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

November 15, 2018 updated by: Memorial Sloan Kettering Cancer Center

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)

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 Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

79

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Winship Cancer Institute of Emory University
    • New Jersey
      • Basking Ridge, New Jersey, United States, 07920
        • Memorial Sloan-Kettering at Basking Ridge
      • New Brunswick, New Jersey, United States, 08903
        • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • New York
      • Commack, New York, United States, 11725
        • Memorial Sloan-Kettering Cancer Center @ Suffolk
      • New York, New York, United States, 10065
        • Memorial Sloan-Kettering Cancer Center
      • New York, New York, United States, 10032
        • Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center
      • Rockville Centre, New York, United States
        • Memorial Sloan-Kettering at Mercy Medical Center
      • Sleepy Hollow, New York, United States
        • Memoral Sloan Kettering Cancer Center@Phelps

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Drug: cyclophosphamide
Given IV
Biological: rituximab
Given IV
Drug: prednisone
Given orally
Drug: bortezomib
Given IV
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.
Drug: cyclophosphamide
Given IV
Biological: rituximab
Given IV
Drug: prednisone
Given orally
Drug: bortezomib
Given IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose
Time Frame: 2 years
Maximum tolerated dose of Bortezomib in combination with Rituximab, Cyclophosphamide and Prednisone in Phase I participants
2 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival
Time Frame: 2 years
2 years
Progression-free Survival
Time Frame: 2 years
2 years
Event-free Survival
Time Frame: 2 years
2 years
Duration of Response (Mean and Median)
Time Frame: 2 years
2 years
Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma
Time Frame: 2 years
Toxicity assessed using NCI-CTC v. 3.0
2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Memorial Sloan Kettering Cancer Center

Collaborators

National Cancer Institute (NCI)
Columbia University
Emory University
Rutgers Cancer Institute of New Jersey

Investigators

  • Principal Investigator: Carol Portlock, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 13, 2005

Primary Completion (Actual)

March 11, 2018

Study Completion (Actual)

March 11, 2018

Study Registration Dates

First Submitted

February 23, 2006

First Submitted That Met QC Criteria

February 23, 2006

First Posted (Estimate)

February 24, 2006

Study Record Updates

Last Update Posted (Actual)

November 20, 2018

Last Update Submitted That Met QC Criteria

November 15, 2018

Last Verified

March 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 05-103
  • MSKCC-05103

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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