Pivotal pancreatic cancer trial given EMEA approval

The endorsement ensures Austrianova is on schedule to develop the first cell therapy medicinal product for a cancer with a mean life expectancy of six months from the time of diagnosis and with a five-year survival rate of less than 5 per cent (compared to 62 per cent for all cancers).

The two-armed phase III trial study intends to evaluate the survival advantage for patients with inoperable pancreatic carcinoma. The tumours will be pre-treated with encapsulated, cytochrome P450/2B1 expressing cells that convert ifosfamide into tumour toxic metabolites.

The trial is scheduled to commence in the second half of 2005 with around 200 patients from a number of European clinical centres being involved. If the endpoints are achieved, market authorization may be a reality in 2008.

Brian Salmons, managing partner for science and technology at Austrianova​ told DrugResearcher.com​: "NovaCaps, consists of genetically modified cells that overexpress cytochrome P450."​

"The cells are encapsulated in polymers of cellulose sulphate and implanted near the tumour. Subsequent treatment with low doses of ifosfamide results in the toxic metabolites being produced where they are required i.e. near the tumour."​

The encapsulated cells focus specifically on the tumour, eliminating the problem of ifosfamide concentrations. An additional advantage is because low doses of ifosfamide are used, there are few if any side effects. In principle, similar strategies could be used for the treatment of any locally occurring solid tumour.

NovaCaps, which was designated an Orphan Drug Medicinal Product by the EMEA last June becomes the first orphan drug to come under a new EMEA category of medicinal product (i.e. an Advanced Therapy Medicinal Product).

Salmons said that Austrianova were currently investigating a number of commercial interests involving the Novacaps therapy with pharmaceutical companies that have expressed an interest in the technology.

Whilst currently the best option, Gemcitabine (Gemzar) is not as effective as it could be due to its method of delivery and lack of precision in targeting the pancreas. This results in a median survival of approximately six months. However, it should be noted that even the best combinational treatments still only result in median survival of 1 year at the most.

Cytochrome P450 enzymes in the liver activate the chemotherapeutic to a tumour toxic form. These active forms have a very short half-life and are distributed by the circulatory system throughout the body where they attack all dividing cells. This leads to the well-known side effects along with the anti-tumour activity. The pancreas is the last organ to be reached from the liver via the circulatory system and so the activated, anti-tumour form is already at relatively low concentrations when it reaches pancreatic tumours.

Pancreatic cancer is the eighth most frequent solid tumour worldwide, it is the fourth most frequent cause of cancer related deaths. This is due to the lack of effective treatment options available at present for the pancreatic cancer patient. Approximately 45,000 new cases of pancreatic cancer occur each year in Europe. The majority of cases of pancreatic cancer are nonresectable and the nonresectable form has a very poor prognosis.

Current and future treatments​

Until the late 90's, 5 flurouracil was often used to treat pancreatic cancer. In the late 90's, the current standard treatment, gemzar, a chemotherapeutic agent from Eli Lilly, was introduced, largely on the basis of an analgesic effect since the median survival was increased by just over 4 weeks to 25 weeks. Pancreatic cancer represents a clear, unmet medical need which has spurred on efforts to develop new treatments for this cancer.

A number of the strategies are already in clinical trials but only a few seem really promising and there is a notable lack of Phase III trials that are now urgently needed to identify the way forward. Among the most promising novel strategies are the use of topoisomerase inhibitors such as the camptothecins.

Nucleoside analogues resulting in chain termination and polymerase inhibition such as troxacitabine, as well as instillation of genetically modified cells show potential too. This technique is able to locally convert the classic chemotherapeutic ifosfamide to its active alkylating metabolites while minimising systemic side effects that have hindered current treatments.

One novel form of treatment causing waves is the use of monoclonal antibodies (mAb) which have already been approved and used in the clinic to treat HER-2-expressing breast cancers (trastuzumab, Herceptin) and CD20 expressing non-Hodgkin¡¦s lymphomas (rituximab, Rituxan). Binding of the mAb to the target, tumour-associated, protein results in recruitment of the body¡¦s natural defences to attack and kill the marked B cells. HER-2 is also overexpressed in less thanƒn 20 percent of pancreatic tumours making this a potential off-label use of trastuzumab.

Genentech's​ Avastin is a recombinant humanised antibody to that binds to and inhibits VEGF. It was granted its first approval - by the US Food and Drug Administration (FDA) - on February 26. It is indicated for use in combination with intravenous 5-fluorouracil-based chemotherapy as a treatment for first-line metastatic colorectal cancer.

These strategies, in combination with each other or with gemcitabine, could enable patients to survive beyond one year. It is likely that the short-term target will be to extend life expectancy well past the one-year mark. The outlook for pancreatic cancer appears promising with current research potentially translating into efficacious therapies.