CuraGen and TopoTarget Announce Initiation of NCI-sponsored Phase II Clinical Trial with PXD101 for Mesothelioma
June 20, 2006
BRANFORD, Conn., CuraGen Corporation and TopoTarget A/S announced today the initiation of patient dosing in a Phase II clinical trial evaluating the activity of PXD101, a small molecule histone deacetylase (HDAC) inhibitor, for the treatment of mesothelioma. This trial is being sponsored by the National Cancer Institute (NCI) under a Clinical Trials Agreement with CuraGen for the clinical development of PXD101.
The Phase II clinical trial is an open-label study being led by Suresh Ramalingam, M.D., Assistant Professor of Medicine at the University of Pittsburgh School of Medicine in Pittsburgh, PA. Patients with unresectable malignant pleural mesothelioma, who have failed one prior line of chemotherapy, will be enrolled and receive PXD101 by intravenous infusion every three weeks. The primary endpoint for the study is response rate, with secondary endpoints evaluating safety and measuring both the time to treatment failure and survival. A total of approximately 37 patients are expected to be enrolled into this study at multiple sites across the United States.
"A significant amount of preclinical research suggests that HDAC inhibitors, including PXD101, alter the regulation of many genes, resulting in growth inhibition of human mesothelioma cells. Given the ability of HDAC inhibitors to down-regulate genes such as BCL-XL and VEGF and up-regulate cell-cycle regulating genes, including p21, we are excited to begin evaluating PXD101 as a potential treatment for this type of cancer," stated Dr. Ramalingam. "There are no proven treatment options beyond the first-line chemotherapy regimen for mesothelioma, highlighting the importance of evaluating promising therapeutics like PXD101 for this patient population."
Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of HDACs in mesothelioma tumor cells from patients enrolled in this trial. Evaluation of the genes regulating proliferation and apoptosis (programmed cell death), as well as acetylation of histone and non-histone proteins, will be performed.
As many as 3,000 new cases of malignant mesothelioma are expected to be diagnosed in the United States in 2006. Mesothelioma is a type of cancer arising from the cells, known as mesothelium, with the majority of cancers beginning in the chest cavity. The incidence of mesothelioma increases with age and is rarely diagnosed in patients under 55 years old. Although environmental exposure to certain chemicals and radiation are believed to play a role in the development of mesothelioma, exposure to asbestos is believed to be the main cause of mesothelioma. The five-year survival rate for mesothelioma is approximately 10%, with an average survival of one to two years following diagnosis.
PXD101 is a promising small molecule HDAC inhibitor being investigated for its role in the treatment of a wide range of solid and hematologic malignancies either as a single-agent, or in combination with other active anti-cancer agents, including 5-fluorouracil (5-FU), carboplatin, paclitaxel and Velcade® (bortezomib) for Injection. HDAC inhibitors represent a new mechanistic class of anti-cancer therapeutics that target HDAC enzymes and have been shown to: arrest growth of cancer cells (including drug resistant subtypes); induce apoptosis, or programmed cell death; promote differentiation; inhibit angiogenesis; and sensitize cancer cells to overcome drug resistance when used in combination with other anti-cancer agents.
PXD101 is currently being evaluated in multiple clinical trials as a
potential treatment for multiple myeloma, T-cell lymphoma, and colorectal
and ovarian cancers, either alone or in combination with anti-cancer therapies.
In August 2004, CuraGen signed a Clinical Trials Agreement with the NCI
under which the NCI will sponsor several clinical trials to investigate
PXD101 for the treatment of various cancers, both as a single-agent and
in combination chemotherapy regimens. In May 2005, TopoTarget announced
the signing of a Cooperative Research and Development Agreement (CRADA)
with the NCI to conduct pre-clinical and non-clinical studies on PXD101
in order to better understand its anti-tumor activity and to provide supporting
information for clinical trials.