Compare Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) With MabThera® in LTB Follicular Lymphoma

Study Overview
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Brief Summary
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The primary objective of the current study is to demonstrate the equivalent efficacy of rituximab (DRL_RI) and MabThera® in subjects with Low Tumor Burden Follicular Lymphoma (LTB-FL). Also evaluated by Pharmacokinetic, safety, and immunogenicity assessment between a proposed biosimilar (DRL_RI) and the RMP, as an component of clinical study program, and collectively providing the evidence of biosimilarity. The study will compare the safety and efficacy of DRL_RI vs MabThera in patients with Low Tumor Burden Follicular Lymphoma (LTB-FL). The primary objective is to establish comparative efficacy as measured by ORR up to week 28

Detailed Description
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It is planned to randomise approx. 312 subjects at approximately ≥ 130 study sites worldwide. Subjects with LTB-FL will be randomized to receive either DRL_RI or MabThera®. Till date, 68 patients have been randomized for the study. The study specific objectives are mentioned below: Primary Objective: • To demonstrate the equivalent efficacy of DRL_RI (biosimilar rituximab) and MabThera in subjects with CD20-positive, LTB FL, as measured by overall response rate (ORR) up to Week 28 evaluated in accordance with Cheson, 1999 response criteria for Non-Hodgkin's Lymphomas. Secondary Objectives: To compare the progression-free survival (PFS), overall survival (OS), and duration of response (DOR) of DRL_RI with MabThera® in subjects with CD20-positive, LTB FL. To compare the safety, tolerability, and immunogenicity of DRL_RI with MabThera in subjects with CD20-positive, LTB-FL. Exploratory Objectives To explore the pharmacokinetic (PK) parameters of DRL_RI and MabThera, using a population-PK modelling approach. To explore the pharmacodynamic parameters of DRL_RI and MabThera.

Official Title
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A Double-blind, Parallel-group, Phase III Study to Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) With MabThera® in Subjects With Previously Untreated (CD)20-Positive LTB Follicular Lymphoma

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Biological: DRL_RI (Proposed rituximab biosimilar)
* Other: MabThera®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is Male or female subjects aged ≥18 years of age. Subject is histologically confirmed, Grade 1-3a, previous ly untreated, CD20-pos itive. Subject has Ann Arbor Stage II to IV and ECOG status of 0 to 1. Subject has Low tumor burden follicular lymphoma as per Groupe d'Etude des Lymphomes Folliculaires (GELF) Criteria Subject has at least 1 measurable tumor mass in 2 dimensions, and the mass must be: Nodal lesion >15 mm in the longest dimension; or Noda l lesion >10 mm to he longest dimension; dimens ion and >10 mm in the shortest dimension; or Extra-nodal lesion with both long and short dimensions ≥10 mm. Subject has Life expectancy ≥3 months. If female subject, then subject should be non-pregnant, non-lactating. Exclusion Criteria: Subject with prior use of rituximab or any CD20 monoclonal antibody for any reason. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or other foreign origin. Any prior therapy for follicular lymphoma (including but not limited to chemotherapy, radiotherapy) or subjects on chronic supra-substitutive doses of systemic gluco-corticosteriods. Subjects who, in the opinion of the Investigator, require additional concomitant treatment for lymphoma. Evidence of histologic transformation to high grade lymphoma or diffuse large B-cell lymphoma. Subjects with known sero-positivity for or history of active viral infection with human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) will be excluded. And if positive for hepatitis B core antibody or hepatitis C virus (HCV) antibody can only be enrolled if HBV - DNA level <20 IU/mL (or 112 copies/mL) and HCV - RNA is negative respectively by PCR test.. Subjects who have received a live vaccine within last 3 months of the first administration of study drug. Subjects with history or presence of a medical condition or disease that in the Investigator's opinion would place the subject at an unacceptable risk for study participation. Participation in any clinical study or having taken any investigational therapy (within 2-months of the first dose of study drug. Women of childbearing potential who do not consent to use highly effective methods of birth control.

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
Interventional Model Description: Clinical Phase III, randomised, multicentre, double-blind study to demonstrate the equivalence of DRL_RI to MabThera® in subjects with previously untreated, LTB-FL.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: DRL_RI<br>DRL_RI (rituximab-Dr. Reddy's Lab) for infusion 375 mg/m2 administered via IV infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36 | Biological: DRL_RI (Proposed rituximab biosimilar)<br>* Proposed rituximab biosimilar, 100mg and 500mg, concentrate for solution for infusion<br>|
| Active Comparator: Arm B: MabThera®<br>MabThera® for infusion 375 mg/m2 administered via IV infusion on Days 1, 8, 15, 22 and Week 12, 20, 28 and 36. | Other: MabThera®<br>* Reference product rituximab, 100mg and 500mg, concentrate for solution for infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Overall Response Rate (BORR) measured for low tumor burden follicular lymphoma, up to week 28 | Primary endpoint: The primary endpoint is Best Overall Response Rate (BORR), up to Month 7 (Week 28) based on central radiology review in accordance with the Cheson, 1999 response criteria for Non-Hodgkin's Lymphomas. | BORR up to Month 7 (Week 28)} | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival | Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL | Upto week 52 | 
| Overall response rate (ORR) at Week 12, 28 & 52 | Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL | at week 12, week 28 and week 52 | 
| Overall survival up to 52 weeks/End of Study (EOS) | Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL | upto week 52 | 
| Duration of response (DOR) up to 52 weeks/EOS | Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL | upto week 52 | 
| The safety and tolerability in terms of serum SGOT levels (U/L) | The liver enzyme levels will be compared between the groups. | upto week 52 | 
| The safety and tolerability in terms of serum SGPT (U/L) | The liver enzyme levels will be compared between the groups | upto week 52 | 
| Safety and tolerability in terms of serum creatinine levels (µmol/L) | serum creatinine levels will be compared between the groups at all scheduled visits | upto week 52 | 
| The safety and tolerability in terms of incidence of adverse events reported. As described below the data will be compared between the groups. | The incidence of infusion related reactions (number of subjects reported the event) and all other Treatment-Emergent Adverse Events reported in the trial (number of subjects reported the event and number of events reported for each type of adverse event) | upto week 52 | 
| The safety and tolerability in terms of Blood Pressure (mm of hg) will be compared between the groups | The change of BP (mm of hg) from baseline to scheduled visits by treatment group | upto week 52 | 
| The safety and tolerability in terms of ECG parameters. As described below the data will be compared between the groups. | Summary of subjects with designated changes in VR (beats/minute) and QT, QTcF, PR, QRS and RR intervals (milli seconds) of ECG from baseline to EOS by treatment group | upto week 52 | 
| The safety and tolerability in terms of absolute Neutrophil count (total count/L) | absolute Neutrophil count will be compared between the groups at all scheduled visits | upto week 52 | 
| The safety and tolerability in terms of Respiratory rate (breaths/minute) will be compared between the groups | The change of Respiratory rate (breaths/minute) from baseline to scheduled visits by treatment group | upto week 52 | 
| The safety and tolerability in terms of Heart rate (beats/minute) will be compared between the groups | The change of Heart rate (beats/minute) from baseline to scheduled visits by treatment group | upto week 52 | 
| The safety and tolerability in terms of temperature (°C) will be compared between the groups | The change of temperature (°C) from baseline to scheduled visits by treatment group | upto week 52 | 
| The safety and tolerability in terms of ECOG change. As described below the data will be compared between the groups. | Summary of ECOG performance status (on a scale of grade 0 to 5) at scheduled visits by treatment group. | upto week 52 | 
| to compare immunogenicity in terms of incidence of anti-drug antibodies | The immunogenicity of the Proposed Rituximab Biosimilar (DRL_RI) with MabThera® among trial subjects will be compared as mentioned below: • Comparison of incidence of subjects developing anti-drug antibodies (in number of individuals) | upto week 52 | 
| to compare immunogenicity in terms of incidence of titres | The immunogenicity of the Proposed Rituximab Biosimilar (DRL_RI) with MabThera® among trial subjects will be compared as mentioned below: • For those positive for anti-drug antibodies their titres will be compared (in dilutions i.e. 1/10, 1/100) | upto week 52 | 
| to compare immunogenicity in terms of incidence of neutralizing antibodies | The immunogenicity of the Proposed Rituximab Biosimilar (DRL_RI) with MabThera® among trial subjects will be compared as mentioned below: • incidence of subjects positive for neutralizing antibodies will be compared (in number of individuals) | upto week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Follicular Lymphoma, Dr. Reddy's Rituximab, Biosimiliar (DRL_RI), FLINTER