A randomized study comparing maintenance therapy with subcutaneous rituximab continued until progression with observation only in patients with relapsed or refractory, indolent non-Hodgkin’s lymphoma who completed and responded to rituximab-based immunochemotherapy induction and initial 2-year rituximab maintenance therapy administered subcutaneously

INTERVENTION: Product Name: rituximab/rHuPH20 SC Product Code: RO0452294/F04 Pharmaceutical Form: Solution for injection INN or Proposed INN: RITUXIMAB CAS Number: 174722‐31‐7 Current Sponsor code: RO0452294 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 1400‐ Trade Name: MabThera Pharmaceutical Form: Concentrate for solution for infusion INN or Proposed INN: RITUXIMAB CAS Number: 174722‐31‐7 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 500‐ CONDITION: Patients with relapsed or refractory CD20+ follicular non‐Hodgkin's lymphoma (NHL) Grade 1, 2 or 3a, or other CD20+ indolent NHL (Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma), according to the WHO classification system, or other not further classified low malignant lymphoma by immunohistochemistry. ; MedDRA version: 14.1 Level: PT Classification code 10061170 Term: Follicle centre lymphoma, follicular grade I, II, III System Organ Class: 10029104 ‐ Neoplasms benign, malignant and unspecified (incl cysts and polyps) Therapeutic area: Diseases [C] ‐ Blood and lymphatic diseases [C15] PRIMARY OUTCOME: Main Objective: To evaluate the efficacy in term of progression‐free survival after randomization (PFSrand) of a subcutaneous (SC) formulation of rituximab in patients who responded to Induction and initial 2 years maintenance therapy (Maintenance I), and were randomized to either prolonged rituximab maintenance until progression (Maintenance II) or observation. Primary end point(s): The primary efficacy endpoint of the study is PFSrand. It is defined as the time from day of randomization to maintenance phase II to the first documented disease progression or death, whichever occurs first. Secondary Objective: To evaluate the efficacy and safety of SC rituximab during Induction, initial 2‐year maintenance (Maintenance I) and randomized treatment period (Maintenance II). Efficacy will be evaluated in terms of Event‐ Free Survival (EFS), Time to Next Lymphoma Treatment (TNLT), Overall survival (OS), Overall Response Rate (ORR), Partial Response (PR) to Complete Response (CR) conversion rate, and PFS measured from the first Induction dose of rituximab (PFSregist). Safety assessments will include frequency of adverse events (AEs), serious adverse events (SAEs), and infusion/injection‐related reactions (IRRs) and immunoglobulin (Ig) quantification. Timepoint(s) of evaluation of this end point: Day 1 every 8 weeks [56 ± 7 days] until PD. SECONDARY OUTCOME: Secondary end point(s): Progression free survival (PFS) measured from the day of first rituximab Induction dose (PFSregist), Event‐free survival (EFS), Time to next lymphoma treatment (TNLT), Overall survival (OS), Overall Response Rate (ORR) and PR to CR conversion rate at the end of Induction and end of Maintenance I. Timepoint(s) of evaluation of this end point: Time Frame: Week 24 (cycle 8) INCLUSION CRITERIA: ‐ Age = 18 years. ‐ Histologically confirmed, CD20+ follicular NHL Grade 1, 2 or 3a, orother CD20+ indolent NHL (Waldenström's macroglobulinemia or lymphoplasmacytic lymphoma, marginal zone lymphoma) according to the WHO classification system, other not further classified low malignant lymphoma by immunohistochemistry. ‐ Patients must have received and must have relapsed or been refractory to one or more lines of adequate induction therapy prior to enrolment, including at least one line consisting of immunotherapy and/or chemotherapy. • Eastern Cooperative Oncology Group (ECOG) performance status = 2. Are the trial subjects under 18? no Number of subjects for this age range: 0 F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 420 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 280