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
Overview
- Phase
- Phase 1
- Intervention
- rituximab [MabThera]
- Conditions
- Lymphocytic Leukemia, Chronic
- Sponsor
- Hoffmann-La Roche
- Enrollment
- 240
- Locations
- 84
- Primary Endpoint
- Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab
- Status
- Completed
- Last Updated
- 7 years ago
Overview
Brief Summary
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Adult patients, \>/=18 years of age
- •Patients with treatment-requiring chronic lymphocytic leukemia (CLL)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- •Life expectancy \>6 months
Exclusion Criteria
- •Transformation to aggressive B-cell malignancy
- •History of other malignancy unless the patient was treated with curative intent and has been in remission for more than 5 years prior to enrolment
- •HIV or Hepatitis B positive unless clearly due to vaccination
- •Inadequate liver or renal function
- •Any coexisting medical or psychological condition that would preclude participation in the required study procedures
- •Additional exclusion criterion for Part 1:
- •Any previous treatment for CLL except for up to 4 cycles of rituximab IV in combination with FC chemotherapy as first-line treatment for CLL
- •Additional exclusion criterion for Part 2:
- •Any previous treatment for CLL
Arms & Interventions
3
Intervention: rituximab [MabThera]
1
Intervention: Cyclophosphamide
1
Intervention: Fludarabine
1
Intervention: rituximab [MabThera]
2
Intervention: Cyclophosphamide
2
Intervention: Fludarabine
2
Intervention: rituximab [MabThera]
3
Intervention: Cyclophosphamide
3
Intervention: Fludarabine
Outcomes
Primary Outcomes
Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab
Time Frame: Pre-dose and post-dose (15 minutes to end of infusion) on Day 1 and on Days 2, 5, 11 and 15 of Cycle 5 and Pre-dose, Post-dose on Days 2, 3, 5,11, 15 and 29 of Cycle 6; Pre-dose was taken 2 hours prior rituximab dose
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.
Part 2: Rituximab C Trough Levels at Cycle 5
Time Frame: +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration
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.
Secondary Outcomes
- Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6(Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6)
- Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6(Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6)
- Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6(Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6)
- Part 2: Terminal Half-Life of Rituximab at Cycle 6(Rituximab IV arm: pre-dose, post-dose and on Days 2, 3, 8 ,15, 29 of Cycle 6; Rituximab SC arm: pre-dose, and on Days 2, 3, 8 ,15, 29 of Cycle 6)
- Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration(Days 4 to 5 in Cycle 6)
- Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV(Days 4-5 in Cycle 6)
- Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV(Days 4-5 in Cycle 6)
- Part 1: Percentage of Participants With Anti-Rituximab Antibodies(Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose)
- Part 2: Percentage of Participants With Anti-Rituximab Antibodies(Day 0 of Cycle 1 and Day 1 of Cycles 1, 2, 3, 4, 5, and 6 and at each follow-up visit until 24 months after the last dose of rituximab.)
- Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit(Day 1 of Cycles 5 and 6 and Follow-up Days 28 and 56 and Follow-up Visits at Months 3, 6, 9, 12, 15,18, 21 and 24)
- Part 1: Percentage of Participants With Total B-Cell Depletion by Visit(Day 1 pre-dose of Cycles 5 and 6 and Follow-up Days 28 and 56 and Follow-up Visits at Months 3, 6, 9, 12, 15, 18, 21 and 24)
- Part 2: Total CD19+ B-Cell Counts by Visit(Cycle 1 pre-dose, 60 minutes post-dose, Days 2 and 3 in Cycle 2, day 1 pre-dose in Cycles 3, 4, 5 and 6, Follow-up Days 28 and 56, and Follow-up Visits at Months 3, 6, 9, 12, 15, and 18 and Withdrawal Visit)
- Part 2: Percentage of Participants With Total B-Cell Depletion by Visit(Cycle 1 Pre-dose, 60 minutes post-dose, Days 2 and 3 in Cycle 2, day 1 in Cycles 3, 4, 5 and 6, Follow-up Days 28 and 56, and Follow-up Visits at Months 3, 6, 9, 12, 15, and 18 and Withdrawal Visit)