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

NCT ID: NCT00295932

Last Updated: 2018-11-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 79 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-12-13
• Study Completion Date: 2018-03-11

Brief Summary

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.

Detailed Description

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.

Conditions

Leukemia; Lymphoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

rituximab

Intervention Type: BIOLOGICAL

Given IV

bortezomib

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

prednisone

Intervention Type: DRUG

Given orally

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.

Group Type: EXPERIMENTAL

rituximab

Intervention Type: BIOLOGICAL

Given IV

bortezomib

Intervention Type: DRUG

Given IV

cyclophosphamide

Intervention Type: DRUG

Given IV

prednisone

Intervention Type: DRUG

Given orally

Interventions

rituximab

Given IV

Intervention Type: BIOLOGICAL

bortezomib

Given IV

Intervention Type: DRUG

cyclophosphamide

Given IV

Intervention Type: DRUG

prednisone

Given orally

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Rutgers Cancer Institute of New Jersey

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: collaborator

Memorial Sloan Kettering Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carol Portlock, MD

Role: PRINCIPAL_INVESTIGATOR

Memorial Sloan Kettering Cancer Center

Locations

Winship Cancer Institute of Emory University

Atlanta, Georgia, United States

Memorial Sloan-Kettering at Basking Ridge

Basking Ridge, New Jersey, United States

Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School

New Brunswick, New Jersey, United States

Memorial Sloan-Kettering Cancer Center @ Suffolk

Commack, New York, United States

Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center

New York, New York, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Memorial Sloan-Kettering at Mercy Medical Center

Rockville Centre, New York, United States

Memoral Sloan Kettering Cancer Center@Phelps

Sleepy Hollow, New York, United States

Countries

United States

References

Gerecitano J, Portlock C, Hamlin P, Moskowitz CH, Noy A, Straus D, Schulman P, Dumitrescu O, Sarasohn D, Pappanicholaou J, Iasonos A, Zhang Z, Mo Q, Horanlli E, Rojas CN, Zelenetz AD, O'Connor OA. Phase I trial of weekly and twice-weekly bortezomib with rituximab, cyclophosphamide, and prednisone in relapsed or refractory non-Hodgkin lymphoma. Clin Cancer Res. 2011 Apr 15;17(8):2493-501. doi: 10.1158/1078-0432.CCR-10-1498. Epub 2011 Feb 23.

Reference Type: RESULT

PMID: 21346146 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Related Links

http://www.mskcc.org

Memorial Sloan Kettering Cancer Center

Other Identifiers

MSKCC-05103

Identifier Type: -

Identifier Source: secondary_id

05-103

Identifier Type: -

Identifier Source: org_study_id

NCT00859443

Identifier Type: -

Identifier Source: nct_alias