Abstracts of Clinical Meeting on 12-July-2002
Forthcoming Phase II/III Studies Of PS-341 In Multiple Myeloma
Jamie Cavenagh, Consultant Haematologist, St Bartholomew's and The Royal London Hospitals. London EC1A 7BE
PS-341 (Velcade™, Millenium Pharmaceuticals) is an active inhibitor of the cellular proteosome. Tumour cells are more dependent than normal cells on proteosome-regulated proteins for growth and proliferation. Indeed, PS-341 has shown significant activity against tumour cells in vitro and also in animal tumour models in vivo.
A number of proteins that are involved in cell proliferation are regulated by the proteosome including p53, cyclins, transcription factors (fos/jun, myc), Ki67 and IkB. This last protein is responsible for maintaining the transcription factor NF-kB in its inactive, cytosolic location. When active and translocated to the nucleus, NF-kB results in the transcription of a number of critical genes involved in inflammatory responses, apoptosis and cell-cell interactions. Examples include IL-6, VEGF, anti-apoptosis factors (eg survivin), cell adhesion molecules (eg ICAM-1, VCAM-1, selectins) and NF-kB itself. All of these proteins are involved in the pathogenesis of many malignancies, including multiple myeloma, and it is highly plausible that the anti-tumour effects of PS-341 are mediated largely through inhibition of NF-kB.
Preliminary results of a Phase II study of PS-341 for patients with relapsed/refractory myeloma have most recently been presented at ASCO, 2002 (Richardson et al). Patients were treated with PS-341 at 1.3 mg/m2 on days 1, 4, 8, 11 of a 21 day cycle for up to 8 cycles. Dexamethasone was added to patients with no response or disease progression at the end of 4 cycles. For the first 75 patients, the median number of prior therapies was 5 (range 2-14), the median interval from diagnosis was 4.4 years and 70% and 54% of patients had previously received thalidomide or been treated with high dose therapy respectively. At the time of last analysis, the PR rate was 41% and 46% after 2 & 4 cycles respectively.
These impressive results have encouraged the initiation of an international, randomised study of PS-341 versus pulsed dexamethasone (study 039) for patients who have progressed after having received up to 4 prior lines of therapy. Non-responders on the dexamethasone arm will be eligible to receive PS-341 on a companion study (study 040), as will patients who have received 4 or more prior lines of therapy.
These studies will be opening in seven UK centres in London (Barts & The London, Hammersmith and Royal Marsden Hospitals), Belfast, Leeds, Manchester (Christie Hospital) and Newcastle.