A Study of Subcutaneous Versus Intravenous MabThera/Rituxan (Rituximab) in Combination With CHOP Chemotherapy in Patients With Previously Untreated CD20-Positive Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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This multicenter, randomized, open label parallel-group study will evaluate the efficacy and safety of subcutaneous versus intravenous MabThera/Rituxan (rituximab) in combination with CHOP chemotherapy in patients with previously untreated CD20-positive diffuse large B-Cell lymphoma. Patients will be randomized to receive either MabThera/Rituxan 1400 mg subcutaneously or MabThera/Rituxan 375 mg/m2 intravenously on Day 1 of each cycle for 8 cycles, in combination with 6-8 cycles of CHOP chemotherapy. Anticipated time on study treatment is 6 months.

Official Title
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A Comparative, Randomized, Parallel-group, Multi-center, Phase IIIB Study to Investigate the Efficacy of Subcutaneous (SC) Rituximab Versus Intravenous (IV) Rituximab Both in Combination With CHOP (R-CHOP) in Previously Untreated Patients With CD20-positive Diffuse Large B-cell Lymphoma (DLBCL)

Conditions
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Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Drug: CHOP
* Drug: rituximab [MabThera/Rituxan]
* Drug: rituximab [MabThera/Rituxan]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients, >/= 18 and </= 80 years of age at time of study inclusion Histologically confirmed, previously untreated CD20-positive diffuse large B-cell lymphoma (DLBCL) according to the WHO classification system Patients with an International Prognostic Index (IPI) score 1-5, or IPI score 0 with bulky disease, defined as one lesion >/= 7.5 cm At least one bi-dimensionally measurable lesion defined as >/= 1.5 cm in its largest dimension on CT scan, PET-CT scan or MRI Adequate hematologic function Eastern Cooperative Oncology Group (EOCD) performance status </= 2 Exclusion Criteria: Primary or secondary central nervous system lymphoma, histologic evidence of transformation to Burkitt lymphoma, primary mediastinal DLBCL, primary effusion lymphoma, primary cutaneous DLBCL, or primary DLBCL of the testis Transformed lymphoma or follicular lymphoma IIIB Prior therapy for DLBCL, with the exception of nodal biopsy or local irradiation History of other malignancy, except for curatively treated basal or squamous cell carcinoma or melanoma of the skin, carcinoma in situ of the cervix, or a malignancy that has been treated without curative intent and has been in remission without treatment for >/= 5 years prior to enrolment Inadequate renal or hepatic function Known human immunodeficiency virus (HIV) infection or HIV seropositive status Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection. Patients with occult or prior HBV infection as defined by protocol may be included. Patients positive for HCV antibody are eligible only if polymerase chain reaction testing for HCV ribonucleic acid is negative. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products Contraindication to any of the individual components of CHOP, including prior receipt of anthracyclines Prior treatment with cytotoxic drugs or rituximab for another condition (e.g. rheumatoid arthritis) or prior use of an anti-CD20 antibody Pregnant or lactating women

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: A: Rituximab SC<br> | Drug: CHOP<br>* CHOP chemotherapy: cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone; 6 or 8 cycles<br>Drug: rituximab [MabThera/Rituxan]<br>* The first rituximab dose will be administered intravenously on Day of Cycle 1 at a dose of 375 mg/m2. Subsequent doses of 1400 mg are administered subcutaneously on Day 1 of each cycle, for a further 7 cycles<br>|
| Active Comparator: B: Rituximab IV<br> | Drug: CHOP<br>* CHOP chemotherapy: cyclophosphamide, doxorubicin, vincristine, prednisone/prednisolone; 6 or 8 cycles<br>Drug: rituximab [MabThera/Rituxan]<br>* 375 mg/m2 intravenously on Day 1 of each cycle, 8 cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) or Complete Response Unconfirmed (CRu) | Tumor response was assessed per criteria published by Cheson et al (1999). According to consensus recommendations, 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 greater than (>) 75 percent (%) but still >1.5 centimeters (cm) in size, and indeterminate bone marrow assessment. The percentage of participants with either response at the end of induction (EOI) was determined with corresponding 95% Pearson-Clopper confidence interval (CI). | Up to approximately 4.25 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cancer Treatment Satisfaction Questionnaire (CTSQ) Domain Scores | The CTSQ is a validated 16-item questionnaire that measures three domains related to 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. | At Cycle 7 (each cycle was 14 or 21 days) | 
| Rituximab Administration Satisfaction Questionnaire (RASQ) Domain Scores | 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. | At Cycle 7 (each cycle was 14 or 21 days) | 
| Median Duration of Rituximab Administration for Each Treatment Cycle | Duration of rituximab administration was defined as the time from start to end of the SC injection or IV infusion. The median duration was reported. | Cycles 1, 2, 3, 4, 5, 6, 7, and 8 (each cycle was 14 or 21 days) | 
| Percentage of Participants by Time Spent in the Infusion Chair/Bed for Each Treatment Cycle | Chair time was defined as the amount of time the participant occupied an infusion chair/bed for a single treatment cycle of rituximab + CHOP chemotherapy. Where the chair time was not documented for a given cycle, it was reported as Missing. | Cycles 1, 2, 3, 4, 5, 6, 7, and 8 (each cycle was 14 or 21 days) | 
| Percentage of Participants by Time Spent in the Hospital for Each Treatment Cycle | Hospital time was defined as the amount of time the participant was in the hospital for the course of one cycle of rituximab + CHOP chemotherapy. Where the hospital time was not documented for a given cycle, it was reported as Missing. | Cycles 1, 2, 3, 4, 5, 6, 7, and 8 (each cycle was 14 or 21 days) | 
| Number of Participants With an Event-Free Survival (EFS) Event | EFS events included disease progression, relapse, initiation of other anti-lymphoma therapy, or death. Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as greater than or equal to (≥) 50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. | Up to approximately 4.25 years | 
| Duration of EFS | EFS was defined as the time from randomization to first occurrence of disease progression, relapse, initiation of other anti-lymphoma therapy, or death, whichever occurred first. Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as a ≥50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. | Up to approximately 4.25 years | 
| Number of Participants With Relapse or Death at the Time of Primary Analysis | Tumor response was assessed according to criteria published by Cheson et al (1999). Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. The number of participants who had experienced relapse or death prior to the clinical cut-off date (October 2014) was determined. | Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 or 21 days], every 3 months thereafter, and/or 4 weeks after early termination) | 
| Duration of Disease-Free Survival (DFS) | DFS was defined as the time from date of initial CR/CRu to the date of relapse or death from any cause. Tumor response was assessed according to criteria published by Cheson et al (1999). Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. | Up to approximately 4.25 years | 
| Number of Participants With Progression, Relapse, or Death | Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as ≥50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. | Up to approximately 4.25 years | 
| Duration of Progression-Free Survival (PFS) | PFS was defined as the time from randomization to first occurrence of disease progression, relapse, or death from any cause. Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as ≥50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. | Up to approximately 4.25 years | 
| Number of Deaths |  | Up to approximately 4.25 years | 
| Duration of Overall Survival (OS) | OS was defined as the time from randomization to death from any cause. | Up to approximately 4.25 years |