CuraGen Corporation and TopoTarget have announced the initiation of patient dosing in a phase II clinical trial evaluating the antitumour activity of intravenous PXD101, a small molecule histone deacetylase (HDAC) inhibitor, for the treatment of ovarian cancer. This trial is being sponsored by the National Cancer Institute (NCI) under a clinical trials agreement with CuraGen for PXD101.
The phase II trial is an open-label study being led by Dr. Amit Oza at Princess Margaret Hospital in Toronto, Canada. Patients with either advanced platinum resistant ovarian tumours or micropapillary/borderline low malignant potential (LMP) ovarian carcinoma may be enrolled for treatment with PXD101. Patients may have received no more than three prior lines of therapy. Upon enrollment, patients will receive intravenous PXD101 daily for five days in three-week cycles until disease progression. The primary endpoint for the study is the determination of objective disease response, as evaluated by the Recist criteria. Secondary endpoints include evaluation of safety and tolerability of PXD101, stable disease rates, duration of response, progression-free survival, as well as median and overall survival. Up to 62 patients at sites across Canada and the US will be enrolled into the study.
"Hypoacetylation appears to play an important role in silencing the expression of genes, including tumour supressors that regulate cell survival, proliferation, and differentiation," commented Dr. Oza. "The ability to reactivate tumour suppressor gene(s), together with the new published preclinical data, provides an excellent rationale to evaluate the role of the histone deacetylase inhibitor, PXD101 in treating two different populations of patients with ovarian cancer, those with advanced refractory tumours and those patients with micropapillary and borderline, or low malignant potential, tumours."
"This NCI-sponsored trial evaluating PXD101 monotherapy complements our ongoing phase Ib/II clinical trial, which is studying intravenous PXD101 in combination with paclitaxel and carboplatin for the treatment of advanced ovarian cancer. Both of these trials will generate data that will allow us to better understand the role of PXD101 in the treatment of this disease, and provide results to enable a decision regarding registrational development for ovarian cancer," stated Dr. Timothy Shannon, executive vice president of research and development and chief medical officer at CuraGen Corporation.
Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of HDACs in ovarian tumour 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.
In an article published in the August 2006 issue of molecular cancer therapeutics, CuraGen and TopoTarget scientists also reported new preclinical data for PXD101 that is relevant to ovarian cancer. Data in the study demonstrates that PXD101 has growth-inhibitory activity as mono or combo therapy on multidrug resistant ovarian cancer lines, as well as on primary clinical cancer specimens grown in culture. Furthermore, PXD101 was found to have anti-tumour activity in animal models of ovarian cancer.
Ovarian cancer causes a significant burden of disease accounting for 5 per cent of all cancer deaths and is the fifth leading cause of death in women in Canada, the US, and Europe. Despite the efficacy of the combination of platinum/paclitaxel chemotherapy in advanced ovarian carcinoma, more than 75per cent of patients with stage III/IV disease ultimately relapse and die from their disease. Recurrent ovarian carcinoma is incurable and is treated with platinum-based therapy when the treatment free interval following initial therapy is longer than 6 months. Patients who have resistant ovarian cancer, whose disease does not respond to first line carboplatin and paclitaxel have a dire prognosis and the likelihood of response to further chemotherapy is very low (approximately 10 per cent). There is therefore a need to develop new agents for the treatment of patients with this malignancy.
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, cis-retinoic acid, azacitidine 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 and B-cell lymphomas, AML, mesothelioma, liver, colorectal, 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 is sponsoring 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 preclinical and nonclinical studies on PXD101 in order to better understand its anti-tumour activity and to provide supporting information for clinical trials.