Trial Information

Phase II Study of Combination Bortezomib, Dexamethasone, and Rituximab in Previously Untreated Patients With Waldenstroms Macroglobulinemia: A Multicenter Trial of the European Myeloma Network

Title: Phase II Study of Combination Bortezomib (VELCADE, PS-341), Dexamethasone, and
Rituximab (MabThera) (BDR) in Patients with previously untreated Waldenstroms
Macroglobulinemia (WM).

Objectives:

The primary objective of this study is:

- To determine the response rate [the combined complete response (CR) + partial response
(PR) + minimal response (MR)] following treatment with BDR in patients with previously
untreated WM.

Secondary objectives are:

- To determine time to progression following treatment with BDR.

- To assess the safety and tolerability of BDR in patients with WM.

Patient population:

Patients with previously untreated WM who have an indication for treatment are candidates
for the study.

Specific inclusion and exclusion criteria are detailed in the protocol.

Number of patients:

Sixty-one patients are to be enrolled in this multicenter study. This study will be
conducted within centers participating in the European Myeloma Network.

Study design and methodology This is a Phase II multicenter study designed to evaluate the
safety and efficacy of combination BDR. BDR will be administered in one 21-day treatment
cycle followed by four 35-day treatment cycles to patients with WM. Bortezomib will be
administered as an iv push over 3 to 5 seconds at a dose of 1.3mg/m2/day on days 1,4,8 and
11 of cycle 1. On cycles 2-5 bortezomib will be given at a dose of 1.6mg/m2/day on days
1,8,15 and 22 of each cycle. Only on cycles 2 and 5, following the administration of
Bortezomib, dexamethasone 40mg iv and Rituximab 375 mg/m2 iv will be administered. A total
of 8 infusions of rituximab will be administered. Subsequently patients rated as CR, PR, MR
or SD will be followed without any treatment until there is evidence of progressive disease.

A Screening visit will be conducted within 28 days before baseline (baseline being Day 1,
Cycle 1, before study drug administration). At this visit, a medical history will be
obtained and a complete physical examination will be performed including vital signs,
height, weight, and a 12-lead electrocardiogram. A neurological questionnaire will also be
completed. Disease assessments will be performed, including performance status, bone marrow
aspirate and biopsy, Beta2-microglobulin, serum protein electrophoresis with quantification
of immunoglobulins and immunofixation studies, CT scanning of the chest, abdomen and pelvis.
Clinical laboratory tests including a complete blood count plus differential, electrolytes,
urea, creatinine, total bilirubin, SGOT (ALT), SGPT (AST), LDH, total protein and albumin.
Patients who meet the eligibility requirements as assessed at the Screening visit will be
enrolled in the study and start study drug treatment. Patients will be evaluated after each
cycle with serum protein electrophoresis to determine their response to therapy. If patients
demonstrate a response or have stable disease at the end of each cycle they will continue to
receive therapy. If the patient demonstrates evidence of progressive disease at the end of
each cycle then the patient will be removed from study. Modified response criteria updated
at the Third International Workshop on Waldenstroms macroglobulinemia will be used to assess
response, stable disease (SD), and progressive disease (PD) in this study. Changes of serum
monoclonal protein concentration will be assessed from serum protein electrophoresis rather
than from nephelometric measurement of serum immunoglobulins. Patients will receive five
cycles of therapy. Subsequently, it is strongly advised that blood stem cells will be
collected from patients <70 years of age for future high-dose therapy.

At the end of each cycle patients will have testing performed to assess for toxicity and
efficacy. A directed questionnaire for neurologic toxicities, review of concomitant
medications and other support therapies, including growth factors and transfusions will also
be performed. Three months after the last dose of study drug, and every three months
thereafter for 2 years, patients are to attend follow-up study visits. At these visits, a
physical examination will be performed and Karnofsky performance status assessed. Patients
will have a neurological questionnaire completed, have tests for disease assessments
including serum and protein electrophoresis with quantification of immunoglobulins and
immunofixation studies, Beta2-microglobulin, bone marrow aspirate and biopsy (only if the
patient is in a complete remission), CT scanning of the chest, abdomen and pelvis (only if
patient had evidence of WM disease on baseline scans). Serum and protein electrophoresis
with quantification of immunoglobulins and immunofixation studies must be repeated > 6 weeks
if a patient attains a complete response. At the follow-up study visits, a complete blood
count plus differential, electrolytes, urea, creatinine, total bilirubin, SGOT, will also be
obtained.