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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT01292603
Registration number
NCT01292603
Ethics application status
Date submitted
8/02/2011
Date registered
9/02/2011
Date last updated
19/12/2018
Titles & IDs
Public title
A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia
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Scientific title
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
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Secondary ID [1]
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2010-021380-32
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Secondary ID [2]
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BO25341
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Lymphocytic Leukemia, Chronic
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Condition category
Condition code
Cancer
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Fludarabine
Treatment: Drugs - rituximab [MabThera]
Treatment: Drugs - rituximab [MabThera]
Treatment: Drugs - rituximab [MabThera]
Experimental: 1 -
Experimental: 2 -
Experimental: 3 -
Treatment: Drugs: Cyclophosphamide
Days 1-3 or Days 1-5 of cycles 1-6
Treatment: Drugs: Fludarabine
Days 1-3 or Days 1-5 of cycles 1-6
Treatment: Drugs: rituximab [MabThera]
One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera
Treatment: Drugs: 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.
Treatment: Drugs: rituximab [MabThera]
6 cycles of intravenous MabThera
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab
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Assessment method [1]
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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.
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Timepoint [1]
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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
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Primary outcome [2]
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Part 2: Rituximab C Trough Levels at Cycle 5
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Assessment method [2]
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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.
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Timepoint [2]
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+/- 25hours around the 28th day post the 5th Cycle of Rituximab administration
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Secondary outcome [1]
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Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6
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Assessment method [1]
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AUC values were calculated by numerical integration using the linear trapezoidal rule. AUC levels were analyzed using the model below: Ln(AUC) = µ + ti + BlTLij + eij wherein, Ln is the natural log, µ denotes the overall mean effect, ti the effect in each treatment group, BlTLij the tumor load at baseline for each patient and eij 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).
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Timepoint [1]
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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
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Secondary outcome [2]
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Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6
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Assessment method [2]
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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.
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Timepoint [2]
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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
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Secondary outcome [3]
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Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6
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Assessment method [3]
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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.
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Timepoint [3]
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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
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Secondary outcome [4]
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Part 2: Terminal Half-Life of Rituximab at Cycle 6
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Assessment method [4]
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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.
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Timepoint [4]
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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
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Secondary outcome [5]
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Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration
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Assessment method [5]
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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
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Timepoint [5]
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Days 4 to 5 in Cycle 6
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Secondary outcome [6]
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Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV
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Assessment method [6]
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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.
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Timepoint [6]
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Days 4-5 in Cycle 6
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Secondary outcome [7]
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Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV
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Assessment method [7]
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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.
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Timepoint [7]
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Days 4-5 in Cycle 6
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Secondary outcome [8]
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Part 1: Percentage of Participants With Anti-Rituximab Antibodies
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Assessment method [8]
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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.
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Timepoint [8]
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Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose
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Secondary outcome [9]
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Part 2: Percentage of Participants With Anti-Rituximab Antibodies
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Assessment method [9]
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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.
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Timepoint [9]
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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.
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Secondary outcome [10]
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Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit
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Assessment method [10]
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CD 19 is a surface antigen (protein) present on B-lymphocytes.
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Timepoint [10]
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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
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Secondary outcome [11]
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Part 1: Percentage of Participants With Total B-Cell Depletion by Visit
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Assessment method [11]
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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.
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Timepoint [11]
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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
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Secondary outcome [12]
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Part 2: Total CD19+ B-Cell Counts by Visit
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Assessment method [12]
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CD 19 is a surface antigen (protein) present on B-lymphocytes.
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Timepoint [12]
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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
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Secondary outcome [13]
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Part 2: Percentage of Participants With Total B-Cell Depletion by Visit
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Assessment method [13]
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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.
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Timepoint [13]
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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
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Eligibility
Key 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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 1
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
18/04/2011
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
17/11/2017
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Sample size
Target
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Accrual to date
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Final
240
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Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC
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Recruitment hospital [1]
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St George Hospital; Department of Haematology - Kogarah
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Recruitment hospital [2]
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Royal Brisbane and Women'S Hospital; Haematology - Herston
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Recruitment hospital [3]
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Ashford Cancer Center Research - Kurralta Park
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Recruitment hospital [4]
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Queen Elizabeth Hospital; Haematology - Woodville South
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Recruitment hospital [5]
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St Vincent'S Hospital; Haematology - Fitzroy
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Recruitment hospital [6]
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Frankston Hospital; Oncology/Haematology - Frankston
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Recruitment postcode(s) [1]
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2217 - Kogarah
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Recruitment postcode(s) [2]
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4029 - Herston
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Recruitment postcode(s) [3]
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5037 - Kurralta Park
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Recruitment postcode(s) [4]
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5011 - Woodville South
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Recruitment postcode(s) [5]
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3065 - Fitzroy
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Recruitment postcode(s) [6]
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3199 - Frankston
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Recruitment outside Australia
Country [1]
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Argentina
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State/province [1]
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Buenos Aires
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Argentina
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Córdoba
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Brazil
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RS
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Brazil
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SP
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Canada
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Nova Scotia
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Canada
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Quebec
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Chile
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Santiago
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Croatia
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Zagreb
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Czechia
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Brno
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Czechia
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Hradec Kralove
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Czechia
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Praha 2
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France
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Caen
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France
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Marseille
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France
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Paris
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France
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Reims
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France
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Vandoeuvre Les Nancy
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Germany
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Berlin
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Germany
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Dresden
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Germany
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Frankfurt an der Oder
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Germany
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Greifswald
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Germany
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Hannover
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Germany
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Kassel
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Germany
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Köln
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Germany
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Landshut
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Germany
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Lübeck
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Germany
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Marburg
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Germany
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Muenchen
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Germany
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München
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Germany
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Neunkirchen/Saar
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Germany
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Recklinghausen
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Greece
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Athens
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Greece
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Thessaloniki
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Italy
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Emilia-Romagna
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Italy
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Friuli-Venezia Giulia
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Italy
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Lombardia
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Italy
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Piemonte
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Italy
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Veneto
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Mexico
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Chihuahua
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Mexico
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Culiacan
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Mexico
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Monterrey
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New Zealand
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Christchurch
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New Zealand
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Newtown
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Poland
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Gdansk
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Poland
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Lublin
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Poland
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Warszawa
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Poland
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Wroclaw
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Portugal
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Lisboa
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Portugal
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Porto
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Russian Federation
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Moscow
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Russian Federation
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Penza
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Russian Federation
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Perm
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Russian Federation
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Saint-Petersburg
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Slovakia
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Bratislava
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Spain
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Barcelona
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Spain
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Madrid
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Spain
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Salamanca
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Spain
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Sevilla
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Spain
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Toledo
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Spain
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Valencia
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Country [60]
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Turkey
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Ankara
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Turkey
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State/province [61]
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Istanbul
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Country [62]
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Turkey
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State/province [62]
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Izmir
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Hoffmann-La Roche
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Address
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Ethics approval
Ethics application status
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Summary
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.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT01292603
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Clinical Trials
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Address
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Hoffmann-La Roche
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Country
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Phone
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT01292603
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