A Phase I/II Trial of VELCADE & Gemcitabine for Patients With Relapsed or Refractory Aggressive B- and T-cell Non-Hodgkin's Lymphoma

OBJECTIVES:

Primary

- Determine the response rate (complete and partial remission) in patients with relapsed
or refractory aggressive B- or T-cell non-Hodgkin's lymphoma treated with gemcitabine
hydrochloride and bortezomib.

- Determine the maximum tolerated dose of bortezomib when administered with gemcitabine
hydrochloride in these patients.

Secondary

- Determine the time to treatment failure, duration of response, and overall survival of
patients treated with this regimen.

- Determine the safety and tolerability of this regimen in these patients.

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

- Phase I: Patients receive gemcitabine hydrochloride IV over 30 minutes and bortezomib
IV over 3-5 seconds on days 1 and 8. Treatment repeats every 21 days for up to 9
courses in the absence of disease progression or unacceptable toxicity.

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 3 or 3
of 6 patients experience dose-limiting toxicity (DLT) OR the dose that at which 2 of 6
patients experience DLT.

- Phase II: Patients receive gemcitabine hydrochloride and bortezomib as in phase I at
the MTD.

After completion of study therapy, patients are followed periodically for 3 years.

PROJECTED ACCRUAL: A total of 37 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

- Diagnosis of B- or T-cell non-Hodgkin's lymphoma (NHL)

- Intermediate histology B-cell NHL, including any of the following:

- Diffuse large B-cell lymphoma

- Transformed large cell lymphoma

- Any T-cell NHL histology

- Cutaneous T-cell lymphoma (CTCL) or mycosis fungoides (MF) allowed

- Relapsed or refractory disease, defined as disease progressed after prior complete
remission (CR), partial remission (PR), or stable disease (SD) to last therapy OR
failure to achieve CR, PR, or SD after completion of last therapy

- Must have received 1-3 prior therapeutic regimens

- Cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (CHOP)
AND cyclophosphamide, vincristine, and prednisone (CVP) OR CHOP with rituximab
(CHOP-R) AND CVP with rituximab (CVP-R) is considered 1 regimen

- Monoclonal antibody (e.g., rituximab) given as maintenance therapy is considered
1 regimen

- Salvage chemotherapy followed by an autologous stem cell transplant is
considered 1 regimen

- No more than 7 prior therapeutic regimens for patients with CTCL or MF

- No mantle cell lymphoma

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy > 3 months

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- At least 50,000/mm^3 if documented bone marrow involvement

- Hemoglobin ≥ 8.0 g/dL

- AST and ALT ≤ 3 times upper limit of normal (ULN)

- Alkaline phosphatase ≤ 3 times ULN

- Bilirubin ≤ 2 times ULN

- Creatinine ≤ 2.0 mg/dL

- No known history of HIV infection

- No other active infection

- No uncontrolled hypertension

- No peripheral neuropathy ≥ grade 2 within the past 2 weeks

- No myocardial infarction within the past 6 months

- No New York Heart Association class III or IV heart failure

- No uncontrolled angina

- No severe uncontrolled ventricular arrhythmias

- No acute ischemia or active conduction system abnormalities by ECG

- No hypersensitivity to bortezomib, boron, or mannitol

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier-method contraception

- No serious medical or psychiatric illness that would preclude study participation

PRIOR CONCURRENT THERAPY:

- Prior autologous and/or allogeneic stem cell transplantation allowed

- More than 3 weeks since prior chemotherapy, radiotherapy, or immunotherapy

- More than 3 weeks since prior systemic biologic anticancer therapy

- More than 3 weeks since prior systemic corticosteroids (e.g., oral prednisone > 10 mg
per day)

- More than 2 weeks since prior investigational drug

- No prior bortezomib or gemcitabine hydrochloride

- No other concurrent systemic cytotoxic chemotherapy or investigational agents