Diffuse Large B-Cell Lymphoma, Diffuse Large-Cell Lymphoma, Lymphoma, Lymphoma, Diffuse Large-Cell
Conditions
Keywords
Diffuse Large B-Cell Lymphoma, Elderly, Newly Diagnosed, Lineberger Comprehensive Cancer Center, University of North Carolina, Bendamustine, Rituximab, Rituxan, Treanda, Phase 2, Geriatric, Lymphoma
Brief summary
The purpose of this research study is to learn about the safety of the treatment with a combination of bendamustine and rituximab and to find out what effects, both good and bad this treatment has on DLBCL. In addition to learning about the combination of bendamustine and rituximab, the researchers are interested in learning about how this cancer treatment affects daily activities. Subjects will be asked to complete a Geriatric Assessment (GA). GAs are designed to gather information on memory, nutritional status, mental health, and level of social support. GAs are also designed to help the health care team understand how well subjects can carry out their day to day activities and to briefly describe what other medical conditions subjects may have. This assessment will help the health care team understand a subject's functional age (the age a subject functions at) as compared to a subject's actual age. The researchers also want to learn how chemotherapy affects the aging process in our bodies. This is done by measuring the amount of p16 in blood. Researchers want to understand if chemotherapy changes the levels of p16 in blood.
Detailed description
This multicenter Phase II clinical study will investigate the complete response (CR) rate after therapy with bendamustine combined with rituximab in older (≥65 years old) patients with previously untreated stage II-IV DLBCL deemed poor candidates for cyclophosphamide, doxorubicin hydrochloride, vincristine (Oncovin®), prednisone, rituximab (CHOP-R); n=37. The hypothesis being tested is that this regimen will be safe and effective as frontline therapy in older DLBCL patients deemed poor candidates for CHOP-R. After 3 cycles of therapy, patients with less than a partial response (PR) will come off study, and be managed at the discretion of their treating physician. Patients who achieve a PR after 3 cycles will continue for a total of 8 cycles of therapy, while patients who achieve a CR will continue for a total of 6 cycles of therapy. Secondary objectives include overall response rates (ORR), disease-free, progression-free and overall survival, and an evaluation of the toxicity and tolerability of the regimen. This trial also includes an exploratory analysis designed to evaluate a potential correlation between expression of the senescence marker p16INK4a and the toxicity associated with this regimen. In addition, patients will be asked to participate in a Geriatric Assessment (GA) tool during the trial.
Interventions
DRUGBendamustine
Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles
DRUGRituximab
Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles
Sponsors
Cephalon
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with previously untreated , histologically confirmed, diffuse large B-cell lymphoma (DLBCL), immunophenotyped for CD20 * Age greater than or equal to 65 years * Stage II-IV * Measurable disease including lesions that can be accurately measured in 2 dimensions by CT and have a greatest transverse diameter of 1cm or greater, and/or by bone marrow histopathology. * ECOG performance status of 0-3 * Deemed poor candidate for CHOP-R due to ejection fraction less than or equal to 45%, ECOG performance status of 2, or in the opinion of the treating physician, patient would not tolerate administration of CHOP-R chemotherapy for other reasons, * Life expectancy of at least 3 months; * Documented negative serologic testing for HIV, Hepatitis B (unless positive due to prior vaccination), and hepatitis C within the year prior to enrollment * Adequate bone marrow function (without transfusion support within one week of screening) function: * Hemoglobin \> 8 g/dL * Absolute neutrophil count (ANC) \>1000 cells/mm3 * Platelet count \> 75,000/mm3 * Adequate hepatic and renal function as demonstrated by: * Aspartate aminotransferase (AST) \< 2.5 x upper limit of normal (ULN) * Total serum bilirubin \< 2.5 x ULN * Serum creatinine \< 1.5 x ULN * If sexually active male of reproductive capability, has agreed to use a medically accepted form of contraception from time of enrollment to completion of all follow-up study visits * Signed an institutional review board (IRB) approved informed consent document
Exclusion criteria
* Central nervous system involvement by lymphoma * History of previous allergic reactions to compounds of similar biological or chemical composition as rituximab or bendamustine * Medical or other condition that would represent an inappropriate risk to the patient or would likely compromise achievement of the primary study objective. * Other active malignancies (except: non-melanoma skin cancer, cervical carcinoma in situ without evidence of disease, prostatic intraepithelial neoplasia without evidence of prostate cancer) * Patients on strong inhibitors of CYP1A2.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) Rate as Defined by The International Harmonization Project for Response Criteria | 2 years | Complete response (CR) is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. The complete response rate is the percentage of participants achieving a CR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 2 years | The ORR consists of the complete response rate + the partial response rate (percentage of participants achieving a complete or partial response). Complete response is defined by The International Harmonization Project for Response Criteria as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response is defined as regression of measurable disease and no new sites. |
| Partial Response Rate | 2 years | The percentage of participants achieving a partial response (PR). PR is defined by The International Harmonization Project for Response Criteria as regression of measurable disease and no new sites. |
| Estimate of Progression-Free Survival | 2 years with the median follow-up of 29 months | Progression-free survival (PFS) will be summarized using the Kaplan-Meier method. PFS was defined as the time from the start of treatment until lymphoma progression or death as a result of any cause. Progression was defined by The International Harmonization Project for Response Criteria as any new lesion or increase by ≥50% of previously involved sites from nadir. |
| Overall Survival | 2 years with the median follow-up of 29 months | This represents the Kaplan-Meier estimates of median overall survival defined as the time from start of treatment until death as a result of any cause. |
| Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Adverse events were collected while patients were on active treatment. The median treatment time was 18 weeks. | The major grade 3 or higher adverse events were haematological toxicities. The results below include common haematological and non-haematological toxicities of grade 3 or higher. A complete record of all adverse events are reported in the adverse events section. National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 were used to assess toxicity. |
Countries
United States
Participant flow
Recruitment details
23 patients were enrolled between March 2011 and May 2013.
Pre-assignment details
28 patients were assessed for eligibility; 4 patients were excluded for not meeting the inclusion criteria and 1 patient eventually declined to participate. Leaving 23 patients enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Bendamustine, Rituximab This is a single arm intervention where patients will receive bendamustine at a dose of 120 mg/m\^2 infused over 60 minutes in days 1 and 2 of each 21 day cycle along with rituximab 375 mg/m\^2 after bendamustine on day 1 of each cycle. Patients with Eastern Cooperative Oncology Group (ECOG) PS of 3 at baseline were allowed to receive bendamustine at a dose of 90 mg/m\^2 daily with a dose increase to 120 mg/m\^2 daily if their ECOG improved.
Bendamustine: Dosage Form: Intravenous (60 minute infusion) Dosage: 120mg/m2 (ECOG = 0-2) or 90mg/m2 (ECOG = 3) Frequency: Day 1 and Day 2; Every 3 weeks of a 21 day cycle. Duration: 3-6 Cycles
Rituximab: Dosage form: Intravenous Dosage: 375 mg/m2 Frequency: Day 1 of every 3 weeks of a 21 day Cycle Duration: 3-6 Cycles | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Clinical deterioration | 1 |
| Overall Study | Death | 2 |
| Overall Study | Disease Progression | 2 |
| Overall Study | Other complicating disease (stroke) | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Bendamustine, Rituximab |
|---|---|
| Age, Continuous | 80 years |
| ECOG Performance Status 0 | 2 Participants |
| ECOG Performance Status 1 | 9 Participants |
| ECOG Performance Status 2 | 6 Participants |
| ECOG Performance Status 3 | 6 Participants |
| International Prognostic Index (IPI) 2 | 5 Participants |
| International Prognostic Index (IPI) 3 | 5 Participants |
| International Prognostic Index (IPI) 4 | 8 Participants |
| International Prognostic Index (IPI) 5 | 5 Participants |
| Lactate Dehydrogenase (LDH) Elevated | 15 Participants |
| Lactate Dehydrogenase (LDH) Normal | 8 Participants |
| Pathology Subtype Germinal Center | 7 Participants |
| Pathology Subtype Non-Germinal Center | 12 Participants |
| Pathology Subtype Not Classified | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 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 | 0 Participants |
| Race (NIH/OMB) White | 21 Participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 12 Participants |
| Stage II | 4 Participants |
| Stage III | 7 Participants |
| Stage IV | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 17 / 23 |
| other Total, other adverse events | 23 / 23 |
| serious Total, serious adverse events | 15 / 23 |
Outcome results
Primary
Complete Response (CR) Rate as Defined by The International Harmonization Project for Response Criteria
Complete response (CR) is defined as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. The complete response rate is the percentage of participants achieving a CR.
Time frame: 2 years
Population: This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine, Rituximab | Complete Response (CR) Rate as Defined by The International Harmonization Project for Response Criteria | 52 percentage of participants |
Secondary
Estimate of Progression-Free Survival
Progression-free survival (PFS) will be summarized using the Kaplan-Meier method. PFS was defined as the time from the start of treatment until lymphoma progression or death as a result of any cause. Progression was defined by The International Harmonization Project for Response Criteria as any new lesion or increase by ≥50% of previously involved sites from nadir.
Time frame: 2 years with the median follow-up of 29 months
Population: This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine, Rituximab | Estimate of Progression-Free Survival | 5.4 Months |
Secondary
Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab
The major grade 3 or higher adverse events were haematological toxicities. The results below include common haematological and non-haematological toxicities of grade 3 or higher. A complete record of all adverse events are reported in the adverse events section. National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 were used to assess toxicity.
Time frame: Adverse events were collected while patients were on active treatment. The median treatment time was 18 weeks.
Population: This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Neutropenia | 17 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Lymphopenia | 70 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Anemia | 26 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Thrombocytopenia | 17 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Lymphocytosis | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Fatigue | 13 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Anorexia | 9 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Hyperglycemia | 9 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Urinary Tract Infection | 9 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Arthralgia | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Heart Failure | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Atrial Fibrillation | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Cognitive Disturbance | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Generalized Muscle Weakness | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Hypoalbuminemia | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Hyponatremia | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Infusion Related Reaction | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Myalgia | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Nausea | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Pleural Effusion | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Maculopapular Rash | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Sepsis | 4 percentage of patients |
| Bendamustine, Rituximab | Evaluate the Toxicity and Tolerability of Bendamustine in Combination With Rituximab | Skin Infection | 4 percentage of patients |
Secondary
Overall Response Rate (ORR)
The ORR consists of the complete response rate + the partial response rate (percentage of participants achieving a complete or partial response). Complete response is defined by The International Harmonization Project for Response Criteria as the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy. Partial response is defined as regression of measurable disease and no new sites.
Time frame: 2 years
Population: This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine, Rituximab | Overall Response Rate (ORR) | 78 percentage of participants |
Secondary
Overall Survival
This represents the Kaplan-Meier estimates of median overall survival defined as the time from start of treatment until death as a result of any cause.
Time frame: 2 years with the median follow-up of 29 months
Population: This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine, Rituximab | Overall Survival | 10.2 Months |
Secondary
Partial Response Rate
The percentage of participants achieving a partial response (PR). PR is defined by The International Harmonization Project for Response Criteria as regression of measurable disease and no new sites.
Time frame: 2 years
Population: This represents the data after inclusion of the first 23 patients at the planned interim analysis. The data analysis was performed prior to the previously determined 3-year follow-up period because the study did not reach the initially planned sample size to determine the survival rates in a statistically significant manner as secondary objectives.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bendamustine, Rituximab | Partial Response Rate | 26 percentage of participants |