Trial Outcomes & Findings for Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia (NCT NCT00281918)

NCT ID: NCT00281918

Last Updated: 2013-09-19

Results Overview

Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

817 participants

Primary outcome timeframe

Median observation time at time of analysis was approximately 21 months

Results posted on

2013-09-19

Participant Flow

Participant milestones

Participant milestones
Measure	Fludarabine+Cyclophosphamide (FC) Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Overall Study STARTED	409	408
Overall Study Safety Population; Received Study Drug	398	402
Overall Study COMPLETED	267	300
Overall Study NOT COMPLETED	142	108

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Fludarabine+Cyclophosphamide (FC) n=407 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=403 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.	Total n=810 Participants Total of all reporting groups
Age Continuous	59.3 years STANDARD_DEVIATION 8.55 • n=5 Participants	59.6 years STANDARD_DEVIATION 8.70 • n=7 Participants	59.5 years STANDARD_DEVIATION 8.62 • n=5 Participants
Sex: Female, Male Female	105 Participants n=5 Participants	105 Participants n=7 Participants	210 Participants n=5 Participants
Sex: Female, Male Male	302 Participants n=5 Participants	298 Participants n=7 Participants	600 Participants n=5 Participants

PRIMARY outcome

Timeframe: Median observation time at time of analysis was approximately 21 months

Population: The Intent-to-treat (ITT) population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=407 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=403 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Progression-free Survival (PFS)	981.0 Days Interval 1.0 to 1343.0	1212.0 Days Interval 1.0 to 1372.0

PRIMARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Participants from the Intent-to-treat population, that included all randomized participants, with PFS events.

Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=297 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=253 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Time to Progression-free Survival Event	998.0 Days Interval 886.0 to 1129.0	1703.0 Days Interval 1543.0 to 1853.0

SECONDARY outcome

Timeframe: Median observation time at time of analysis was approximately 21 months

Population: The ITT population was comprised of all patients randomized in the study, irrespective of whether they received treatment or not. Informed consent was unavailable at the time of analysis for 2 patients in the FC group and 5 patients in the FCR group. ITT population: FC = 407; FCR = 403.

Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=407 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=403 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Event-free Survival (EFS)	947.0 Days Interval 1.0 to 1343.0	1212.0 Days Interval 1.0 to 1372.0

SECONDARY outcome

Timeframe: Median observation time at time of analysis was approximately 21 months

Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=407 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=403 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Overall Survival (OS) Minimum number of days to an event	5 Days Interval 83.0 to 90.0	4 Days Interval 89.0 to 95.0
Overall Survival (OS) Maximum number of days to an event	1373 Days	1372 Days

SECONDARY outcome

Timeframe: Median observation time at time of analysis was approximately 21 months

CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=407 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=403 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). Minimum number of days to an event	84 Days to an event Interval 0.0 to 0.0	91 Days to an event Interval 939.0 to 9999.0
Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). Maximum number of days to an event	1164 Days to an event	1226 Days to an event

SECONDARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Participants from the Intent-to-treat population, that included all randomized participants who died.

Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=154 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=125 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Time to Overall Survival Event	2613.0 Days Interval 2354.0 to Upper limit of the 95% confidence interval has not been reached.	NA Days Interval 2745.0 to Median time to event and upper limit of the 95% confidence have not been reached.

SECONDARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Participants from the Intent-to-treat population, that included all randomized participants, with disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death.

Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=301 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=257 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Time to Event-free Survival Event	951.0 Days Interval 843.0 to 1039.0	1666.0 Days Interval 1415.0 to 1799.0

SECONDARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Participants from the Intent-to-treat population, all randomized participants, with complete response who experienced a disease free survival event (disease relapse or death).

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=58 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=97 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR)	1488.0 Days Interval 1198.0 to 1836.0	1854.0 Days Interval 1646.0 to 2208.0

SECONDARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Participants from the Intent-to-treat population, all randomized participants, with complete response or partial response who experienced an event (disease progression or death due to any cause).

Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=214 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=207 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Duration of Response	1102.0 Days Interval 977.0 to 1249.0	1718.0 Days Interval 1618.0 to 1859.0

SECONDARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Intent-to-treat population included all randomized participants.

CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=409 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=408 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response	72.4 Percentage of participants Interval 67.8 to 76.7	85.8 Percentage of participants Interval 82.0 to 89.0

SECONDARY outcome

Timeframe: Median observation time was approximately 66.4 months

Population: Participants from the Intent-to-treat population, that included all randomized participants, who started a new CLL treatment.

The time from randomization to the start of a new treatment.

Outcome measures

Outcome measures
Measure	Fludarabine+Cyclophosphamide (FC) n=251 Participants Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=206 Participants Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL)	1455.0 Days Interval 1324.0 to 1577.0	2082.0 Days Interval 1926.0 to 2253.0

Adverse Events

Fludarabine+Cyclophosphamide (FC)

Serious events: 164 serious events

Other events: 122 other events

Deaths: 0 deaths

Fludarabine+Cyclophosphamide+Rituximab (FCR)

Serious events: 186 serious events

Other events: 185 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Fludarabine+Cyclophosphamide (FC) n=398 participants at risk Fludarabine+cyclophosphamide (FC) intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV on Days 1, 2, 3 for 6 cycles.	Fludarabine+Cyclophosphamide+Rituximab (FCR) n=402 participants at risk Rituximab intravenously for a total of 6 treatment cycles at intervals of 28 days. Cycle 1: 375 mg/m² IV on Day 0; Cycles 2-6: 500 mg/m² IV on Day 1. FC intravenously for a total of 6 treatment cycles at intervals of 28 days. Fludarabine: 25 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles. Cyclophosphamide: 250 mg/m² IV over 15-30 min on Days 1, 2, 3 for 6 cycles.
Blood and lymphatic system disorders Neutropenia	17.8% 71/398 • Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months). The safety population included all participants who received at least one dose of study drug.	28.9% 116/402 • Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months). The safety population included all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Leukopenia	11.3% 45/398 • Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months). The safety population included all participants who received at least one dose of study drug.	21.9% 88/402 • Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months). The safety population included all participants who received at least one dose of study drug.
Blood and lymphatic system disorders Thrombocytopenia	8.8% 35/398 • Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months). The safety population included all participants who received at least one dose of study drug.	5.2% 21/402 • Adverse Events were recorded until 28 days after completion of study treatment (median time approximately 21 months). Serious Adverse Events reported until 1 year post-treatment or initiation of new CLL treatment (median time approximately 42 months). The safety population included all participants who received at least one dose of study drug.

Additional Information

Medical Communications

Hoffmann-LaRoche

Phone: 800-821-8590

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 that 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