A drug for patients with Gleevec-resistant chronic myeloid leukaemia (CML) has passed Phase I clinical trials and has just entered Phase II.

A drug offering hope to patients with Gleevec-resistant chronic myeloid leukaemia (CML) has passed Phase I clinical trials with flying colours, claim researchers, and has just entered Phase II.

The drug, AMN107, was developed to provide an alternative for patients resistant to the standard therapy, Gleevec (imatinib). Phase I trials tested only Gleevec-resistant patients but AMN107 will also be tested as a frontline therapy. Researchers hope that as part of a combination therapy, AMN107 may one day provide a cure for CML - a disease that affects one in 100 000 people worldwide each year.

Gleevec is effective against CML but most patients develop resistance to it over time as the disease mutates. AMN107, a kinase inhibitor, works similarly to Gleevec. By selectively deactivating the abnormal protein that causes the rapid growth of cancerous cells, the leukaemia can be stopped.

Laboratory and pre-clinical trials show that AMN107 binds more strongly to the abnormal protein than does Gleevec, and is less toxic. The drug is active against 15 of the 16 mutations of the disease protein that are resistant to Gleevec. The study is led by Francis Giles, professor of medicine at the University of Texas M D Anderson Cancer Center, US, along with researchers at the University of Frankfurt, Germany.

Giles has been involved in the project for two years and believes AMN107 will perform well as a frontline therapy. The Phase II clinical trial comprises six parallel studies expected to involve more than 500 patients. AMN107 will be evaluated against all stages of CML and some other cancers.

The Phase I trial proved so successful that the study was extended to include more patients. Originally, only patients with advanced CML were allowed to take part but chronic, or early-stage, patients have now also entered. Unusually, the Phase I trial also used a new treatment protocol. As the trial progressed, the drug doses were steadily increased to optimise patient responses.

About 90 per cent of chronic-stage patients showed a marked improvement in their condition after just two weeks. Response rates for patients with advanced CML are 55 per cent. ’The drug works very well indeed.The latest results are phenomenal,’ said Giles.

Possibilities also exist to treat the remaining mutant protein that does not respond to AMN107. Combining AMN107 with another drug that is active against the remaining mutation could offer a cure, claims Giles.

There are several drugs that could work synergistically with AMN107, he says. Trials of such combinations are expected by the end of the year. One such drug is Zarnestra (tipifarnib). Zarnestra, a farnesyl transferase inhibitor, works differently to AMN107 and may be effective against the final CML mutation.

If effective, a combination of drugs could be tailored to provide a synergistic response for patients. Zarnestra was considered in May by the Food and Drug Administration but was rejected for accelerated approval and now requires results from Phase III trials. So combination trials will have to wait.

John Goldman at the haematology branch of the National Heart, Lung, and Blood Institute, US, says that the efficacy of AMN107 against disease mutations still needs to be confirmed along with proof that AMN107 outperforms Gleevec. Nevertheless, he is impressed by the study. ’This whole area is very exciting and has already transformed research strategies for developing active new anti-cancer drugs,’ he said. Vikki Allen