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)

• ClinicalTrials.gov Identifier: NCT02213263
• Recruitment Status: Completed
• First Posted: August 11, 2014
• Results First Posted: October 30, 2018
• Last Update Posted: June 20, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: August 7, 2014
• First Posted Date: August 11, 2014
• Results First Submitted Date: October 2, 2018
• Results First Posted Date: October 30, 2018
• Last Update Posted Date: June 20, 2019
• Actual Study Start Date: September 30, 2014
• Actual Primary Completion Date: October 23, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 2, 2018)

Overall Response Rate (ORR): Percentage of Participants With Overall Response (OR) at Week 26 [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: August 7, 2014): Objective Response Rate (ORR) according to the revised response criteria for malignant lymphoma [ Time Frame: Week 26 ]

Current Secondary Outcome Measures (submitted: March 15, 2019)

• Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 52 ]
  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.
• Number of Participants With Treatment Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to Week 52 ]
  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.
• 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 [ Time Frame: Baseline up to Week 52 ]
  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.
• 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 [ Time Frame: Baseline up to Week 52 ]
  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.
• Number of Participants With Clinically Significant Laboratory Abnormalities [ Time Frame: Baseline up to Week 52 ]
  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.
• Time to Treatment Failure (TTF) [ Time Frame: From randomization until disease progression, death or permanent discontinuation from treatment/study due to any reason, or up to Week 52 ]
  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.
• Progression-Free Survival (PFS) [ Time Frame: From randomization until disease progression or death due to any cause or up to Week 52 ]
  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.
• Percentage of Participants With Complete Remission (CR) at Week 26 [ Time Frame: 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.
• Duration of Response (DOR) [ Time Frame: 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 ]
  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.
• Overall Survival [ Time Frame: From randomization until death due to any cause or up to Week 52 ]
  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.
• Maximum Observed Serum Concentration (Cmax) of PF-05280586 and Rituximab-EU [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline, Week 2, 3, 4, 5, 13, 26, 39, 52 ]
• Number of Participants With Positive Anti-Drug Antibodies (ADAs) and Neutralizing Antibodies (NAbs) [ Time Frame: Baseline up to Week 52 ]
  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.
• Number of Participants Reporting Immune-Based Adverse Effects [ Time Frame: Baseline up to Week 52 ]
  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).

Original Secondary Outcome Measures (submitted: August 7, 2014)

• Time to Treatment Failure (TTF) [ Time Frame: Week 52 ]
• Progression-Free Survival (PFS) [ Time Frame: Week 52 ]
• Complete Remission (CR) rate [ Time Frame: Week 26 ]
• Duration of response [ Time Frame: Week 52 ]
• Overall survival [ Time Frame: Week 52 ]
• Maximum observed plasma concentration (Cmax) [ Time Frame: Week 52 ]
• Minimum observed plasma concentration (Cmin) [ Time Frame: Week 52 ]
• CD19-positive B-cell counts [ Time Frame: Week 52 ]
• Incidence of anti-drug antibodies (ADA) and safety associated with immune response [ Time Frame: Week 52 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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)
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Follicular Lymphoma

Intervention

• Biological: PF-05280586
  PF-05280586 (rituximab-Pfizer) concentrate for solution for infusion 375mg/m2 administered via IV infusion on Days 1, 8, 15, and 22
• Biological: MabThera®
  MabThera® (rituximab-EU) concentrate for solution for infusion 375mg/m2 administered via IV infusion on Days 1, 8, 15, and 22

Study Arms

• Experimental: PF-05280586
  Intervention: Biological: PF-05280586
• Active Comparator: MabThera®
  Intervention: Biological: MabThera®

Publications *

• Courville J, Nastoupil L, Kaila N, Kelton J, Zhang J, Alcasid A, Nava-Parada P. Factors Influencing Infusion-Related Reactions Following Dosing of Reference Rituximab and PF-05280586, a Rituximab Biosimilar. BioDrugs. 2021 Jul;35(4):459-468. doi: 10.1007/s40259-021-00487-6. Epub 2021 Jun 21.
• Sharman JP, Liberati AM, Ishizawa K, Khan T, Robbins J, Alcasid A, Rosenberg JA, Aurer I. A Randomized, Double-Blind, Efficacy and Safety Study of PF-05280586 (a Rituximab Biosimilar) Compared with Rituximab Reference Product (MabThera(R)) in Subjects with Previously Untreated CD20-Positive, Low-Tumor-Burden Follicular Lymphoma (LTB-FL). BioDrugs. 2020 Apr;34(2):171-181. doi: 10.1007/s40259-019-00398-7.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 7, 2014): 394
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 19, 2018
• Actual Primary Completion Date: October 23, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belarus, Belgium, Brazil, Croatia, France, Georgia, Germany, Greece, India, Italy, Japan, Korea, Republic of, Lebanon, Mexico, Peru, Philippines, Poland, Portugal, Puerto Rico, Romania, Russian Federation, South Africa, Spain, Switzerland, Thailand, Turkey, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT02213263
• Other Study ID Numbers: B3281006; 2014-000132-41 ( EudraCT Number ); REFLECTIONS ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Same as current
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: June 2019