Official Title: “A Phase I/II Study of the Novel Proteasome Inhibitor Bortezomib in Combination With Rituximab, Cyclophosphamide and Prednisone in Patients With Relapsed/Refractory Indolent B-Cell Lymphoproliferative Disorders and Mantle Cell Lymphoma (MCL)”

RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread.

Others find cancer cells and help kill them or carry cancer-killing substances to them.

Giving bortezomib together with cyclophosphamide, prednisone, and rituximab may be an effective treatment for non-Hodgkin's lymphoma.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of bortezomib when given together with cyclophosphamide, prednisone, and rituximab and to see how well it works in treating patients with relapsed or refractory indolent B-cell non-Hodgkin's lymphoma.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label

Study Primary Completion Date: September 2010

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 with follicular lymphoma only): 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.

PROJECTED ACCRUAL: A total of 115 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Biological: rituximab
  • Given IV
• Drug: bortezomib
  • Given IV
• Drug: cyclophosphamide
  • Given IV
• Drug: prednisone
  • Given orally

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 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.
• Experimental: 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.

Primary Measures

• Maximum tolerated dose
  • Safety Issue?: Yes

Secondary Measures

• Progression-free survival
  • Safety Issue?: No
• Duration of response (mean and median)
  • Safety Issue?: No
• Event-free survival
  • Safety Issue?: No
• Overall survival
  • Safety Issue?: No
• Toxicity
  • Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• Histologically confirmed diagnosis of 1 of the following:
• Chronic lymphocytic leukemia (CLL) (phase I)
• B-cell small lymphocytic leukemia (SLL) (phase I)
• Any marginal zone lymphoma (phase I)
• Grade 1-3A follicular lymphoma (phase I and II)
• Waldenstrom's macroglobulinemia (phase I)
• Mantle cell lymphoma (phase I)
• Transformed indolent lymphoma (phase I)
• 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/mm^3 (more than 500/mm^3 if known lymphomatous involvement)
• Platelet count ≥ 50,000/mm^3
• 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Memorial Sloan-Kettering Cancer Center

Overall Clinical Trial Officials and Contacts

John F. Gerecitano, MD, PhD Study Chair Memorial Sloan-Kettering Cancer Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00295932

Study ID Number: CDR0000456444

ClinicalTrials.gov Identifier: NCT00295932

Health Authority: Unspecified

Clinical trial summary from the National Cancer Institute's PDQ® database