Follicular Lymphoma
Conditions
Keywords
Follicular Lymphoma, Dr. Reddy's Rituximab, Biosimilar (DRL_RI), FLINTER
Brief summary
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
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.
Interventions
BIOLOGICALDRL_RI (Proposed rituximab biosimilar)
Proposed rituximab biosimilar, 100mg and 500mg, concentrate for solution for infusion
OTHERMabThera®
Reference product rituximab, 100mg and 500mg, concentrate for solution for infusion
Sponsors
Parexel
Dr. Reddy's Laboratories Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject is Male or female subjects aged ≥18 years of age. 2. Subject is histologically confirmed, Grade 1-3a, previous ly untreated, CD20-pos itive. 3. Subject has Ann Arbor Stage II to IV and ECOG status of 0 to 1. 4. Subject has Low tumor burden follicular lymphoma as per Groupe d'Etude des Lymphomes Folliculaires (GELF) Criteria 5. Subject has at least 1 measurable tumor mass in 2 dimensions, and the mass must be: 1. Nodal lesion \>15 mm in the longest dimension; or 2. Noda l lesion \>10 mm to he longest dimension; dimens ion and \>10 mm in the shortest dimension; or 3. Extra-nodal lesion with both long and short dimensions ≥10 mm. 6. Subject has Life expectancy ≥3 months. 7. If female subject, then subject should be non-pregnant, non-lactating.
Exclusion criteria
1. Subject with prior use of rituximab or any CD20 monoclonal antibody for any reason. 2. Subjects with known hypersensitivity to rituximab or its excipients, or to proteins of murine or other foreign origin. 3. Any prior therapy for follicular lymphoma (including but not limited to chemotherapy, radiotherapy) or subjects on chronic supra-substitutive doses of systemic gluco-corticosteriods. 4. Subjects who, in the opinion of the Investigator, require additional concomitant treatment for lymphoma. 5. Evidence of histologic transformation to high grade lymphoma or diffuse large B-cell lymphoma. 6. 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.. 7. Subjects who have received a live vaccine within last 3 months of the first administration of study drug. 8. 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. 9. Participation in any clinical study or having taken any investigational therapy (within 2-months of the first dose of study drug. 10. Women of childbearing potential who do not consent to use highly effective methods of birth control.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate (BORR) for Low Tumor Burden Follicular Lymphoma | Month 7 (Week 28) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate | Week 28 | 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 | Week 28 | 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) | Week 52 | 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. |
| Overall Response Rate (ORR) | Week 12, Week 28 | 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. |
| Overall Survival (OS) | Week 52 | 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. |
| Number of Participants With Adverse Events | From Screening (Day -28 to -1) up to 52 weeks | The safety and tolerability of DRL\_RI and MabThera® in participants with CD20-positive, LTB-FL was evaluated. |
| Number of Participants With Positive Anti-drug Antibody (ADA) | On Day 1, Week 2, Week 3, Week 4, Week 12 post dose | The immunogenicity of the Proposed Rituximab Biosimilar (DRL\_RI) with MabThera® among trial participants was compared. |
| Progression-free Survival (PFS) | Week 52 | 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. |
Countries
United States
Participant flow
Recruitment details
The trial was conducted at 4 sites in the United States from 15 May 2019 to 27 February 2023. The final participant was examined or received an intervention for the purposes of final collection of data for the primary outcome on 28 September 2022.
Pre-assignment details
All the assessments were performed as per the schedule of the assessments.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: DRL_RI 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 | 162 |
| Arm B: MabThera® 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 | 155 |
| Total | 317 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Lost to Follow-up | 0 | 2 |
| Overall Study | Not related to Covid-19 | 9 | 13 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Arm A: DRL_RI | Total | Arm B: MabThera® |
|---|---|---|---|
| Age, Continuous | 57.6 Years STANDARD_DEVIATION 12.37 | 56.7 Years STANDARD_DEVIATION 12.7 | 55.8 Years STANDARD_DEVIATION 13.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 89 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 118 Participants | 228 Participants | 110 Participants |
| Race/Ethnicity, Customized Aboriginal/Torres Strait Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 51 Participants | 97 Participants | 46 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 5 Participants | 6 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 104 Participants | 211 Participants | 107 Participants |
| Sex: Female, Male Female | 82 Participants | 160 Participants | 78 Participants |
| Sex: Female, Male Male | 80 Participants | 157 Participants | 77 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 162 | 2 / 153 |
| other Total, other adverse events | 47 / 162 | 49 / 153 |
| serious Total, serious adverse events | 22 / 162 | 21 / 153 |
Outcome results
Primary
Best Overall Response Rate (BORR) for Low Tumor Burden 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.
Time frame: Month 7 (Week 28)
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DRL_RI | Best Overall Response Rate (BORR) for Low Tumor Burden Follicular Lymphoma | 80.2 percentage of participants |
| Arm B: MabThera® | Best Overall Response Rate (BORR) for Low Tumor Burden Follicular Lymphoma | 79.4 percentage of participants |
Secondary
Complete Response Rate
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.
Time frame: Week 28
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DRL_RI | Complete Response Rate | 32.7 percentage of participants |
| Arm B: MabThera® | Complete Response Rate | 34.2 percentage of participants |
Secondary
Complete Response Rate as a Best Response
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.
Time frame: Week 28
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: DRL_RI | Complete Response Rate as a Best Response | 34.0 percentage of participants |
| Arm B: MabThera® | Complete Response Rate as a Best Response | 35.5 percentage of participants |
Secondary
Duration of Response (DOR)
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.
Time frame: Week 52
Population: The ITT Analysis Set included all randomized participants. The number analyzed are the participants with complete response, unconfirmed complete response or partial response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: DRL_RI | Duration of Response (DOR) | NA Weeks |
| Arm B: MabThera® | Duration of Response (DOR) | NA Weeks |
Secondary
Number of Participants With Adverse Events
The safety and tolerability of DRL\_RI and MabThera® in participants with CD20-positive, LTB-FL was evaluated.
Time frame: From Screening (Day -28 to -1) up to 52 weeks
Population: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: DRL_RI | Number of Participants With Adverse Events | Infusion related AEs | 28 Participants |
| Arm A: DRL_RI | Number of Participants With Adverse Events | Serious TEAEs | 22 Participants |
| Arm A: DRL_RI | Number of Participants With Adverse Events | Non-TEAEs | 13 Participants |
| Arm A: DRL_RI | Number of Participants With Adverse Events | TEAEs related to study drug | 48 Participants |
| Arm A: DRL_RI | Number of Participants With Adverse Events | TEAE>=Common terminology Criteria for Adverse events (CTCAE) grade 3 | 30 Participants |
| Arm A: DRL_RI | Number of Participants With Adverse Events | Fatal TEAEs | 3 Participants |
| Arm A: DRL_RI | Number of Participants With Adverse Events | Treatment-emergent adverse events (TEAEs) | 113 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | Fatal TEAEs | 2 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | Treatment-emergent adverse events (TEAEs) | 103 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | Non-TEAEs | 18 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | Infusion related AEs | 32 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | TEAE>=Common terminology Criteria for Adverse events (CTCAE) grade 3 | 24 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | Serious TEAEs | 21 Participants |
| Arm B: MabThera® | Number of Participants With Adverse Events | TEAEs related to study drug | 50 Participants |
Secondary
Number of Participants With Positive Anti-drug Antibody (ADA)
The immunogenicity of the Proposed Rituximab Biosimilar (DRL\_RI) with MabThera® among trial participants was compared.
Time frame: On Day 1, Week 2, Week 3, Week 4, Week 12 post dose
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: DRL_RI | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 2 | 2 Participants |
| Arm A: DRL_RI | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 4 | 2 Participants |
| Arm A: DRL_RI | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 3 | 1 Participants |
| Arm A: DRL_RI | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 12 | 2 Participants |
| Arm A: DRL_RI | Number of Participants With Positive Anti-drug Antibody (ADA) | Day 1 | 2 Participants |
| Arm B: MabThera® | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 12 | 0 Participants |
| Arm B: MabThera® | Number of Participants With Positive Anti-drug Antibody (ADA) | Day 1 | 0 Participants |
| Arm B: MabThera® | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 2 | 0 Participants |
| Arm B: MabThera® | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 3 | 0 Participants |
| Arm B: MabThera® | Number of Participants With Positive Anti-drug Antibody (ADA) | Week 4 | 0 Participants |
Secondary
Overall Response Rate (ORR)
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.
Time frame: Week 12, Week 28
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: DRL_RI | Overall Response Rate (ORR) | Week 12 | 62.3 percentage of particpants |
| Arm A: DRL_RI | Overall Response Rate (ORR) | Week 28 | 75.3 percentage of particpants |
| Arm B: MabThera® | Overall Response Rate (ORR) | Week 12 | 63.9 percentage of particpants |
| Arm B: MabThera® | Overall Response Rate (ORR) | Week 28 | 73.5 percentage of particpants |
Secondary
Overall Survival (OS)
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.
Time frame: Week 52
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: DRL_RI | Overall Survival (OS) | NA Weeks |
| Arm B: MabThera® | Overall Survival (OS) | NA Weeks |
Secondary
Progression-free Survival (PFS)
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.
Time frame: Week 52
Population: The ITT Analysis Set included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: DRL_RI | Progression-free Survival (PFS) | NA Weeks |
| Arm B: MabThera® | Progression-free Survival (PFS) | NA Weeks |