A Study Comparing Maintenance Subcutaneous Rituximab With Observation Only in Participants With Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma Who Had Responded to Rituximab-based Immunochemotherapy Induction and 2-year Maintenance With Subcutaneous Rituximab

Phase 3

Completed

Conditions: Non-Hodgkin's Lymphoma

Interventions: Drug: Chemotherapy (Induction Period)
Drug: Rituximab

Registration Number: NCT01461928

Lead Sponsor: Hoffmann-La Roche

Brief Summary: This multicenter, randomized, open-label, parallel-group study will evaluate the efficacy and safety of subcutaneously administered rituximab in comparison with observation only as maintenance therapy in participants with relapsed or refractory indolent Non-Hodgkin's lymphoma (NHL). All participants will receive induction therapy with rituximab (375 milligrams per square meter \[mg/m\^2\] intravenously \[IV\] in Cycle 1, then 1400 mg subcutaneous \[SC\] every 3-4 weeks) plus standard chemotherapy for 6-8 months; followed by 24 months of maintenance I period with rituximab (1400 mg SC every 8 weeks). Participants completing therapy and showing partial or complete response will be randomized to receive either rituximab (1400 mg SC every 8 weeks) or observation with no treatment during maintenance II period and will be followed for at least 15 months. Anticipated time on study treatment is until disease progression, unacceptable toxicity or end of study, whichever occurs first.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 692

Inclusion Criteria

Histologically confirmed Cluster of Differentiation 20-positive (CD20+) follicular NHL Grade 1, 2 or 3a, or other CD20+ indolent NHL (Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma) according to World Health Organization (WHO) classification system
Participants must have received and must have relapsed or been refractory to, one or more lines of adequate therapy prior to enrollment, including at least one line consisting of immunotherapy and/or chemotherapy and/or radiotherapy
Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 2

Exclusion Criteria

Transformation to high-grade lymphoma
Aggressive lymphoma (for example, mantle cell lymphoma [MCL])
Presence or history of central nervous system (CNS) lymphomatous disease
Other malignancy within 5 years prior to enrollment, except for curatively treated carcinoma in situ of the cervix, squamous cell carcinoma of the skin or basal cell skin cancer, or cervical carcinoma Stage 1B or less, breast cancer in situ or localized prostate cancer Stage T1c if treated with curative intent and relapse- and metastasis-free for at least 2 years prior to enrollment
Inadequate hematological, hepatic or renal function
Known human immunodeficiency virus (HIV) infection
Active and/or severe infection (e.g. tuberculosis, sepsis and opportunistic infections, active hepatitis B or C)
Pregnant or breastfeeding women

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Maintenance II Period Observation Only	Chemotherapy (Induction Period)	Participants will receive standard chemotherapy regimen in combination with 375 mg/m\^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); no treatment in Maintenance II period until disease progression or end of study, whichever occurs first.
Maintenance II Period Rituximab	Chemotherapy (Induction Period)	Participants will receive standard chemotherapy regimen in combination with 375 mg/m\^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); 1400 mg rituximab SC every 8 weeks until disease progression or end of study, whichever occurs first (Maintenance II period).
Maintenance II Period Observation Only	Rituximab	Participants will receive standard chemotherapy regimen in combination with 375 mg/m\^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); no treatment in Maintenance II period until disease progression or end of study, whichever occurs first.
Maintenance II Period Rituximab	Rituximab	Participants will receive standard chemotherapy regimen in combination with 375 mg/m\^2 rituximab IV in Cycle 1 (3-4 week-cycles), followed by 1400 mg rituximab SC every 3-4 weeks for 8 cycles (induction period); 1400 mg rituximab SC every 8 weeks for 24 months (Maintenance I period); 1400 mg rituximab SC every 8 weeks until disease progression or end of study, whichever occurs first (Maintenance II period).

Primary Outcome Measures

Name	Time	Method
Maintenance II: Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia	From randomization (Maintenance II) up to disease progression or death, whichever occurs first (up to approximately 24 months)	Progression free survival from randomization (PFSrand) is defined as the time from date of randomization to the date of first documented disease progression or death, whichever occurs first. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed. The Observation arm did not include one participant with AE outcome of death reported retrospectively 2 months after discontinuation from study (censored as having no event on Day 456 post-randomization).

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Adverse Events (AEs), Serious AEs, and Infusion/Administration-related Reactions (IRRs/ARRs)	From day of first rituximab induction dose up to day of disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)	An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. Not all AEs were followed up for the randomized Observation arm. Only Serious AEs and AE grade 3-5 (obtained retrospectively) were collected for this arm. Therefore arms are not comparable overall.
Overall Survival	From day of first rituximab induction dose up to death (up to approximately 87 months)	Overall survival from first induction treatment (OSRegist) is defined as the time from date of first rituximab induction dose to the date of death, irrespective of cause. One participant died in Induction before randomization and one participant died in Maintenance II Observation arm due to an SAE and were not considered in the analysis as no death page was completed.
Time to Next Lymphoma Treatment (TNLT)	From day of first rituximab induction dose up to any new lymphoma treatment (up to approximately 87 months)	Time to next lymphoma treatment (TNLT) is defined as the time from date of first rituximab induction dose to the date date of first documented intake of any new antilymphoma treatment (chemotherapy, radiotherapy, immunotherapy, etc.).
Maintenance I: Percentage of Participants With Conversion of PR to CR Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia	From day of first rituximab induction dose up to end of Maintenance I period (up to approximately 32 months)
Progression-free Survival (PFS) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia	From day of first rituximab induction dose up to disease progression or death, whichever occurs first (up to approximately 87 months)	Progression free survival from first induction treatment (PFSregist) is defined as the time from date of first rituximab induction dose to the date of first documented disease progression or death by any cause, whichever occurs first.
Maintenance II: Overall Survival	From randomization (Maintenance II) up to death (up to approximately 24 months)	Overall survival from randomization (OSrand) is defined as the time from date of randomization to the date of death, irrespective of cause.
Event-free Survival (Time to Treatment Failure) Using 1999 International Working Group (Cheson) Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia	From day of first rituximab induction dose up to day of any treatment failure, including disease progression, or discontinuation of treatment for any reason (up to approximately 87 months)	Event-Free Survival was measured from the day of first rituximab Induction dose through Maintenance I and Maintenance II rituximab arm until the date of any treatment failure, including disease progression, or discontinuation of treatment for any reason (e.g. disease progression, toxicity, patient preference, initiation of new anti-lymphoma treatment, or death). Treatment discontinuation was considered as an event and was not applicable to the randomized observation arm.
Percentage of Participants With Partial or Complete Tumor Response (PR/CR) Assessment at End of Induction Using 1999 International Working Group Response Criteria for Lymphoma or by the Recommendations for Waldenström's Macroglobulinemia	From day of first rituximab induction dose up to end of induction period (up to approximately 8 months)	Overall response rate is defined as the proportion of responders at the end of the Induction period. A responder is defined as a participant experiencing either CR or PR tumor response according to the Cheson response criteria for indolent lymphoma or the recommendations for Waldenström's macroglobulinemia.

Trial Locations

Locations (180): University "Mother Theresa" Hospital Center; Oncology Department
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Tirana, Albania
CEMIC Saavedra
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Buenos Aires, Argentina
Instituto Damic
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Cordoba, Argentina
Hospital Privado de Comunidad; Oncology
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Mar Del Plata, Argentina
Lkh-Univ. Klinikum Graz; Klin. Abt. Für Hämatologie
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Graz, Austria
Tiroler Landeskrankenanstalten Ges.M.B.H.; Innere Medizin Abt. Für Hämatologie & Onkologie
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Innsbruck, Austria
Kepler Universitätskliniken GmbH - Med Campus III; III. Medizinische Abteilung
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Linz, Austria
Landeskrankenhaus Rankweil; Interne E
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Rankweil, Austria
Medizinische Universität Wien; Univ.Klinik für Innere Medizin I - Hämatologie & Hämostaseologie
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Wien, Austria
Centro de Tratamento Oncologico - CETRON
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Rio de janeiro, RJ, Brazil
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University "Mother Theresa" Hospital Center; Oncology Department
🇦🇱Tirana, Albania