Non-Hodgkin's Lymphoma
Conditions
Keywords
Follicular NHL, NHL, Large B-Cell NHL
Brief summary
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).
Interventions
DRUGRituximab
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.
Commercial preparations of CHOP were used. Prednisone was administered prior to rituximab infusion.
DRUGCVP (cyclophosphamide, vincristine, prednisone)
Commercial preparations of CVP were used. Prednisone was administered prior to rituximab infusion.
DRUGAnalgesic/antipyretic and antihistamine drugs
An analgesic/antipyretic (eg, acetaminophen) and an antihistamine (eg, diphenhydramine) were administered 30 minutes before each infusion of rituximab.
Sponsors
Genentech, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Day 1 of each of Cycles 1 to 6 or 8 | The median duration of the rituximab infusion on Day 1 of each cycle, including the duration of dose interruptions, is reported. |
| 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) | Day 1 of Cycles 2 and either 6 or 8 (last cycle) | 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. |
| Percentage of Patients Who Had Undetectable Levels of CD19+ Lymphocytes at Cycle 2 and Either Cycle 6 or 8 (Last Cycle) | Day 1 of 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). |
Participant flow
Pre-assignment details
Of 451 enrolled patients, 26 withdrew before receiving treatment and are not included in the Baseline Characteristics nor any of the Outcome Measures.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab 375 mg/m^2 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. | 425 |
| Total | 425 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Enrolled in Study | Physician decision to withdraw patient | 1 |
| Enrolled in Study | Subject decision to withdraw | 8 |
| Enrolled in Study | Various Reasons | 17 |
| Received Cycle 1 Treatment | Adverse Event | 8 |
| Received Cycle 1 Treatment | Death | 5 |
| Received Cycle 1 Treatment | Eligibility criteria for Cycle 2 not met | 11 |
| Received Cycle 1 Treatment | Physician decision to withdraw patient | 7 |
| Received Cycle 1 Treatment | Subject decision to withdraw | 9 |
| Received Cycle 1 Treatment | Various Reasons | 13 |
| Received Cycle 2 Treatment | Adverse Event | 12 |
| Received Cycle 2 Treatment | Death | 6 |
| Received Cycle 2 Treatment | Disease progression | 3 |
| Received Cycle 2 Treatment | Lost to Follow-up | 3 |
| Received Cycle 2 Treatment | Physician decision to withdraw patient | 13 |
| Received Cycle 2 Treatment | Subject decision to withdraw | 6 |
| Received Cycle 2 Treatment | Various Reasons | 25 |
Baseline characteristics
| Characteristic | Rituximab 375 mg/m^2 |
|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 13.4 |
| Sex: Female, Male Female | 191 Participants |
| Sex: Female, Male Male | 234 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 421 / 425 |
| serious Total, serious adverse events | 107 / 425 |
Outcome results
Primary
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.
Time frame: Days 1 and 2 of Cycle 2
Population: Per-protocol evaluable population: All patients who received rituximab by faster infusion in Cycle 2 and who did not experience a Grade 3 or 4 infusion-related reaction during the rituximab infusion given at the standard rate during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 375 mg/m^2 | 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 | 1.1 Percentage of participants |
Secondary
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.
Time frame: Day 1 of each of Cycles 1 to 6 or 8
Population: Per-protocol evaluable population: All patients who received rituximab by faster infusion in Cycle 2 and who did not experience a Grade 3 or 4 infusion-related reaction during the rituximab infusion given at the standard rate during Cycle 1.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 1 (n=362) | 245 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 2 (n=363) | 91 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 3 (n=344) | 91 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 4 (n=329) | 91 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 5 (n=312) | 91 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 6 (n=303) | 91 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 7 (n=59) | 91 Minutes |
| Rituximab 375 mg/m^2 | Duration of Rituximab Infusion Including Dose Interruption Times | Cycle 8 (n=59) | 91 Minutes |
Secondary
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.
Time frame: Day 1 of Cycles 2 and either 6 or 8 (last cycle)
Population: Pharmacokinetic evaluable population: All patients who received at least 1 infusion of rituximab and had rituximab concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab 375 mg/m^2 | 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) | Cycle 2 (n=335) | 228.0 µg/mL | Standard Deviation 63.7 |
| Rituximab 375 mg/m^2 | 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) | Cycle 6 (n=238) | 275.0 µg/mL | Standard Deviation 71.5 |
| Rituximab 375 mg/m^2 | 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) | Cycle 8 (n=36) | 299.0 µg/mL | Standard Deviation 90.6 |
Secondary
Percentage of Patients Who Had an Adverse Event of Any Grade or Seriousness During Cycle 1
Time frame: Cycle 1
Population: Intent-to-treat (ITT) population: All patients who received at least 1 dose of rituximab regardless of infusion rate.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 375 mg/m^2 | Percentage of Patients Who Had an Adverse Event of Any Grade or Seriousness During Cycle 1 | 91.8 Percentage of participants |
Secondary
Percentage of Patients Who Had an Adverse Event of Any Grade or Seriousness During Cycle 2 Through Cycle 6 or 8 (End of Study)
Time frame: Cycle 2 through Cycle 6 or 8 (end of study)
Population: Per-protocol evaluable population: All patients who received rituximab by faster infusion in Cycle 2 and who did not experience a Grade 3 or 4 infusion-related reaction during the rituximab infusion given at the standard rate during Cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab 375 mg/m^2 | Percentage of Patients Who Had an Adverse Event of Any Grade or Seriousness During Cycle 2 Through Cycle 6 or 8 (End of Study) | 98.6 Percentage of participants |
Secondary
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).
Time frame: Day 1 of Cycle 2 and either Cycle 6 or 8 (last cycle)
Population: Per-protocol evaluable population: All patients who received rituximab by faster infusion in Cycle 2 and who did not experience a Grade 3 or 4 infusion-related reaction during the rituximab infusion given at the standard rate during Cycle 1. Only patients with pre-dose CD19+ lymphocyte counts at each time point were included in the analyses.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Rituximab 375 mg/m^2 | Percentage of Patients Who Had Undetectable Levels of CD19+ Lymphocytes at Cycle 2 and Either Cycle 6 or 8 (Last Cycle) | Cycle 8 (n=32) | 87.5 Percentage of participants | 0 |
| Rituximab 375 mg/m^2 | Percentage of Patients Who Had Undetectable Levels of CD19+ Lymphocytes at Cycle 2 and Either Cycle 6 or 8 (Last Cycle) | Cycle 2 (n=338) | 50.5 Percentage of participants | 24 |
| Rituximab 375 mg/m^2 | Percentage of Patients Who Had Undetectable Levels of CD19+ Lymphocytes at Cycle 2 and Either Cycle 6 or 8 (Last Cycle) | Cycle 6 (n=240) | 68.3 Percentage of participants | 4 |