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

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ClinicalTrials.gov Identifier: NCT01292603
Recruitment Status : Completed
First Posted : February 9, 2011
Results First Posted : December 15, 2015
Last Update Posted : December 18, 2017
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Type: Interventional
Study Design: Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition: Lymphocytic Leukemia, Chronic
Interventions: Drug: Cyclophosphamide
Drug: Fludarabine
Drug: rituximab [MabThera]

  Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
In Part 1 a single dose of subcutaneous (SC) rituximab was administered at Cycle 6 to select a dose resulting in trough concentration (Ctrough) non-inferior to intravenous (IV) dose. In Part 2, participants were randomized to receive rituximab IV or SC, to demonstrate non-inferiority of rituximab Ctrough levels of SC dose compared with IV dose.

Reporting Groups
  Description
Part 1: Rituximab SC 1400 Milligrams (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 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).

Part 1: Rituximab SC 1600 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).

Part 1: Rituximab SC 1870 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 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).

No SC Dose Received These participants were withdrawn prior to SC treatment.
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: 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 SC 1600 mg

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).


Participant Flow for 6 periods

Period 1:   Part 1: Pilot Dose Selection Period
    Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   No SC Dose Received   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg
STARTED   16   17   23 [1]   8 [2]   0   0 
COMPLETED   16   17   23   0   0   0 
NOT COMPLETED   0   0   0   8   0   0 
Adverse Event                0                0                0                4                0                0 
Death                0                0                0                1                0                0 
Protocol Violation                0                0                0                2                0                0 
Withdrawal by Subject                0                0                0                1                0                0 
[1] 1 participant received a dose of 1000mg of rituximab by oversight.
[2] These participants were withdrawn prior to SC treatment.

Period 2:   Part 1: Regular Follow-Up Period
    Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   No SC Dose Received   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg
STARTED   16   17   23   0   0   0 
COMPLETED   0 [1]   0 [1]   0 [1]   0   0   0 
NOT COMPLETED   16   17   23   0   0   0 
Ongoing Regular Follow-Up                11                15                19                0                0                0 
Death                1                0                2                0                0                0 
Disease Progression                3                2                2                0                0                0 
Adverse Event                1                0                0                0                0                0 
[1] Participants withdrawn from regular follow-up who were still alive entered survival follow-up

Period 3:   Part 1: Survival Follow-Up
    Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   No SC Dose Received   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg
STARTED   4   2   2   0   0   0 
COMPLETED   0   0   0   0   0   0 
NOT COMPLETED   4   2   2   0   0   0 
Death                1                0                1                0                0                0 
Ongoing Survival Follow-UP                3                2                1                0                0                0 

Period 4:   Part 2: Dose Confirmation Period
    Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   No SC Dose Received   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg
STARTED   0   0   0   0   88   88 
COMPLETED   0   0   0   0   72   73 
NOT COMPLETED   0   0   0   0   16   15 
Death                0                0                0                0                1                0 
Physician Decision                0                0                0                0                2                0 
Withdrawn Prior to Treatment                0                0                0                0                1                1 
Adverse Event                0                0                0                0                7                9 
Protocol Violation                0                0                0                0                5                3 
Withdrawal by Subject                0                0                0                0                0                2 

Period 5:   Part 2: Regular Follow-Up
    Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   No SC Dose Received   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg
STARTED   0   0   0   0   78   78 
COMPLETED   0   0   0   0   0   0 
NOT COMPLETED   0   0   0   0   78   78 
Death                0                0                0                0                2                2 
Ongoing Regular Follow-Up                0                0                0                0                73                72 
Disease Progression                0                0                0                0                2                4 
Noncompliance                0                0                0                0                1                0 

Period 6:   Part 2: Survival Follow-UP
    Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   No SC Dose Received   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg
STARTED   0   0   0   0   11   13 
COMPLETED   0   0   0   0   0   0 
NOT COMPLETED   0   0   0   0   11   13 
Death                0                0                0                0                1                3 
Ongoing survival Follow-Up                0                0                0                0                10                10 



  Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
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.

Reporting Groups
  Description
Part 1: Rituximab SC 1400 Milligrams (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 1600 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).

Part 1: Rituximab SC 1870 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 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 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: 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 SC 1600 mg

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).

Total Total of all reporting groups

Baseline Measures
   Part 1: Rituximab SC 1400 Milligrams (mg)   Part 1: Rituximab SC 1600 mg   Part 1: Rituximab SC 1870 mg   Part 2 : Rituximab IV 500 mg/m^2   Part 2: Rituximab SC 1600 mg   Total 
Overall Participants Analyzed 
[Units: Participants]
 16   17   22   89   85   229 
Age 
[Units: Years]
Mean (Standard Deviation)
 56.6  (10.13)   60.4  (8.18)   56.9  (6.79)   58.7  (9.03)   59.0  (8.88)   58.8  (8.8) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
           
Female      6  37.5%      2  11.8%      7  31.8%      36  40.4%      25  29.4%      76  33.2% 
Male      10  62.5%      15  88.2%      15  68.2%      53  59.6%      60  70.6%      153  66.8% 


  Outcome Measures

1.  Primary:   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 ]

2.  Primary:   Part 2: Rituximab C Trough Levels at Cycle 5   [ Time Frame: +/- 25hours around the 28th day post the 5th Cycle of Rituximab administration ]

3.  Secondary:   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 ]

4.  Secondary:   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 ]

5.  Secondary:   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 ]

6.  Secondary:   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 ]

7.  Secondary:   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 ]

8.  Secondary:   Part 2: Physician/Nurse Opinion on Time Savings With Rituximab SC Compared With Rituximab IV   [ Time Frame: Days 4-5 in Cycle 6 ]

9.  Secondary:   Part 2: Physician/Nurse Opinion on Convenience of Rituximab SC Compared With Rituximab IV   [ Time Frame: Days 4-5 in Cycle 6 ]

10.  Secondary:   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 ]

11.  Secondary:   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. ]

12.  Secondary:   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 ]

13.  Secondary:   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 ]

14.  Secondary:   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 ]

15.  Secondary:   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 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Communications
Organization: Hoffmann- LaRoche
phone: 1-800-821-8590
e-mail: genentech@druginfo.com


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 ( EudraCT Number )
First Submitted: February 8, 2011
First Posted: February 9, 2011
Results First Submitted: September 23, 2015
Results First Posted: December 15, 2015
Last Update Posted: December 18, 2017