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出境医 / 临床实验 / Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) With MabThera® in LTB Follicular Lymphoma (FLINTER) (FLINTER)

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

Study Description
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 at week 28


Condition or disease Intervention/treatment Phase
Follicular Lymphoma Biological: DRL_RI (Proposed rituximab biosimilar) Other: MabThera® Phase 3

Detailed Description:

It is planned to randomise approx. 284 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) at Week 28 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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 284 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : February 1, 2019
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : September 1, 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Arm A: DRL_RI
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)
Proposed rituximab biosimilar, 100mg and 500mg, concentrate for solution for infusion
Active Comparator: Arm B: MabThera®
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®
Reference product rituximab, 100mg and 500mg, concentrate for solution for infusion
Outcome Measures
Primary Outcome Measures :
  1. Overall Response Rate (ORR) measured for follicular lymphoma [ Time Frame: Month 7 (Week 28) ]
    The primary endpoint is ORR, defined as the proportion of subjects in each treatment group that achieve complete response (CR), unconfirmed complete response (CRu) or partial response (PR) at Month 7 (Week 28) with the response criteria for malignant lymphoma


Secondary Outcome Measures :
  1. Progression-free survival [ Time Frame: 52 Weeks ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL

  2. Overall response rate [ Time Frame: 12 Weeks ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL

  3. Overall survival [ Time Frame: 52 Weeks/End of Study ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL

  4. Duration of response [ Time Frame: 52 Weeks/End of Study ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL

  5. Safety in terms of Adverse Events [ Time Frame: 52 Weeks ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL in terms of Adverse events (AEs) as assessed by the NCI CTCAE version 5.0.

  6. Tolerability in terms of Adverse Events [ Time Frame: 52 Weeks ]
    Compared between DRL_RI with MabThera® for subjects with severity (Grade 3 or Higher) of Treatment Emergent Adverse Events, as assessed by the NCI CTCAE v5.0.

  7. Analysis of BAb and NAb in Blood [ Time Frame: 52 Weeks ]
    Immunogenicity compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL in terms of Anti-DRL_RI antibodies


Other Outcome Measures:
  1. Overall Response Rate (52 Weeks) [ Time Frame: 52 Weeks ]
    Overall response rate based on the Lugano criteria for those subjects with available positron emission tomography (PET) data, treated with either DRL_RI or MabThera®

  2. Volume distribution [ Time Frame: 52 weeks ]
    Pharmacokinetic parameter volume distribution for DRL_RI and MabThera® will be derived using a population-PK modeling approach.

  3. Clearance [ Time Frame: 52 weeks ]
    Pharmacokinetic parameter drug clearance for DRL_RI and MabThera® will be derived using a population-PK modeling approach.

  4. AUEC of B-cell depletion-time curve [ Time Frame: 52 Weeks ]
    Potential differences in pharmacodynamics parameter area under the effect curve (AUEC) of the B-cell depletion-time curve for DRL_RI and MabThera®


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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) positive or hepatitis B core antibody positive, hepatitis C virus (HCV) antibody positive.
  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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Narendra Maharaj, MBBS, MD +914044644500 narendramaharaj@drreddys.com
Contact: Sonica S Batra, MBBS, MD +914044644500 sonicabatra@drreddys.com

Locations
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United States, Maryland
Rcca Md Llc Recruiting
Bethesda, Maryland, United States, 20817
United States, Texas
University Cancer & Diagnostic Centers Recruiting
Houston, Texas, United States, 77089
Sponsors and Collaborators
Dr. Reddy's Laboratories Limited
Parexel
Investigators
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Study Director: Carina Flemmig, MD Parexel
Tracking Information
First Submitted Date  ICMJE April 15, 2019
First Posted Date  ICMJE June 5, 2019
Last Update Posted Date April 9, 2020
Actual Study Start Date  ICMJE February 1, 2019
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 3, 2019) 		Overall Response Rate (ORR) measured for follicular lymphoma [ Time Frame: Month 7 (Week 28) ]
The primary endpoint is ORR, defined as the proportion of subjects in each treatment group that achieve complete response (CR), unconfirmed complete response (CRu) or partial response (PR) at Month 7 (Week 28) with the response criteria for malignant lymphoma
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 3, 2019)
  • Progression-free survival [ Time Frame: 52 Weeks ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL
  • Overall response rate [ Time Frame: 12 Weeks ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL
  • Overall survival [ Time Frame: 52 Weeks/End of Study ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL
  • Duration of response [ Time Frame: 52 Weeks/End of Study ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL
  • Safety in terms of Adverse Events [ Time Frame: 52 Weeks ]
    Compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL in terms of Adverse events (AEs) as assessed by the NCI CTCAE version 5.0.
  • Tolerability in terms of Adverse Events [ Time Frame: 52 Weeks ]
    Compared between DRL_RI with MabThera® for subjects with severity (Grade 3 or Higher) of Treatment Emergent Adverse Events, as assessed by the NCI CTCAE v5.0.
  • Analysis of BAb and NAb in Blood [ Time Frame: 52 Weeks ]
    Immunogenicity compared between DRL_RI with MabThera® in subjects with CD20 positive, LTB FL in terms of Anti-DRL_RI antibodies
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 3, 2019)
  • Overall Response Rate (52 Weeks) [ Time Frame: 52 Weeks ]
    Overall response rate based on the Lugano criteria for those subjects with available positron emission tomography (PET) data, treated with either DRL_RI or MabThera®
  • Volume distribution [ Time Frame: 52 weeks ]
    Pharmacokinetic parameter volume distribution for DRL_RI and MabThera® will be derived using a population-PK modeling approach.
  • Clearance [ Time Frame: 52 weeks ]
    Pharmacokinetic parameter drug clearance for DRL_RI and MabThera® will be derived using a population-PK modeling approach.
  • AUEC of B-cell depletion-time curve [ Time Frame: 52 Weeks ]
    Potential differences in pharmacodynamics parameter area under the effect curve (AUEC) of the B-cell depletion-time curve for DRL_RI and MabThera®
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Compare the Efficacy, Safety, and Immunogenicity of Proposed Rituximab Biosimilar (DRL_RI) With MabThera® in LTB Follicular Lymphoma (FLINTER)
Official Title  ICMJE 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
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 at week 28
Detailed Description

It is planned to randomise approx. 284 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) at Week 28 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Follicular Lymphoma
Intervention  ICMJE
  • Biological: DRL_RI (Proposed rituximab biosimilar)
    Proposed rituximab biosimilar, 100mg and 500mg, concentrate for solution for infusion
  • Other: MabThera®
    Reference product rituximab, 100mg and 500mg, concentrate for solution for infusion
Study Arms  ICMJE
  • Experimental: Arm A: DRL_RI
    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
    Intervention: Biological: DRL_RI (Proposed rituximab biosimilar)
  • Active Comparator: Arm B: MabThera®
    MabThera® for infusion 375 mg/m2 administered via IV infusion on Days 1, 8, 15, 22 and Week 12, 20, 28 and 36.
    Intervention: Other: MabThera®
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 3, 2019) 		284
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2020
Estimated Primary Completion Date September 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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) positive or hepatitis B core antibody positive, hepatitis C virus (HCV) antibody positive.
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Narendra Maharaj, MBBS, MD +914044644500 narendramaharaj@drreddys.com
Contact: Sonica S Batra, MBBS, MD +914044644500 sonicabatra@drreddys.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03976102
Other Study ID Numbers  ICMJE RI-01-006
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Dr. Reddy's Laboratories Limited
Study Sponsor  ICMJE Dr. Reddy's Laboratories Limited
Collaborators  ICMJE Parexel
Investigators  ICMJE
Study Director: Carina Flemmig, MD Parexel
PRS Account Dr. Reddy's Laboratories Limited
Verification Date April 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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