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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Rutgers Cancer Institute of New Jersey
Columbia University
Winship Cancer Institute of Emory University
Information provided by (Responsible Party):
Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier:
NCT00295932
First received: February 23, 2006
Last updated: September 11, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Leukemia
Lymphoma
Biological: rituximab
Drug: bortezomib
Drug: cyclophosphamide
Drug: prednisone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 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)

Resource links provided by NLM:


Further study details as provided by Memorial Sloan-Kettering Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Progression-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Duration of response (mean and median) [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Event-free survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
  • Toxicity [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 117
Study Start Date: December 2005
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Biological: rituximab
Given IV
Drug: bortezomib
Given IV
Drug: cyclophosphamide
Given IV
Drug: prednisone
Given orally
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.
Biological: rituximab
Given IV
Drug: bortezomib
Given IV
Drug: cyclophosphamide
Given IV
Drug: prednisone
Given orally

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00295932

Locations
United States, Georgia
Winship Cancer Institute of Emory University
Atlanta, Georgia, United States, 30322
United States, New Jersey
Memorial Sloan-Kettering at Basking Ridge
Basking Ridge, New Jersey, United States, 07920
Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
New Brunswick, New Jersey, United States, 08903
United States, New York
Memorial Sloan-Kettering Cancer Center @ Suffolk
Commack, New York, United States, 11725
Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
New York, New York, United States, 10032
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
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
Sponsors and Collaborators
Memorial Sloan-Kettering Cancer Center
Rutgers Cancer Institute of New Jersey
Columbia University
Winship Cancer Institute of Emory University
Investigators
Study Chair: John F. Gerecitano, MD, PhD Memorial Sloan-Kettering Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: Memorial Sloan-Kettering Cancer Center
ClinicalTrials.gov Identifier: NCT00295932     History of Changes
Obsolete Identifiers: NCT00859443
Other Study ID Numbers: 05-103, MSKCC-05103
Study First Received: February 23, 2006
Last Updated: September 11, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Memorial Sloan-Kettering Cancer Center:
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent small lymphocytic lymphoma
recurrent marginal zone lymphoma
Waldenstrom macroglobulinemia
recurrent mantle cell lymphoma
refractory chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma

Additional relevant MeSH terms:
Leukemia
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Rituximab
Bortezomib
Prednisone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on April 23, 2014