Bortezomib, Rituximab, Cyclophosphamide, and Prednisone in Treating Patients With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of bortezomib when given in combination with rituximab, cyclophosphamide, and prednisone (R-CP) in patients with relapsed or refractory indolent B-cell lymphoproliferative disorders or mantle cell lymphoma. (phase I)
• Determine the frequency and duration of complete and partial responses in patients treated with two different treatment regimes. (phase II)

Secondary

• Evaluate the progression-free survival, event-free survival, and overall survival of patients treated with this regimen. (phase II)
• Evaluate the toxicity profile of this regimen.

OUTLINE: This is a phase I dose-escalation study of bortezomib followed by a phase II randomized, multicenter study. Patients in phase II are stratified according to disease (mantle cell lymphoma vs indolent B-cell lymphoproliferative disorder vs transformed lymphoma).

• Phase I: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV on days 2 and 7. Treatment repeats every 21 days for 8 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 1 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2, 5, 9, and 12. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive cyclophosphamide IV and rituximab IV on day 1, oral prednisone on days 2-6, and bortezomib IV (at the MTD determined in phase I) on days 2 and 8. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed at 1 month, every 4 months for 2 years, and then every 6 months thereafter.

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:

• Chronic lymphocytic leukemia (CLL)
• B-cell small lymphocytic leukemia (SLL)
• Any marginal zone lymphoma
• Grade 1-3A follicular lymphoma
• Waldenstrom's macroglobulinemia
• Mantle cell lymphoma
• No transformed indolent lymphoma
• Assessable disease (phase I)
• Measurable disease (phase I and II), defined as ≥ one lesion that can be accurately measured in ≥ 1 dimension as ≥ 2 cm by conventional techniques OR ≥ 1 cm by spiral CT scan

• Lymph nodes measuring ≤ 1 cm in the short axis are considered normal
• Relapsed or refractory disease

• Must have received at least 1 prior therapeutic regimen but no more than 3 prior conventional cytotoxic therapy regimens
• No known brain metastases or meningeal disease

PATIENT CHARACTERISTICS:

• Karnofsky performance status > 50%
• Absolute neutrophil count > 1,000/mcl (more than 500/mcl if known lymphomatous involvement)
• Platelet count ≥ 50,000/mcl
• Total bilirubin < 1.5 times upper limit of normal (ULN) (less than 5 mg/dL if known history of Gilbert's disease)
• AST and ALT ≤ 2.5 times ULN (4 times ULN if liver involvement)
• Creatinine < 1.5 times ULN OR creatinine clearance > 50 mL/min
• Patients may have febrile episodes up to 38.5ºC without evidence of active infection
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No New York Heart Association class III or IV congestive heart failure
• No uncontrolled intercurrent illness, including any of the following:

• Ongoing or active infection
• Cerebrovascular accident or transient ischemic attack within 6 months of study entry
• Unstable angina pectoris
• Cardiac arrhythmia
• EKG evidence of acute ischemia
• Psychiatric illness/social situations that would limit compliance with study requirements
• No uncontrolled hypertension requiring active manipulation of antihypertensive medications
• No known or active HIV infection
• No history of hypersensitivity to bortezomib, boron, or mannitol
• No peripheral neuropathy > grade 2
• No other malignancy within the past 5 years except curatively treated non life-threatening malignancies, such as cutaneous basal cell or squamous cell carcinoma or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior therapy
• Prior stem cell transplantation allowed

• Preparative cytoreductive and high-dose therapies considered 1 prior therapy
• At least 4 weeks since prior cytotoxic chemotherapy (6 weeks since prior nitrosoureas or mitomycin C)
• At least 12 weeks since prior radioimmunotherapy

• One prior course comprising tositumomab or ibritumomab tiuxetan allowed
• At least 1 week since prior palliative steroids for NHL
• No therapeutic monoclonal antibodies (e.g., rituximab, tositumomab, ibritumomab, alemtuzumab, etc.) within 3 months of study entry

• Patients treated with monoclonal antibodies within 3 months allowed provided disease progressed on this therapy AND no treatment received 7 days prior to study entry
• Seven days since prior rituximab (for patients enrolled in phase I portion)
• No major surgery within 4 weeks of study entry
• No other concurrent investigational agents
• No other concurrent anticancer therapy