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Belinostat (PXD 101) is a novel HDAC inhibitor in late stage clinical development with more than 600 patients treated. Belinostat is well tolerated which allows combination with traditional chemotherapy without causing further bone marrow toxicity. In pre-clinical trials belinostat has shown to be effective against multiple cancers by inhibiting cell proliferation (the cancer is prevented from growing) and inducing programmed cell death (“apoptosis”) in tumour cells (the tumour cells are forced to self-destruct). Belinostat has been tested in a number of Phase I/II clinical trials in haematological cancers and solid tumours. Data from these trials has provided proof for the anti-tumour effect of belinostat as monotherapy in two types of T-cell lymphomas (PTCL and CTCL) and in thymoma, and have demonstrated that belinostat has beneficial effects in combination with other anti-cancer drugs for the treatment of multiple types of cancer including ovarian cancer, CUP, multiple myeloma, acute myeloid leukaemia and bladder cancer.
The high number of clinical trials allows the evaluation of belinostat in several combinations and tumour settings. TopoTarget has already obtained proof of concept in some of these clinical trials. However there is continuing data emerging, albeit preliminary and unconfirmed, which lends support to the contention that belinostat has the potential to be used for other indications, including as monotherapy in thymoma, hepatocellular cancer and in continuous intravenous infusion (CIV) in leukaemia as well as oral belinostat in certain specific B-cell lymphomas.
Drug resistance is the major obstacle in cancer treatment, and modern effective cancer therapy attempts to fight resistance by administering combinations of drugs that target cancer in different ways. However, the resistance problem is far from solved, and it is therefore important to find new cancer drugs that hit new targets.
Cancer drugs can be divided into two groups identified by the specificity of their interaction with targets on the outside or within cancer cells. Some drugs interact with a single target, e.g. the herceptin interaction with the her2neu receptor, and their development is solely directed at tumours expressing this target. Many other modern drugs are multi-targeted, e.g. drugs such as sorafenib, sunitinib and belinostat, and their use is not limited to one single target. From cancer models it is possible to find strong indications on how to optimise the use of such multi-targeted drugs. However such data can only provide guidance and proof is ultimately provided by clinical trials in patients. Development of several drugs has been stopped at this stage because of toxicity in man and/or because effective dose levels cannot be achieved. Fortunately, belinostat has a very low toxicity and already at the lowest doses tested we could see from markers that the drug hits the cancer cells where we expect it to in patients. As belinostat has limited toxicity in patients, the drug can be investigated in high doses not only alone, but also in almost all successful drug combinations. In the Company’s tumor models, belinostat is active in cancer cells with resistance to existing therapies and belinostat adds substantial treatment value to several important drug combinations.
The continued support from the National Cancer Institute in the U.S (NCI) has helped the Company to build a comprehensive programme which has identified the optimal development route for belinostat. TopoTarget’s development of belinostat is planned in collaboration with NCI, and all trials are born from laboratory data showing the most favourable methods of use and combinations. Belinostat has received and receives substantial and pivotal financial and scientific support form NCI.
Based on the available data, TopoTarget believes that belinostat has the potential to become the “best in class” HDAC inhibitor. The efficacy of belinostat noted in ongoing clinical trials is likely to be linked to the high blood concentrations of drug achieved using intravenous (“IV”) dosing. This high blood concentration may not be attainable for “oral only” HDAC inhibitors. Belinostat also exhibits a favourable safety profile compared to other HDAC inhibitors at a similar stage of develop-ment. For example, only a few cases of thrombocytopenia have been noted (reduced risk of bleeding), and there have been no reports of pericarditis (reduced risk of cardiac side-effects). This allows for a combination of belinostat at full dose with a full dose of chemotherapy, thereby maximising clinical effect.
Belinostat is also the only HDAC inhibitor in clinical development with the possibility of IV dosing in the form of continuous intravenous infusion (“CIV”) and oral administration routes, which provides additional flexibility in the clinical setting.
Registrational program
TopoTarget initiated its pivotal study in PTCL in December 2008. Registration opportunities also exist in other haematological malignancies including AML and multiple myeloma. Preliminary discussions with relevant regulatory authorities have been conducted for a number of indications.
TopoTarget is currently evaluating multiple opportunities for other registrational programs including the possibilities based on the compelling data in ovarian cancer in combination treatment (including “BelCaP”). The carboplatin/paclitaxel combination represents standard of care for a number of significant cancer indications, including non small cell lung cancer (“NSCLC”), cancer of unknown primary (“CUP”), ovarian cancer and bladder cancer, and these indications could therefore represent registration opportunities for belinostat as the BelCaP combination. A direct step in taking advantage of the BelCaP option is to obtain proof-of-concept in a randomised study. TopoTarget initiated a randomised Phase II trial in CUP in Q1 2009. Positive data in this trial would be the basis for initiation of pivotal trials in CUP and NSCLC together representing more than 10% of all cancers. Simultaneously TopoTarget will explore the opportunities in ovarian cancer especially in platinum resistant disease.
Evolving data from studies both with intravenously and orally administered belinostat indicate registration opportunities in further large solid tumor indications, e.g. colorectal, pancreatic, and hepatocellular (liver) cancer. A development including a patient selection strategy in colorectal and/or pancreatic cancer building on the encouraging outcome of the Phase I/II dose escalation trial of belinostat in combination with 5-fluorouracil (“BelFU”), also supported by the long treatment durations seen in heavily pre-treated patients with these indications in the ongoing Phase I monotherapy trial with oral belinostat, would be a logical step. Likewise, a development in hepatocellular carcinoma building on evolving clinical data from belinostat monotherapy studies, and pre-clinical data showing strong synergy for efficacy when combining belinostat with sorafenib (Nexavar; registered as first line treatment for hepatocellular carcinoma), indicates an interesting registration opportunity.
In the ongoing Phase I monotherapy trial with oral belinostat, treatment duration on belinostat given as 6th line therapy has been similar to treatment durations on sorafenib and erlotinib administered in earlier lines of therapy, and in the ongoing Phase II portion of a NCI-sponsored belinostat monotherapy study in patients with unresectable hepatocellular carcinoma it appears that the high dose of belinostat administered (intravenous 1400 mg/m2/day, days 1-5 every 3rd week), except stabilisation of disease, might lead to objective tumor response (preliminary information; timing of data presentation to be determined by NCI). Useful links :
Therapeutic Areas
- Solid Tumours
Science
- Histone Deacetylase (HDAC)
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