Diffuse Large B-cell Lymphoma Refractory, Follicular B-cell Non-Hodgkin's Lymphoma
Conditions
Brief summary
This is a randomized, open-label, multicenter, Phase 2 clinical trial designed to evaluate the efficacy and safety of brentuximab vedotin in combination with rituximab and bendamustine for the treatment of patients with relapsed or refractory CD30-positive diffuse large B-cell lymphoma (DLBCL) after failure of second-line salvage therapy or as second-line treatment in patients ineligible for autologous stem cell transplant (ASCT).
Detailed description
Patients will be randomized in a 1:1 manner to receive rituximab plus bendamustine with or without brentuximab vedotin. Patients who respond to combination treatment containing brentuximab vedotin and do not experience excessive toxicity may receive additional single-agent brentuximab vedotin following combination treatment, for up to an additional 10 cycles (up to 16 total cycles of treatment).
Interventions
DRUGBrentuximab Vedotin
DRUGRituximab
DRUGBendamustine
Sponsors
Seagen Inc.
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
1. Patients with confirmed CD30-positive DLBCL or grade 3b follicular non-Hodgkin lymphoma (NHL). 2. Patients must have relapsed or refractory disease following: 1. second-line or greater salvage systemic therapy, or 2. frontline cytotoxic systemic therapy, for patients who are ineligible for stem cell transplant (SCT). 3. Age 18 years and older. 4. Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET). 5. An Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2. 6. Acceptable blood test results. 7. Females of childbearing potential must have a negative pregnancy test result within 7 days prior to the first dose of study drug. 8. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraceptive method during the study and for 6 months following the last dose of brentuximab vedotin or 12 months following the last dose of rituximab, whichever is later. 9. Patients must provide written informed consent.
Exclusion criteria
1. History of another invasive malignancy that has not been in remission for at least 1 year. (Exceptions are nonmelanoma skin cancer, curatively treated localized prostate cancer, ductal carcinoma, and cervical carcinoma or a squamous intraepithelial lesion on PAP smear). 2. History of progressive multifocal leukoencephalopathy (PML). 3. Cerebral/meningeal disease related to the underlying malignancy, unless definitively treated. 4. Viral, bacterial, or fungal infection within 2 weeks prior to the first dose of treatment. 5. Chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed 4 weeks prior to first dose of study drug. 6. Females who are pregnant or breastfeeding. 7. Known allergy to any study drug or ingredient contained in the drug formulation of any of the study drugs. 8. Known to be positive for hepatitis B. Known to have active hepatitis C infection or on antiviral therapy for hepatitis C within the last 6 months. 9. Known to be positive for human immunodeficiency virus (HIV). 10. Patients with previous allogeneic stem cell transplant. 11. Previous treatment with brentuximab vedotin or bendamustine. 12. Intolerable toxicity to prior rituximab therapy. 13. Current therapy with other investigational agents. 14. Lung disease unrelated to underlying malignancy. 15. History of a stroke or transient ischemic attack, unstable angina, myocardial infarction, or cardiac symptoms within 6 months prior to the first dose of treatment. 16. Congestive heart failure. 17. Significant peripheral sensory or motor neuropathy at the start of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Approximately 1 year | ORR is defined as the percentage of patients who achieve a Complete Response (CR) (including Complete Metabolic Response (CMR)) or Partial Response (PR) (including Partial Metabolic Response (PMR)) as best response to combination therapy on study |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 11.8 months | PFS is defined as the time from randomization to disease progression/relapse, receipt of subsequent lymphoma chemotherapy other than the components of the study treatment regimen, or death from any cause, whichever occurs first. |
| Complete Remission (CR) Rate | Approximately 1 year | CRR is the proportion of patients who achieve CR (including Complete Metabolic Response (CMR)) as best response to combination therapy on study. |
| Duration of Response (DOR) | Up to 10.5 months | DOR is defined as the time from first observation of response to disease progression/relapse, receipt of subsequent lymphoma chemotherapy other than the components of the study treatment regimen, or death from any cause, whichever occurs first. |
| Overall Survival (OS) | Up to 1.5 years | OS is defined as the time randomization to death from any cause |
| Number and Severity of Adverse Events (AEs) | Approximately 1 year | All AEs are included in the summaries, unless treatment-emergent is specified. |
Countries
Czechia, France, Italy, Poland, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab, Bendamustine Control Subjects randomized to the control arm will receive IV infusions of rituximab on day 1 or day 2 and bendamustine on both days 1 and 2 of each 21 day cycle.
Rituximab
Bendamustine | 12 |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine Subjects randomized to the brentuximab vedotin arm will receive IV infusions of brentuximab vedotin followed by bendamustine on day 1, and rituximab followed by bendamustine on day 2 of each 21 day cycle.
Brentuximab Vedotin
Rituximab
Bendamustine | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Adverse Event | 0 | 1 |
| Follow-up Period | Death | 2 | 5 |
| Follow-up Period | Lost to Follow-up | 1 | 0 |
| Follow-up Period | Physician Decision | 0 | 1 |
| Follow-up Period | Progressive Disease | 2 | 0 |
| Follow-up Period | Study Termination by Sponsor | 6 | 4 |
| Follow-up Period | Withdrawal by Subject | 0 | 1 |
| Treatment Period | Adverse Event | 1 | 5 |
| Treatment Period | Other, Non-AE | 1 | 0 |
| Treatment Period | Physician Decision | 1 | 3 |
| Treatment Period | Progressive disease | 2 | 3 |
| Treatment Period | Study termination by sponsor | 2 | 1 |
Baseline characteristics
| Characteristic | Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Rituximab, Bendamustine Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 6 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 6 Participants | 10 Participants |
| Age, Continuous | 68.0 years | 64.5 years | 68.0 years |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0: Normal Activity | 6 Participants | 7 Participants | 13 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1: Symptoms but ambulatory | 4 Participants | 5 Participants | 9 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2: In bed less than 50% of the time | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 7 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) White | 11 Participants | 9 Participants | 20 Participants |
| Region of Enrollment Czechia | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 2 participants | 4 participants | 6 participants |
| Region of Enrollment Italy | 4 participants | 3 participants | 7 participants |
| Region of Enrollment Poland | 0 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 4 participants | 1 participants | 5 participants |
| Region of Enrollment United States | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 6 Participants | 8 Participants | 14 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 12 | 5 / 13 |
| other Total, other adverse events | 11 / 12 | 13 / 13 |
| serious Total, serious adverse events | 3 / 12 | 8 / 13 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR is defined as the percentage of patients who achieve a Complete Response (CR) (including Complete Metabolic Response (CMR)) or Partial Response (PR) (including Partial Metabolic Response (PMR)) as best response to combination therapy on study
Time frame: Approximately 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab, Bendamustine Control | Objective Response Rate (ORR) | 91.7 percentage of participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Objective Response Rate (ORR) | 61.5 percentage of participants |
Secondary
Complete Remission (CR) Rate
CRR is the proportion of patients who achieve CR (including Complete Metabolic Response (CMR)) as best response to combination therapy on study.
Time frame: Approximately 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab, Bendamustine Control | Complete Remission (CR) Rate | 8 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Complete Remission (CR) Rate | 7 Participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from first observation of response to disease progression/relapse, receipt of subsequent lymphoma chemotherapy other than the components of the study treatment regimen, or death from any cause, whichever occurs first.
Time frame: Up to 10.5 months
Population: Patients achieving a CR (including CMR) or PR (including PMR)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab, Bendamustine Control | Duration of Response (DOR) | 3.7 months |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Duration of Response (DOR) | 4.1 months |
Secondary
Number and Severity of Adverse Events (AEs)
All AEs are included in the summaries, unless treatment-emergent is specified.
Time frame: Approximately 1 year
Population: Safety population
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Treatment-Related Adverse Event | 10 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Serious Adverse Event | 3 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Rituximab-Related Adverse Event | 6 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Treatment-Related Serious Adverse Event | 3 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Treatment-Emergent Adverse Event | 11 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Adverse Event Leading to Dose Delay | 3 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Bendamustine-Related Adverse Event | 10 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Adverse Event Leading to Treatment Discontinuation | 1 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Brentuximab Vedotin-Related Adverse Event | 0 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Grade 3-5 Treatment-Emergent Adverse Event | 4 Participants |
| Rituximab, Bendamustine Control | Number and Severity of Adverse Events (AEs) | Adverse Event with Outcome of Death | 0 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Grade 3-5 Treatment-Emergent Adverse Event | 11 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Treatment-Emergent Adverse Event | 13 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Treatment-Related Adverse Event | 13 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Brentuximab Vedotin-Related Adverse Event | 11 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Rituximab-Related Adverse Event | 10 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Bendamustine-Related Adverse Event | 13 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Adverse Event with Outcome of Death | 1 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Serious Adverse Event | 8 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Treatment-Related Serious Adverse Event | 3 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Adverse Event Leading to Dose Delay | 0 Participants |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Number and Severity of Adverse Events (AEs) | Adverse Event Leading to Treatment Discontinuation | 5 Participants |
Secondary
Overall Survival (OS)
OS is defined as the time randomization to death from any cause
Time frame: Up to 1.5 years
Population: Intent-to-treat analysis set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab, Bendamustine Control | Overall Survival (OS) | 14.3 months |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Overall Survival (OS) | 6.5 months |
Secondary
Progression-free Survival (PFS)
PFS is defined as the time from randomization to disease progression/relapse, receipt of subsequent lymphoma chemotherapy other than the components of the study treatment regimen, or death from any cause, whichever occurs first.
Time frame: Up to 11.8 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab, Bendamustine Control | Progression-free Survival (PFS) | 4.9 months |
| Brentuximab Vedotin Plus Rituximab Plus Bendamustine | Progression-free Survival (PFS) | 3.7 months |