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Rituximab

Antineoplastic Agents, Immunological

Immunologic Factors

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

MabThera® for infusion 375 mg/m2 administered via IV infusion on Days 1, 8, 15, 22 and Week 12, 20, 28 and 36.

Proposed rituximab biosimilar, 100mg and 500mg, concentrate for solution for infusion

DRL_RI (Proposed rituximab biosimilar)

Reference product rituximab, 100mg and 500mg, concentrate for solution for infusion

MabThera®

Eliso Sopia, MD

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

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.

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

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

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

Best Overall Response Rate (BORR) is defined as the proportion of participants in each treatment group that achieved a best overall response of either Complete response (CR), unconfirmed Complete response (CRu) or Partial response (PR), up to Month 7 (Week 28) based on central radiology review in accordance with the Cheson, 1999 response criteria for Non-Hodgkin's Lymphomas. As per Cheson 1999, response criteria for target lesions and assessed by radiology: Complete response (CR): All lesions with a longest diameter should be regressed to normal size (≤ 15 mm) or short axis regressed to ≤ 10 mm with confirmed Bone marrow normalization; unconfirmed Complete response (CRu): All lesions with a longest diameter should be regressed to normal size (≤ 15 mm) or short axis regressed to ≤ 10 mm with non-confirmed Bone marrow normalization; Partial Response (PR): ≥ 50 % decrease of sum of products of diameter(SPD) of all the target lesions; Overall Response (OR)=CR+CRu+PR.

The overall response rate (ORR) is defined as proportion of participants in each treatment group achieved a complete response or partial response at week 12 and week 28 based on central radiology review in accordance with published response criteria for malignant lymphoma. As per Cheson 1999, response criteria for target lesions and assessed by radiology: Complete response (CR): All lesions with a longest diameter should be regressed to normal size (≤ 15 mm) or short axis regressed to ≤ 10 mm with confirmed Bone marrow normalization; unconfirmed Complete response (uCR): All lesions with a longest diameter should be regressed to normal size (≤ 15 mm) or short axis regressed to ≤ 10 mm with non-confirmed Bone marrow normalization; Partial Response (PR): ≥ 50 % decrease of sum of products of diameter(SPD) of all the target lesions; Overall Response (OR)=CR+uCR+PR.

Complete Response rate is defined as the proportion of participants in each treatment group who achieved complete response up to particular visit based on investigator assessment in accordance with the response criteria for malignant lymphoma. As per Cheson 1999, response criteria for target lesions and assessed by radiology: Complete response (CR): All lesions with a longest diameter should be regressed to normal size (≤ 15 mm) or short axis regressed to ≤ 10 mm with confirmed Bone marrow normalization.

Complete Response Rate as a Best Response is defined as the proportion of participants in each treatment group that achieved the best complete response up to Week 28 based on central radiology review in accordance with the Cheson 1999, response criteria for malignant lymphoma. As per Cheson 1999, response criteria for target lesions and assessed by radiology: Complete response (CR): All lesions with a longest diameter should be regressed to normal size (≤ 15 mm) or short axis regressed to ≤ 10 mm with confirmed Bone marrow normalization.

Duration of response (DOR) defined as the time from date of the first documentation of tumor response (Complete Response, unconfirmed complete response or partial response) to the date of first documentation of progressive disease (PD) or to death due to any cause up to 52 weeks/ End of study (EOS). Progression is defined as per Cheson 1999, response criteria is:

Target Nodal SPD Progression: at least one node must be abnormal, and the SPD of all nodes must increase by ≥ 50% from its nadir SPD.

Target Extranodal SPD Progression: at least one extranodal lesion must be present and the SPD of all extranodal lesions must increase by ≥ 50% from its nadir SPD.

Also, if a patient had any unequivocal progression in non-target lesions; and detection of any new nodal lesion (longest diameter \[LDi\] 15mm with an absolute increase of 5mm) his/her response was considered as Progressive disease.

Progression-free survival (PFS) is defined as the time from date of randomization to the date of documented progressive disease or death due to any cause. Progression is defined as per Cheson 1999, response criteria is:

Target Nodal SPD Progression: at least one node must be abnormal, and the SPD of all nodes must increase by ≥ 50% from its nadir SPD.

Target Extranodal SPD Progression: at least one extranodal lesion must be present and the SPD of all extranodal lesions must increase by ≥ 50% from its nadir SPD.

Also, if a patient had any unequivocal progression in non-target lesions; and detection of any new nodal lesion (LDi 15mm with an absolute increase of 5mm) his/her response was considered as Progressive disease.

The Overall survival (OS) defined as the time from date of randomization to the date of death from any cause up to 52 weeks or EOS.

The safety and tolerability of DRL_RI and MabThera® in participants with CD20-positive, LTB-FL was evaluated.

The immunogenicity of the Proposed Rituximab Biosimilar (DRL_RI) with MabThera® among trial participants was compared.

Parexel

Dr. Reddy's Laboratories Limited

The SAF include all participants who have received at least 1 dose of study drug and will be used for safety analysis. The number of participants analyzed for safety analysis is different from ITT analysis population (ITT population was defined as all patients randomized). Two participants were randomized but did not receive the treatment with MabThera and therefore were not included in the SAF but included in ITT.

Randomized participants were administered DRL_RI 375mg/m\^2 via IV infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36.

Arm A: DRL_RI

Randomized participants were administered MabThera® 375 mg/m\^2 via IV infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36.

Arm B: MabThera®

Randomized participants were administered DRL_RI 375 mg/m\^2 via IV infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36

Randomized participants were administered MabThera® 375 mg/m\^2 via IV infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

White

Asian

Black or African American

Aboriginal/Torres Strait Islander

Unknown

Not Reported

Race/Ethnicity, Customized

The Intent to Treat (ITT) Analysis Set included all randomized participants.

Head - Clinical Development

The ITT Analysis Set included all randomized participants.

Best Overall Response Rate (BORR) for Low Tumor Burden Follicular Lymphoma

Week 12

Week 28

Overall Response Rate (ORR)

Complete Response Rate

Complete Response Rate as a Best Response

Randomized participants were administered DRL_RI 375mg/m\^2 via intravenous (IV) infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36.

The ITT Analysis Set included all randomized participants. The number analyzed are the participants with complete response, unconfirmed complete response or partial response.

Duration of Response (DOR)

Progression-free Survival (PFS)

Overall Survival (OS)

Treatment-emergent adverse events (TEAEs)

Non-TEAEs

Infusion related AEs

TEAE>=Common terminology Criteria for Adverse events (CTCAE) grade 3

Serious TEAEs

TEAEs related to study drug

Fatal TEAEs

The Safety Analysis Set (SAF) will include all the participants who have received at least one dose of study drug. The SAF will be used for safety analysis.

Number of Participants With Adverse Events

Day 1

Week 2

Week 3

Week 4

Number of Participants With Positive Anti-drug Antibody (ADA)

Randomized participants were administered rituximab biosimilar-Dr. Reddy's Lab (DRL_RI) 375mg/m\^2 via intravenous (IV) infusion on Days 1, 8, 15, 22 and Weeks 12, 20, 28 and 36.

Spots Global Cancer Trial Database for drl ri (proposed rituximab biosimilar)