Trial Information

Phase II Study of the Association of Velcade to R-CHOP in the Treatment of B Cell Lymphoma

The association of the monoclonal antibody Rituximab to chemotherapy regimen of B-cell
lymphoma is associated with an increase response rate and event free survival when compared
to chemotherapy alone (Coiffier et al NEJM 2002). It has been observed in almost all
histological type of B-cell lymphomas. No significant increase of toxicity was observed
especially in the most used regimen CHOP and the association R-CHOP is a standard for most
B-cell malignancies CD20 positive.

However, in patients with diffuse large cell lymphoma progress should be made as the
complete response rate is below 75% in most situation and in low grade lymphoma, although
patients respond well to chemotherapy complete remission rate averaged generally 50% (Marcus
et al 2003), Czuczman et al 1999) .

There is a need to improve this association with new innovative agent. Before running
randomized study it is important to evaluate the like hood of getting improvement by phase 2
study testing tolerance and efficacy on a well established regimen.

Bortezomib (Velcade formerly PS 341) is a proteasome inhibitor which has shown promising
activity in the treatment of refractory myeloma. As single agent in indolent lymphomas,
administered twice per weeks for 2 weeks followed by one week rest period it has already
showed activity in phase 2 study. It is well tolerated and main toxicity was neuropathy and
thrombocytopenia.

Proteasome inhibitors can act through multiple mechanisms to arrest tumor growth, tumor
spread, and angiogenesis. In vitro studies have shown a synergistic effect of the
association of Velcade and doxorubicin on myeloma cell lines resistant to chemotherapy.

Association of Velcade to standard chemotherapy regimen is under study with the aim of
improving on the results.

Association of Velcade to one of the most efficient treatment of B-cell lymphoma, R-CHOP,
might increase the response rate.

However, different schedules should be explored in order to better appreciate efficacy and
toxicity.

This randomized phase 2 study is designed to evaluate the response rate and the toxicity of
two schedules of administration of Velcade in association with R-CHOP. The aim of the study
is to establish a well tolerated regimen giving a response rate in the limit upper/lower of
what is observed with conventional R-CHOP used in all the different histological subtypes of
B cell lymphomas patients requiring treatment.

The heterogeneity of the population will preclude any meaningful subgroup analysis.

It is important to evaluate tolerability before exploring the efficacy of this new regimen
in large randomized studies or in specific phases II study which will need 50 patients for
each subgroup of patients.