Diffuse Large B-Cell Lymphoma
Conditions
Keywords
Diffuse Large B-Cell Lymphoma, Ofatumumab, Bendamustine
Brief summary
This is a single-arm, Phase II study designed to enroll and treat up to 64 patients. All patients in this study will receive ofatumumab and bendamustine as an IV infusion for 6 cycles (a cycle is defined as 21 days in length). Patients will receive as an IV infusion bendamustine Days 1 and 2 of Cycles 1 through 6 and ofatumumab Days 1 and 8 during Cycle 1 only and on Day 1 of Cycles 2 through 6.
Detailed description
While R-CHOP has improved survival and is considered standard of care for patients with DLBCL, the toxicities associated with R-CHOP are substantial in the elderly population. This is one of several reasons the outcome of older patients is worse than the corresponding younger patients. Bendamustine is an alkylating agent which causes intra- and inter-strand cross-links between DNA bases. Ofatumumab is a fully human anti-CD 20 antibody well tolerated by elderly patients. Ofatumumab targets a novel epitope of the CD20 molecule on B cells and remains on the cell surface twice as long as rituximab. The combination of both agents allows for a potentially efficacious, less toxic regimen.
Interventions
DRUGBendamustine
Patients will receive as an IV infusion bendamustine 90 mg/m\^2 Days 1 and 2 of Cycles 1 through 6.
DRUGOfatumumab
Patients will receive as an IV infusion ofatumumab 1000-mg IV Days 1 and 8 during Cycle 1 only, and on Day 1 of Cycles 2 through 6
Sponsors
Novartis
GlaxoSmithKline
Cephalon
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed CD20-positive DLBCL. 2. Newly diagnosed, stage III-IV DLBCL considered poor candidates for R-CHOP. 3. Age \>=70 years 4. At least one of the following criteria: * ECOG PS 2 * Cardiac compromise precluding anthracycline therapy * Previous anthracycline therapy for other malignancy precluding further anthracycline therapy. * Severe coexisting medical problems * General frailty 5. ECOG 0-2 6. Measurable disease with at least one bidimensional lymph node or tumor mass \>1.5 cm in the longest diameter that can be followed for response as a target lesion as measured by CT 7. Patients must be HBV sAg and HBV cAb negative within 6 weeks of screening. 8. Patient must understand and voluntarily sign the IRB-approved informed consent. 9. Life expectancy \>= 3 months 10. Laboratory parameters: * Absolute neutrophil count \>=1,000 cells/mm3 * Platelet count \>=75,000 cells/mm3 * Hemoglobin \>=8 g/dL * Creatinine \<=2.0 mg/dL or Creatinine Clearance \>= 40 mL/min (calculated or 24 hour urine sample) * AST/SGOT \<=2.0 x ULN (\<=5.0 x ULN if secondary to lymphoma) * ALT/SGPT \<=2.0 x ULN (\<=5.0 x ULN if secondary to lymphoma) * Bilirubin level of \<2.0 mg/dL unless secondary to Gilbert's disease (or pattern consistent with Gilbert's)
Exclusion criteria
1. Patients with active/symptomatic central nervous system (CNS) involvement based on clinical evaluation by lumbar puncture, PET, CT or MRI. 2. Known sensitivity to bendamustine or any component of bendamustine. 3. Known anaphylaxis or sensitivity to ofatumumab. 4. Major surgery within 28 days of Cycle 1, Day 1. Patients undergoing minor surgery within 7 days of Cycle 1, Day 1. (no wait needed for port placement) 5. Prior chemotherapy, immunotherapy, or irradiation for lymphoma. 6. Prior use of investigational anti-cancer agents for lymphoma. 7. HIV-related lymphoma. 8. Known active HIV or HCV infection, or known seropositivity for HIV, or current or chronic HBV or HCV infection. HBV test required at screening or a negative result within 6 weeks of screening. 9. Concurrent active or history of other malignancies, except non-melanoma skin cancer or carcinoma in situ of cervix or breast. Patients with previous malignancies are eligible provided they have been treated with curative intent and disease free for \>= 1 year. 10. Serious (grade 3-4), active, intercurrent infection requiring therapy, or deep seated or systemic mycotic infections. 11. Myocardial infarction within 6 months prior to registration or New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or significant conduction system abnormalities, in the judgment of the Investigator. 12. Concurrent uncontrolled serious medical or psychiatric conditions likely to interfere with participation in this clinical study, in the judgment of the Investigator 13. Patients who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment). 14. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study. 15. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient. 16. Male patients unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Complete Response | 18 months | Disease response assessments will be performed using the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). Complete response requires a disappearance of all evidence of disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression (TTP) | After cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter until progression or relapse from complete response for up to 40 months | Defined as the time from date of first treatment to the date of first documented disease progression or relapse from complete response as defined by the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). This criteria categorizes the response of a patient's tumor to treatment as Complete Response (CR): the disappearance of all disease evidence; Partial Response (PR): regression of measurable disease and no new sites; Stable Disease (SD): less than a PR but not progressive disease (PD); Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. |
| Overall Survival (OS) | every 3 cycles during treatment and every 3 months thereafter until progression or death from any cause, projected 18 months | Defined as the time from Day 1 of study drug administration to date of death from any cause. |
| Duration of Response | After cycles 3 and 6 of each 21-day cycle and every 3 months thereafter until disease progression or relapse from complete response for up to 38 months | Defined as the time from date of first documented confirmed response to date of disease progression or relapse from complete response as defined by the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). This criteria categorizes the response of a patient's tumor to treatment as Complete Response (CR): the disappearance of all disease evidence; Partial Response (PR): regression of measurable disease and no new sites; Stable Disease (SD): less than a PR but not progressive disease (PD); Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. Patients who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who begin further anticancer therapy prior to disease progression will be censored at the date of last tumor assessment prior to the start date of the anticancer therapy. |
| Number of Patients With Treatment-Related Adverse Events (AEs) as a Measure of Safety | after cycles 3 and 6 of each 21-day cycle, and up to 30 days after last dose, projected 24 weeks | A treatment-related adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events were evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0. |
| Progression-free Survival | After cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter until progression or relapse from complete response for up to 40 months | Defined as the time from first treatment until objective tumor progression, relapse from complete response, or death from any cause. Tumor response is defined by the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). This criteria categorizes the response of a patient's tumor to treatment as Complete Response (CR): the disappearance of all disease evidence; Partial Response (PR): regression of measurable disease and no new sites; Stable Disease (SD): less than a PR but not progressive disease (PD); Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. Patients who are alive and free from disease progression will be censored at the date of last tumor assessment. |
| Overall Response (OR) | after cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter, projected 18 months | Overall response is the number of patients with observed complete or partial response (CR or PR) as assessed using the International Working Group (IMW) revised response criteria for malignant lymphoma (Cheson 2007). Complete response requires disappearance of all evidence of disease. Partial response requires regression of measurable disease and no new sites. |
Countries
United States
Participant flow
Recruitment details
Between October 2012 to July 2014, 22 subjects with newly diagnosed Diffuse Large B-Cell Lymphoma (DLBCL) were screened for enrollment in the study at 12 investigational sites in the U.S.. Of those, 21 were treated.
Participants by arm
| Arm | Count |
|---|---|
| Bendamustine/Ofatumumab All patients in this study will receive ofatumumab and bendamustine as an IV infusion for 6 cycles (a cycle is defined as 21 days in length).
Bendamustine: via IV infusion, 90 mg/m\^2 Days 1 and 2 of Cycles 1 through 6 Ofatumumab: via IV infusion, 1000-mg IV Days 1 and 8 during Cycle 1 only and on Day 1 of Cycles 2 through 6 | 21 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
| Overall Study | Disease Progression | 3 |
| Overall Study | Intercurrent Illness | 2 |
| Overall Study | Never Treated | 1 |
| Overall Study | Non-Compliance | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bendamustine/Ofatumumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 21 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 83 years |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 20 Participants |
| Region of Enrollment United States | 21 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 21 |
| other Total, other adverse events | 20 / 21 |
| serious Total, serious adverse events | 9 / 21 |
Outcome results
Primary
Number of Patients With a Complete Response
Disease response assessments will be performed using the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). Complete response requires a disappearance of all evidence of disease.
Time frame: 18 months
Population: All patients treated with study drugs and having a post baseline response assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bendamustine/Ofatumumab | Number of Patients With a Complete Response | 7 Participants |
Secondary
Duration of Response
Defined as the time from date of first documented confirmed response to date of disease progression or relapse from complete response as defined by the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). This criteria categorizes the response of a patient's tumor to treatment as Complete Response (CR): the disappearance of all disease evidence; Partial Response (PR): regression of measurable disease and no new sites; Stable Disease (SD): less than a PR but not progressive disease (PD); Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. Patients who are alive and free from disease progression will be censored at the date of last tumor assessment. Patients who begin further anticancer therapy prior to disease progression will be censored at the date of last tumor assessment prior to the start date of the anticancer therapy.
Time frame: After cycles 3 and 6 of each 21-day cycle and every 3 months thereafter until disease progression or relapse from complete response for up to 38 months
Population: All patients treated with study drugs and having a post baseline response assessment of a complete or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine/Ofatumumab | Duration of Response | 5.6 months |
Secondary
Number of Patients With Treatment-Related Adverse Events (AEs) as a Measure of Safety
A treatment-related adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events were evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
Time frame: after cycles 3 and 6 of each 21-day cycle, and up to 30 days after last dose, projected 24 weeks
Population: All enrolled patients who received the study treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bendamustine/Ofatumumab | Number of Patients With Treatment-Related Adverse Events (AEs) as a Measure of Safety | 16 Participants |
Secondary
Overall Response (OR)
Overall response is the number of patients with observed complete or partial response (CR or PR) as assessed using the International Working Group (IMW) revised response criteria for malignant lymphoma (Cheson 2007). Complete response requires disappearance of all evidence of disease. Partial response requires regression of measurable disease and no new sites.
Time frame: after cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter, projected 18 months
Population: All patients treated with study drugs and having a post baseline response assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Bendamustine/Ofatumumab | Overall Response (OR) | 19 Participants |
Secondary
Overall Survival (OS)
Defined as the time from Day 1 of study drug administration to date of death from any cause.
Time frame: every 3 cycles during treatment and every 3 months thereafter until progression or death from any cause, projected 18 months
Population: All enrolled patients who have received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine/Ofatumumab | Overall Survival (OS) | 12.0 months |
Secondary
Progression-free Survival
Defined as the time from first treatment until objective tumor progression, relapse from complete response, or death from any cause. Tumor response is defined by the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). This criteria categorizes the response of a patient's tumor to treatment as Complete Response (CR): the disappearance of all disease evidence; Partial Response (PR): regression of measurable disease and no new sites; Stable Disease (SD): less than a PR but not progressive disease (PD); Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir. Patients who are alive and free from disease progression will be censored at the date of last tumor assessment.
Time frame: After cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter until progression or relapse from complete response for up to 40 months
Population: All enrolled patients who have received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine/Ofatumumab | Progression-free Survival | 8.6 months |
Secondary
Time to Progression (TTP)
Defined as the time from date of first treatment to the date of first documented disease progression or relapse from complete response as defined by the International Working Group (IMW)-revised response criteria for malignant lymphoma (Cheson 2007). This criteria categorizes the response of a patient's tumor to treatment as Complete Response (CR): the disappearance of all disease evidence; Partial Response (PR): regression of measurable disease and no new sites; Stable Disease (SD): less than a PR but not progressive disease (PD); Relapsed Disease or PD: Any new lesion or increase by ≥ 50% of previously involved sites from nadir.
Time frame: After cycles 3 and 6 of each 21-day cycle, and every 3 months thereafter until progression or relapse from complete response for up to 40 months
Population: All enrolled patients who have received study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bendamustine/Ofatumumab | Time to Progression (TTP) | 10.5 months |