A Study of Participant Preference With Subcutaneous Versus Intravenous MabThera/Rituxan in Participants With CD20+ Diffuse Large B-Cell Lymphoma or CD20+ Follicular Non-Hodgkin's Lymphoma Grades 1, 2 or 3a

Study Overview
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Brief Summary
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This multi-center, open-label, randomized study will evaluate the participant preference with subcutaneous versus intravenous administration of MabThera/Rituxan (rituximab) in participants with CD20+ diffuse large B-cell lymphoma or CD20+ follicular non-Hodgkin's lymphoma. In Arm A, participants will receive MabThera/Rituxan 375 mg/m2 intravenously (IV) on Day 1 of Cycle 1 and MabThera/Rituxan 1400 mg subcutaneously (SC) on Day 1 of Cycles 2-4, followed by MabThera/Rituxan IV in Cycles 5-8. Participants in Arm B will receive MabThera/Rituxan IV in Cycles 1-4 and SC in Cycles 5-8. All participants will receive 6-8 cycles of standard chemotherapy (according to local country practice) with 8 cycles of MabThera/Rituxan. Anticipated time on study treatment is up to 24 weeks.

Official Title
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A Randomized, Open-label, Mutli-centre Study to Evaluate Patient Preference With Subcutaneous Administration of Rituximab Versus Intravenous Rituximab in Previously Untreated Patients With CD20+ Diffuse Large B-cell Lymphoma or CD20+ Follicular Non-Hodgkin's Lymphoma Grades 1, 2, OR 3A

Conditions
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Diffuse Large B-Cell Lymphoma, Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone/Prednisolone (CHOP)
* Drug: Cyclophosphamide, Vincristine, Prednisone/Prednisolone (CVP)
* Drug: Bendamustine
* Drug: Rituximab
* Drug: Rituximab
* Drug: Rituximab
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult participants , >/= 18 and </= 80 years of age Histologically confirmed, previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL) or CD20+ follicular non-Hodgkin's lymphoma (NHL) Grade 1, 2, or 3a, according to World Health Organization (WHO) classification An International Prognostic Index (IPI) score of 1-4 or IPI score of 0 with bulky disease, defined as one lesion >/= 7.5 cm, or Follicular Lymphoma International Prognostic Index (FLIPI; low, intermediate or high risk) At least one bi-dimensionally measurable lesion defined as >/=1.5 cm in its largest dimension on CT scan Eastern Cooperative Oncology Group (ECOG) performance status </= 3 Exclusion Criteria: Transformed lymphoma or follicular lymphoma IIIB Primary central nervous system (CNS) lymphoma, histologic evidence of transformation to Burkitt lymphoma, primary mediastinal DLBCL, primary effusion lymphoma, primary cutaneous DLBCL, or primary DLBCL of the testis History of other malignancy that could affect compliance with the protocol or interpretation of the results; this includes a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission for >/= 5 years prior to enrolment; participants with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible Prior therapy for DLBCL or NHL, with the exception of nodal biopsy or local irradiation Prior treatment with cytotoxic drugs (with the exclusion of intrathecal methotrexate for CNS prophylaxis in DLBCL) or rituximab for another condition, or prior use of an anti-CD20 drug Prior use of monoclonal antibody within 3 months prior to randomization Chemotherapy or other investigational therapy within 28 days prior to randomization Ongoing corticosteroid use > 30 mg/day prednisolone or equivalent Inadequate renal. hematologic or hepatic function Active and/or severe infection or any major episode of infection within 4 weeks prior to randomization Active hepatitis B virus or active hepatitis C virus infection History of human immunodeficiency (HIV) seropositive status A positive pregnancy test in women of childbearing potential Life expectancy of less than 6 months

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Participants in Arm A received one cycle of rituximab 375 mg/m^2 intravenously (IV), then three cycles of rituximab 1400mg subcutaneously (SC), followed by four cycles of rituximab 375 mg/m^2 IV in combination with a standard chemotherapy of cyclophosphamide, hydroxydaunorubicin, Oncovin, prednisone/prednisolone (CHOP), cyclophosphamide, vincristine, prednisone/prednisolone (CVP), or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | Drug: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone/Prednisolone (CHOP)<br>* Standard chemotherapy<br>Drug: Cyclophosphamide, Vincristine, Prednisone/Prednisolone (CVP)<br>* Standard chemotherapy<br>Drug: Bendamustine<br>* Standard chemotherapy<br>* Other names: Treanda;Drug: Rituximab<br>* 1400 mg subcutaneously (SC), Day 1 Cycles 2-4<br>* Other names: MabThera;Drug: Rituximab<br>* 375 mg/m2 intravenously (IV), Day 1 Cycles 1 and 4-8<br>* Other names: MabThera;|
| Experimental: Arm B<br>Participants in Arm B received four cycles of rituximab 375 mg/m^2 IV followed by four cycles of rituximab 1400mg SC in combination with a standard chemotherapy of CHOP, CVP, or bendamustine. Rituximab was administered on Day 1 of each treatment cycle followed by administration of the preselected chemotherapy. Cycles were repeated every 14, 21, or 28 days, depending on the combination chemotherapy regimen selected by the investigator. | Drug: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone/Prednisolone (CHOP)<br>* Standard chemotherapy<br>Drug: Cyclophosphamide, Vincristine, Prednisone/Prednisolone (CVP)<br>* Standard chemotherapy<br>Drug: Bendamustine<br>* Standard chemotherapy<br>* Other names: Treanda;Drug: Rituximab<br>* 375 mg/m2 IV, Day 1 Cycles 1-4<br>* Other names: MabThera;Drug: Rituximab<br>* 1400 mg SC, Day 1 Cycles 5-8<br>* Other names: MabThera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Indicating a Preference for Rituximab Subcutaneous (SC) Over Rituximab Intravenously (IV) at Cycle 6 | Participants who preferred rituximab SC over rituximab IV, along with the corresponding 95% confidence interval (CI), were estimated using the patient preference questionnaire (PPQ) after completing cycle 6. | Cycle 6 (Up to 24 weeks) | 
| Percentage of Participants Indicating a Preference for Rituximab Subcutaneous (SC) Over Rituximab Intravenously (IV) at Cycle 8 | Participants who preferred rituximab SC over rituximab IV, along with the corresponding 95% confidence interval (CI), were estimated using the patient preference questionnaire (PPQ) after completing Cycle 8. | Cycle 8 (Up to 32 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (AEs) | An AE was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | Randomization of first participant to clinical cutoff date (Up to 4 years) | 
| Time Required for Rituximab Administration (Subcutaneous [SC] or Intravenous [IV]) | Administration time was defined as the time from start to end of the SC injection or from start to end of the IV infusion | Cycle 1-4, Cycle 5-8 for both SC and IV (Up to 32 weeks) | 
| Cancer Therapy Satisfaction Questionnaire (CTSQ) Score | CTSQ is a validated 16-item questionnaire that measures three domains related to participants' satisfaction with cancer therapy. These include expectations of therapy, feelings about side effects, and satisfaction with therapy. 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. | During Cycle 4, 8 of treatment (Up to 32 weeks) | 
| Rituximab Administration Satisfaction Questionnaire (RASQ) Score | The RASQ is a 20-item questionnaire that measures five domains related to the impact of treatment administration. These include physical impact, psychological impact, impact on activities of daily living (ADLs), convenience, and satisfaction. 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. | During Cycle 4, 8 of treatment (Up to 32 weeks) | 
| Complete Response (CR) Rate | CR rate was assessed according to the International Working Group (IWG) Response Criteria (CHESON ET AL. 1999) and included CR and CR unconfirmed (CRu). CR was defined as complete disappearance of all clinical and radiographic evidence of disease and disease-related symptoms, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. CRu was defined as disappearance of clinical and radiographic evidence of disease and absence of splenomegaly, with regression of lymph nodes by > 75 % but still >1.5 cm in size, and indeterminate bone marrow assessment. Tumor assessments were based on computed tomography (CT) scans with contrast of the neck, chest, and abdomen (if detectable by these techniques) or other diagnostic means, if applicable. Other methods (e.g., MRI) were acceptable for participants in whom contrast CT scans were contraindicated. Due to the limited availability of FDG-PET scanners, an FDG-PET scan was not mandated in the study. | 28 days (± 3 days) after Day 1 of the last dose of induction treatment | 
| Event-free Survival (EFS) | EFS was defined as the time from randomization to first occurrence of progression or relapse according to IWG response criteria. IWG criteria is defined using the following response categories: CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy; partial response (PR): At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses; stable disease (SD): participants fails to attain the criteria needed for a CR or PR, but does not fulfill those for progressive disease (PD); PD: Lymph nodes considered abnormal if the long axis is more than 1.5 centimeter (cm) regardless of the short axis. Lymph node has a long axis of 1.1 to 1.5 cm, it is considered abnormal if its short axis is more than 1.0. Lymph nodes less than or equal to (<=) 1.0 × <= 1.0 cm would not be considered as abnormal for PD. | From the time of randomization until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years) | 
| Disease-free Survival (DFS) | DFS was defined as the period from the data of the initial CR/CRu until the date of relapse or death from any cause, whichever occurred first. | From the time of randomization until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years) | 
| Progression-free Survival (PFS) | PFS was defined as the time from randomization to the first occurrence of progression or relapse, according to the IWG response criteria. IWG criteria is defined criteria using the following response categories: CR: Complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy; PR: At least a 50% decrease in SPD of up to six of the largest dominant nodes or nodal masses; SD: participants fails to attain the criteria needed for a CR or PR, but does not fulfill those for PD; PD: Lymph nodes considered abnormal if the long axis is more than 1.5 cm regardless of the short axis. Lymph node has a long axis of 1.1 to 1.5 cm, it is considered abnormal if its short axis is more than 1.0. Lymph nodes <= 1.0 × <= 1.0 cm would not be considered as abnormal for PD. | From the time of randomization until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years) | 
| Overall Survival (OS) | OS was defined as the time from randomization to death from any cause. | From the time of randomization until disease progression or 24 months post treatment follow up or which ever occur first (Up to 4 years) | 
| Percentage of Participants With Anti-Rituximab Antibodies Over Time |  | Pre-dose Cycle 1 to 8, interim staging, final staging, 6, 12 months follow-up, end of study (Up to 4 years) | 
| Percentage of Participants With Anti-Recombinant Human Hyaluronidase (rHuPH20) Antibodies Over Time |  | Pre-dose Cycle 1 to 8, interim staging, final staging, 6, 12 months follow-up, end of study (Up to 4 years) | 
| Summary of Observed Serum Rituximab Concentration |  | Pre-dose Cycle 1 to 8, interim staging, final staging, 6, 12 months follow-up, end of study (Up to 4 years) |