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A Study of Rituximab (MabThera) Subcutaneous (SC) Versus Rituximab (MabThera) Intravenous (IV) in Participants 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: January 23, 2017
Last verified: January 2017
  Purpose
This two-stage, multi-center, randomized, controlled, open-label study will investigate the pharmacokinetics, efficacy and safety of rituximab SC versus rituximab IV in participants with previously untreated follicular non-Hodgkin's lymphoma. Participants will be randomized to receive 375 milligrams per meter square (mg/m^2) rituximab as IV infusion or 1400 milligrams (mg) rituximab SC. In addition, participants will receive standard chemotherapy. Participants who achieved a complete or partial response (PR) 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. 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. The anticipated time on study treatment is 96 weeks.

Condition Intervention Phase
Non-Hodgkin's Lymphoma Drug: Rituximab SC Drug: Rituximab IV Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone/Prednisolone Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Masking Description:
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 (Cy) 7 Day (D) 21 (within 2 hours [hrs] predose on Cy 8) of induction treatment (1 Cy=3 weeks) ]
    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: Baseline up to end of induction treatment Cy 8 (24 weeks) (1 Cy=3 weeks) ]
    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 Cy 8 (24 weeks) (1 Cy=3 weeks) ]
    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: Baseline up to end of induction treatment Cy 8 (24 weeks) (1 Cy=3 weeks) ]
    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: Baseline up to end of induction treatment Cy 8 (24 weeks) (1 Cy=3 weeks) ]
    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: Baseline up to end of induction treatment Cy 8 (24 weeks) (1 Cy=3 weeks) ]
    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 Cy 8 (24 weeks) (1 Cy=3 weeks) ]
    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: Baseline up to 78 days after last maintenance dose (last maintenance dose: maintenance Cy 12/Study Cy 20 [30 months] [1 Cy=8 weeks]) ]
    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: Baseline up to 78 days after last maintenance dose (last maintenance dose: maintenance Cy 12/Study Cy 20 [30 months] [1 Cy=8 weeks]) ]
    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, D1 of all cycles (Cy 1-20), at early withdrawal, at follow-up, every 12 weeks for 96 weeks or until documented disease progression/relapse or death (up to median of 27 months;up to data cutoff of 3 February 2014 [up to 4 years]) ]
    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, D1 of all cycles (Cy 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 [up to 4 years]) ]
    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 [up to approximately 105 months]) ]
  • 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 [up to approximately 105 months]) ]
    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 Cycle 7 [ Time Frame: Stage I (Induction): predose (0 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (0 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion on Cy 7 D1 for rituximab IV (up to data cutoff of 11 April 2012 [up to 26 months]) ]
    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): predose (0 hr) and 24 hrs postdose on Cy 7 (D1,3,7,15), predose (0 hr) on Cy 8 D1 (1 Cy=3 weeks); additionally within 15 minutes after end of infusion on Cy 7 D1 for rituximab IV (up to data cutoff of 11 April 2012 [up to 26 months]) ]
    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: Stage I and II (induction): rituximab IV - predose (0 hr) on D1 of Cy 1 to 8 (1 Cy=3 weeks and 4 weeks for Cy8); rituximab SC - predose (0 hr) on D1 of Cy 1 and Cy 3 to 8, predose (0 hr) on D0 of Cy2 (up to data cutoff of 3 February 2014 [up to 4 years]) ]
    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: Stage I and II (maintenance): D29 of Cy 8 (induction; 1Cy=4 weeks), predose (0 hr) on D1 of Cy 9 to 19 (maintenance Cycle 1 to 12 [1 Cy=8 weeks]; up to data cutoff of 3 February 2014 [up to 4 years]) ]
    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 [up to 4 years]) ]
    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 - D1 of Cy 1 to 8 (1 Cy=3 weeks); for rituximab SC - D1 of Cy 1 and Cy 3 to 8, D0 of Cy 2, thereafter at follow-up visits every 12 weeks after the last rituximab administration until 72 weeks ]
    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): D1 of Cy 9 to 20 (1 Cy=8 weeks) (up to data cutoff of 3 February 2014 [up to 4 years]) ]
    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 (Cy 1 D1 [induction] up to follow-up [1 Cy=3 weeks]) (a median of 27 months; up to data cutoff of 3 February 2014 [up to 4 years]) ]
    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.

  • Stage I and II (Pooled): Percentage of Participants Who Saved Time of Staff as Per Physician/Nurse Opinions With Each Administration of Rituximab SC as Compared to Rituximab IV at the End of Cy 8, 15 and 20 [ Time Frame: Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1 Cy=3 weeks); after 48 weeks of maintenance treatment (after Cy15) and after the end of the maintenance treatment (after Cy20) (up to data cutoff of 3 February 2014 [up to 4 year]) ]
    All investigator physicians and nurses involved in this study were asked to provide the staff time that could be saved with each administration of rituximab SC as compared with rituximab IV to participants in routine practice afetr Cy 8, 15, 20 and categorized as less than (<) 1 hr, at least 1 hr but <2 hrs, at least 2 hrs but <3 hrs, at least 3 hrs but <4 hrs, >/=4 hrs. Staff were asked not to consider the time needed for the first IV administration.

  • Stage I and II (Pooled): Percentage of Participants With Preferred Rituximab SC Formulations as Compared to IV Formulation as Assessed by Physician/Nurse at the End of Cy 8, 15, and 20 [ Time Frame: Stage I and II: Baseline up to end of induction treatment Cy8 (24 weeks) (1Cy=3 weeks); after 48 weeks of maintenance treatment (after Cy15) and after the end of the maintenance treatment (after Cy20) (up to data cutoff of 3 February 2014 [up to 4 years]) ]
    All investigator physicians and nurses involved in this study were asked to answer the following question for convenience of rituximab SC formulation over IV formulation across all participants: Rituximab SC is much more convenient; Rituximab SC is a little more convenient; Both formulations are equally convenient.


Enrollment: 410
Actual Study Start Date: February 2011
Estimated Study Completion Date: November 2017
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Stage I and II: Rituximab IV + Chemotherapy (CHOP/CVP)
Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) in combination with up to 8 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) or cyclophosphamide, vincristine, prednisolone (CVP) chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
Drug: Rituximab IV
Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
Other Name: MabThera
Drug: Cyclophosphamide
Eight cycles of cyclophosphamide (750 mg/m^2 IV) administered every 3 weeks.
Drug: Doxorubicin
Eight cycles of doxorubicin (50 mg/m^2 IV) administered every 3 weeks.
Drug: Vincristine
Eight cycles of doxorubicin (1.4 mg/m^2 IV) administered every 3 weeks.
Drug: Prednisone/Prednisolone
Eight cycles of prednisone/prednisolone (100 mg/day or 40 mg/m^2/day IV/orally) administered Days 1 to 5 of every 21 days cycle.
Experimental: Stage I and II: Rituximab SC + Chemotherapy (CHOP/CVP)
First cycle of rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in combination with up to 8 cycles of CHOP or CVP chemotherapy (as per institutional practice) administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Drug: Rituximab SC
First cycle of rituximab IV infusion (375 mg/m^2) + 7 cycles of rituximab SC (1400 mg; rituximab induction) in administered every 3 weeks. Participants achieving at least PR entered rituximab SC (1400 mg) maintenance therapy once every 8 weeks for 24 months.
Other Name: MabThera
Drug: Rituximab IV
Eight cycles of rituximab IV infusion (375 mg/m^2; rituximab induction) administered every 3 weeks. Participants achieving at least PR during induction, entered rituximab IV maintenance therapy (375 mg/m^2) once every 8 weeks for 24 months.
Other Name: MabThera
Drug: Cyclophosphamide
Eight cycles of cyclophosphamide (750 mg/m^2 IV) administered every 3 weeks.
Drug: Doxorubicin
Eight cycles of doxorubicin (50 mg/m^2 IV) administered every 3 weeks.
Drug: Vincristine
Eight cycles of doxorubicin (1.4 mg/m^2 IV) administered every 3 weeks.
Drug: Prednisone/Prednisolone
Eight cycles of prednisone/prednisolone (100 mg/day or 40 mg/m^2/day IV/orally) administered Days 1 to 5 of every 21 days cycle.

  Eligibility

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

Inclusion Criteria:

  • Cluster of differentiation 20 (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
  • Eastern Cooperative Oncology Group (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 central nervous system (CNS) disease
  • Corticoid therapy during the last 4 weeks, except prednisone treatment less than (<) 20 milligrams per day (mg per day)
  • Known active bacterial, viral, fungal, or mycobacterial, or any major episode of infections requiring hospitalization or treatment with IV antibiotics within 4 weeks of start of study medication, or oral antibiotics within 2 weeks prior to start of study medication
  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

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: January 23, 2017

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Doxorubicin
Liposomal doxorubicin
Prednisone
Cyclophosphamide
Rituximab
Vincristine
Prednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Antibiotics, Antineoplastic
Antineoplastic Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Glucocorticoids

ClinicalTrials.gov processed this record on June 23, 2017