ChemGenex anti-cancer drug set for Phase II trial

Few expect much of a new and unproven cancer drug undergoing its first test in Phase I clinical trial to determine its safety and tolerability -- so when it exhibits a clear therapeutic benefit in seriously ill cancer patients, people become excited.

Last June, ChemGenex Pharmaceuticals (ASX:CXS), based in Geelong, Victoria, and Menlo Park, California, was entitled to be excited with the results of an unusual Phase I trial of its anti-cancer drug Quinamed (amonafide dihydrochloride).

Conducted at two centres -- the Sarah Cannon Cancer Centre in San Antonio, Texas, and Tennessee Oncology in Nashville, Tennessee -- the trial involved 32 volunteer patients with advanced lung, ovarian, prostate, breast, colon and other tumours.

The diversity of the tumours, and the fact that all had become refractory to standard chemotherapy drugs, made it the toughest possible test for any new drug.

Dose-ranging studies are typically performed in Phase II trials, to establish an optimal dose, and dosing regimen, for the new drug. But from the outset, ChemGenex pursued the personal touch, using a simple genetic test to tailor the Quinamed dose to each volunteer.

On the basis of the genetic test, patients were assigned to high- and lower-dose treatment groups. It accurately identified those who could tolerate a higher dose that would maximise the prospect of killing their tumours, without toxic side-effects. The other patients were given a lower dose to minimise side-effects, which may be so severe that treatment must be discontinued.

This week, ChemGenex announced it will begin recruiting patients with prostate, breast, ovarian or lung cancer for a Phase II clinical trial of Quinamed, with a focus on prostate cancer patients.

In the Phase I trial, Quinamed showed promising anti-tumour activity against all these types of cancers, but ChemGenex has decided to focus in prostate cancer because of the unmet need for new drugs to treat this most common male cancer.

ChemGenex president Dr Dennis Brown said the company believed Quinamed had "enormous potential" for treating a range of solid tumour types.

The Phase II trial will also be conducted at same cancer centres in Texas and Kentucky, and will involve research teams from the University of Texas Health Science Centre in San Antonio, and the University of Louisville, in Kentucky.

ChemGenex vice-president Dr James Campbell said the test used to assign patients to the two different dosage groups identified high- and low-activity alleles of the N-acetyltransferase 2 (NAT2) gene, whose enzyme that performs an acetylation reaction on amonafide hydrochloride.

Both the drug and its acetylated metabolite are toxic to cancerous cells, but the toxic side-effects of the drug are solely due to the metabolite, so patients who are 'slow acetylators' can tolerate a high dose without suffering side-effects.

Quinamed is a 'rebirthed' drug. In the early 1990s, the National Cancer Institutes in the US experimented with amonafide monohydrochloride as anti-tumour drugs in about 700 cancer patients in Phase I/II trials, with promising results. The responses were most pronounced in patients with advanced, hormone-dependent tumours of the breast (18-25 per cent) and prostate (12 per cent).

However, about 400 of the 700 patients developed severe side-effects, including abnormal white-cell counts, anaemia, and blood-clotting, and researchers concluded the drug was too toxic for general use.

It is now clear that 'rapid acetylator' patients were most severely affected; these patients can now be identified, and given a lower dose to minimise toxicity.

Moreover, the company says it appears that patients are likely to derive greater therapeutic benefits from a single, high dose of Quinamed once every three to four weeks, rather than a five-times-a-day, low-dose regimen.

Campbell said the new understanding of how individual patients metabolise the drug represented a substantial advance towards the era of personalized medicine. "We can use the patient's genotype to predict the benefit, and to maximise the tolerable dose," he said.

Quinamed is a topoisomerase-II inhibitor, that disrupts the cell-replication cycle. It blocks tumour growth by shutting down cancerous cells and inducing apoptosis.

Campbell said ChemGenex would pitch the drug at the refractory cancer market, because it presented a greater commercial opportunity. But there was no reason to believe Quinamed would not be equally effective in treating early-stage cancers.