A Study of Rituximab in Combination With Fludarabine and Cyclophosphamide in Participants With Chronic Lymphocytic Leukemia and Favorable Somatic Status

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01271010
• Collaborator: (none)
• Enrollment: 89
• Locations: 10
• Arm: 1
• Actual Duration (Months): 58.6
• Patients Per Site: 8.9
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This multi-center, single-arm study evaluated the efficacy and safety of rituximab in combination with fludarabine and cyclophosphamide in participants with B-cell chronic lymphocytic leukemia (CLL) and favorable somatic status.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Rituximab	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective Study of Efficacy and Safety of RFC (Rituximab, Fludarabine, Cyclophosphamide) Regimen as a First-Line Therapy in Patients With B-Cell Chronic Lymphocytic Leukemia and Favorable Somatic Status
• Actual Study Start Date: Jun 17, 2011
• Actual Primary Completion Date: May 4, 2016
• Actual Study Completion Date: May 4, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Rituximab + Fludarabine + Cyclophosphamide Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.

Drug: Cyclophosphamide; Participants received cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle.; Drug: Fludarabine; Participants received fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle.; Drug: Rituximab; Participants received 375 mg/m^2 IV on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle.; Other Names: MabThera

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Complete Remission [Up to approximately 5 years]

   Complete remission was defined as the disappearance of all signs of disease.

2. Percentage of Participants With Disease Progression [Up to approximately 5 years]

   Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen.

3. Percentage of Participants With Stable Disease [Up to approximately 5 years]

   Stable disease was defined as not meeting the criteria for partial remission or disease progression

4. Percentage of Participants With Partial Remission [Up to approximately 5 years]

   Partial remission was defined as a reduction in tumor size by >50%.

5. Duration of Response [Up to approximately 5 years]

   Duration of Response was defined as the time period from the last day of study treatment to the day when disease progression occurred in participants who previously had complete or partial remission. Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen. Complete remission was defined as the disappearance of all signs of disease. Partial remission was defined as a reduction in tumor size by >50%.

6. Progression-free Survival [Up to approximately 5 years]

   Progression-free survival was defined as the time period from the first day of study treatment to the day when disease progression occurred. Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen.

7. Event-free Survival [Up to approximately 5 years]

   Event-free survival was defined as the time period from the first day of study treatment to occurrence of any of the following events: appearance of disease progression or relapse; prescription of a new treatment for disease relapse; death caused by B-cell chronic lymphocytic leukemia (B-CLL); or complications from B-CLL or therapy. Relapse was defined as disease progression in participants with complete or partial remission lasting at least 6 months after treatment completion. Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen. Complete remission was defined as the disappearance of all signs of disease. Partial remission was defined as a reduction in tumor size by >50%.

8. Overall Survival [Up to approximately 5 years]

   Overall survival was defined as the time period from the first day of study treatment to participant death.

9. Percentage of Participants With Phenotypic Remission [Up to approximately 5 years]

   Phenotypic remission was considered achieved if a participant had a negative test for minimal residual disease. A negative test for minimal residual disease was defined as tumor cells ≤0.01% of the total number of peripheral leukocytes.

10. Percentage of Participants With Adverse Events (AEs) and Serious AEs [Up to approximately 5 years]

    An AE was defined as any unfavorable medical occurrence in a participant receiving a study drug, regardless of relationship the study drug. An AE was considered serious if it met any of the following criteria: was fatal or life-threatening; required hospitalization or prolonged hospitalization; led to persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was clinically significant and/or required an intervention to prevent any of the listed criteria.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of previously untreated B-cell CLL confirmed immunophenotypically

• For participants, age 60-70 years: Cumulative Illness Rating Scale (CIRS) comorbidity score less than or equal to (</=) 6

• Binet stage B, C or A with progression

• Life expectancy greater than or equal to (>/=) 12 months

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

• Women of child bearing potential and men should agree to use highly reliable contraceptive method throughout the treatment period and within 12 months after treatment completion

Exclusion Criteria:

• Participants with small-cell lymphoma

• Participants with auto-immune hemolytic anemia

• Concomitant malignant disease during enrollment, except basal cell carcinoma of the skin

• Chemotherapy for concomitant malignant disease given within 12 months prior to study enrollment

• Participants with Richter's Syndrome

• Participants with symptomatic Hepatitis B infection

• Any clinically significant infection that could not be cured prior to enrollment, including Human Immunodeficiency Virus (HIV) infection

• Creatinine clearance less than (<) 30 milliliters per minute (mL/min)

• Participants with congestive heart failure (CHF) New York Heart Association (NYHA) III-IV

• Participants with liver failure and acute hepatitis of any etiology

• Any other medical or mental condition which may preclude from receiving the entire course of protocol specified treatment or signing the informed consent

• History of an anaphylactic reaction to murine antibodies, proteins, or any other ingredient of rituximab

• Pregnancy and breast-feeding women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The order of Honour pin Irkutsk regional clinical hospital; Hematology Department	Irkutsk		Russian Federation	664079
2	Kemerovo Regional Clinical Hospital	Kemerovo		Russian Federation	650066
3	Regional Clinical Oncology Despensary #1; Hematology Department	Krasnodar		Russian Federation	350040
4	N.N.Blokhin Russian Cancer Research Center; Dept. of Chemotherapy & Hemoblastosis	Moscow		Russian Federation	115478
5	City Clinical Hospital After Botkin; Hematology	Moscow		Russian Federation	125101
6	City Clinical Hospital #15; Hematology department	Saint-Petersburg		Russian Federation	198205
7	Leningrad Regional Clinical Hospital; Hematology #1	St Petersburg		Russian Federation
8	Saint-Petersburg SHI City Clinical Hospital #31	St. Petersburg		Russian Federation	197110
9	GUZ Tula Regioanal Clinical Hospital; Hematology	Tula		Russian Federation	300053
10	Republican clinical hospital named after G.G. Kuvatov	UFA		Russian Federation	450005

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01271010
• Other Study ID Numbers: ML25136
• First Posted: Jan 6, 2011
• Last Update Posted: Mar 20, 2018
• Last Verified: Aug 1, 2017

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Rituximab; Fludarabine

Study Results

Participant Flow

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Period Title: Overall Study
STARTED	89
COMPLETED	28
NOT COMPLETED	61

Baseline Characteristics

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Overall Participants	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (6.39)
Sex: Female, Male (Count of Participants)
Female	31 34.8%
Male	58 65.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Complete Remission
Description	Complete remission was defined as the disappearance of all signs of disease.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

All enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	73
Number [percentage of participants]	49.3 55.4%

2. Primary Outcome

Title	Percentage of Participants With Disease Progression
Description	Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

All enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	73
Number [percentage of participants]	5.5 6.2%

3. Primary Outcome

Title	Percentage of Participants With Stable Disease
Description	Stable disease was defined as not meeting the criteria for partial remission or disease progression
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

All enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	73
Number [percentage of participants]	4.1 4.6%

4. Primary Outcome

Title	Percentage of Participants With Partial Remission
Description	Partial remission was defined as a reduction in tumor size by >50%.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

All enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	73
Number [percentage of participants]	41.1 46.2%

5. Primary Outcome

Title	Duration of Response
Description	Duration of Response was defined as the time period from the last day of study treatment to the day when disease progression occurred in participants who previously had complete or partial remission. Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen. Complete remission was defined as the disappearance of all signs of disease. Partial remission was defined as a reduction in tumor size by >50%.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

Enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	61
Median (95% Confidence Interval) [days]	NA

6. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival was defined as the time period from the first day of study treatment to the day when disease progression occurred. Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

Enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	85
Median (95% Confidence Interval) [days]	NA

7. Primary Outcome

Title	Event-free Survival
Description	Event-free survival was defined as the time period from the first day of study treatment to occurrence of any of the following events: appearance of disease progression or relapse; prescription of a new treatment for disease relapse; death caused by B-cell chronic lymphocytic leukemia (B-CLL); or complications from B-CLL or therapy. Relapse was defined as disease progression in participants with complete or partial remission lasting at least 6 months after treatment completion. Disease progression was defined as an increase in lymphocytosis, or enlargement of the lymph nodes or spleen. Complete remission was defined as the disappearance of all signs of disease. Partial remission was defined as a reduction in tumor size by >50%.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

Enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	85
Median (95% Confidence Interval) [days]	1567

8. Primary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time period from the first day of study treatment to participant death.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

Enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	89
Median (95% Confidence Interval) [days]	NA

9. Primary Outcome

Title	Percentage of Participants With Phenotypic Remission
Description	Phenotypic remission was considered achieved if a participant had a negative test for minimal residual disease. A negative test for minimal residual disease was defined as tumor cells ≤0.01% of the total number of peripheral leukocytes.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

Enrolled participants who were evaluable for this outcome measure.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	63
Number [percentage of participants]	66.7 74.9%

10. Primary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious AEs
Description	An AE was defined as any unfavorable medical occurrence in a participant receiving a study drug, regardless of relationship the study drug. An AE was considered serious if it met any of the following criteria: was fatal or life-threatening; required hospitalization or prolonged hospitalization; led to persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was clinically significant and/or required an intervention to prevent any of the listed criteria.
Time Frame	Up to approximately 5 years

Outcome Measure Data

Analysis Population Description

All enrolled participants.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
Measure Participants	89
Non-serious AEs	78.65 88.4%
Serious AEs	13.48 15.1%

Adverse Events

Time Frame	Up to approximately 5 years
Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants received rituximab 375 milligrams per square meter (mg/m^2) intravenously (IV) on Day 1 of Cycle 1, then 500 mg/m^2 IV on Day 1 of each subsequent cycle; fludarabine 25 mg/m^2 IV or 40 mg/m^2 orally on Days 1-3 of each cycle and cyclophosphamide 250 mg/m^2 IV or 250 mg/m^2 orally on Days 1-3 of each cycle. Treatment duration was 6 cycles, 28 days each.
All Cause Mortality
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	12/89 (13.5%)
Blood and lymphatic system disorders
Agranulocytosis	1/89 (1.1%)
Endocrine disorders
Neuroendocrine tumour	1/89 (1.1%)
Gastrointestinal disorders
Abdominal pain	1/89 (1.1%)
Duodenal ulcer	1/89 (1.1%)
Infections and infestations
Herpes zoster	2/89 (2.2%)
Appendicitis	1/89 (1.1%)
Peritonitis	1/89 (1.1%)
Proctitis infectious	1/89 (1.1%)
Injury, poisoning and procedural complications
Brain contusion	1/89 (1.1%)
Injury	1/89 (1.1%)
Musculoskeletal and connective tissue disorders
Contusion	1/89 (1.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon adenoma	1/89 (1.1%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/89 (1.1%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	2/89 (2.2%)
Pulmonary fibrosis	1/89 (1.1%)
Squamous cell carcinoma of lung	1/89 (1.1%)
Vascular disorders
Duodenal ulcer haemorrhage	1/89 (1.1%)
Other (Not Including Serious) Adverse Events
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	70/89 (78.7%)
Blood and lymphatic system disorders
Thrombocytopenia	10/89 (11.2%)
Anaemia	9/89 (10.1%)
Leukocytosis	5/89 (5.6%)
Gastrointestinal disorders
Nausea	9/89 (10.1%)
Infections and infestations
Respiratory tract infection	8/89 (9%)
Investigations
Neutrophil count decreased	37/89 (41.6%)
White blood cell count decreased	20/89 (22.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.