Safety and Efficacy Study of BCD-020 in Therapy of Indolent Non-Hodgkin's Lymphoma

Study Overview
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Brief Summary
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This international multi-center, randomized, controlled, open-label study investigated the pharmacokinetics, pharmacodynamics, efficacy and safety of BCD-020 (INN: rituximab, CJSC Biocad) versus MabThera® (INN: rituximab, F. Hoffmann La Roche, Ltd.) both administered as a monotherapy of patients with indolent non-Hodgkin's lymphoma. Patients were randomized to receive 375 mg/m² BCD-020 as intravenous infusion once a week for 4 weeks or MabThera® at the same regimen.

Official Title
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A Multicenter Open-label Randomized Study of BCD-020 (Rituximab, CJSC BIOCAD, Russia) Efficacy and Safety in Comparison With MabThera (F. Hoffmann-La Roche Ltd., Switzerland) in Monotherapy of CD20-positive Indolent Non-Hodgkin's Lymphoma

Conditions
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Follicular Non-Hodgkin's Lymphoma, Nodal Marginal Zone Lymphoma, Splenic Marginal Zone Lymphoma

Intervention / Treatment
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* Biological: rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Having signed a written informed consent; Patients' age is 18 years or more; Diagnosis of CD20-positive indolent non-Hodgkin lymphoma of following morphological types:Follicular non-Hodgkin lymphoma stage II-IV according to Ann Arbor, grade I-II;Nodal marginal zone lymphoma stage II-IV according to Ann Arbor; Splenic marginal zone lymphoma. Life expectancy of not less than 3 months after the enrollment in the study; Morphological and immunohistochemical examination of the tumor (both lymph node biopsy and bone marrow biopsy) - within 3 months before the enrollment in the study ; Performance status ≤2 on the ECOG scale; Hemoglobin > 80 g/l; leukocyte count ≥ 3.0×109/l but less than 25×109/l, absolute neutrophil count ≥1.5×109/l, platelet count ≥100×109/l; Presence of at least one measurable lesion; Patient's ability in the investigator's opinion to comply with the protocol procedures; Willingness of patients with preserved reproductive function to use reliable contraception methods (at least two contraception methods in women, e.g., spermicide and condom). Exclusion Criteria: Bulky disease - size of any single lesion more than 10 cm in the greatest diameter; Secondary transformation to high-grade lymphoma; Other types of non-Hodgkin lymphomas apart from follicular non-Hodgkin stage II-IV lymphoma according to Ann Arbor, grade 1,2; nodal marginal zone lymphoma stage II-IV according to Ann Arbor; splenic marginal zone lymphoma. Patients regularly taking corticosteroids during 1 month preceding the enrollment in the study; Occurrence of other (aside from NHL) diseases that can distort the assessment of the main disease symptoms expression; mask, enhance, modify the main disease symptoms or induce clinical and laboratory-instrumental symptoms similar to the non-Hodgkin lymphomas; Severe resistant hypertension; Decompensated forms of heart (NYHA class ХСН III, IV), liver and kidney disorders (creatinine level >133 µmol/l, AST, ALT, and bilirubin level 3 times exceeding the norm) except for the cases where the symptom is caused by lymphoma; Decompensated respiratory failure; Tumor infiltration of the lungs; Decompensated diabetes mellitus; Active autoimmune diseases; Ongoing infections requiring antimicrobial therapy. Usage of the drugs: At any time prior to the enrollment into the study - interferon-based drugs or monoclonal antibodies for the treatment of NHL; Chemotherapy or radiotherapy was completed less than 21 day prior to the enrollment into the study; Vaccination within 1 week prior to the enrollment into the study; Presence of any psychiatric disorders including major depressive conditions and/or suicidal thoughts in anamnesis that in opinion of the investigator may put a patient at an excessive risk or influence the ability of patients to fulfill the study protocol; Myocardial infarction less than 1 month before the enrollment into the study; Severe CNS or PNS dysfunctions; Drug and alcohol addiction; Known HIV, HBV, HCV infection, syphilis; Known primary or secondary immunodeficiency; Primary CNS lymphoma or metastasis in the CNS; Known intolerance or allergy to mouse proteins or any components of the study drugs, and also to the premedication drugs; Pregnancy or lactation; Prior or concomitant malignances except for adequately treated basal cell carcinoma and in situ cervical cancer; Any restraints or impossibility to administer the study drug via an intravenous infusion; Major surgery within 1 week prior to the enrollment into the study; Simultaneous participation in any other clinical study or any preceding participation in other studies within 3 months prior to enrollment in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MabThera<br>Reference rituximab at a dose of 375 mg/m2 intravenously once a week for four weeks (on days 1, 8, 15 and 22) | Biological: rituximab<br>* Patients will receive rituximab at a dose of 375 mg/m2 intravenously once a week for 4 weeks (on day 1,8,15,22)<br>* Other names: Biological: BCD-020, MabThera;|
| Experimental: BCD-020<br>Proposed rituximab biosimilar at a dose of 375 mg/m2 intravenously once a week for four weeks (on days 1, 8, 15 and 22) | Biological: rituximab<br>* Patients will receive rituximab at a dose of 375 mg/m2 intravenously once a week for 4 weeks (on day 1,8,15,22)<br>* Other names: Biological: BCD-020, MabThera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Estimation of the overall response rate in each treatment arm at the end of treatment | day 50 (cycle 4) | 
| CD20-positive cells count | Comparison of peripheral blood B-cell depletion and repletion after BCD-020 and MabThera intravenous administration | day 50 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Estimation of maximum rituximab serum concentrations after administration of BCD-020 to that obtained after administration of MabThera | day 22 | 
| AUC(0-168) | Estimation of rituximab exposition after administration of BCD-020 to that obtained after administration of MabThera | 168 hours | 
| Complete response rate | Assessment of complete response rates of BCD-020 and MabThera given as a monotherapy at the end/completion of the treatment | day 50 | 
| Frequency of AEs/sAEs grade 3-4 (CTCAE v.4.03) | Evaluation of the safety profiles of BCD-020 and MabThera | day 50 | 
| Levels of binding and neutralizing antibodies to rituximab | Immunogenicity assessment of BCD-020 and MabThera | day 50 | 
| AUC(0-1176), AUC(0-inf) | Estimation of rituximab serum concentrations after administration of BCD-020 to that obtained after administration of MabThera | day 50 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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lymphoma, non-Hodgkin's