Geron Corporation announced enrolment of the first patient in a randomized phase 2 clinical trial of its telomerase inhibitor drug, imetelstat (GRN163L), in combination with paclitaxel (with or without bevacizumab) in patients with locally recurrent or metastatic breast cancer.

“We are pleased to initiate our second randomized phase 2 clinical trial of imetelstat,” said Stephen M. Kelsey, MD, Geron's executive vice president and chief medical officer, oncology. “We are applying what we learned in our phase 1 programme and leveraging our preclinical data that showed imetelstat's activity against cancer stem cells from a broad range of tumour types, including breast cancer.”

“We look forward to assessing imetelstat in this phase 2 clinical trial in breast cancer," said Kathy D. Miller, M.D., Associate Professor and Sheila D. Ward Scholar at the Indiana University Melvin and Bren Simon Cancer Centre and lead investigator of the trial. "The Phase 1 trial of imetelstat combined with paclitaxel and bevacizumab in locally recurrent or metastatic breast cancer showed an encouraging preliminary response rate, particularly in context of the reduced doses of chemotherapy that were administered during treatment cycles.”

The clinical trial is an open label, multi-centre, randomized phase 2 study of the efficacy and safety of treatment with imetelstat plus paclitaxel (with or without bevacizumab) versus paclitaxel (with or without bevacizumab) for patients with locally recurrent or metastatic breast cancer (MBC) who have not received chemotherapy or have received one non-taxane based chemotherapy for MBC.

The primary efficacy endpoint for this phase 2 trial is to estimate progression-free survival (PFS) for patients receiving imetelstat in addition to paclitaxel with or without bevacizumab. Secondary efficacy endpoints are objective response rate and clinical benefit of imetelstat when added to paclitaxel with or without bevacizumab. Safety and tolerability will also be assessed.

Patients eligible for the trial are randomly assigned in a 1:1 ratio to receive either imetelstat in addition to paclitaxel or paclitaxel only. Patients may receive bevacizumab based on the investigator?s decision and drug availability to the patient, but bevacizumab therapy is not required. Patients in the trial will be stratified based on two parameters: whether bevacizumab is used in combination with paclitaxel; and line of therapy (first line versus second line).

Imetelstat is administered at a dose of 300 mg/m2 on day one of a 21 day treatment cycle. Paclitaxel is administered at 90 mg/m2 on days one and eight and bevacizumab is administered at 15 mg/kg on day one of the 21 day cycle. The dose and dosing schedule of imetelstat was established during the Phase 1 clinical trial of imetelstat in combination with paclitaxel and bevacizumab in locally advanced or MBC. Enrollment is estimated at 150 patients at approximately 80 clinical sites across the US and Canada.

Results from phase 1 clinical trials using imetelstat have documented imetelstat's safety profile. Data from preclinical studies have demonstrated imetelstat's activity against bulk breast cancer cells as well as breast cancer stem cells.

The prior phase 1 clinical trial testing the safety of imetelstat in combination with paclitaxel and bevacizumab in patients with locally recurrent or MBC showed an objective response rate of 53.8% (95% confidence interval: 28.7% to 77.6%) despite reduced doses of paclitaxel and/or imetelstat in the majority of patients. Median response duration was 21.7 weeks (7.3 to 48.3 weeks). These data provided the rationale for conducting the current phase 2 study.

The phase 2 dose and dosing schedule of 300 mg/m2 of imetelstat on day one of a 21 day treatment cycle was selected to achieve extended exposures to imetelstat that exceed the levels that have been associated with efficacy in xenograft models of human cancers, while minimizing haematological toxicities.

In addition, previously published in vitro studies showed that imetelstat synergizes with paclitaxel in inhibiting the growth of breast cancer cells. Synergy between imetelstat and bevacizumab was demonstrated in a xenograft model of human breast cancer.

Cancer stem cells are rare populations of malignant cells with the capacity for endless self-renewal because of high telomerase activity. Cancer stem cells are believed to be responsible for tumour growth, recurrence and metastasis. Their resistance to chemotherapy and conventional anti-cancer agents make them important targets for novel therapies. By inhibiting breast cancer stem cells, the use of imetelstat in combination with standard debulking chemotherapy, such as paclitaxel, may result in a more durable tumour response than with chemotherapy alone.

Breast cancer stem cell function was inhibited by imetelstat in preclinical models. Imetelstat treatment of breast cancer cells in vitro led to inhibition of self-renewal capacity and cell death. In animal models of human breast cancer, imetelstat treatment reduced the formation of new tumours by 50%. These data were published by Geron scientists and collaborators in the November 15, 2010 issue of Cancer Research.

Breast cancer is the most frequent cancer affecting women worldwide and remains the leading cause of cancer death among women. In 2007, an estimated 1.3 million new cases of breast cancer were diagnosed and an estimated 468,000 breast cancer-related deaths occurred. The highest incidence of breast cancer is in the United States, where, in 2010, an estimated 207,090 new cases will be diagnosed in women and 1,940 in men, and an estimated 40,230 people will die of the disease (American Cancer Society, Cancer Facts and Figures 2010).

Telomerase is a critical and broadly applicable tumour target. The enzyme is expressed in a wide range of malignant tumours, and its activity is essential for the indefinite replicative capacity of cancer that enables malignant cell growth. Telomerase has now also been shown to be a target of cancer stem cells. Telomerase is absent or expressed only transiently at low levels in most normal adult tissues.

Imetelstat is a lipidated short chain oligonucleotide that binds with high affinity and specificity to the catalytic site of telomerase, resulting in competitive inhibition of enzyme activity. Proprietary manufacturing chemistry and the addition of a 5' lipid chain have enabled the molecule to penetrate cells and tissues throughout the body. Imetelstat has demonstrated anti-tumour effects in a wide range of preclinical xenograft models of human solid and haematological tumours, and potent activity against cancer stem cells derived from primary patient samples or cancer cell lines from multiple tumour types.

Imetelstat has been tested in six Geron-sponsored Phase 1 clinical trials at 22 US medical centres treating over 180 patients examining the safety, tolerability, pharmacokinetics and pharma co-dynamics of the drug, alone or in combination with other standard therapies, in patients with different haematological and solid tumours.

A randomized phase 2 clinical trial of imetelstat has been initiated in non-small cell lung cancer. Two single arm Phase 2 clinical trials are planned in multiple myeloma and essential thrombocythemia. All are malignancies in which cancer stem cells are believed to play an important role in relapse after standard therapy.

Geron is developing first-in-class biopharmaceuticals for the treatment of cancer and chronic degenerative diseases, including spinal cord injury, heart failure and diabetes. The company is advancing an anti-cancer drug and a cancer vaccine that target the enzyme telomerase through multiple Phase 2 clinical trials in different cancers.