Data was presented on patients with locally recurrent or metastatic breast cancer that were given imetelstat by 2 hour intravenous infusions on days 1, 8 and 15 of 28 day treatment cycles. The preliminary confirmed overall response rate was 53.8% (95% confidence interval: 28.7% to 77.6%) based on investigator assessment of disease status using the Response Evaluation Criteria in Solid Tumors.
This data from the clinical trial of imetelstat (GRN163L), Geron’s telomerase inhibitor drug, in combination with paclitaxel and bevacizumab in patients with breast cancer was presented at the 2010 American Society of Clinical Oncology (OTC:ASCO) annual meeting in Chicago.
Telomerase is a critical and broadly applicable tumor target. The enzyme is expressed in a wide range of malignant tumors, and its activity is essential for the indefinite replicative capacity of cancer that enables malignant cell growth. Telomerase is absent or expressed only transiently at low levels in most normal adult tissues. Imetelstat is a 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-tumor effects in a wide range of preclinical hematological and solid tumor models.
Preclinical studies have also demonstrated that imetelstat can inhibit clonogenic growth of both primary patient samples and subpopulations from cell lines enriched for cancer stem cells from multiple tumor types. These subpopulations show resistance to several conventional chemotherapeutic agents. Cancer stem cells capable of clonogenic growth may play an important role in the rapid re-growth of tumors after initial reduction by standard treatments.
Infusions of imetelstat were generally well tolerated and acute dose limiting toxicities were not observed. Neutropenia (low neutrophils) and/or thrombocytopenia (low platelets) in later treatment cycles led to reductions in the dose of imetelstat and/or paclitaxel in 12 (85.7%) patients. Alternative dosing schedules are being evaluated in additional patients to further increase exposure to imetelstat and to enable administration of full doses of standard therapy while minimizing hematological toxicities.
A randomized Phase 2 clinical trial of imetelstat in patients with metastatic breast cancer is now planned for Q4/10. The trial plans to assess the effect on progression-free survival of adding imetelstat to paclitaxel and bevacizumab as first line therapy. The trial will recruit approximately 150 patients from up to 50 medical centers in the US.
Imetelstat has been tested in 6 Geron-sponsored Phase 1 clinical trials at 22 US medical centers treating over 180 patients examining the safety, tolerability, pharmacokinetics and pharmacodynamics of the drug, alone or in combination with other standard therapies, in patients with different hematological and solid tumors. 4 of the trials have completed patient enrollment. 2 randomized Phase 2 clinical trials of imetelstat will start this year in non-small cell lung and breast cancer, and 2 single arm Phase 2 clinical trials will begin in multiple myeloma and essential thrombocythemia – all malignancies in which cancer stem cells have been shown to play an important role in relapse after standard therapy.