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One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera

rituximab [MabThera]

After 4 cycles of intravenous MabThera without experiencing grade 3 or 4 infusion-related reactions. patients will receive 1 additional cycle of intravenous MabThera and 1 cycle of subcutaneous MabThera.

Clinical Trials

This randomized, parallel-group, multi-center study will compare the pharmacokinetics and safety of subcutaneous administration of MabThera (rituximab) versus intravenous MabThera in combination with chemotherapy in previously untreated patients with chronic lymphocytic leukemia (CLL). The study consists of 2 parts. In part 1, patients who have previously received 4 cycles of intravenous MabThera will receive in Cycle 5 intravenous MabThera and in Cycle 6 subcutaneous MabThera. In part 2, patients will be randomized to receive either 6 cycles of intravenous MabThera, or 1 cycle of intravenous MabThera and 5 cycles of subcutaneous MabThera. Additionally, all patients will receive chemotherapy (fludarabine and cyclophosphamide) on Days 1-3 or Days 1-5 of every cycle. The anticipated time on study drug is 24 weeks.

A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia

An Adaptive, Comparative, Randomized, Parallel-group, Multi Center, Phase Ib Study of Subcutaneous (SC) Rituximab Versus Intravenous (IV) Rituximab Both in Combination With Chemotherapy (Fludarabine and Cyclophosphamide), in Patients With Previously Untreated CLL

Ctrough is defined as the trough or minimum serum concentration. Pharmacokinetic parameters for rituximab were assessed during Cycles 5 (IV rituximab) and 6 (SC rituximab). Rituximab pharmacokinetic (PK) data from Part 1 were integrated into a population PK model using parametric, nonlinear, mixed-effects modelling. Rituximab IV 500 mg/m\^2 administered once every 4 weeks was compared to fixed doses of rituximab SC between 1400 mg and 1870 mg. The dose selection was performed on Ctrough concentrations at Cycle 5 (pre-dose Cycle 6). A test of the probability of success was applied to each of the 100 replicates, and the percentage of replicates with a positive test corresponded to the probability of success of the trial.

Ctrough is defined as the trough or minimum serum concentration in a given cycle of treatment. The objective of Part 2 was to demonstrate the comparability of the observed Ctrough of rituximab SC 1600 mg and rituximab IV 500 mg/m2 at Cycle 5, as assessed by a non-inferiority test with a lower boundary of at least 0.8 for the 90% CI.

AUC values were calculated by numerical integration using the linear trapezoidal rule. AUC levels were analyzed using the model below: Ln(AUC) = μ + τi + BlTLij + εij wherein, Ln is the natural log, μ denotes the overall mean effect, τi the effect in each treatment group, BlTLij the tumor load at baseline for each patient and εij a random error variable with normal distribution and mean 0. The treatment effect therein was based on a contrast statement in the model to calculate 90 % confidence intervals for ln(AUC SC)- ln(AUC IV).

Cmax was obtained directly from the measured concentration-time curves. The concentration-time curve is the result of time points of blood sampling and its measured concentration of rituximab in the blood samplings.

Multiple blood samples were obtained at pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6 in Rituximab IV arm, and at pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6 in Rituximab SC arm and time to peak plasma concentration of rituximab was determined.

The terminal half-life (t1/2) of rituximab is defined as the time required for the plasma concentration of rituximab to reach half of its original concentration.

In part 1 of the trial, upon completion of dosing in cycle 6, participants and their treating nurses were asked whether they have a preference of dosing route, IV vs SC

Physicians and nurses who administered rituximab were asked to answer the following question: " If used in routine practice, on average, how much staff time could be saved with each administration of rituximab SC as compared to rituximab IV? (Please do not consider the time needed for the first IV administration, consider only the subsequent ones)". The number of nurses that responded for both the IV and SC arms was 70. The number of physicians that responded for the IV and SC arms were 78 and 81 respectively.

Physicians and nurses who administered rituximab were asked to answer the following question: "Which formulation of rituximab (SC or IV) do you think is more convenient?" with pre-specified responses as below. Percentage of participants with specified answers were reported. The number of nurses that responded for both the IV and SC arms was 70. The number of physicians that responded for the IV and SC arms were 78 and 81 respectively.

Blood samples for the assessment of antibodies against rituximab (HACAs) were drawn pre-dose at Cycle 5 and Cycle 6 in Part 1 and at each follow up visit until 24 months after the last dose.

In Part 2, samples for the HACA assay were collected at each treatment cycle prior to the administration of rituximab and at each follow-up visit until 24 months after the last dose of rituximab.

CD 19 is a surface antigen (protein) present on B-lymphocytes.

Total B-cell depletion (normal B-cell plus Malignant B-cell depletion) was defined for each individual participant when the sum of CD5-/CD19+ (normal B-cells) and CD5+/CD19+ (malignant B-cells) cell counts decreased below 80 cells/μL.

Hoffmann-La Roche

New infections and all unrelated SAEs were reported until 9 months after the last dose of study treatment. All related SAEs were reported indefinitely. Secondary malignancies were reported until the end of the study or initiation of a new anti-leukemia treatment, whichever was earlier.

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1400 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 1: Rituximab SC 1400 mg

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1600 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 1: Rituximab SC 1600 mg

PParticipant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1870 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 1: Rituximab SC 1870 mg

One participant enrolled in the rituximab SC 1870 mg subcohort received 1000 mg rituximab SC during Cycle 6 in error.

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1000 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 1: Rituximab SC 1000 mg

These participants were withdrawn prior to SC treatment.

Part 1: No SC Dose Received

Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 0 Cycles 2-6: IV rituximab 500 mg/m\^2 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 2 : Rituximab IV 500 mg/m^2

Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 0 Cycles 2-6: SC rituximab 1600 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 2: Rituximab SC 1600 mg

Participant could have been enrolled any time during their treatment with rituximab IV in combination with fludarabine/cyclophosphamide (FC) prior to Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1400 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 1: Rituximab SC 1400 Milligrams (mg)

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1600 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Total

Age, Continuous

Sex: Female, Male

Safety Analysis Population (SAP): all participants who received at least one dose of study medication whether prematurely withdrawn or not. In Part 2 two participants randomized to the rituximab SC 1600 mg arm were included in Rituximab IV 500 mg/m\^2 arm as they received only the first cycle of rituximab IV 375 mg/m\^2.

Medical Communications

Participant could have been enrolled any time during their treatment with rituximab IV in combination with FC prior to Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1400, 1600 or 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Part 1: Rituximab SC

Enrolled (non-randomized) Pharmacokinetic Evaluable Population (Part 1) included all participants from Part 1 who did not significantly violate the inclusion or exclusion criteria, deviate significantly from the protocol or have unavailable or incomplete data which could influence the pharmacokinetic analysis.

Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab

Only participants who entered Part 2 of the study and had pharmacokinetic (PK) data available were included in the analysis.

Part 2: Rituximab C Trough Levels at Cycle 5

Only participants who entered Part 2 of the study and had PK data available were included in the analysis.

Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6

Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6

Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6

Part 2: Terminal Half-Life of Rituximab at Cycle 6

Participants who preferred SC

Participants who preferred IV

Nurses who preferred SC

Nurses who preferred IV

Participant could have been enrolled any time during treatment with rituximab IV in combination with fludarabine/cyclophosphamide (FC) prior to Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1400 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1870 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

All participants in Part 1 were included in this analysis including 8 participants that did not receive SC rituximab.

Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration

Nurse: 4 or more hours

Nurse: At least 3 hours but less than 4 hours

Nurse: At least 2 hours but less than 3 hours

Nurse: At least 1 hour but less than 2 hours

Nurse: Less than 1 hour

Physician: 4 or more hours

Physician: At least 3 hours but less than 4 hours

Physician: At least 2 hours but less than 3 hours

Physician: At least 1 hour but less than 2 hours

Physician: Less than 1 hour

All the physicians and nurses who responded to the questionnaire were included in the analysis.

Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV

Nurse: Rituximab SC is much more convenient

Nurse: Rituximab SC is a little more convenient

Nurse: Both formulations are equally convenient

Nurse: Rituximab IV is a little more convenient

Nurse: Rituximab IV is much more convenient

Physician: Rituximab SC is much more convenient

Physician: Rituximab SC a little more convenient

Physician: Both formulations equally convenient

Physician: Rituximab IV a little more convenient

Physician: Rituximab IV is much more convenient

Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV

Pre-Dose Cycle 5: positive for HACAs (n=59)

Pre-Dose Cycle 5: negative for HACAs (n=59)

Post-Dose: positive for HACAs (n=61)

Post-Dose: negative for HACAs (n=61)

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1400, 1600 or 1870 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Safety Analysis Population (SAP): all participants who received at least one dose of study medication, whether prematurely withdrawn from the study or not. This included 8 participants that did not receive SC rituximab. n = number of participants analyzed.

Part 1: Percentage of Participants With Anti-Rituximab Antibodies

Baseline pre Cycle 1: positive for HACAs (n=87,85)

Baseline pre Cycle 1: negative for HACAs (n=87,85)

Post-Baseline: positive for HACAs (n=89,85)

Post-Baseline: negative for HACAs (n=89,85)

SAP; n = number of participants analyzed for the specific parameter.

Part 2: Percentage of Participants With Anti-Rituximab Antibodies

Cycle 5 Day 1 (n=15,13,19,1,2)

Cycle 6 Day 1 (n=15,14,18,1,0)

FU 28 Day Visit (n=15,11,19,1,0)

FU 56 Day Visit (n=15,9,15,1,0)

FU 3 Month Visit (n=16,8,18,0,0)

FU 6 Month Visit (n=15,13,17,1,0)

FU 9 Month Visit (n=15,13,15,1,0)

FU 12 Month Visit (n=14,14,20,0,0)

FU 15 Month Visit (n=14,11,15,0,0)

FU 18 Month Visit (n=13,14,15,0,0)

FU 21 Month Visit (n=13,12,16,0,0)

FU 24 Month Visit(n=12, 4,16,0,0)

Part 1 SAP; n = number of participants analyzed at the specified visit.

Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit

Cycle 5 Day 1 (n=15,1319,1,2)

Cycle 6 Day 1(n= 15,14,18,1,0)

FU 24 Month Visit (n=12,14,16,0,0)

Participant could have been enrolled any time during treatment with rituximab IV in combination with FC before Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 mg/m\^2 on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1000 on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Rituximab SC 1000 mg

Part 1: Percentage of Participants With Total B-Cell Depletion by Visit

Cycle 1 - Baseline (n=80,80)

Cycle 2 - Pre-dose (n=71,74)

Cycle 2 - Post-dose (n=65, 66)

Cycle 2 Day 2 (n=54, 59)

Cycle 2 Day 3 (n=48, 54)

Cycle 3 Day 1 (n=67,68)

Cycle 4 Day 1 (n=71,69)

Cycle 5 Day 1 (n=68,67)

Cycle 6 Day 1 (n=71,64)

FU 28 Day Visit (n=66,64)

FU 56 Day Visit (n=63,67)

FU 3 Month Visit (n=67,67)

FU 6 Month Visit (n=60,69)

FU 9 Month Visit (n=65,64)

FU 12 Month Visit (n=60,61)

FU 15 Month Visit (n=59,60)

FU 18 Month Visit (n=57,58)

FU 21 Month Visit (n=55,52)

FU 24 Month Visit (n=56,51)

Withdrawn/Termination (n=17,15)

Part 2 SAP; n = number of participants analyzed at the specified visit.

Part 2: Total CD19+ B-Cell Counts by Visit

Cycle 1 - Baseline (n=80,80))

Cycle 2 - Pre-dose (n=71, 74)

Part 2 SAP; n= number of participants analyzed at the specified visit.

Part 2: Percentage of Participants With Total B-Cell Depletion by Visit

Participant could have been enrolled any time during their treatment with rituximab IV in combination with fludarabine/cyclophosphamide (FC) prior to Cycle 5. Participants received the following in 28-day cycles. Cycle 1: IV rituximab 375 milligrams per square meter (mg/m\^2) on Day 1 or Day 0 (according to local practice) Cycles 2-5: IV rituximab 500 mg/m\^2 on Day 1 Cycle 6: SC rituximab 1400 mg on Day 1 Cycles 1-6: IV fludarabine 25 mg/m\^2 on Days 1-3 (or as an oral dose of 24 mg/m\^2 on Days 1-5 or 30-40 mg/m\^2 on Days 1-3), and IV cyclophosphamide 250 mg/m\^2 on Days 1-3 (or as an oral dose of 150 mg/m\^2 on Days 1-5 or 200-250 mg/m\^2 on Days 1-3).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia	NCT01292603	Lymphocytic Leu...	Cyclophosphamid... Fludarabine rituximab [MabT... rituximab [MabT... rituximab [MabT...	18 Years -	Hoffmann-La Roche
A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia	NCT01292603	Lymphocytic Leu...	Cyclophosphamid... Fludarabine rituximab [MabT... rituximab [MabT... rituximab [MabT...	18 Years -	Hoffmann-La Roche

Spots Global Cancer Trial Database for rituximab [mabthera]