A Study Of PF-05280586 (Rituximab-Pfizer) Or MabThera® (Rituximab-EU) For The First-Line Treatment Of Patients With CD20-Positive, Low Tumor Burden, Follicular Lymphoma (REFLECTIONS B328-06)

Study Overview
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Brief Summary
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This study will compare the safety and effectiveness of PF-05280586 versus rituximab-EU in patients with CD20-positive, low tumor burden follicular lymphoma. The primary hypothesis to be tested in this study is that the effectiveness of PF-05280586, as measured by the Overall Response Rate, is similar to that of rituximab-EU.

Official Title
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A PHASE 3, RANDOMIZED, DOUBLE-BLIND STUDY OF PF-05280586 VERSUS RITUXIMAB FOR THE FIRST-LINE TREATMENT OF PATIENTS WITH CD20-POSITIVE, LOW TUMOR BURDEN, FOLLICULAR LYMPHOMA

Conditions
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Follicular Lymphoma

Intervention / Treatment
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* Biological: PF-05280586
* Biological: MabThera®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of low tumor burden, CD20-positive follicular lymphoma Ann Arbor Stage II, III, or IV Exclusion Criteria: Not a candidate for treatment with rituximab as a single-agent Evidence of transformation to a high grade or diffuse large B-cell lymphoma Any previous systemic therapy for B-cell NHL, including chemotherapy, immunotherapy, or steroids Any prior treatment with rituximab Active, uncontrolled infection

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-05280586<br> | Biological: PF-05280586<br>* PF-05280586 (rituximab-Pfizer) concentrate for solution for infusion 375mg/m2 administered via IV infusion on Days 1, 8, 15, and 22<br>|
| Active Comparator: MabThera®<br> | Biological: MabThera®<br>* MabThera® (rituximab-EU) concentrate for solution for infusion 375mg/m2 administered via IV infusion on Days 1, 8, 15, and 22<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR): Percentage of Participants With Overall Response (OR) at Week 26 | ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR) in accordance with the revised response criteria for malignant lymphoma (Cheson 2007). CR was defined as disappearance of all evidence of disease. PR was defined as regression of measureable disease and no new sites. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in participants who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events after first dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious. | Baseline up to Week 52 | 
| Number of Participants With Treatment Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events after first dose of study drug that were absent before treatment or that worsened relative to pretreatment state. Relatedness to treatment was assessed by investigator. AEs included both serious and non-serious AEs. | Baseline up to Week 52 | 
| Number of Participants With Grade 3 or Higher Treatment-Emergent Adverse Events (AEs) as Graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 | An AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 1=Mild, asymptomatic or mild symptoms, Grade 2=Moderate; minimal, local or noninvasive intervention indicated, Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life threatening) events caused participant to be in imminent danger of death. Grade 5 = death. Treatment-emergent were events after first dose of study drug that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to Week 52 | 
| Number of Participants With Grade 3 or Higher Treatment-Related Treatment-Emergent Adverse Events (AEs) as Graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03 | Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. Grade 1=Mild, asymptomatic or mild symptoms, Grade 2=Moderate; minimal, local or noninvasive intervention indicated; Grade 3 (Severe) events=unacceptable or intolerable events, significantly interrupting usual daily activity, require systemic drug therapy/other treatment. Grade 4 (Life-threatening) events caused participant to be in imminent danger of death. Grade 5 = death. Treatment-emergent were events after first dose of study drug that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to Week 52 | 
| Number of Participants With Clinically Significant Laboratory Abnormalities | Criteria for clinically significant laboratory abnormalities included total bilirubin (TB) less than (<) 2*upper limit of normal (ULN), alanine aminotransferase (ALT)<3*ULN; TB<2*ULN, ALT more than (>) 3 equal to (=) *ULN; TB<2*ULN, aspartate aminotransferase (AST)<3*ULN; TB<2*ULN, AST>=3*ULN. Data for only those categories are reported for which at least one participant had clinically significant laboratory abnormality. | Baseline up to Week 52 | 
| Time to Treatment Failure (TTF) | TTF was defined as the time (in months) from date of randomization to first progression of disease based on central review, death due to any cause, or permanent discontinuation from treatment, or discontinuation from study for any reason, whichever came first. Progression was defined as any new lesion or increase by greater than or equal to (>=) 50% of previously involved sites from nadir. TTF was calculated using Kaplan-Meier method. | From randomization until disease progression, death or permanent discontinuation from treatment/study due to any reason, or up to Week 52 | 
| Progression-Free Survival (PFS) | PFS was defined as the time (in months) from date of randomization to first progression of disease (PD) based on central review or death due to any cause in the absence of documented PD. PD was defined as any new lesion or increase by >=50% of previously involved sites from nadir. PFS was calculated using Kaplan-Meier method. | From randomization until disease progression or death due to any cause or up to Week 52 | 
| Percentage of Participants With Complete Remission (CR) at Week 26 | Complete Remission (CR) was defined as disappearance of all evidence of disease. CR was assessed by central review based on scans done at Week 26. | Week 26 | 
| Duration of Response (DOR) | DOR was defined as the time (in months) from date of the first documentation of overall response (CR or PR) to the first documentation of progressive disease (PD) based on central review or to death due to any cause in the absence of documented PD. CR was defined as disappearance of all evidence of disease. PR was defined as regression of measureable disease and no new sites. PD was defined as any new lesion or increase by >=50% of previously involved sites from nadir. DOR was calculated using Kaplan-Meier method. | From date of first documentation of overall response to first documentation of PD or to death due to any cause in absence of PD or up to Week 52 | 
| Overall Survival | Overall survival was defined as the time (in months) from date of randomization to death due to any cause. For participants who were alive, overall survival was censored at the last contact. Overall survival was calculated using Kaplan-Meier method. | From randomization until death due to any cause or up to Week 52 | 
| Maximum Observed Serum Concentration (Cmax) of PF-05280586 and Rituximab-EU |  | Predose (within 4 hours prior to start of infusion) on Days 1, 8, 15 and 22; within 15 minutes prior to end of infusion on Days 1 and 22 | 
| Minimum Observed (Trough) Serum Concentration (Ctrough) of PF-05280586 and Rituximab-EU |  | Predose (within 4 hours prior to the start of dosing) on Day 1, 8, 15, and 22 | 
| Cluster of Differentiation (CD) 19-Positive B-Cell Counts |  | Baseline, Week 2, 3, 4, 5, 13, 26, 39, 52 | 
| Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) | Human serum ADA samples were analyzed for the presence or absence of anti-rituximab antibodies or anti-PF-05280586 antibodies using the validated drug-specific assay with a tiered approach using screening, confirmation and titer/quantitation. Human NAb serum samples testing ADA positive were analyzed for the presence or absence of neutralizing anti-rituximab antibody and neutralizing anti-PF-05280586 antibody using the validated drug-specific assay with a tiered approach using screening, confirmation and titer/quantitation. Participants with their ADA titer >= 1.88 were considered to be ADA positive. Only participants with a positive ADA result were further tested for NAb. | Baseline up to Week 52 | 
| Number of Participants Reporting Immune-Based Adverse Effects | Immune-based adverse effects included infusion related reaction (IRR), adverse events which fulfill Sampson's criteria, and adverse events which belong to the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Queries (SMQs) anaphylaxis or hypersensitivity reactions. Potential allergic and anaphylactic reactions were identified programmatically based on the criteria of Sampson et al, (2006). | Baseline up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rituximab, follicular lymphoma, Non-Hodgkin lymphoma, Non-Hodgkin's lymphoma