Leukemia, Lymphoma
Conditions
Keywords
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
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.
Interventions
BIOLOGICALrituximab
Given IV
DRUGbortezomib
Given IV
DRUGcyclophosphamide
Given IV
DRUGprednisone
Given orally
Sponsors
National Cancer Institute (NCI)
Rutgers Cancer Institute of New Jersey
Columbia University
Emory University
Memorial Sloan Kettering Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | 2 years | Maximum tolerated dose of Bortezomib in combination with Rituximab, Cyclophosphamide and Prednisone in Phase I participants |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 2 years | — |
| Duration of Response (Mean and Median) | 2 years | — |
| Event-free Survival | 2 years | — |
| Overall Survival | 2 years | — |
| Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 2 years | Toxicity assessed using NCI-CTC v. 3.0 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide Phase I Weekly 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide | 4 |
| 1.6 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide Phase I Weekly 1.6 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide | 6 |
| 1.6 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide Phase I Weekly 1.6 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | 3 |
| 1.8 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide Phase I Weekly 1.8 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | 4 |
| Dose Level 1- 1.0 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamid Phase I Twice Weekly 1.0 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide | 2 |
| Dose Level 2 - 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamid Phase I Twice Weekly 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide | 18 |
| Dose Level 3 - 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophospham Phase I Twice Weekly 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | 3 |
| Dose Level 4 - 1.5 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphami Phase I Twice Weekly 1.5 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | 4 |
| Dose Level 5 - 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphami Phase I Twice Weekly 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide; Pegylated G-CSF | 10 |
| Weekly Bortezomib Dosing Schedule Phase II Randomized Weekly bortezomib dosing schedule | 12 |
| Twice-weekly Bortezomib Dosing Schedule Phase II Randomized Twice-weekly bortezomib dosing schedule | 13 |
| Total | 79 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Not Treated | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Total | 1.6 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide | 1.6 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | 1.8 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | Dose Level 1- 1.0 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamid | Dose Level 2 - 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamid | Dose Level 3 - 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophospham | 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamide | Dose Level 4 - 1.5 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphami | Dose Level 5 - 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphami | Weekly Bortezomib Dosing Schedule | Twice-weekly Bortezomib Dosing Schedule |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 37 Participants | 5 Participants | 2 Participants | 2 Participants | 2 Participants | 8 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants | 1 Participants | 1 Participants | 2 Participants | 0 Participants | 10 Participants | 1 Participants | 3 Participants | 3 Participants | 9 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 68 Participants | 6 Participants | 3 Participants | 3 Participants | 0 Participants | 17 Participants | 2 Participants | 4 Participants | 3 Participants | 8 Participants | 11 Participants | 11 Participants |
| Sex: Female, Male Female | 39 Participants | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 12 Participants | 1 Participants | 3 Participants | 1 Participants | 4 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 40 Participants | 2 Participants | 1 Participants | 2 Participants | 1 Participants | 6 Participants | 2 Participants | 1 Participants | 3 Participants | 6 Participants | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 6 / 6 | 2 / 3 | 3 / 4 | 1 / 2 | 13 / 18 | 2 / 3 | 3 / 4 | 7 / 10 | 4 / 12 | 5 / 13 |
| other Total, other adverse events | 4 / 4 | 6 / 6 | 3 / 3 | 4 / 4 | 2 / 2 | 18 / 18 | 3 / 3 | 4 / 4 | 10 / 10 | 12 / 12 | 13 / 13 |
| serious Total, serious adverse events | 0 / 4 | 3 / 6 | 2 / 3 | 2 / 4 | 0 / 2 | 5 / 18 | 1 / 3 | 2 / 4 | 1 / 10 | 4 / 12 | 8 / 13 |
Outcome results
Primary
Maximum Tolerated Dose
Maximum tolerated dose of Bortezomib in combination with Rituximab, Cyclophosphamide and Prednisone in Phase I participants
Time frame: 2 years
Population: This outcome is only applicable for Phase I portion of the study. The purpose of the Phase I portion of the study is to determine the Maximum Tolerated Dose and for this reason the results are not separated by dose level.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I | Maximum Tolerated Dose | Weekly Bortezomib | 1.8 mg/m^2 of Bortezomib |
| Arm I | Maximum Tolerated Dose | Twice-Weekly Bortezomib | 1.5 mg/m^2 of Bortezomib |
Secondary
Duration of Response (Mean and Median)
Time frame: 2 years
Population: Data were not collected
Secondary
Event-free Survival
Time frame: 2 years
Population: Data were not collected
Secondary
Overall Survival
Time frame: 2 years
Population: Data were not collected
Secondary
Progression-free Survival
Time frame: 2 years
Population: Data were not collected
Secondary
Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma
Toxicity assessed using NCI-CTC v. 3.0
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 4 Participants |
| Arm II | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 6 Participants |
| 1.6 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 3 Participants |
| 1.8 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphamide | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 4 Participants |
| Dose Level 1- 1.0 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamid | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 2 Participants |
| Dose Level 2 - 1.3 mg/m2 Bortezomib; 750 mg/m2 Cyclophosphamid | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 18 Participants |
| Dose Level 3 - 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophospham | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 3 Participants |
| Dose Level 4 - 1.5 mg/m2 Bortezomib; 1000 mg/m2 Cyclophosphami | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 4 Participants |
| Dose Level 5 - 1.3 mg/m2 Bortezomib; 1000 mg/m2 Cyclophospham | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 10 Participants |
| Weekly Bortezomib Dosing Schedule | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 12 Participants |
| Twice-weekly Bortezomib Dosing Schedule | Toxicity of Participants Receiving Bortezomib, Rituximab, Cyclophosphamide, and Prednisone for Treatment of Non-Hodgkin's Lymphoma | 13 Participants |