Multiple myeloma - CC-5013
Hailed as a wonder drug at its launch as a hypnotic in the 1950s, thalidomide was later prescribed freely to pregnant women to ease their morning sickness. The consequences were disastrous as unforeseen teratogenic effects caused horrific defects in their unborn children. However, it remains as a treatment for leprosy, with very strict controls on who can use it, and has immunomodulatory activity, making it useful to treat a range of inflammatory diseases. But perhaps the most promising indication is for treating cancer,1 notably in patients with advanced cancer and refractory multiple myeloma. However, the side-effects remain a significant problem, with peripheral neuropathy, constipation and somnolence affecting patients in addition to its severe teratogenicity.
As a result, Celgene has been investigating thalidomide analogues to find a compound with similar potent anticancer activity but lacking these side-effects. The result is CC-5013, which stimulates T-cell proliferation and the production of interleukin 2 and interferon gamma to a greater degree than thalidomide, without its side-effect profile.2
Multiple myeloma is the second most common form of blood cancer, and it affects the plasma cells. These white blood cells are involved in the production of immunoglobulin, and are found in the bone marrow. In multiple myeloma, they invade both bone marrow and bone, damaging the skeleton and causing pain and fractures.
In a Phase I single centre open label escalating dose trial, 15 multiple myeloma patients who had relapsed after high-dose chemotherapy were given 5, 10, 25 or 50mg/day of CC-5013 for four weeks.3 No response was seen at the two lowest doses, but antitumour activity was seen in patients at the higher doses. Side-effects included cardiovascular problems and myelosuppression.
In a second Phase I dose escalation study, 27 patients with relapsed, refractory disease were given 5, 10, 25 or 50mg doses once a day for four weeks.4 The 25mg dose was tolerated better than 50mg, and around 18 of the patients had a good response. No significant side-effects were seen.
A multicentre, randomised Phase II trial has also been carried out.5 A total of 70 patients were given 15mg twice a day or 30mg once a day, either alone or in combination with dexamethasone. Of the 46 patients who were evaluated, 14 patients had their disease stabilised, and 7 had progression. The once a day regime was better tolerated.
The FDA has granted CC-5013 fast-track status for this indication, and Phase III trials are now under way.