Proteosome inhibitors, notably bortezomib (Takeda's Velcade), can be used to treat blood cancers such as multiple myeloma (MM) and non-Hodgkin's lymphoma.
The proteasome is a proteinase complex that degrades most intra-cellular proteins, including those involved in both cell cycle regulation and apoptosis. But resistance is already a problem with bortezomib, and toxic side-effects are also an issue, so a more selective proteasome inhibitor could be of great therapeutic benefit; Proteolix is working on a new drug in this class, carfilzomib.
In one trial, the drug was given to a total of 54 patients with MM, non-Hodgkin's lymphoma, Hodgkin's disease and Waldenstroem's macro-globulinaemia (WM). Two dosing schedules were employed. In one, the drug was given once a day for five days with nine days rest on a two- week cycle,1 and in the other four-week cycle it was given for two consecutive days at the beginning of each week for three weeks, followed by a week off.2 The minimal effective dose for the former regimen was 11mg/m2, and it was 15mg/m2 for the latter.
One patient with multiple myeloma achieved a partial response and one with WM achieved a minimal response in the first study. In the second, three of the eight MM patients achieved a partial response. Overall, six patients also achieved stable disease, and symptomatic improvement was seen across the two groups. It was well tolerated both at and above the minimum effective dose, and at the highest dose level blood sample analysis showed that proteasome inhibition was above 80%.
In another, open label trial 46 patients with MM who had relapsed from at least two previous therapies, including bortezomib and thalidomide or lenalidomide, and were refractory to other treatments, were given 20mg/m2 of the drug intravenously on the two consecutive days regimen for up to 12 four-week cycles, with a 4mg dose of oral dexamethasone given ahead of each dose during the first cycle.3 Initial analysis indicated that three of 39 evaluable patients achieved a partial response, three had a minimal response and 40% achieved stable disease.
A further open label study again looked at relapsed MM patients. Thirty-one patients were given the same dose regimen, and in the 14 who had not previously been treated with bortezomib, there was an overall response rate of 57% and median duration of eight months. In those who had received bortezomib in the past, the overall response rate was 18%.4 Trials continue.
Reference:
1. R.Z. Orlowski et al. Blood 2007, 110 (11), Abst. 2430
2. M. Alsina et al. Blood 2007, 110 (11), Abst. 409
3. S. Jagannath et al. Blood, 2008, 112 (11) Abst 865
4. R. Vij et al. J. Clin. Oncol. 2009, 27 (15, Suppl.), Abst 8537