MabionCD20 Compared to MabThera in Lymphoma Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized, Parallel-group, Double-blind, Comparative Bioequivalence Trial of MabionCD20 Compared to MabThera (Rituximab by Hoffman-La Roche) in Patients With Diffuse Large B-cell Lymphoma

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Doxorubicin
* Drug: Vincristine
* Drug: Cyclophosphamide
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histological confirmed CD20 (cluster of differentiation 20) positive diffuse large B cell lymphoma (DLBCL) Patients that had been diagnosed according to the WHO classification; 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: Life expectance less than 6 months; Any chemotherapy, radiotherapy, immunotherapy, biologic, investigational or hormonal therapy for treatment of lymphoma within 28 days prior to treatment; 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;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MabionCD20<br>A course of MabionCD20 consists of intravenous infusions in dose 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles. Intervention: Drug: Rituximab | Drug: Rituximab<br>* 375 mg/m2 IV on day 1 of each 21 days chemotherapy cycle. Number of Cycles: 8.<br>* Other names: MabThera®, MabionCD20®;Drug: Doxorubicin<br>* 50 mg of doxorubicin per square meter administrated IV on day 1 of each chemotherapy cycle<br>* Other names: Hydroxydaunorubicin;Drug: Vincristine<br>* 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<br>* Other names: Oncovine;Drug: Cyclophosphamide<br>* 750 mg of cyclophosphamide per square meter of body-surface area administrated IV on day 1 of each chemotherapy cycle<br>Drug: prednisone<br>* 100 mg of prednisone administrated PO per day for five days, day 1-5 of each chemotherapy cycle<br>|
| Active Comparator: MabThera<br>A course of MabThera consists of intravenous infusions in dose 375 mg/m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles. Intervention: Drug: Rituximab | Drug: Rituximab<br>* 375 mg/m2 IV on day 1 of each 21 days chemotherapy cycle. Number of Cycles: 8.<br>* Other names: MabThera®, MabionCD20®;Drug: Doxorubicin<br>* 50 mg of doxorubicin per square meter administrated IV on day 1 of each chemotherapy cycle<br>* Other names: Hydroxydaunorubicin;Drug: Vincristine<br>* 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<br>* Other names: Oncovine;Drug: Cyclophosphamide<br>* 750 mg of cyclophosphamide per square meter of body-surface area administrated IV on day 1 of each chemotherapy cycle<br>Drug: prednisone<br>* 100 mg of prednisone administrated PO per day for five days, day 1-5 of each chemotherapy cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline to Week 4 | 
| 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). | Week 13 to Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ctrough (Before 8th Infusion) | Trough serum concentration measured at the end of a dosing interval at steady state, taken directly before eighth infusion. | Week 22 | 
| Cmax (Post 5th and 8th Infusion) | Maximum serum drug concentration (Cmax) at steady state after the 5th and 8th infusions. | Week 13 (5th infusion) and Week 22 (8th infusion) | 
| Kel (Post 5th and 8th Infusions) | Elimination Rate Constant at steady stade after the 5th and 8th infusions. | Week 13 (5th infusion) and Week 22 (8th infusion) | 
| T1/2 (Post 5th and 8th Infusions) | Elimination half-life at steady state after the 5th and 8th infusions. | Week 13 to Week 16 and Week 22 to Week 26 | 
| CLss (Post 5th and 8th Infusions) | Clearance at steady state after the 5th and 8th infusions. | Week 13 to Week 16 and Week 22 to Week 26 | 
| 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). | baseline to Week 26 | 
| AUC (W1-W26) | Area under the serum concentration-time curve measured after the first administration (Week 1) until Week 26 (AUC(1-26)) | Week 1 until Week 26 | 
| 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. | Week 26 | 
| 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). | from baseline to Week 46 |