Mantle Cell Lymphoma
Conditions
Brief summary
The purpose of this study is to determine the efficacy and safety of the combination of bendamustine and rituximab in patients with relapsed/refractory mantle cell lymphoma.
Interventions
DRUGBendamustine
Bendamustine at 90 mg/m\^2 intravenously (iv) on days 1 and 2 of each 28-day cycle. Dosage calculations for bendamustine are based on the patient's body surface area (BSA) at baseline, using actual weight for calculations. If there is a 10% change in a patient's weight during treatment, the most recent weight is used to recalculate the BSA. The new BSA is used in determining the doses to be administered in any subsequent cycles.
DRUGRituximab
Patients receive 375 mg/m\^2 of rituximab, administered by iv infusion on day 1 of every 28-day cycle of treatment. Dosage calculations for rituximab are based on the patient's BSA at baseline, using actual weight for calculations. If there is a 10% change in a patient's weight during treatment, the most recent weight is used to recalculate the BSA. The new BSA is used in determining the doses to be administered in any subsequent cycles.
Sponsors
Cephalon
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
* histopathologically confirmed diagnosis of typical or atypical mantle cell lymphoma, except for blastoid type. * documented relapsed/refractory mantle cell lymphoma. * CD20 positive B cells in the lymph node biopsy or other lymphoma pathology specimen. * adequate hematologic function according to specific trial parameters. * bidimensionally measurable disease with at least 1 lesion measuring 2.0 cm or more in a single dimension, or the patient is in the leukemic phase of the disease. * patient has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. * patient has an estimated life expectancy of at least 3 months. * women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study. * men not surgically sterile or who are capable of producing offspring must practice abstinence or use a barrier method of birth control, and must agree to continue use of this method for the duration of study drug treatment and for 30 days after participation in the treatment period.
Exclusion criteria
* has received more than 3 previous standard chemotherapy regimens. * has the blastoid subtype of mantle cell lymphoma. * documented history of central nervous system (CNS) lymphomatous involvement. * a history of previous high-dose chemotherapy with allogeneic stem cell transplantation (history of autologous stem cell transplantation is allowed). * previous treatment with bendamustine. * has an active malignancy other than MCL, or has had a malignancy other than MCL within the past 3 years, except for controlled prostate cancer without evidence of bone metastases, localized bladder cancer, cervical carcinoma in situ, breast cancer in situ, or non-melanoma skin cancer. * has New York Heart Association (NYHA) Class III or IV heart failure, arrhythmias or unstable angina, electrocardiographic evidence of active ischemia or active conduction system abnormalities, or myocardial infarction within the last 6 months. * has serum creatinine of more than 2.0 mg/dL or creatinine clearance of less than 30 mL/min based on the Cockcroft-Gault method or from a 24-hour urine collection. * does not have adequate hepatic organ function as evidenced by specific trial parameters. * has known human immunodeficiency virus (HIV) infection. * has active hepatitis B infection. Hepatitis B surface antigen must be tested. * a pregnant or lactating woman. (Any women becoming pregnant during the study will be withdrawn from the study.) * has received corticosteroids within 28 days of study entry unless chronically administered (prednisone ≤20 mg/day) for indications other than lymphoma or lymphoma-related complications. * any serious uncontrolled, medical or psychological disorder that would impair the ability of the patient to participate in or complete this study. * any condition which places the patient at unacceptable risk or confounds the ability of the investigators to interpret study data. * patient has received other investigational agent(s) within 28 days of study entry. * patient has received chemotherapy within the prior 28 days. * patient has a known hypersensitivity to bendamustine, mannitol, or rituximab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (Complete Response + Partial Response) at the End of Cycles 3 and 6 Using the 2007 International Working Group Criteria | Month 3 (end of cycle 3), Month 6 (end of cycle 6) | The International Working Group (IWG) criteria (Cheson et al 2007) for a complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed. 95% CIs are calculated using binomial exact method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate for Duration of Response | Day 1 up to Month 43 | Duration of response is defined as the time between the date of the first response to date of progression or death. Response is determined on the basis of the 2007 IWG criteria. A complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed. |
| Kaplan-Meier Estimate for Progression-Free Survival | Day 1 up to Month 45 | Progression-free survival is defined as the time from first exposure to study medication to disease progression or relapse, or death due to any cause. Progression is defined using the 2007 International Working Group criteria, as any new lesion or increase by at least 50% of previously involved sites from nadir. |
| Kaplan-Meier Estimate for Overall Survival | Day 1 up to Month 57 | Overall survival is defined as the time from first exposure to study medication to death, or to last date from adverse events, concomitant medications, vital signs, lost to follow-up, or last known alive, for overall survival censoring date. |
| Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET) | Baseline (Days -30 to 0), post treatment (up to Month 9, 30 days following completion of therapy) | Participants had a whole-body PET at baseline and at the end of cycle 6 or the end-of-treatment visit. Negative PET refers to PET results showing no abnormal lymph nodes; conversely, positive PET refers to PET results showing abnormal lymph nodes. |
| Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Day 0 (baseline) up to Month 8 | The ECOG scale is: * Grade 0: Fully active, able to carry on all pre-disease activities without restriction; * Grade 1: Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; * Grade 2: Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours; * Grade 3: Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; * Grade 4: Completely disabled. Cannot carry on any self-care. Confined to bed or Chair. The shift table compares baseline ECOG scores to the ECOG scores as of the last treatment visit. |
Countries
Canada, United States
Participant flow
Pre-assignment details
Forty-five patients were screened and all were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Bendamustine+Rituximab Participants receive bendamustine at 90 mg/m\^2 intravenously (iv) on days 1 and 2, and 375 mg/m\^2 of rituximab by iv on day 1 of each 28-day cycle. Six 28-day cycles were planned and up to 8 cycles permitted for patients who do not have progressive disease and who have not achieved a complete response (CR). | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Disease progression | 3 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Bendamustine+Rituximab |
|---|---|
| Age, Continuous | 69.5 years STANDARD_DEVIATION 8.02 |
| Ann Arbor Staging System of Lymphoma Stage I | 0 participants |
| Ann Arbor Staging System of Lymphoma Stage II | 4 participants |
| Ann Arbor Staging System of Lymphoma Stage III | 4 participants |
| Ann Arbor Staging System of Lymphoma Stage IV | 37 participants |
| Body Surface Area (BSA) | 1.9 m^2 STANDARD_DEVIATION 0.2 |
| B-Symptoms Absent | 36 participants |
| B-Symptoms Present | 9 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 172.7 cm STANDARD_DEVIATION 9.87 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 39 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 32 Participants |
| Weight | 80.3 kg STANDARD_DEVIATION 13.59 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 45 / 45 |
| serious Total, serious adverse events | 18 / 45 |
Outcome results
Primary
Overall Response Rate (Complete Response + Partial Response) at the End of Cycles 3 and 6 Using the 2007 International Working Group Criteria
The International Working Group (IWG) criteria (Cheson et al 2007) for a complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed. 95% CIs are calculated using binomial exact method.
Time frame: Month 3 (end of cycle 3), Month 6 (end of cycle 6)
Population: Safety population consisting of all participants treated with at least 1 dose of bendamustine HCL.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine+Rituximab | Overall Response Rate (Complete Response + Partial Response) at the End of Cycles 3 and 6 Using the 2007 International Working Group Criteria | end of Cycle 3 | 71 percentage of participants |
| Bendamustine+Rituximab | Overall Response Rate (Complete Response + Partial Response) at the End of Cycles 3 and 6 Using the 2007 International Working Group Criteria | end of Cycle 6 | 82 percentage of participants |
Secondary
Kaplan-Meier Estimate for Duration of Response
Duration of response is defined as the time between the date of the first response to date of progression or death. Response is determined on the basis of the 2007 IWG criteria. A complete response is a complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. A partial response is at least a 50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest dominant nodes or nodal masses, no increase should be observed in the size of other nodes, liver or spleen, and no new sites of disease should be observed.
Time frame: Day 1 up to Month 43
Population: Safety population of participants who had a response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine+Rituximab | Kaplan-Meier Estimate for Duration of Response | 18.9 months |
Secondary
Kaplan-Meier Estimate for Overall Survival
Overall survival is defined as the time from first exposure to study medication to death, or to last date from adverse events, concomitant medications, vital signs, lost to follow-up, or last known alive, for overall survival censoring date.
Time frame: Day 1 up to Month 57
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine+Rituximab | Kaplan-Meier Estimate for Overall Survival | 38.4 months |
Secondary
Kaplan-Meier Estimate for Progression-Free Survival
Progression-free survival is defined as the time from first exposure to study medication to disease progression or relapse, or death due to any cause. Progression is defined using the 2007 International Working Group criteria, as any new lesion or increase by at least 50% of previously involved sites from nadir.
Time frame: Day 1 up to Month 45
Population: Safety population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine+Rituximab | Kaplan-Meier Estimate for Progression-Free Survival | 17.2 months |
Secondary
Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status
The ECOG scale is: * Grade 0: Fully active, able to carry on all pre-disease activities without restriction; * Grade 1: Restricted in physically strenuous activity, ambulatory and able to carry out work of a light nature; * Grade 2: Ambulatory and capable of all self-care but unable to work. Up and about more than 50% of waking hours; * Grade 3: Capable of only limited self-care, confined to bed or chair \> 50% of waking hours; * Grade 4: Completely disabled. Cannot carry on any self-care. Confined to bed or Chair. The shift table compares baseline ECOG scores to the ECOG scores as of the last treatment visit.
Time frame: Day 0 (baseline) up to Month 8
Population: Safety population. One participant dropped out prior to obtaining a post-treatment ECOG evaluation.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine+Rituximab | Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Improved | 8 participants |
| Bendamustine+Rituximab | Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Stayed the same | 32 participants |
| Bendamustine+Rituximab | Shifts in Baseline Eastern Cooperative Oncology Group (ECOG) Performance Status | Deteriorated | 4 participants |
Secondary
Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET)
Participants had a whole-body PET at baseline and at the end of cycle 6 or the end-of-treatment visit. Negative PET refers to PET results showing no abnormal lymph nodes; conversely, positive PET refers to PET results showing abnormal lymph nodes.
Time frame: Baseline (Days -30 to 0), post treatment (up to Month 9, 30 days following completion of therapy)
Population: Safety population of participants with PET data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine+Rituximab | Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET) | Baseline Negative - Study Negative | 0 participants |
| Bendamustine+Rituximab | Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET) | Baseline Positive - Study Negative | 0 participants |
| Bendamustine+Rituximab | Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET) | Baseline Negative - Study Positive | 23 participants |
| Bendamustine+Rituximab | Shifts in Baseline to Post-Treatment in Positron Emission Tomography (PET) | Baseline Positive - Study Positive | 15 participants |