Indolent Lymphoma, Lymphoma, Mantle Cell Lymphoma, SLL
Conditions
Keywords
recurrent mantle cell lymphoma, stage III mantle cell lymphoma, stage IV mantle cell lymphoma, recurrent marginal zone lymphoma, stage III marginal zone lymphoma, stage IV marginal zone lymphoma, Waldenstrom macroglobulinemia, recurrent small lymphocytic lymphoma, stage III small lymphocytic lymphoma, stage IV small lymphocytic lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma, stage III grade 1 follicular lymphoma, stage III grade 2 follicular lymphoma, stage III grade 3 follicular lymphoma, stage IV grade 1 follicular lymphoma, stage IV grade 2 follicular lymphoma, stage IV grade 3 follicular lymphoma, extranodal marginal zone BCL mucosa assoc lymphoid tissue, nodal marginal zone B Cell lymphoma, splenic marginal zone lymphoma
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.
Interventions
DRUGbortezomib
1.3 mg/m2 IV Days 1 and 4. Repeat every 28 days for a maximum of 6 cycles.
DRUGcladribine
4 mg/m2 IV over 2 hours Days 1-5. Repeat every 28 days for a maximum of 6 cycles.
DRUGrituximab
375 mg/m2 IV Day 1. Repeat every 28 days for a maximum of 6 cycles.
Sponsors
National Cancer Institute (NCI)
University of Arizona
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame |
|---|---|
| Overall Survival at 2 Years | 2 years |
| Complete Response Rate | Two years |
| Partial Response | Two years |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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
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. | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | VCR (Velcade, Cladribine and Rituximab) |
|---|---|
| Age, Continuous | 66.5 years STANDARD_DEVIATION 11.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Histology Follicular lymphoma | 5 Participants |
| Histology Lymphoplasmacytic lymphoma | 3 Participants |
| Histology Mantle-cell lymphoma | 11 Participants |
| Histology Marginal zone lymphoma | 4 Participants |
| Histology Small lymphocytic lymphoma | 1 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 8 / 24 |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 14 / 24 |
Outcome results
Primary
Progression-free Survival at 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.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VCR (Velcade, Cladribine and Rituximab) | Progression-free Survival at 2 Years | 15 Participants |
Secondary
Complete Response Rate
Time frame: Two years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VCR (Velcade, Cladribine and Rituximab) | Complete Response Rate | 8 Participants |
Secondary
Overall Survival at 2 Years
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VCR (Velcade, Cladribine and Rituximab) | Overall Survival at 2 Years | 18 Participants |
Secondary
Partial Response
Time frame: Two years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VCR (Velcade, Cladribine and Rituximab) | Partial Response | 14 Participants |