Diffuse Large B-Cell Lymphoma
Conditions
Brief summary
The aim of the study is to demonstrate the high level of biosimilarity between MabionCD20 (MABION SA) and the reference product: MabThera (rituximab by Hoffman-La Roche) in patients with CD20-positive diffuse large B-cell lymphoma.
Detailed description
Patients who meet criteria for participation in this study receive 8 intravenous infusions of MabionCD20® or MabThera® 21 days interval in combination with standard dosage regimen of CHOP. The duration of the study is 12 months. The treatment and observation period will last 26 weeks starting from Day 1, until Week 26 - one month after last IMP infusion.
Interventions
DRUGRituximab
375 mg/m2 IV on day 1 of each 21 days chemotherapy cycle. Number of Cycles: 8.
DRUGDoxorubicin
50 mg of doxorubicin per square meter administrated IV on day 1 of each chemotherapy cycle
DRUGVincristine
1.4 mg of vincristine per square meter, up to a maximal dose of 2 mg, administrated IV on day 1 of each chemotherapy cycle
DRUGCyclophosphamide
750 mg of cyclophosphamide per square meter of body-surface area administrated IV on day 1 of each chemotherapy cycle
DRUGprednisone
100 mg of prednisone administrated PO per day for five days, day 1-5 of each chemotherapy cycle
Sponsors
Mabion SA
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histological confirmed CD20 (cluster of differentiation 20) positive diffuse large B cell lymphoma (DLBCL) 2. Patients that had been diagnosed according to the WHO classification; 3. Performance status ≤ 2 on the ECOG (Eastern Cooperative Oncology Group) / WHO (world Health Organization) scale, performance status of 3 will be accepted if impairment is caused by DLBCL complications and improvement is expected once therapy is initiated;
Exclusion criteria
1. Life expectance less than 6 months; 2. Any chemotherapy, radiotherapy, immunotherapy, biologic, investigational or hormonal therapy for treatment of lymphoma within 28 days prior to treatment; 3. Rituximab, other anti-CD20 mAb (Monoclonal Antibodies) drug treatment, treatment with any cell depleting therapies - e.g., anti-CD4 (cluster of differentiation 4) anti-CD5 (cluster of differentiation 5), anti-CD3 (cluster of differentiation 3), anti-CD19 (cluster of differentiation 19), anti CD11 (cluster of differentiation 11), anti-CD22 (cluster of differentiation 11), BLys/BAFF (B Lymphocyte Stimulator/B-cell activating factor) within 1,5 years before screening;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration-time Curve From Week 13 to Week 26 (AUC[W13-W26]) | Week 13 to Week 26 | Area under the serum concentration-time curve from time zero to final time point measured from Week 13 until Week 26 (AUC\[W13-W26\]). PK blood samples for this endpoint were drawn at Day 85 ± 4 (before and after completion of the fifth infusion), Day 106 ± 4 (before and after completion of sixth infusion), Day 127 ± 4 (before and after completion of the seventh infusion), Day 148 ± 4 (before and after completion of the eight infusion), Day 155 ± 4 (one week after last infusion) and Day 176 ± 4 (one month after last infusion). |
| Area Under the Serum Concentration-time Curve From Day 1 to Week 4 (AUC[1-4]) | Baseline to Week 4 | Area under the serum concentration-time curve from time zero (Day 1) to final time point measured after the first administration (Week 1) until Week 4 (AUC(W1-W4)). PK blood samples for this endpoint were drawn at Day 1 (before and after the first infusion), Day 8 ± 1 (7 days after first infusion), Day 15 ± 1 (14 days after first infusion), Day 22 ± 2 (before and after completion of the second infusion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kel (Post 5th and 8th Infusions) | Week 13 (5th infusion) and Week 22 (8th infusion) | Elimination Rate Constant at steady stade after the 5th and 8th infusions. |
| Ctrough (Before 8th Infusion) | Week 22 | Trough serum concentration measured at the end of a dosing interval at steady state, taken directly before eighth infusion. |
| Cmax (Post 5th and 8th Infusion) | Week 13 (5th infusion) and Week 22 (8th infusion) | Maximum serum drug concentration (Cmax) at steady state after the 5th and 8th infusions. |
| CLss (Post 5th and 8th Infusions) | Week 13 to Week 16 and Week 22 to Week 26 | Clearance at steady state after the 5th and 8th infusions. |
| AUC (W1-W26) | Week 1 until Week 26 | Area under the serum concentration-time curve measured after the first administration (Week 1) until Week 26 (AUC(1-26)) |
| Efficacy Assessment at Week 26 | Week 26 | An efficacy assessment was made after 8 treatment cycles (at Week 26) based on tumour responses classified according to the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al. 1999). Response was assessed based on clinical, radiologic (CT scan) and pathologic (bone marrow) criteria. Possible efficacy responses were: complete response, partial response, stable disease, and progressive disease. Efficacy reported here includes all patients included in the ITT set. |
| Adverse Events | from baseline to Week 46 | Percentage of patients with at least one AE in a given category. Data from the entire follow-up are included (Period 1 and Period 2). |
| AUC (W1-W26) B-cell | baseline to Week 26 | Area under the serum concentration-time curve of CD19+ B cell counts, measured from the first administration to the final time point at Week 26 (AUC(1-26) B-cell). |
| T1/2 (Post 5th and 8th Infusions) | Week 13 to Week 16 and Week 22 to Week 26 | Elimination half-life at steady state after the 5th and 8th infusions. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity | from baseline to Week 46 | Percentage of patients with positive ADA or NAb results in a given category. Data pertain to the entire follow-up period (from Baseline to Week 46). |
Countries
Bosnia and Herzegovina, Croatia, Georgia, Moldova, Poland, Serbia, Ukraine
Participant flow
Recruitment details
The trial was initiated in 7 countries (Croatia, Bosnia and Herzegovina, Georgia, Moldova, Poland, Serbia, and Ukraine), but finally only 5 countries with 21 study sites recruited patients (Bosnia and Herzegovina, Georgia, Moldova, Poland, and Ukraine). Start date of recruitment: 29.03.2016
Pre-assignment details
Screening lasted 28 days (from Day -35 to -8 before randomization), during which the eligibility status of patients was verified. Forty-eight patients were excluded before randomization: 45 patients did not meet eligibility criteria, one patient declined participation and two patients could not be randomized because of the limited availability of investigational drugs.
Participants by arm
| Arm | Count |
|---|---|
| MabionCD20 Patients assigned to this arm received 375 mg/m2 of MabionCD20 intravenously every 3 weeks for 8 cycles on Days 1, 22 (Week 4), 43 (Week 7), 64 (Week 10), 85 (Week 13), 106 (Week 16), 127 (Week 19), and 148 (Week 22). | 100 |
| MabThera Patients assigned to this arm received 375 mg/m2 of MabThera intravenously every 3 weeks for 8 cycles on Days 1, 22 (Week 4), 43 (Week 7), 64 (Week 10), 85 (Week 13), 106 (Week 16), 127 (Week 19), and 148 (Week 22). | 40 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up Period | Adverse Event | 1 | 0 |
| Follow-up Period | Disease progression | 2 | 1 |
| Follow-up Period | Need for CNS prophylaxis | 1 | 0 |
| Follow-up Period | Patient needed bone marrow transplantation | 1 | 0 |
| Follow-up Period | Patient needed radiotherapy | 9 | 5 |
| Follow-up Period | Withdrawal by Subject | 1 | 0 |
| Treatment and Observation Period | Adverse Event | 9 | 1 |
| Treatment and Observation Period | Lack of Efficacy | 1 | 2 |
| Treatment and Observation Period | Patient needed radiotherapy | 1 | 0 |
| Treatment and Observation Period | Physician Decision | 0 | 1 |
| Treatment and Observation Period | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | MabionCD20 | MabThera | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 22 Participants | 11 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 78 Participants | 29 Participants | 107 Participants |
| Age, Continuous | 51.5 years STANDARD_DEVIATION 16.2 | 54.3 years STANDARD_DEVIATION 13.5 | 52.3 years STANDARD_DEVIATION 15.5 |
| Body weight | 76.2 kilograms STANDARD_DEVIATION 17.4 | 73.6 kilograms STANDARD_DEVIATION 17 | 75.5 kilograms STANDARD_DEVIATION 17.2 |
| BSA | 1.9 cubic metre STANDARD_DEVIATION 0.2 | 1.8 cubic metre STANDARD_DEVIATION 0.2 | 1.8 cubic metre STANDARD_DEVIATION 0.2 |
| 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 100 Participants | 40 Participants | 140 Participants |
| Sex: Female, Male Female | 54 Participants | 20 Participants | 74 Participants |
| Sex: Female, Male Male | 46 Participants | 20 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 100 | 0 / 40 |
| other Total, other adverse events | 70 / 100 | 26 / 40 |
| serious Total, serious adverse events | 19 / 100 | 5 / 40 |
Outcome results
Primary
Area Under the Serum Concentration-time Curve From Day 1 to Week 4 (AUC[1-4])
Area under the serum concentration-time curve from time zero (Day 1) to final time point measured after the first administration (Week 1) until Week 4 (AUC(W1-W4)). PK blood samples for this endpoint were drawn at Day 1 (before and after the first infusion), Day 8 ± 1 (7 days after first infusion), Day 15 ± 1 (14 days after first infusion), Day 22 ± 2 (before and after completion of the second infusion).
Time frame: Baseline to Week 4
Population: PP W1-4 set (subset of ITT population based on patients without major protocol deviations to Week 4 (visit 4) and having a PK assessment on this visit. Completion of the study was not necessary for inclusion into this population).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MabionCD20 | Area Under the Serum Concentration-time Curve From Day 1 to Week 4 (AUC[1-4]) | 1559.51 (μg*day)/mL | Standard Deviation 358.092 |
| MabThera | Area Under the Serum Concentration-time Curve From Day 1 to Week 4 (AUC[1-4]) | 1509.79 (μg*day)/mL | Standard Deviation 382.559 |
Comparison: Estimated Geo LS-means ratio.90% CI: [0.9565, 1.1321]
Primary
Area Under the Serum Concentration-time Curve From Week 13 to Week 26 (AUC[W13-W26])
Area under the serum concentration-time curve from time zero to final time point measured from Week 13 until Week 26 (AUC\[W13-W26\]). PK blood samples for this endpoint were drawn at Day 85 ± 4 (before and after completion of the fifth infusion), Day 106 ± 4 (before and after completion of sixth infusion), Day 127 ± 4 (before and after completion of the seventh infusion), Day 148 ± 4 (before and after completion of the eight infusion), Day 155 ± 4 (one week after last infusion) and Day 176 ± 4 (one month after last infusion).
Time frame: Week 13 to Week 26
Population: PP W13-26 set (subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MabionCD20 | Area Under the Serum Concentration-time Curve From Week 13 to Week 26 (AUC[W13-W26]) | 16498.9 (μg*day)/mL | Standard Deviation 3492.39 |
| MabThera | Area Under the Serum Concentration-time Curve From Week 13 to Week 26 (AUC[W13-W26]) | 15647.4 (μg*day)/mL | Standard Deviation 3629.83 |
Comparison: Estimated Geo LS-means ratio.90% CI: [0.9822, 1.1464]
Secondary
Adverse Events
Percentage of patients with at least one AE in a given category. Data from the entire follow-up are included (Period 1 and Period 2).
Time frame: from baseline to Week 46
Population: SAF set (all patients randomized into the study and receiving at least one infusion of MabionCD20 or MabThera).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MabionCD20 | Adverse Events | TEAEs | 71.0 percent |
| MabionCD20 | Adverse Events | related severe TEAEs | 29.0 percent |
| MabionCD20 | Adverse Events | severe TEAEs | 40.0 percent |
| MabionCD20 | Adverse Events | related TESAEs | 13.0 percent |
| MabionCD20 | Adverse Events | TESAEs | 19.0 percent |
| MabionCD20 | Adverse Events | TEAEs leading to death | 8.0 percent |
| MabionCD20 | Adverse Events | related TEAEs | 53.0 percent |
| MabionCD20 | Adverse Events | related TEAEs leading to death | 2.0 percent |
| MabionCD20 | Adverse Events | all AEs | 71.0 percent |
| MabThera | Adverse Events | related TEAEs leading to death | 0 percent |
| MabThera | Adverse Events | all AEs | 67.5 percent |
| MabThera | Adverse Events | TEAEs | 65.0 percent |
| MabThera | Adverse Events | TESAEs | 12.5 percent |
| MabThera | Adverse Events | severe TEAEs | 22.5 percent |
| MabThera | Adverse Events | related TEAEs | 42.5 percent |
| MabThera | Adverse Events | related severe TEAEs | 22.5 percent |
| MabThera | Adverse Events | related TESAEs | 5.0 percent |
| MabThera | Adverse Events | TEAEs leading to death | 0 percent |
Secondary
AUC (W1-W26)
Area under the serum concentration-time curve measured after the first administration (Week 1) until Week 26 (AUC(1-26))
Time frame: Week 1 until Week 26
Population: PP W1-W26 set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MabionCD20 | AUC (W1-W26) | 28413.6 (μg*day)/mL | Standard Deviation 5194.98 |
| MabThera | AUC (W1-W26) | 26955.3 (μg*day)/mL | Standard Deviation 5849.22 |
Secondary
AUC (W1-W26) B-cell
Area under the serum concentration-time curve of CD19+ B cell counts, measured from the first administration to the final time point at Week 26 (AUC(1-26) B-cell).
Time frame: baseline to Week 26
Population: ITT set (a subset of safety population based on patients who had at least one complete post baseline assessment of the area under the serum concentration-time curve from time zero to final time point (AUC(0-t)), measured after the first administration (Week 1) until the second administration at Week 4(AUC(1-4)).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MabionCD20 | AUC (W1-W26) B-cell | 3395.82 cells*days/mL blood | Standard Deviation 22364.5 |
| MabThera | AUC (W1-W26) B-cell | 10476.2 cells*days/mL blood | Standard Deviation 56943 |
Secondary
CLss (Post 5th and 8th Infusions)
Clearance at steady state after the 5th and 8th infusions.
Time frame: Week 13 to Week 16 and Week 22 to Week 26
Population: PP W13-26 set (subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MabionCD20 | CLss (Post 5th and 8th Infusions) | 5th infusion | 198.701 mL/day | Standard Deviation 53.427 |
| MabionCD20 | CLss (Post 5th and 8th Infusions) | 8th infusion | 179.168 mL/day | Standard Deviation 58.509 |
| MabThera | CLss (Post 5th and 8th Infusions) | 5th infusion | 206.905 mL/day | Standard Deviation 78.213 |
| MabThera | CLss (Post 5th and 8th Infusions) | 8th infusion | 191.272 mL/day | Standard Deviation 89.016 |
Secondary
Cmax (Post 5th and 8th Infusion)
Maximum serum drug concentration (Cmax) at steady state after the 5th and 8th infusions.
Time frame: Week 13 (5th infusion) and Week 22 (8th infusion)
Population: PP W13-26 set (subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MabionCD20 | Cmax (Post 5th and 8th Infusion) | 5th infusion | 273.356 μg/mL | Standard Deviation 65.452 |
| MabionCD20 | Cmax (Post 5th and 8th Infusion) | 8th infusion | 296.784 μg/mL | Standard Deviation 58.295 |
| MabThera | Cmax (Post 5th and 8th Infusion) | 5th infusion | 266.439 μg/mL | Standard Deviation 66.086 |
| MabThera | Cmax (Post 5th and 8th Infusion) | 8th infusion | 296.462 μg/mL | Standard Deviation 69.641 |
Secondary
Ctrough (Before 8th Infusion)
Trough serum concentration measured at the end of a dosing interval at steady state, taken directly before eighth infusion.
Time frame: Week 22
Population: PP W13-26 set (subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MabionCD20 | Ctrough (Before 8th Infusion) | 102.246 μg/mL | Standard Deviation 43.897 |
| MabThera | Ctrough (Before 8th Infusion) | 90.61 μg/mL | Standard Deviation 41.994 |
Secondary
Efficacy Assessment at Week 26
An efficacy assessment was made after 8 treatment cycles (at Week 26) based on tumour responses classified according to the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al. 1999). Response was assessed based on clinical, radiologic (CT scan) and pathologic (bone marrow) criteria. Possible efficacy responses were: complete response, partial response, stable disease, and progressive disease. Efficacy reported here includes all patients included in the ITT set.
Time frame: Week 26
Population: ITT population including all randomized patients
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MabionCD20 | Efficacy Assessment at Week 26 | Partial | 42 Participants |
| MabionCD20 | Efficacy Assessment at Week 26 | Progressive disease | 10 Participants |
| MabionCD20 | Efficacy Assessment at Week 26 | Stable disease | 10 Participants |
| MabionCD20 | Efficacy Assessment at Week 26 | Missing | 4 Participants |
| MabionCD20 | Efficacy Assessment at Week 26 | Complete | 34 Participants |
| MabThera | Efficacy Assessment at Week 26 | Missing | 2 Participants |
| MabThera | Efficacy Assessment at Week 26 | Complete | 14 Participants |
| MabThera | Efficacy Assessment at Week 26 | Partial | 18 Participants |
| MabThera | Efficacy Assessment at Week 26 | Stable disease | 4 Participants |
| MabThera | Efficacy Assessment at Week 26 | Progressive disease | 2 Participants |
Secondary
Kel (Post 5th and 8th Infusions)
Elimination Rate Constant at steady stade after the 5th and 8th infusions.
Time frame: Week 13 (5th infusion) and Week 22 (8th infusion)
Population: PP W13-26 set (subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MabionCD20 | Kel (Post 5th and 8th Infusions) | 5th infusion | 0.05663 1/day | Standard Deviation 0.01794 |
| MabionCD20 | Kel (Post 5th and 8th Infusions) | 8th infusion | 0.04335 1/day | Standard Deviation 0.01528 |
| MabThera | Kel (Post 5th and 8th Infusions) | 5th infusion | 0.05418 1/day | Standard Deviation 0.01884 |
| MabThera | Kel (Post 5th and 8th Infusions) | 8th infusion | 0.04379 1/day | Standard Deviation 0.0123 |
Secondary
T1/2 (Post 5th and 8th Infusions)
Elimination half-life at steady state after the 5th and 8th infusions.
Time frame: Week 13 to Week 16 and Week 22 to Week 26
Population: PP W13-26 set (subset of ITT population based on patients without major protocol deviations and having a PK assessment from Week 13 to Week 26).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MabionCD20 | T1/2 (Post 5th and 8th Infusions) | 5th infusion | 14.801 days | Standard Deviation 12.218 |
| MabionCD20 | T1/2 (Post 5th and 8th Infusions) | 8th infusion | 18.301 days | Standard Deviation 7.92 |
| MabThera | T1/2 (Post 5th and 8th Infusions) | 5th infusion | 15.217 days | Standard Deviation 7.889 |
| MabThera | T1/2 (Post 5th and 8th Infusions) | 8th infusion | 16.997 days | Standard Deviation 4.515 |
Other Pre-specified
Immunogenicity
Percentage of patients with positive ADA or NAb results in a given category. Data pertain to the entire follow-up period (from Baseline to Week 46).
Time frame: from baseline to Week 46
Population: SAF set (sample from one patient not collected)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MabionCD20 | Immunogenicity | Persistent ADA | 4 participants |
| MabionCD20 | Immunogenicity | Treatment-boosted ADA | 0 participants |
| MabionCD20 | Immunogenicity | Transient ADA | 2 participants |
| MabionCD20 | Immunogenicity | NAb positive | 0 participants |
| MabionCD20 | Immunogenicity | Treatment-induced ADA | 6 participants |
| MabThera | Immunogenicity | NAb positive | 0 participants |
| MabThera | Immunogenicity | Treatment-induced ADA | 1 participants |
| MabThera | Immunogenicity | Persistent ADA | 1 participants |
| MabThera | Immunogenicity | Transient ADA | 0 participants |
| MabThera | Immunogenicity | Treatment-boosted ADA | 0 participants |