Trial Outcomes & Findings for A Study of Induction and Maintenance Treatment With MabThera (Rituximab) in Patients With Indolent B-Cell Nonfollicular Lymphomas (NCT NCT01153971)

Last Updated: 2017-08-01

Results Overview

Percentage of participants who at 2 years from the start of treatment remained free from documented disease progression, relapse, or death. Failure status was based on tumor evaluation performed on Month 28. Participants who did not have a tumor evaluation at Month 28 were counted as failures.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

47 participants

Primary outcome timeframe

Month 28

Results posted on

2017-08-01

Participant Flow

Participant milestones

Participant milestones
Measure	Rituximab + Fludarabine + Cyclophosphamide Cycle 1 (28-day cycle): Participants received fludarabine 25 milligrams per square meter (mg/m\^2) intravenously (IV) and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with complete response (CR), unconfirmed complete response (CRu), or partial response (PR), received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Induction Phase (Months 1 to 7 of Study) STARTED	47
Induction Phase (Months 1 to 7 of Study) COMPLETED	44
Induction Phase (Months 1 to 7 of Study) NOT COMPLETED	3
Maintenance Phase (Months 8-16 of Study) STARTED	44
Maintenance Phase (Months 8-16 of Study) COMPLETED	41
Maintenance Phase (Months 8-16 of Study) NOT COMPLETED	3
Follow-up (Months 17-40 of Study) STARTED	41
Follow-up (Months 17-40 of Study) COMPLETED	37
Follow-up (Months 17-40 of Study) NOT COMPLETED	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Rituximab + Fludarabine + Cyclophosphamide Cycle 1 (28-day cycle): Participants received fludarabine 25 milligrams per square meter (mg/m\^2) intravenously (IV) and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with complete response (CR), unconfirmed complete response (CRu), or partial response (PR), received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Induction Phase (Months 1 to 7 of Study) Adverse Event	2
Induction Phase (Months 1 to 7 of Study) Withdrawal by Subject	1
Maintenance Phase (Months 8-16 of Study) Adverse Event	2
Maintenance Phase (Months 8-16 of Study) Clinical relapse	1
Follow-up (Months 17-40 of Study) Adverse Event	1
Follow-up (Months 17-40 of Study) Protocol Violation	1
Follow-up (Months 17-40 of Study) Disease progression	2

Baseline Characteristics

A Study of Induction and Maintenance Treatment With MabThera (Rituximab) in Patients With Indolent B-Cell Nonfollicular Lymphomas

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Age, Continuous	57.3 years STANDARD_DEVIATION 8.2 • n=5 Participants
Sex: Female, Male Female	18 Participants n=5 Participants
Sex: Female, Male Male	28 Participants n=5 Participants

PRIMARY outcome

Timeframe: Month 28

Population: ITT population

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Percentage of Participants Remaining Failure-Free After 2 Years From Treatment Start Date	73.9 percentage of participants Interval 61.22 to 86.6

SECONDARY outcome

Timeframe: Baseline, Months 4, 7 (Induction Phase), 11, 16 (Maintenance Phase),22, 28, 34, and 40(Follow-Up Phase)

Population: ITT population

CR: complete disappearance of all symptoms/objective signs of disease (enlarged lymph nodes, hepatomegaly, splenomegaly) for at least 3 months following definitive re-evaluation at end of therapy. For initial bone marrow involvement, clearance of bone marrow documented by biopsy, normalization of blood counts with granulocytes greater than (\>)1,500 per microliter (/µL), hemoglobin \>12 grams per deciliter (g/dL), platelets \>100,000/µL. CRu: disappearance of all symptoms and nearly all measurable lesions, but persistence of some radiologic abnormalities with normalization of all biologic abnormalities; normalization of the performance status for at least 3 months after the definite evaluation of therapy. PR: at least 50 percent (%) reduction of measurable and evaluable lymphoma involvement for at least 4 weeks without occurrence of new manifestations, normalization of blood counts. Participants without evaluation at end of induction/maintenance phase were considered nonresponders.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Percentage of Participants Achieving a Best Overall Response of CR, CRu, or PR by Study Phase Induction Phase	95.7 percentage of participants Interval 89.76 to 100.0
Percentage of Participants Achieving a Best Overall Response of CR, CRu, or PR by Study Phase Maintenance Phase	80.4 percentage of participants Interval 68.97 to 91.9

SECONDARY outcome

Timeframe: Baseline, Months 4, 7, 11, 16, 22, 28, 34, and 40

Population: ITT population

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Percentage of Participants Achieving a Response by Response Type and Study Phase CR at end of induction phase	41.3 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase CR at end of maintenance phase	45.7 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase CR at final assessment	45.7 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase CRu at end of induction phase	21.7 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase CRu at end of maintenance phase	15.2 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase CRu at final assessment	19.6 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase PR at end of induction phase	32.6 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase PR at end of maintenance phase	19.6 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase PR at final assessment	13.0 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase Relapse at end of induction phase	0 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase Relapse at end of maintenance phase	0 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase Relapse at final assessment	2.2 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase Unknown at end of induction phase	4.3 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase Unknown at end of maintenance phase	19.6 percentage of participants
Percentage of Participants Achieving a Response by Response Type and Study Phase Unknown at final assessment	19.6 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

FFS data were analyzed using Kaplan-Meier survival analysis. FFS was measured from the date of treatment start to the date of documented disease progression, relapse, or death from any cause. Responding participants, participants who were lost to follow up, who withdrew consent, or dropped out due to adverse events (AE) were censored at their last assessment date. The reported data refer to values up to 40 months.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Failure-Free Survival (FFS), Percentage of Participants Estimated to be Free of Documented Disease Progression, Relapse, or Death	90.12 percentage of participants Interval 75.48 to 96.23

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

FFS was measured from the date of treatment start to the date of documented disease progression, relapse, or death from any cause. Responding participants, participants who were lost to follow up, who withdrew consent, or who dropped out due to AEs were censored at their last assessment date.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
FFS - Percentage of Participants With an Event	8.7 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

FFS was measured from the date of treatment start to the date of documented disease progression, relapse or death from any cause. Responding participants, participants who were lost to follow up, who withdrew consent or dropped out due to AEs were censored at their last assessment date. NOTE: The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
FFS - Time to Event	39.14 months Standard Error 0.70

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

OS data were analyzed using Kaplan-Meier survival analysis. OS was defined as the time from first dosage of study drug to the date of death from any cause. Reported data refer to values up to 40 months.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Overall Survival (OS) - Percentage of Participants Estimated to be Alive	97.44 percentage of participants Interval 83.16 to 99.64

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40.

Population: ITT population

OS was defined as the time from first dosage of study drug to the date of death from any cause.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
OS - Percentage of Participants With an Event	2.17 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40.

Population: ITT population

Overall survival was defined as the time from first dosage of study drug to the date of death from any cause.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
OS - Time to Event	38.6 months Standard Error NA Standard error could not be determined because the largest observation was censored and the estimation was restricted to the largest event time.

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population; only participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase were included in the analysis.

DFS data were analyzed using Kaplan-Meier survival analysis. DFS was defined for all participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of CR to the date of relapse. Participants without relapse were censored at their last assessment date. Participants who died due to tumour burden were considered in relapse. Participants who died due to any other causes were censored as of the death date. The reported data refer to values up to 40 months.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=29 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Disease-Free Survival (DFS) - Percentage of Participants Estimated to be Disease-Free	87.70 percentage of participants Interval 65.84 to 95.96

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40.

Population: ITT population; only participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase were included in the analysis.

DFS was defined for all patients who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase (month 7 of the study) and was measured from the time of complete response to the date of relapse. Participants without relapse were censored at their last assessment date. Participants who died due to tumour burden were considered in relapse. Participants who died due to any other causes were censored on the death date.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=29 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
DFS - Percentage of Participants With an Event	10.34 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40.

Population: ITT population; only participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase were included in the analysis.

DFS was defined for all participants who achieved a complete response (CR/CRu) at month 1 after the completion of treatment of the induction phase (month 7 of the study) and was measured from the time of complete response to the date of relapse. Participants without relapse were censored at their last assessment date. Participants who died due to tumour burden were considered in relapse. Participants who died due to any other causes were censored on the death date. NOTE: The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=29 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
DFS - Time to Event	32.51 months Standard Error 0.58

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

PFS data were analyzed using Kaplan-Meier survival analysis. PFS was defined as the time from treatment start to the date of documented disease progression. Reported data refer to values up to 40 months.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Progression-free Survival (PFS) - Percentage of Participants Estimated to Be Progress Free	90.12 percentage of participants Interval 75.48 to 96.23

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

Progression-free survival was defined as the time from the date of treatment start to the date of documented disease progression.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
PFS - Percentage of Participants With an Event	8.70 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population

Progression-free survival was defined as the time from treatment start to the date of documented disease progression. NOTE: The mean survival time and its standard error were underestimated because the largest observation was censored and the estimation was restricted to the largest event time.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=46 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
PFS - Time to Event	39.14 months Standard Error 0.70

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population; only participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase of the study were included in the analysis.

DR data were analyzed using Kaplan-Meier survival analysis. DR was defined for all participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of response until the date of progression or relapse. Participants without relapse or progression were censored at their last assessment date. Participants who died due to tumour were considered in progression. Participants who died for any other cause were censored to the death date.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=44 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Duration of Response (DR) - Percentage of Participants Expected to Maintain a Response	90.07 percentage of participants Interval 75.45 to 96.19

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population; only participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase of the study were included in the analysis.

DR was defined for all participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase (Month 7 of the study) and was measured from the time of response until the date of progression or relapse. Participants without relapse or progression were censored at their last assessment date. Participants who died due to tumour were considered in progression. Participants who died for any other cause were censored to the death date.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=44 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
DR - Percentage of Participants With an Event	9.09 percentage of participants

SECONDARY outcome

Timeframe: Baseline, Months 1-8, 10-12, 14, 16, 22, 28, 34 and 40

Population: ITT population: only participants who achieved a response (CR, CRu and PR) at month 1 after the completion of treatment of the induction phase of the study were included in the analysis.

Outcome measures

Outcome measures
Measure	Rituximab + Fludarabine + Cyclophosphamide n=44 Participants Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
DR - Time to Event	32.19 months Standard Error 0.72

Adverse Events

Rituximab + Fludarabine + Cyclophosphamide

Serious events: 16 serious events

Other events: 47 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Rituximab + Fludarabine + Cyclophosphamide n=47 participants at risk Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Blood and lymphatic system disorders Febrile neutropenia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Neutropenia	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Cardiac disorders Mitral valve incompetence	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Congenital, familial and genetic disorders Renal dysplasia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Pyrexia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Hepatobiliary disorders Cholecystitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Bronchopneumonia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Pneumonia	6.4% 3/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Staphylococcal infection	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Arthralgia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Neuropathy peripheral	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Reproductive system and breast disorders Benign prostatic hyperplasia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).

Other adverse events

Other adverse events
Measure	Rituximab + Fludarabine + Cyclophosphamide n=47 participants at risk Cycle 1 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 1, 2, and 3 and rituximab 375 mg/m\^2 IV on Day 8, followed by 20 days of rest. Cycles 2-3 and Cycle 6 (28-day cycle): Participants received rituximab 375 mg/m\^2 IV on Day 1 and fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 followed by 24 days of rest. Cycles 4-5 (28-day cycle): Participants received fludarabine 25 mg/m\^2 IV and cyclophosphamide 250 mg/m\^2 IV on Days 2, 3, and 4 and rituximab 375 mg/m\^2 IV on Day 14, followed by 14 days of rest. Cycles 7-10 (2-month cycle): Following 2 months rest after the completion of Cycle 6, participants with CR, CRu, or PR, received maintenance therapy with rituximab 375 mg/m\^2 IV on Day 1, followed by 2 months rest; cycle was repeated 4 times.
Immune system disorders Amyloidosis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Immune system disorders Hypersensitivity	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Immune system disorders Hypogammaglobulinaemia	10.6% 5/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Bronchitis	12.8% 6/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Conjunctivitis infective	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Conjunctivitis viral	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Cystitis	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Ear infection	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Erythema induratum	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Fungal infection	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Haemophilus infection	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Herpes simplex	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Herpes zoster	17.0% 8/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Influenza	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Labyrinthitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Oral candidiasis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Pharyngitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Pneumonia	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Pulmonary mycosis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Rhinitis	8.5% 4/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Sinusitis	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Upper respiratory tract infection	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Infections and infestations Urinary tract infection	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Injury, poisoning and procedural complications Contusion	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Alanine aminotransferase increased	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Aspartate aminotransferase increased	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Beta 2 microglobulin increased	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Blood lactate dehydrogenase increased	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Gamma-glutamyltransferase increased	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Red blood cell sedimentation rate increased	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Investigations Transaminases increased	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Metabolism and nutrition disorders Anorexia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Metabolism and nutrition disorders Hyperglycaemia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Metabolism and nutrition disorders Hyperuricaemia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Arthralgia	10.6% 5/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Arthritis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Groin pain	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Musculoskeletal pain	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Myalgia	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Musculoskeletal and connective tissue disorders Tenosynovitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder cancer	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Multiple myeloma	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostatic adenoma	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Amnesia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Cerebral ischaemia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Headache	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Neuropathy	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Syncope	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Nervous system disorders Transient ischaemic attack	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Psychiatric disorders Anxiety	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Psychiatric disorders Depression	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Psychiatric disorders Insomnia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Renal and urinary disorders Dysuria	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Renal and urinary disorders Polyuria	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Renal and urinary disorders Renal colic	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Renal and urinary disorders Renal pain	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Reproductive system and breast disorders Amenorrhoea	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Reproductive system and breast disorders Gynaecomasatia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Bronchospasm	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Cough	44.7% 21/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.6% 5/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Pneumonitis	6.4% 3/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Erythema	6.4% 3/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Hyperhidrosis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Night sweats	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Periorbital oedema	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Pityriasis rosea	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Pruritus	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Rash	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Skin disorder	8.5% 4/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Skin fissures	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Skin and subcutaneous tissue disorders Urticaria	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Surgical and medical procedures Ureterectomy	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Vascular disorders Aortic thrombosis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Vascular disorders Flushing	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Vascular disorders Hypotension	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Vascular disorders Phlebitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Vascular disorders Raynaud's phenomenon	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Anaemia	17.0% 8/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Febrile neutropenia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Leukopenia	38.3% 18/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Neutropenia	61.7% 29/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Pancytopenia	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Blood and lymphatic system disorders Thrombocytopenia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Cardiac disorders Pericardial effusion	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Congenital, familial and genetic disorders Hydrocele	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Ear and labyrinth disorders Ear pain	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Ear and labyrinth disorders Vertigo	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Eye disorders Conjunctivitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Eye disorders Dry eye	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Eye disorders Visual disturbance	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Abdominal distension	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Abdominal pain upper	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Colitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Constipation	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Diarrhoea	10.6% 5/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Dysphagia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Enteritis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Gastritis	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Nausea	42.6% 20/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Stomatitis	21.3% 10/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Gastrointestinal disorders Vomiting	10.6% 5/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Asthenia	34.0% 16/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Chills	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Fatigue	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Hyperthermia	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Mucosal inflammation	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Oedema	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Oedema peripheral	4.3% 2/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Pain	8.5% 4/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
General disorders Pyrexia	48.9% 23/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Hepatobiliary disorders Cholelithiasis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Hepatobiliary disorders Hepatitis	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).
Immune system disorders Allergy to arthropod bite	2.1% 1/47 • Treatment-emergent adverse events (AEs) were reported throughout the study (up to 40 months).

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Study being conducted under this agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request the Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER