High-risk Diffuse Large B-cell Lymphoma
Conditions
Brief summary
The study will estimate the MRD-negative response rate after treatment with blinatumomab in subjects with high-risk DLBCL who are MRD-positive following aHSCT. The clinical hypothesis is that the MRD-negative response rate will be greater than 10%. Achieving an MRD-negative response rate of 30% would be of scientific and clinical interest.
Detailed description
This is a phase 2, multicenter, open-label, single arm estimation study in adult subjects with high-risk DLBCL in complete remission. The study will consist of up to a 28-day screening period, a run-in period of up to 24 months, a 12-week treatment period (8 weeks of blinatumomab treatment followed by a 4-week treatment free period), a 30-day safety follow-up visit after the last dose of blinatumomab, and a long-term follow-up period that begins after the safety follow-up visit is completed until 1 year from the first dose of blinatumomab. The study will enroll approximately 90 subjects in the screening period with biopsy proven, high-risk DLBCL that are positron emission tomography-computer tomography (PET-CT) negative 90 days (± 30 days) post aHSCT. During the run-in period subjects will be followed by clinic visits at regular interval for up to 24 months for monitoring of MRD status in plasma by a next generation sequencing (NGS)-based assay. It is estimated 30 subjects will be either MRD-positive at screening or become MRD-positive during the 24-month run-in period. The number of subjects enrolled may be altered in order to ensure that approximately 30 subjects are assigned to treatment with blinatumomab. Enrollment may be stopped, once approximately 30 subjects have been assigned to treatment with blinatumomab.
Interventions
DRUGBlinatumomab
Blinatumomab is administered as a continuous IV infusion.
Sponsors
Amgen
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
Inclusion and
Exclusion criteria
- Part 1 Inclusion Criteria - Part 1 * Subject has provided informed consent prior to initiation of any study-specific activities/procedures or subject's legally acceptable representative has provided informed consent prior to any study-specific activities/procedures being initiated when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent. * Age ≥ 18 at time of informed consent * Biopsy-proven DLBCL excluding DLBCL that represents transformation of indolent non-Hodgkin's lymphoma (NHL) Note: Lymphoblastic Lymphoma and Burkitt Lymphoma histology are not eligible * Subject has ≥ 1 characteristic feature of high-risk DLBCL: * High-risk first complete remission (defined as interim positron emission tomography - computed tomography (PET-CT) positive or \< complete remission to frontline chemotherapy AND achieved complete remission to platinum-containing salvage) * Relapse within 1 year of diagnosis * Secondary age-adjusted international prognostic index \> 1 * Partial response/partial metabolic response after minimum of 2 cycles of platinum-containing salvage chemotherapy * C-myc rearrangement * aHSCT with high-dose chemotherapy following first (or later) salvage treatment. * PET-CT negative (Deauville score ≤ 3) 90 days (± 30 days) post aHSCT * Available relapsed and/or diagnostic pathology formalin-fixed paraffin-embedded (FFPE) tumor block or slide samples at the time of enrollment including the successful identification of malignant clone sequences by the central laboratory. * MRD plasma sample collected ≤ 3 weeks after the post aHSCT PET-CT scan * Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. * Adequate organ function determined ≤ 3 weeks prior to enrollment defined as follows: * Hematological: Absolute neutrophil count (ANC) ≥ 1.0 x 109/L Platelet count ≥ 75 x 109/L Hemoglobin ≥ 8 g/dL * Renal: Creatinine clearance ≥ 50 mL/min Cockcroft-Gault equation * Hepatic: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x upper limit of normal (ULN) Total bilirubin \< 2 x ULN (unless Gilbert's Disease or if liver involvement with lymphoma) * Subject will be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge including but not limited to: * Completion of up to a 24-month run-in period * Completion of all regularly scheduled study visits including blood draws for MRD assessment, clinical disease state assessment, PET-CT scans (ie, at time of MRD positivity or relapse), assignment to treatment with blinatumomab * Other Inclusion criteria may apply. See Inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MRD-Negative Rate at the End of Cycle 1 | 12 weeks (84 days) | The estimated MRD-negative rate, calculated as the percentage of participants with MRD-negative status after treatment with blinatumomab. MRD-negative status was assessed by positron emission tomography-computed tomography (PET-CT) or computed tomography (CT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kaplan-Meier Estimate: Overall Survival (OS) | up to 1 year from first dose of blinatumomab | OS, defined as time from the first dose of blinatumomab treatment until death due to any cause. Participants still alive at the time of the analysis were censored at date last known to be alive. |
| Kaplan-Meier Estimate: Progression-Free Survival (PFS) | up to 1 year from first dose of blinatumomab | PFS, calculated as the time from the date of first dose of blinatumomab until the date of diagnosis of relapse of lymphoma (by PET-CT, CT, clinical assessment or relapse biopsy, whichever was the preferred method), or date of death, whichever was earliest. Participants who were alive and who did not have progression or new anti-tumor treatment (excluding any stem cell transplantation) were to be censored at last date of tumor assessment. |
| Kaplan-Meier Estimate: Duration of MRD-Negative Status | up to 1 year from first dose of blinatumomab | The duration of MRD-negative status, assessed only in participants who achieve MRD-negative status after blinatumomab treatment, was defined as the time when a negative MRD result was first established until documented MRD-positive re-occurrence, disease progression or, death due to any cause. Participants without any of these events at the time of the analysis were to be censored at their last disease assessment date. MRD-negative status was assessed by PET-CT or CT. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | From first dose of study drug through 30 days after the last dose of study drug. The treatment duration for the participant who received blinatumomab was 57 days. | An adverse event (AE) is defined as any untoward medical occurrence. A serious AE is defined as an AE that is: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; a congenital anomaly/birth defect; other medically important serious event. TEAEs are events with an onset after the administration of the first dose of blinatumomab treatment through 30 days after the end of blinatumomab treatment. Events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death). |
Countries
Australia, Belgium, France, Greece, Italy, Switzerland, United States
Participant flow
Recruitment details
The study enrolled participants from Australia, France, Greece, Italy, Switzerland, and the United States. The first participant enrolled on 23 May 2018, and the last participant enrolled on 05 August 2019.
Pre-assignment details
The study included a Screening period (up to 28 days), and a run-in period of up to 24 months to evaluate minimal residual disease (MRD) status and assess eligibility for treatment assignment.
Participants by arm
| Arm | Count |
|---|---|
| Blinatumomab After a run-in period of up to 24 months to evaluate MRD status and assess eligibility for treatment assignment, participants received blinatumomab intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1).
Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Run-in Period | Decision by Sponsor | 6 |
| Run-in Period | Disease Progression | 1 |
| Run-in Period | Ineligibility Determined | 1 |
| Run-in Period | Other, Not Specified | 1 |
Baseline characteristics
| Characteristic | Blinatumomab |
|---|---|
| Age, Continuous | 48.7 years STANDARD_DEVIATION 18.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 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 | 3 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
MRD-Negative Rate at the End of Cycle 1
The estimated MRD-negative rate, calculated as the percentage of participants with MRD-negative status after treatment with blinatumomab. MRD-negative status was assessed by positron emission tomography-computed tomography (PET-CT) or computed tomography (CT).
Time frame: 12 weeks (84 days)
Population: Full analysis set (all participants who received any infusion of blinatumomab).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Blinatumomab | MRD-Negative Rate at the End of Cycle 1 | 100 percentage of participants |
Secondary
Kaplan-Meier Estimate: Duration of MRD-Negative Status
The duration of MRD-negative status, assessed only in participants who achieve MRD-negative status after blinatumomab treatment, was defined as the time when a negative MRD result was first established until documented MRD-positive re-occurrence, disease progression or, death due to any cause. Participants without any of these events at the time of the analysis were to be censored at their last disease assessment date. MRD-negative status was assessed by PET-CT or CT.
Time frame: up to 1 year from first dose of blinatumomab
Population: Full analysis set (all participants who received any infusion of blinatumomab).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Blinatumomab | Kaplan-Meier Estimate: Duration of MRD-Negative Status | 10.26 months |
Secondary
Kaplan-Meier Estimate: Overall Survival (OS)
OS, defined as time from the first dose of blinatumomab treatment until death due to any cause. Participants still alive at the time of the analysis were censored at date last known to be alive.
Time frame: up to 1 year from first dose of blinatumomab
Population: Full analysis set (all participants who received any infusion of blinatumomab).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Blinatumomab | Kaplan-Meier Estimate: Overall Survival (OS) | NA months |
Secondary
Kaplan-Meier Estimate: Progression-Free Survival (PFS)
PFS, calculated as the time from the date of first dose of blinatumomab until the date of diagnosis of relapse of lymphoma (by PET-CT, CT, clinical assessment or relapse biopsy, whichever was the preferred method), or date of death, whichever was earliest. Participants who were alive and who did not have progression or new anti-tumor treatment (excluding any stem cell transplantation) were to be censored at last date of tumor assessment.
Time frame: up to 1 year from first dose of blinatumomab
Population: Full analysis set (all participants who received any infusion of blinatumomab).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Blinatumomab | Kaplan-Meier Estimate: Progression-Free Survival (PFS) | NA months |
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) is defined as any untoward medical occurrence. A serious AE is defined as an AE that is: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; a congenital anomaly/birth defect; other medically important serious event. TEAEs are events with an onset after the administration of the first dose of blinatumomab treatment through 30 days after the end of blinatumomab treatment. Events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE): Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death).
Time frame: From first dose of study drug through 30 days after the last dose of study drug. The treatment duration for the participant who received blinatumomab was 57 days.
Population: Full Analysis Set: all participants who received at least 1 dose of blinatumomab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Blinatumomab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Any TEAE | 1 participants |
| Blinatumomab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Grade 3 TEAE | 1 participants |
| Blinatumomab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | Serious TEAE | 0 participants |
| Blinatumomab | Number of Participants With Treatment Emergent Adverse Events (TEAEs) | TEAE Leading to Study Drug Discontinuation | 0 participants |