A Study of MabThera (Rituximab) Subcutaneous Vs. MabThera (Rituximab) Intravenous in Patients With Follicular Non-Hodgkin's Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01200758
First received: September 10, 2010
Last updated: August 7, 2015
Last verified: August 2015
  Purpose

This two-stage, multi-center, randomized, controlled, open-label study will investigate the pharmacokinetics, efficacy and safety of MabThera (rituximab) subcutaneous versus MabThera (rituximab) intravenous in patients with previously untreated follicular non-Hodgkin's lymphoma. Patients will be randomized to receive 375 mg/m² MabThera as intravenous infusion or 1400 mg MabThera given subcutaneously. In addition, patients will receive standard chemotherapy. Patients who achieved a complete or partial response after 8 treatment cycles, will receive maintenance treatment for a further maximum number of 12 cycles. Maintenance treatment cycles will be repeated every 8 weeks. The anticipated time on study treatment is 96 weeks.


Condition Intervention Phase
Non-Hodgkin's Lymphoma
Drug: MabThera subcutaneous
Drug: Mabthera intravenous
Drug: Standard Chemotherapy
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two-stage Phase III, International, Multi-center, Randomized, Controlled, Open-label Study to Investigate the Pharmacokinetics, Efficacy and Safety of Rituximab SC in Combination With CHOP or CVP Versus Rituximab IV in Combination With CHOP or CVP in Patients With Previously Untreated Follicular Lymphoma Followed by Maintenance Treatment With Either Rituximab SC or Rituximab IV

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Stage I: Trough Serum Concentrations (Ctrough) of IV and SC Rituximab [ Time Frame: Stage I: Cycle 7 Day 21 (within 2 hours pre-dose on Cycle 8) of induction treatment ] [ Designated as safety issue: No ]
    Number of participants = participants analyzed for this endpoint.

  • Stage II: Percentage of Participants With Overall Response at the End of Induction Treatment [ Time Frame: Stage II: up to end of induction treatment Cycle 8 (24 weeks) ] [ Designated as safety issue: No ]
    Overall Response comprised complete response (CR), CR unconfirmed (CRu), or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and computed tomography (CT) scans. Assessment of tumor response was performed according to the International Working Group response criteria for Non-Hodgkin lymphoma (NHL). CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by more than (>) 75% in the sum of the products of greatest diameters (SPD); PR: Greater than or equal to (≥) 50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.

  • Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Induction Treatment [ Time Frame: Stage I and II: Baseline up to end of induction treatment Cycle 8 (24 weeks) ] [ Designated as safety issue: No ]
    Overall Response comprised of CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.


Secondary Outcome Measures:
  • Stage I: Percentage of Participants With Overall Response at the End of Induction Treatment [ Time Frame: Stage I: up to end of induction treatment Cycle 8 (24 weeks) ] [ Designated as safety issue: No ]
    Overall Response comprised CR, CRu, or PR. A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in the SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI was estimated for one sample binomial using Pearson-Clopper.

  • Stage I: Percentage of Participants With Complete Response at the End of Induction Treatment [ Time Frame: Stage I: up to end of induction treatment Cycle 8 (24 weeks) ] [ Designated as safety issue: No ]
    Complete Response was comprised CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses.

  • Stage II: Percentage of Participants With Complete Response at the End of Induction Treatment [ Time Frame: Stage II: up to end of induction treatment Cycle 8 (24 weeks) ] [ Designated as safety issue: No ]
    Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

  • Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Induction Treatment [ Time Frame: Stage I and II: Baseline up to end of induction treatment Cycle 8 (24 weeks) ] [ Designated as safety issue: No ]
    Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper.

  • Stage I and II (Pooled): Percentage of Participants With Complete Response at the End of Maintenance Treatment [ Time Frame: Stage I and Stage II: up to 78 days after last maintenance dose (last maintenance dose: maintenance Cycle 12/Study Cycle 20 [30 months]) ] [ Designated as safety issue: No ]
    Complete Response comprised of CR and CRu. A participant was defined as a responder if they sustained a CR or CRu at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumor response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. Number of subjects analysed = participants evaluable for the analysis.

  • Stage I and II (Pooled): Percentage of Participants With Overall Response at the End of Maintenance Treatment [ Time Frame: Stage I and II: up to 78 days after last maintenance dose (last maintenance dose: maintenance Cycle 12/Study Cycle 20 [30 months]) ] [ Designated as safety issue: No ]
    Overall Response comprised of CR, CRu, or PR . A participant was defined as a responder if they sustained a CR, CRu or PR at the end of induction treatment. Response assessment was based on clinical examination and CT scans. Assessment of tumour response was performed according to the International Working Group response criteria for NHL. CR: complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy; CRu: CR along with regression in lymph node mass by >75% in SPD; PR: ≥50% decrease in SPD of 6 largest dominant nodes or nodal masses. The 95% CI for the response rates was estimated for one sample binomial using Pearson-Clopper. Number of subjects analysed = participants evaluable for the analysis.

  • Stage 1 and II (Pooled): Progression-Free Survival (PFS) [ Time Frame: Baseline, Day 1 of all cycles (Cycles 1-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 3 February 2014) ] [ Designated as safety issue: No ]
    PFS was defined as the time from randomization to disease progression/relapse or death due to any cause. If the specified event (disease progression/relapse, death) did not occur, PFS was censored at the last tumor assessment date showing no disease progression, either during treatment or follow-up. Disease progression was defined as progression in the participant's clinical symptoms according to the International Working Group response criteria for NHL. PFS analysis was performed using Kaplan - Meier curves.

  • Percentage of Participants With Disease Progression or Death [ Time Frame: Baseline, Day 1 of all cycles (Cycles 1-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to a median of 27 months; up to data cutoff of 3 February 2014) ] [ Designated as safety issue: No ]
    Disease progression was defined as progression in the participant's clinical symptoms according to the International Working Group response criteria for NHL.

  • Stage I and II (Pooled): Event-Free Survival [ Time Frame: Baseline until documented disease progression/relapse or death (up to study completion) ] [ Designated as safety issue: No ]
  • Stage I and II (Pooled): Median Time to Overall Survival (OS) [ Time Frame: Baseline until documented disease progression/relapse or death (up to study completion) ] [ Designated as safety issue: No ]
    OS was defined as the time from randomization to death due to any cause. Participants without event were censored at the time of last follow-up information for survival (i.e., at the last time known to be alive).

  • Stage 1: Observed Area Under the Serum Concentration-Time Curve (AUC) of IV and SC Rituximab at Week 7 [ Time Frame: Stage I (Induction): pre-dose and 24 hours post-dose on Cycle 7 (Days 1, 3, 7, and 15), pre-dose on Cycle 8 Day 1; additionally within 15 minutes after end of infusion on Cycle 7 Day 1 for rituximab IV (up to data cutoff of 11 April 2012) ] [ Designated as safety issue: No ]
    AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption. Number of participants with evaluable PK data contributing to summary statistics were included.

  • Stage I: Maximum Serum Concentrations (Cmax) of IV and SC Rituximab at Cycle 7 [ Time Frame: Stage I (Induction): pre-dose and 24 hours post-dose on Cycle 7 (Days 1, 3, 7, and 15), pre-dose on Cycle 8 Day 1; additionally within 15 minutes after end of infusion on Cycle 7 Day 1 (up to cutoff date of 11 April 2012) ] [ Designated as safety issue: No ]
    Number of participants with evaluable PK data contributing to summary statistics were included.

  • Stage I and II (Pooled): Trough Serum Concentrations (Ctrough) of Rituximab at Each Induction Treatment Cycle [ Time Frame: C-trough values are based upon samples scheduled 21 days after study drug administration (before the next scheduled cycle), except for cycle 8 which were scheduled 28 days after drug administration. ] [ Designated as safety issue: No ]
    n = number of participants analyzed for the endpoint at the specified timepoint. The data was provided up to data cutoff of 3 February 2014.

  • Stage I and II (Pooled): Ctrough of Rituximab at Each Maintenance Treatment Cycle [ Time Frame: C-trough values are based upon samples scheduled before each maintenance Cycle 9 to 20 (maintenance Cycle 1 to 12). i.e. 'Cycle 8' and 'Cycle 19' are before the first and last maintenance administration at 'Cycle 9' and 'Cycle 20', respectively. ] [ Designated as safety issue: No ]
    n (number) = participants analyzed in specified cycle for this endpoint. The data was provided up to data cutoff of 3 February 2014.

  • Stage I and II (Pooled): Rituximab Levels 12 Weeks, 24 Weeks, and 36 Weeks After the Last Rituximab Administration [ Time Frame: 12 weeks, 24 weeks, and 36 weeks after the last rituximab administration (median treatment duration: 383.5 days for IV dose and 406 days for SC dose; up to data cutoff of 3 February 2014) ] [ Designated as safety issue: No ]
    n = number of participants analyzed for the endpoint at the specified timepoint.

  • Percentage of Participants With B-Cell Depletion by Cycle for Induction Phase [ Time Frame: Stage I and II (induction): for rituximab IV - Day 1 of Cycle 1 to 8; for rituximab SC - Day 1 of Cycle 1 and Cycle 3 to 8, Day 0 of Cycle 2, thereafter at follow-up visits every 12 weeks after the last rituximab administration until 72 weeks ] [ Designated as safety issue: No ]
    n = number of participants analyzed for the endpoint at the specified timepoint. The data was presented up to data cutoff of 3 February 2014.

  • Percentage of Participants With B-Cell Depletion by Cycle for Maintenance Phase [ Time Frame: Stage I and II (maintenance): Day 1 of Cycle 9 to 20 (up to data cutoff of 3 February 2014) ] [ Designated as safety issue: No ]
    n = number of participants analyzed for the endpoint at the specified timepoint.

  • Stage I and II (Pooled): Percentage of Participants Positive for Human Anti-Chimeric Antibodies (HACAs) [ Time Frame: Baseline, Post-Baseline (Cycle 1 Day 1 [induction] up to follow-up) (a median of 27 months; up to data cutoff of 3 February 2014) ] [ Designated as safety issue: No ]
    Levels of HACA in serum were collected at Day of each cycle up to Cycle 8 and at follow-up visit. n = number of participants analyzed for the endpoint at the specified timepoint.


Enrollment: 410
Study Start Date: February 2011
Estimated Study Completion Date: November 2017
Estimated Primary Completion Date: November 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1 Drug: Mabthera intravenous
MabThera intravenous infusion 375 mg/m2 at cycle 1 on day 0, day 1 and day 2 and at cycles 2-8 on day 1. In addition, standard chemotherapy is given. Additional maintenance treatment for a maximum of 12 cycles.
Drug: Standard Chemotherapy
up to 8 cycles of standard chemotherapy consisted of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks.
Experimental: 2 Drug: MabThera subcutaneous
At cycle 1 on day 0, day 1 or day 2, MabThera is given as intravenous infusion 375 mg/m2. MabThera subcutaneous 1400 mg at cycle 2 on day 0 and at cycles 3-8 on day 1. In addition, standard chemotherapy is given. Additional maintenance treatment for a maximum of 12 cycles.
Drug: Standard Chemotherapy
up to 8 cycles of standard chemotherapy consisted of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks.

Detailed Description:

This is a two-stage study. Stage 1 was designed to confirm the chosen rituximab SC dose resulting in comparable rituximab serum Ctrough levels compared with rituximab IV, when given as part of induction treatment every 3 weeks. Enrollment for Stage 2 started after the rituximab SC dose was established in Stage 1. Stage 2 aimed to further investigate the efficacy and safety of rituximab SC compared with rituximab IV.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients, >/=18 years of age
  • CD20-positive, follicular Non-Hodgkin's lymphoma grade 1, 2, 3a. A tumor biopsy must have been performed within 6 months before study entry with material available for central review.
  • No prior treatment
  • ECOG performance status 0-2

Exclusion Criteria:

  • Grade 3b follicular lymphoma
  • Transformation to high-grade lymphoma secondary to follicular lymphoma
  • Types of Non-Hodgkin's lymphoma other than follicular lymphoma
  • Presence or history of CNS disease
  • Corticoid therapy during the last 4 weeks, except prednisone treatment <20 mg per day
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01200758

  Show 150 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01200758     History of Changes
Other Study ID Numbers: BO22334, 2010-021377-36
Study First Received: September 10, 2010
Results First Received: July 7, 2015
Last Updated: August 7, 2015
Health Authority: To: be added

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Rituximab
Antineoplastic Agents
Antirheumatic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on September 03, 2015