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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01292603
First received: February 8, 2011
Last updated: November 10, 2015
Last verified: November 2015
  Purpose
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 of every cycle. The anticipated time on study drug is 20 weeks.

Condition Intervention Phase
Lymphocytic Leukemia, Chronic
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: rituximab [MabThera]
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official 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

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

    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).


  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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

  • Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV [ Time Frame: Days 4-5 in Cycle 6 ] [ Designated as safety issue: No ]

    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). Percentage of participants with specified answers were reported.

    • A- Less than 1 hour
    • B- At least 1 hour but less than 2 hours
    • C- At least 2 hours but less than 3 hours
    • D- At least 3 hours but less than 4 hours
    • E- 4 or more hours

  • Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV [ Time Frame: Days 4-5 in Cycle 6 ] [ Designated as safety issue: No ]

    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.

    • A - Rituximab SC is much more convenient.
    • B - Rituximab SC is a little more convenient.
    • C - Both formulations are equally convenient.
    • D - Rituximab IV is a little more convenient.
    • E - Rituximab IV is much more convenient

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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. ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    CD 19 is a surface antigen (protein) present on B-lymphocytes.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    CD 19 is a surface antigen (protein) present on B-lymphocytes.

  • Part 2: Percentage of Participants With Total B-Cell Depletion by Visit [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 240
Study Start Date: April 2011
Estimated Study Completion Date: November 2017
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: Cyclophosphamide
Days 1-3 of cycles 1-6
Drug: Fludarabine
Days 1-3 of cycles 1-6
Drug: 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.
Experimental: 2 Drug: Cyclophosphamide
Days 1-3 of cycles 1-6
Drug: Fludarabine
Days 1-3 of cycles 1-6
Drug: rituximab [MabThera]
6 cycles of intravenous MabThera
Experimental: 3 Drug: Cyclophosphamide
Days 1-3 of cycles 1-6
Drug: Fludarabine
Days 1-3 of cycles 1-6
Drug: rituximab [MabThera]
One cycle of intravenous MabThera, followed by 5 cycles of subcutaneous MabThera

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  • 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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01292603

  Show 83 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01292603     History of Changes
Other Study ID Numbers: BO25341  2010-021380-32 
Study First Received: February 8, 2011
Results First Received: September 23, 2015
Last Updated: November 10, 2015
Health Authority: Spain: Agencia Espanola del Medicamento y Productos Sanitarios

Additional relevant MeSH terms:
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Rituximab
Alkylating Agents
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on April 27, 2016