Phase I/II Trial of VELCADE Plus Zevalin in Patients With Relapsed or Refractory Follicular Lymphoma

This is a phase I, dose-escalation study of bortezomib followed by a phase II study.

Phase I:

- Induction therapy: Patients receive bortezomib IV over 3-5 seconds on days 1, 8, 15, and
22, rituximab IV on days 8 and 15, and yttrium Y 90 ibritumomab tiuxetan IV over 10 minutes
on day 15.

Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6
patients experience dose-limiting toxicity.

- Consolidation therapy: Beginning 6-7 weeks after completing induction therapy, patients
receive bortezomib IV over 3-5 seconds on days 1, 8, and 15. Treatment repeats every 28 days
for 3 courses in the absence of disease progression or unacceptable toxicity.

Phase II: Patients receive induction therapy and consolidation therapy as in phase I, with
bortezomib administered at the MTD determined in phase I.

After completion of study treatment, patients are followed every 3 months for 1 year, every 6
months for 1 year, and then annually thereafter.

A total of 24 patients will be accrued for this study.

Inclusion Criteria:

- Histologically confirmed follicular lymphoma

- CD20+ at time of diagnosis or subsequently

- More than 4 weeks since prior rituximab

- More than 3 weeks since prior anticancer therapy (6 weeks for nitrosourea or mitomycin
C)

- More than 4 weeks since prior major surgery

- More than 2 weeks since prior investigational drugs

Exclusion Criteria:

- AIDS-related lymphoma

- History or evidence of CNS involvement

- Pregnant or nursing

- known HIV positivity

- serious medical or psychiatric illness that would preclude study participation

- myocardial infarction within the past 6 months

- congestive heart failure, uncontrolled angina, severe uncontrolled ventricular
arrhythmias, or ECG evidence of acute ischemia or active conduction system
abnormalities

- known hypersensitivity to rituximab, bortezomib, boron, or mannitol

- prior autologous or allogeneic stem cell transplantation

- prior radioimmunoconjugate therapy or prior exposure to murine antibodies

- prior external-beam irradiation to > 25% of active bone marrow