TriangleNCT01292603 · CITED IN SOURCE DOCUMENTS
A Study to Compare Subcutaneous Versus Intravenous MabThera (Rituximab) in Combination With Chemotherapy in Patients With Chronic Lymphocytic Leukemia
An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.
- Phase
- PHASE1
- Status at capture
- COMPLETED
- Registry last update
- 2018-12-19
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.
Open the original ClinicalTrials.gov record → · Download preserved record
What did the study report?
Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.
Participant flow
Baseline characteristics
Part 1: Subcutaneous Rituximab Dose Resulting in Trough Concentration (Ctrough) Levels Non-Inferior to Intravenous Rituximab
Part 2: Rituximab C Trough Levels at Cycle 5
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
Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration
Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV
Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV
Part 1: Percentage of Participants With Anti-Rituximab Antibodies
Part 2: Percentage of Participants With Anti-Rituximab Antibodies
Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit
Part 1: Percentage of Participants With Total B-Cell Depletion by Visit
Part 2: Total CD19+ B-Cell Counts by Visit
Part 2: Percentage of Participants With Total B-Cell Depletion by Visit
Adverse events
Limitations, agreements, and source contact
Who could take part
- 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
- healthy Volunteers
- false
- minimum Age
- 18 Years
- sex
- ALL
- std Ages
- ADULT
- OLDER_ADULT
Treatment arms and interventions
- arm Groups
- intervention Names
- Drug: Cyclophosphamide
- Drug: Fludarabine
- Drug: rituximab [MabThera]
- label
- 1
- type
- EXPERIMENTAL
- intervention Names
- Drug: Cyclophosphamide
- Drug: Fludarabine
- Drug: rituximab [MabThera]
- label
- 2
- type
- EXPERIMENTAL
- intervention Names
- Drug: Cyclophosphamide
- Drug: Fludarabine
- Drug: rituximab [MabThera]
- label
- 3
- type
- EXPERIMENTAL
- interventions
- arm Group Labels
- 1
- 2
- 3
- description
- Days 1-3 or Days 1-5 of cycles 1-6
- name
- Cyclophosphamide
- type
- DRUG
- arm Group Labels
- 1
- 2
- 3
- description
- Days 1-3 or Days 1-5 of cycles 1-6
- name
- Fludarabine
- type
- DRUG
- arm Group Labels
- 3
- description
- One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera
- name
- rituximab [MabThera]
- type
- DRUG
- arm Group Labels
- 1
- description
- 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.
- name
- rituximab [MabThera]
- type
- DRUG
- arm Group Labels
- 2
- description
- 6 cycles of intravenous MabThera
- name
- rituximab [MabThera]
- type
- DRUG
Study design
- intervention Model
- PARALLEL
- masking Info
- masking
- NONE
- primary Purpose
- TREATMENT
Enrollment
- count
- 240
- type
- ACTUAL
Registered outcome plans (not posted results)
- primary Outcomes
- description
- 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.
- measure
- 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
- description
- 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.
- measure
- Part 2: Rituximab C Trough Levels at Cycle 5
- time Frame
- +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration
- secondary Outcomes
- description
- 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).
- measure
- Part 2: Observed Area Under the Serum Concentration-Curve (AUC) of Rituximab at Cycle 6
- time Frame
- 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
- description
- 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.
- measure
- Part 2: Maximum Observed Concentration (Cmax) of Rituximab at Cycle 6
- time Frame
- 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
- description
- 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.
- measure
- Part 2: Time to Cmax (Tmax) of Rituximab at Cycle 6
- time Frame
- 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
- description
- 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.
- measure
- Part 2: Terminal Half-Life of Rituximab at Cycle 6
- time Frame
- 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
- description
- 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
- measure
- Part 1: Percentage of Participants and Nurses Recording a Preference For Either SC or IV Administration
- time Frame
- Days 4 to 5 in Cycle 6
- description
- 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.
- measure
- Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV
- time Frame
- Days 4-5 in Cycle 6
- description
- 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.
- measure
- Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV
- time Frame
- Days 4-5 in Cycle 6
- description
- 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.
- measure
- Part 1: Percentage of Participants With Anti-Rituximab Antibodies
- time Frame
- Predose at Cycles 5 and 6 and at each follow up visit until 24 months after the last dose
- description
- 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.
- measure
- Part 2: Percentage of Participants With Anti-Rituximab Antibodies
- time Frame
- 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.
- description
- CD 19 is a surface antigen (protein) present on B-lymphocytes.
- measure
- Part 1: Total Cluster Differentiation19 Positive (CD19+) B-Cell Counts by Visit
- time Frame
- 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
- description
- 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.
- measure
- Part 1: Percentage of Participants With Total B-Cell Depletion by Visit
- time Frame
- 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
- description
- CD 19 is a surface antigen (protein) present on B-lymphocytes.
- measure
- Part 2: Total CD19+ B-Cell Counts by Visit
- time Frame
- 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
Full study description
- 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.
Source references
- references
- citation
- Assouline S, Buccheri V, Delmer A, Gaidano G, Trneny M, Berthillon N, Brewster M, Catalani O, Li S, McIntyre C, Sayyed P, Badoux X. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016 Mar;3(3):e128-38. doi: 10.1016/S2352-3026(16)00004-1.
- pmid
- 26947201
- type
- DERIVED
- citation
- Assouline S, Buccheri V, Delmer A, Gaidano G, McIntyre C, Brewster M, Catalani O, Hourcade-Potelleret F, Sayyed P, Badoux X. Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. 2015 Nov;80(5):1001-9. doi: 10.1111/bcp.12662. Epub 2015 Jul 29.
- pmid
- 25900065
- type
- DERIVED
- citation
- Mao CP, Brovarney MR, Dabbagh K, Birnbock HF, Richter WF, Del Nagro CJ. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys. PLoS One. 2013 Nov 12;8(11):e80533. doi: 10.1371/journal.pone.0080533. eCollection 2013.
- pmid
- 24265828
- type
- DERIVED
- citation
- Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and trastuzumab (Herceptin) using hyaluronidase. Br J Cancer. 2013 Sep 17;109(6):1556-61. doi: 10.1038/bjc.2013.371. Epub 2013 Sep 3.
- pmid
- 24002601
- type
- DERIVED
Source notices and limitations
Discovery and provenance
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- patients with event 63 (17%) 29 (15%) Hazard Ratio [95% CI] (unstratified Cox model) 1.08 [0.70;1.68] 14.3 Chronic Lymphocytic Leukemia (CLL) The SAWYER study [NCT01292603] was a randomized, two-part, open-label, multicenter study that enrolled a total of 176 patients with previously untreated CLL. Patients were randomized (1:1)
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Preserved source evidence · Not medical advice