chemotherapy-resistance is a severe problem for ovarian cancer patients. About 70% of diagnosed patients will fail first-line therapy and require second-line therapy within the first two years of being diagnosed.  This is because they are either chemotherapy-resistant from the outset or suffer relapse within two years after diagnosis. Unfortunately, there are no broadly effective second-line treatment regimens for these patients as there is significant resistance to popular second-line therapies.

The World Health Organization’s GLOBOCAN 2008 reports that there were about 21,600 new cases of ovarian cancer in the US in 2008 and this number is expected to increase to about 26,500 by 2020. Given these statistics, by 2020 about 19,000 women in the US and nearly 90,000 worldwide will require second-line therapy, the focus of our initial work. Ovarian cancer is a growing problem.

Platinum-based chemotherapy, before or after surgery, is first-line standard of care treatment for ovarian cancer patients.  About 20% of women will not respond to first-line treatment and will need second-line therapy within a few months of surgery. Of the 80% that initially respond to platinum drugs more than 50% will relapse within two years. In total, over two-thirds of women diagnosed with ovarian cancer are likely to require second-line therapy. DOXIL® is the most effective choice for second-line therapy.  However, less than 20% of women will show any response to DOXIL with only about 4% being complete responses. While single agent DOXIL therapy has historically been the second-line therapy of choice, many recent development efforts are focusing on development of multi-agent therapies combining two or more cytotoxic drugs into one regimen. Unfortunately, multi-agent therapies, such as the recently announced DOXIL/Avastin combination may be of limited usefulness due to increased toxicity. It is clear that a new form of treatment is critical.

Ovarian cancer has been the focus of most of RTI’s initial preclinical work.  We have demonstrated in multiple in vitro studies with a number of ovarian cancer cell lines, that RTI-79 materially enhances the efficacy of Doxorubicin.  We have also shown that this effect can be translated to animal models and have seen complete arrestment of tumor growth in repeated xenograft models using a variety of drug-resistant ovarian cancer cell lines.  In addition to demonstrated anti-tumor activity, in-life observation and histology have shown no overt toxicity due to RTI-79.

Xenograft using nude mice implanted with NCI/ADR-RES cells. Study started when tumor nodules reached 90 mm3 in size. DOXIL or saline (control) were administered every seven days for six cycles. One DOXIL group also received RTI-79 by oral gavage 24 and 48 hours after DOXIL administration. No-treatment mice received vehicle. Treated mice were treated with 7 mg/kg DOXIL IV. Mice receiving RTI-79 received 25 mg/kg by oral gavage 24 and 48 hours after each DOXIL administration. After 41 days (Six DOXIL cycles) the tumor volume in the RTI-79 treated mice was 66% less than the tumor volume for mice receiving only DOXIL.

Xenograft using nude mice implanted with NCI/ADR-RES cells. Study started when tumor nodules reached 90 mm3 in size. DOXIL or saline (control) were administered every seven days for six cycles. One DOXIL group also received RTI-79 by oral gavage 24 and 48 hours after DOXIL administration. No-treatment mice received vehicle. Treated mice were treated with 7 mg/kg DOXIL IV. Mice receiving RTI-79 received 25 mg/kg by oral gavage 24 and 48 hours after each DOXIL administration. After 41 days (Six DOXIL cycles) the tumor volume in the RTI-79 treated mice was 66% less than the tumor volume for mice receiving only DOXIL.

RTI is in the planning process for a Phase I study in second-line ovarian cancer care and expects to start the study in early 2014.