A Study to Evaluate Safety, Efficacy and Pharmacokinetics of Rituximab (MabThera/Rituxan) in Participants With Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL)

Study Overview
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Brief Summary
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This single arm, multicenter study will evaluate the safety, efficacy and pharmacokinetic (PK) of subcutaneous (SC) rituximab in previously untreated participants with cluster of differentiation 20 positive (CD20+) DLBCL or FL. In addition to standard chemotherapy, participants will receive at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period.

Official Title
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A Single Arm, Multicentre, Phase IIIB Study to Evaluate Safety, Efficacy and Pharmacokinetic (PK) of Subcutaneous (SC) Rituximab Administered During Induction Phase or Maintenance in Previously Untreated Patients With CD20+ Diffuse Large B Cell Lymphoma (DLBCL) or Follicular Lymphoma (FL)

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Doxorubicin
* Drug: Prednisone
* Drug: Bendamustine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, CD20+ DLBCL or CD20+ follicular non-Hodgkin's lymphoma (NHL) Grade 1, 2 or 3a, according to the World Health Organization (WHO) classification system Currently being treated with rituximab intravenously (IV) in the Induction or Maintenance period, having received at least one full dose of rituximab IV, defined as standard full dose of rituximab IV 375 milligrams per square-meter (mg/m^2) administered without interruption or early discontinuation (i.e. tolerability issues) Expectation and current ability for the participant to receive at least 4 additional cycles of treatment during the Induction period or 6 additional cycles of treatment during the Maintenance period (participants with follicular NHL) An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with bulky disease, defined as one lesion greater than or equal to (>=) 7.5 centimeters (cm), or Follicular Lymphoma International Prognostic Index (FLIPI) (low, intermediate or high risk) assessed before the first rituximab IV administration in Induction period At least one bi-dimensionally measurable lesion defined as >=1.5 cm in its largest dimension on computed tomography (CT) scan Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (<=) 3 Exclusion Criteria: Transformed lymphoma or FL IIIB Primary central nervous system lymphoma, histologic evidence of transformation to a Burkitt lymphoma, primary effusion lymphoma, primary mediastinal DLBCL, DLBCL of the testis, or primary cutaneous DLBCL History of other malignancy Ongoing corticosteroid use greater than (>) 30 milligrams per day (mg/day) of prednisone or equivalent Inadequate renal, hematologic, or hepatic function History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products Contraindications to any of the individual components of standard chemotherapy Other serious underlying medical conditions, which, in the Investigator's judgement, could impair the ability of the participant to participate in the study Recent major surgery (within 4 weeks prior to dosing, other than for diagnosis) Active hepatitis B virus (HBV), active hepatitis C virus (HCV) infection, or human immunodeficiency virus (HIV) infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Participants will receive at least 4 doses of rituximab 1400 mg SC once a month during the Induction period, and at least 6 doses of rituximab 1400 mg SC once every two months during the Maintenance period, in addition to standard chemotherapy. Standard chemotherapy regimen included cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP); or cyclophosphamide, vincristine and prednisone (CVP); or bendamustine as per standard local practice. | Drug: Rituximab<br>* Rituximab will be administered at a dose of 1400 mg SC once a month for at least 4 doses during the Induction period, and at a dose of 1400 mg SC once every two months for at least 6 doses during the Maintenance period.<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* Cyclophosphamide will be administered as per standard local practice as a part of standard chemotherapy regimen.<br>Drug: Vincristine<br>* Vincristine will be administered as per standard local practice as a part of standard chemotherapy regimen.<br>Drug: Doxorubicin<br>* Doxorubicin will be administered as per standard local practice as a part of standard chemotherapy regimen.<br>Drug: Prednisone<br>* Prednisone will be administered as per standard local practice as a part of standard chemotherapy regimen.<br>Drug: Bendamustine<br>* Bendamustine will be administered as per standard local practice as a part of standard chemotherapy regimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Administration-Associated Reactions (AAR) | AARs were defined as all adverse events (AEs) occurring within 24 hours of rituximab administration and which were considered related to study drug. AARs included infusion/injection-related reactions (IIRRs), injection-site reactions, administration site conditions and all symptoms thereof. Grading was completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | Baseline up to 54 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With At Least One Grade ≥ 3 Treatment-Emergent Adverse Events (TEAEs) | An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with the treatment. An adverse event was therefore any unfavourable 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. Pre-existing conditions which worsened during the study were also considered as adverse events. Grading was completed according to the CTCAE, version 4.0. | Baseline up to 54 months | 
| Percentage of Participants With At Least One Grade ≥ 3 Infusion/ Injection Related Reactions (IIRRs) | Grading of IIRRs was completed according to the CTCAE, version 4.0. | Baseline up to 54 months | 
| Percentage of Participants With At Least One Treatment-Emergent Serious Adverse Events | SAE was defined as any experience that suggested a significant hazard, contraindication, side effect, or precaution, and fulfilled any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/ birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here. | Baseline up to 54 months | 
| Percentage of Participants With Event-Free Survival (EFS) According to IWG Response Criteria | EFS was defined as the time from first dose of rituximab to first occurrence of progression or relapse, according to the International Working Group (IWG) response criteria or other country standards, or initiation of a non-protocol-specified anti-lymphoma therapy or death, whichever occurred first. | Day 1 up to first occurrence of progression or relapse, or initiation of a non-protocol-specified anti-lymphoma therapy or death, whichever occurs first (up to maximum 54 months) | 
| Percentage of Participants With Progression-Free Survival (PFS) According to IWG Response Criteria | PFS was defined as the time from first dose of rituximab to the first occurrence of disease progression or relapse, according to the International Working Group (IWG) response criteria or other country standards, or death from any cause, whichever occurred first. | Day 1 up to first occurrence of progression or relapse, or death, whichever occurs first (up to maximum 54 months) | 
| Percentage of Participants With Overall Survival (OS) | OS was defined as the time from first dose of rituximab to death from any cause. | Day 1 until death (up to maximum 54 months) | 
| Percentage of Participants With Disease-Free Survival (DFS) According to IWG Response Criteria | DFS assessed in participants achieving complete response (CR) including complete response unconfirmed (Cru) and was defined as the period from 4 to 8 weeks after end of Induction period up to relapse or death from any cause, whichever occured first. | From 4 to 8 weeks after end of Induction period up to relapse or death from any cause, whichever occurs first (up to maximum 54 months) (end of Induction period = up to 8 months) | 
| Percentage of Participants With Complete Response (CR) According to IWG Response Criteria | Complete response required: 1) the complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy, and normalization of those biochemical abnormalities, 2) all lymph nodes and nodal masses had regressed to normal size, 3) the spleen, if considered to be enlarged before therapy on the basis of a CT scan, must have regressed in size and not be palpable on physical examination and 4) if the bone marrow was involved by lymphoma before treatment, the infiltrate was cleared on repeat bone marrow aspirate and biopsy of the same site. CR/unconfirmed (CRu) included those patients who fulfilled criteria 1 and 3 above as well as 1) a residual lymph node mass greater than 1.5 cm in greatest transverse diameter that regressed by more than 75% in the SPD and 2) indeterminate bone marrow. Response was assessed according to the IWG response criteria. | At 4 to 8 weeks after end of Induction period (end of Induction period = up to 8 months) | 
| FL: Plasma Trough Concentrations of Rituximab | FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. Pharmacokinetic (PK) data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days. | Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1 | 
| FL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab | FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. PK data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days. | Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1 | 
| FL: Plasma Trough Concentrations of Rituximab in Participants With Complete Response/Complete Response Unconfirmed (CR/CRu) | FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. PK data only collected for participants enrolled during Induction. During the induction phase each Cycle is 21 days. | Induction collection: Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, and Cycle 8 Predose on Day 1 | 
| DLBCL: Plasma Concentrations of Rituximab | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| DLBCL: Plasma Trough Concentrations of Rituximab | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 pre-dose on Day 1 | 
| DLBCL: Area Under the Plasma Concentration-Time Curve (AUC) of Rituximab | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| DLBCL: Maximum Plasma Concentration (Cmax) of Rituximab | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| DLBCL: Apparent Total Clearance (CL/F) of Rituximab | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| DLBCL: Plasma Trough Concentrations of Rituximab in Participants With Complete Response/Complete Response Unconfirmed (CR/CRu) | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| DLBCL: Overall Geometric Least Square (LS) Mean Plasma Trough Concentrations of Rituximab | DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| DLBCL: Plasma Concentrations During Different Scheduling of Rituximab SC R-CHOP-14 or R-CHOP-21 | Plasma concentrations of rituximab in participants with DLBCL by chemotherapy regimen cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 14 days (R-CHOP-14) or cyclophosphamide, oncovine (vincristine), doxorubicin, prednisone/prednisolone given every 21 days (R-CHOP-21) in the PK) population.DLBCL participants received at least 1 infusion of rituximab and must have been able to receive at least 4 cycles of rituximab SC; therefore DLBCL participants could be enrolled at Cycle 2, Cycle 3, Cycle 4, or Cycle 5 and as a result the baseline PK sample could be collected at Cycle 2, Cycle 3, Cycle 4, or Cycle 5. Each Cycle is 21 days. | Cycle 2 Predose, Cycle 3 Predose, Cycle 4 Predose, Cycle 5 Predose, Baseline Predose, Cycle 7 Predose on Day 1, Cycle 7 Day 7, Cycle 7 Day 14, Cycle 8 Predose on Day 1 | 
| Rituximab Administration Satisfaction Questionnaire (RASQ) Convenience and Satisfaction Domain Scores | Patient-assessed satisfaction was evaluated using RASQ. Participants were asked questions regarding convenience and satisfaction for rituximab SC. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all participants. DLBCL participants could be enrolled at cycle 2, cycle 3, or cycle 4. FL participants could be enrolled during induction or maintenance phase and they should have received at least 1 infusion of rituximab and must be able to receive at least 4 cycles of rituximab SC if enrolled during induction or 4 cycles of rituximab SC if enrolled during maintenance. Each Cycle is 21 days for DLBCL. Each Cycle 21 days during the Induction phase and 2 months during Maintenance phase for FL. | DLBCL: Cycle (C) 2, C3, C4, C5, C6, End of C8; FL: Induction: C3, C4, C5, C6, C8, Maintenance: C2, C3, C4, C5, C6, C7, C8, C10, C12, End of treatment (4-8 weeks after last dose) |