A Study of Rituximab Alternative Dosing Rate in Patients With Previously Untreated Diffuse Large B-cell or Follicular Non-Hodgkin's Lymphoma (RATE)

Study Overview
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Brief Summary
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This was a prospective, open-label, Phase III, multicenter, single-arm trial designed to assess the safety, pharmacokinetics, and pharmacodynamics of an alternative dosing rate of rituximab in previously untreated patients with diffuse large B-cell lymphoma (DLBCL) and follicular non-Hodgkin lymphoma (NHL).

Official Title
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A Phase III Multicenter, Open-label Study of Rituximab Alternative Dosing Rate in Patients With Previously Untreated Diffuse Large B-cell or Follicular Non-Hodgkin's Lymphoma

Conditions
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Non-Hodgkin's Lymphoma

Intervention / Treatment
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* Drug: Rituximab
* Drug: CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone)
* Drug: CVP (cyclophosphamide, vincristine, prednisone)
* Drug: Analgesic/antipyretic and antihistamine drugs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Age ≥ 18 years Patients with previously untreated diffuse large B-cell lymphoma (DLBCL) who are scheduled to receive rituximab 375 mg/m^2 plus CHOP (cyclophosphamide, hydroxydaunorubicin [also called doxorubicin or adriamycin], Oncovin [vincristine], prednisone or prednisolone) chemotherapy, or previously untreated follicular non-Hodgkin lymphoma (NHL) who are scheduled to receive rituximab 375 mg/m^2 plus CVP (cyclophosphamide, vincristine, prednisolone) chemotherapy Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Exclusion Criteria: * Clinically significant cardiovascular disease (eg, uncontrolled hypertension, myocardial infarction, unstable angina), New York Heart Association (NYHA) Classification Grade II or greater congestive heart failure, a ventricular arrhythmia requiring medication within 1 year prior to Day 1, or NYHA Grade II or greater peripheral vascular disease on Day 1 (first day of treatment) Patients who meet any of the following criteria will be excluded from further study participation after Cycle 1: Circulating lymphocyte count > 5,000/μL before the Cycle 2 rituximab infusion Development of a serious and/or Grade 3 or 4 adverse event during Cycle 1 judged by the investigator to be related to the rituximab infusion Prior premedication with additional corticosteroids other than the prednisone included in the chemotherapy regimens

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab 375 mg/m^2<br>Patients received 6 or 8 21-day cycles of CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone) or CVP (cyclophosphamide, vincristine, prednisone) in combination with rituximab 375 mg/m^2 administered by intravenous (IV) infusion on Day 1 of each cycle. | Drug: Rituximab<br>* During Cycle 1 rituximab was administered at an initial rate of 50 mg/hour. In the absence of infusion toxicity during Cycle 1, the infusion rate was escalated by 50 mg/h increments every 30 minutes to a maximum rate of 400 mg/hour. In case of infusion-related reactions, the infusion was interrupted or the infusion rate reduced. In case of Grade 3/4 infusion reactions, the rituximab infusion was discontinued and medical treatment provided. If the rituximab infusion in Cycle 1 was tolerated without a serious adverse event (AE) or Grade 3/4 infusion-related AE, as judged by the investigator, infusions in Cycle 2 onwards were administered as follows: 20% of the total dose was given over 30 minutes and the remaining 80% of the dose was given over the next 60 minutes, for a total infusion time of 90 minutes. Commercial preparations of rituximab were used.<br>Drug: CHOP (cyclophosphamide, hydroxydaunorubicin [doxorubicin], Oncovin [vincristine], prednisone)<br>* Commercial preparations of CHOP were used. Prednisone was administered prior to rituximab infusion.<br>Drug: CVP (cyclophosphamide, vincristine, prednisone)<br>* Commercial preparations of CVP were used. Prednisone was administered prior to rituximab infusion.<br>Drug: Analgesic/antipyretic and antihistamine drugs<br>* An analgesic/antipyretic (eg, acetaminophen) and an antihistamine (eg, diphenhydramine) were administered 30 minutes before each infusion of rituximab.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Developed Grade 3 or 4 Infusion-related Reactions (IRR) Resulting From Faster Infusion of Rituximab During Days 1 and 2 of Cycle 2 | The percentage of patients who developed Grade 3 or 4 IRRs resulting from faster infusion of rituximab at Cycle 2 was assessed in patients who had previously received rituximab at the standard infusion rate without experiencing a Grade 3 or 4 IRR at Cycle 1. IRRs were a predefined list of Medical Dictionary for Regulatory Activities (MedDRA) terms for infusion-related adverse events occurring on the day of and/or the day after rituximab infusion. The list of IRR terms was compiled based on IRRs observed in the present and previous studies in which rituximab was infused at the standard rate. | Days 1 and 2 of Cycle 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients Who Had an Adverse Event of Any Grade or Seriousness During Cycle 1 |  | Cycle 1 | 
| Percentage of Patients Who Had an Adverse Event of Any Grade or Seriousness During Cycle 2 Through Cycle 6 or 8 (End of Study) |  | Cycle 2 through Cycle 6 or 8 (end of study) | 
| Duration of Rituximab Infusion Including Dose Interruption Times | The median duration of the rituximab infusion on Day 1 of each cycle, including the duration of dose interruptions, is reported. | Day 1 of each of Cycles 1 to 6 or 8 | 
| Maximum Serum Concentration (Cmax) of Rituximab Post-dose at the First Alternative Dosing Rate (Cycle 2) and the Last Cycle (Either Cycle 6 or 8) | Serum samples for rituximab pharmacokinetic analysis were taken pre-dose (within 15 minutes before rituximab infusion) and post-dose (within 15 minutes after the end of the rituximab infusion) after the first faster infusion (Cycle 2) and after the last infusion (either Cycle 6 or 8). An enzyme-linked immunosorbent assay (ELISA) was used to measure rituximab levels in the serum samples. | Day 1 of Cycles 2 and either 6 or 8 (last cycle) | 
| Percentage of Patients Who Had Undetectable Levels of CD19+ Lymphocytes at Cycle 2 and Either Cycle 6 or 8 (Last Cycle) | Serum samples for measurement of CD19+ lymphocytes were taken pre-dose (within 15 minutes before rituximab infusion). CD19+ lymphocyte counts were measured by flow cytometry using a fluorescent-activated cell sorter (FACS). | Day 1 of Cycle 2 and either Cycle 6 or 8 (last cycle) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Follicular NHL, NHL, Large B-Cell NHL