VCR: Bortezomib, Cladribine, and Rituximab in Treating Patients With Advanced Mantle Cell Lymphoma or Indolent Lymphoma

Sponsor
University of Arizona (Other)
Overall Status
Completed
CT.gov ID
NCT00980395
Collaborator
National Cancer Institute (NCI) (NIH)
24
Enrollment
1
Location
1
Arm
109.2
Actual Duration (Months)
0.2
Patients Per Site Per Month

Study Details

Study Description

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 cladribine, 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 cladribine and rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving bortezomib together with cladribine and rituximab works in treating patients with advanced mantle cell lymphoma or indolent lymphoma.

Detailed Description

OBJECTIVES:

Primary

  • Determine the 2-year progression-free survival of patients with advanced mantle cell lymphoma or indolent lymphoma treated with bortezomib, cladribine, and rituximab.

Secondary

  • Determine the 2-year overall survival of patients treated with this regimen.

  • Determine the complete response and overall response rate in patients treated with this regimen.

  • Describe the long- and short-term toxicity of this regimen in these patients.

  • Determine the prognostic importance of Aurora kinase A in patients treated with this regimen.

  • Determine the cytokine profiles for each lymphoma subtype and how they change with this regimen.

  • Evaluate the prognostic importance of major carcinogenic pathways using tissue microarray.

OUTLINE: Patients receive bortezomib IV on days 1 and 4, cladribine IV over 2 hours on days 1-5, and rituximab IV on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and after course 1 for cytokine profile studies. Previously collected tissue samples are obtained for analysis of Aurora kinase A and B, Ki-67, cyclin D, Bcl-2, phosphor-HisH3, c-Met, and VEGF expression by using tissue microarray (IHC staining), reverse transcriptase-PCR, and/or western blotting.

After completion of study therapy, patients are followed up every 3 months for 2 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
24 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II, Open-Label Study of Bortezomib (Velcade), Cladribine and Rituximab (VCR) in Advanced, Newly Diagnosed and Relapsed/Refractory Mantle Cell and Indolent Lymphomas
Actual Study Start Date :
Jul 7, 2009
Actual Primary Completion Date :
Sep 12, 2014
Actual Study Completion Date :
Aug 14, 2018

Arms and Interventions

ArmIntervention/Treatment
Experimental: VCR (Velcade, Cladribine and Rituximab)

Rituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles

Drug: rituximab
375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles.
Other Names:
  • Rituxan
  • Drug: bortezomib
    1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles.
    Other Names:
  • Velcade
  • Drug: cladribine
    4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Other Names:
  • Leustatin
  • Outcome Measures

    Primary Outcome Measures

    1. Progression-free Survival at 2 Years [2 years]

      PFS was calculated from the first dose of study drug to the first documentation of disease progression, death regardless of cause, or change in therapy due to disease progression, whichever occurred first. If disease progression did not occur by the end of treatment, patients were evaluated every 3 months until progression with physical examination, laboratory studies, and conventional computed tomographic imaging, up to a maximum of 2 years. The Kaplan-Meier product-limit method will be used to estimate progression-free survival in the presence of censoring.

    Secondary Outcome Measures

    1. Overall Survival at 2 Years [2 years]

    2. Complete Response Rate [Two years]

    3. Partial Response [Two years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Voluntary consent before performance of any study-related procedure

    • Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control

    • Male subject agrees to use an acceptable method for contraception for the duration of the study.

    • Biopsy-proven mantle cell, marginal zone, lymphoplasmacytic, small lymphocytic lymphoma, or follicular lymphoma

    • CD20-positive disease

    • Patients with marginal zone, lymphoplasmacytic, small lymphocytic, or follicular lymphoma - at least one criterion for initiation of treatment must be met:

    • Symptomatic disease

    • Cytopenia related to lymphoma

    • Leukemic phase (> 5,000 malignant lymphocytes/µl)

    • Mass over 5 cm in greatest diameter

    • For lymphoplasmacytic lymphoma: additional treatment criteria are serum viscosity ≥ 4 cp, serum monoclonal protein > 5 g/L, concurrent primary systemic AL amyloidosis, cold agglutinin disease

    • Age over 18

    • Prior treatment with bortezomib and/or rituximab is acceptable

    • For follicular lymphoma only, at least one prior treatment

    Exclusion Criteria:
    • Platelet count of < 100 X10 /L within 14 days before enrollment, unless due to bone marrow infiltration with lymphoma, or due to autoimmune thrombocytopenia because of lymphoma.

    • Patient has an absolute neutrophil count of < 1.0 X 10/L within 14 days before registration, unless due to bone marrow infiltration with lymphoma.

    • Patient has a calculated or measured creatinine clearance of <20 mL/minute within 14 days before registration. (Creatinine Clearance is indicated through the Serum Creatinine. If the Serum Creatinine is abnormal, the physician may then due a 24 hour urine to further clarify Creatinine Clearance. A 24 hour urine test is not required per study.)

    • Patient has ≥ Grade 2 peripheral neuropathy within 14 days before registration.

    • Myocardial infarction within 6 months prior to registration or has New York Heart Association (NYHA) Class III or IV heart failure. uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.

    • Hypersensitivity to bortezomib, boron or mannitol.

    • Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant

    • Patient received other investigational drugs with 14 days before registration

    • Serious medical or psychiatric illness likely to interfere with study participation

    • Diagnosed or treated for another malignancy within 3 years of registration, w/ the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

    • CNS involvement with lymphoma.

    • Known HIV-positive.

    • History of disease refractory to a purine analog (defined as remission duration of < 6 months to therapy that included fludarabine, pentostatin, or cladribine).

    • History of intolerance of bortezomib, boron, mannitol, cladribine, or rituximab.

    • Patient has > 1.5 X ULN Total Bilirubin

    • Radiation therapy within 3 weeks before randomization. Enrollment of subjects who require concurrent radiotherapy (which must be localized in its field size) should be deferred until the radiotherapy is completed and 3 weeks have elapsed since the last date of therapy.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1The University of Arizona Cancer CenterTucsonArizonaUnited States85724-5024

    Sponsors and Collaborators

    • University of Arizona
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Daniel O. Persky, MD, University of Arizona

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    University of Arizona
    ClinicalTrials.gov Identifier:
    NCT00980395
    Other Study ID Numbers:
    • 0800001071
    • P30CA023074
    • UARIZ-08-1071-04
    • X05260
    • CDR0000655078
    • 0800001071
    • 08-1071-04
    First Posted:
    Sep 21, 2009
    Last Update Posted:
    Dec 30, 2019
    Last Verified:
    Dec 1, 2019

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Period Title: Overall Study
    STARTED24
    COMPLETED24
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Overall Participants24
    Age (years) [Median (Standard Deviation) ]
    Median (Standard Deviation) [years]
    66.5
    (11.4)
    Sex: Female, Male (Count of Participants)
    Female
    6
    25%
    Male
    18
    75%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    8.3%
    Not Hispanic or Latino
    22
    91.7%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    24
    100%
    Histology (Count of Participants)
    Mantle-cell lymphoma
    11
    45.8%
    Follicular lymphoma
    5
    20.8%
    Marginal zone lymphoma
    4
    16.7%
    Lymphoplasmacytic lymphoma
    3
    12.5%
    Small lymphocytic lymphoma
    1
    4.2%

    Outcome Measures

    1. Primary Outcome
    TitleProgression-free Survival at 2 Years
    DescriptionPFS was calculated from the first dose of study drug to the first documentation of disease progression, death regardless of cause, or change in therapy due to disease progression, whichever occurred first. If disease progression did not occur by the end of treatment, patients were evaluated every 3 months until progression with physical examination, laboratory studies, and conventional computed tomographic imaging, up to a maximum of 2 years. The Kaplan-Meier product-limit method will be used to estimate progression-free survival in the presence of censoring.
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Measure Participants23
    Count of Participants [Participants]
    15
    62.5%
    2. Secondary Outcome
    TitleOverall Survival at 2 Years
    Description
    Time Frame2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Measure Participants23
    Count of Participants [Participants]
    18
    75%
    3. Secondary Outcome
    TitleComplete Response Rate
    Description
    Time FrameTwo years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Measure Participants23
    Count of Participants [Participants]
    8
    33.3%
    4. Secondary Outcome
    TitlePartial Response
    Description
    Time FrameTwo years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    Measure Participants23
    Count of Participants [Participants]
    14
    58.3%

    Adverse Events

    Time Frame107 months
    Adverse Event Reporting Description
    Arm/Group TitleVCR (Velcade, Cladribine and Rituximab)
    Arm/Group DescriptionRituximab 375 mg/m2 IV day1 Cladribine 4 mg/m2 IV over 2 hours days 1-5 Bortezomib 1.3 mg/m2 IV days 1 and 4 Repeat every 28 days for a maximum of 6 cycles rituximab: 375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles. bortezomib: 1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles. cladribine: 4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
    All Cause Mortality
    VCR (Velcade, Cladribine and Rituximab)
    Affected / at Risk (%)# Events
    Total8/24 (33.3%)
    Serious Adverse Events
    VCR (Velcade, Cladribine and Rituximab)
    Affected / at Risk (%)# Events
    Total14/24 (58.3%)
    Blood and lymphatic system disorders
    Thrombocytopenia6/24 (25%)
    Neutropenia5/24 (20.8%)
    Anemia2/24 (8.3%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnea1/24 (4.2%)
    Other (Not Including Serious) Adverse Events
    VCR (Velcade, Cladribine and Rituximab)
    Affected / at Risk (%)# Events
    Total24/24 (100%)
    General disorders
    Fatigue19/24 (79.2%)
    Fever4/24 (16.7%)
    Nervous system disorders
    Neuropathy1/24 (4.2%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/TitleAmy Selegue, NCTN Program Coordinator
    OrganizationUniversity of Arizona
    Phone520-626-0301
    Emailaselegue@email.arizona.edu
    Responsible Party:
    University of Arizona
    ClinicalTrials.gov Identifier:
    NCT00980395
    Other Study ID Numbers:
    • 0800001071
    • P30CA023074
    • UARIZ-08-1071-04
    • X05260
    • CDR0000655078
    • 0800001071
    • 08-1071-04
    First Posted:
    Sep 21, 2009
    Last Update Posted:
    Dec 30, 2019
    Last Verified:
    Dec 1, 2019