A Study of Rituximab (MabThera) in Participants With Chronic Lymphocytic Leukemia (CLL)

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02533401
• Collaborator: (none)
• Enrollment: 34
• Locations: 9
• Arm: 1
• Duration (Months): 106
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of rituximab in combination with chemotherapy (fludarabine and cyclophosphamide) in participants with B-cell CLL.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Rituximab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 34 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Single-Arm, Phase II Study to Evaluate the Efficacy and Safety of Rituximab Plus Fludarabine and Cyclophosphamide (FCR) as First-Line Treatment in Patients With B-Cell Chronic Lymphocytic Leukemia (CLL)
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Rituximab + Fludarabine + Cyclophosphamide Participants will receive rituximab (375 milligrams per meter-squared [mg/m^2] intravenously [IV]) on Cycle 1 Day 1, followed by fludarabine (25 mg/m^2 once daily IV) and cyclophosphamide (250 mg/m^2 once daily IV) for Days 2 to 4 of Cycle 1. Then rituximab (500 mg/m^2 IV) will be administered on Day 1 of Cycles 2 to 6, followed by IV fludarabine (25 mg/m^2 once daily IV) and cyclophosphamide (250 mg/m^2 once daily IV) on Days 1 to 3 of Cycles 2 to 6. Each cycle will be 28 days or 4 weeks in length, and the overall duration of treatment will be approximately 6 months.

Drug: Cyclophosphamide; Cyclophosphamide will be administered IV at 250 mg/m^2/day on Day 2-4 of Cycle 1 and then on Day 1-3 of Cycles 2 to 6. Each cycle will be 28 days or 4 weeks in length.; Drug: Fludarabine; Fludarabine will be administered IV at 25 mg/m^2/day on Day 2-4 of Cycle 1 and then on Day 1-3 of Cycles 2 to 6. Each cycle will be 28 days or 4 weeks in length.; Drug: Rituximab; Rituximab will be administered IV at 375 mg/m^2 on Day 1 of Cycle 1 and then at 500 mg/m^2 on Day 1 of Cycles 2 to 6. Each cycle will be 28 days or 4 weeks in length.; Other Names: MabThera/Rituxan

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Death or Disease Progression [Up to 5 years (from Baseline until disease progression or death, whichever occurred first)]

   Treatment response was monitored throughout the study and assessed using standardized criteria. Disease progression was defined as the occurrence of at least one of the following: greater than or equal to (≥) 50 percent (%) increase in the longest diameter of at least two enlarged lymph nodes, increase in spleen and/or liver size by at least 2 centimeters (cm) from Baseline as determined by measurement below the costal margin, or ≥50% increase in the number of circulating lymphocytes. The percentage of participants with death or documented disease progression at any time during the study was calculated.

2. Progression-Free Survival (PFS) [Up to 5 years (from Baseline until disease progression or death, whichever occurred first)]

   Treatment response was monitored throughout the study and assessed using standardized criteria. Disease progression was defined as the occurrence of at least one of the following: ≥50% increase in the longest diameter of at least two enlarged lymph nodes, increase in spleen and/or liver size by at least 2 cm from Baseline as determined by measurement below the costal margin, or ≥50% increase in the number of circulating lymphocytes. PFS was defined as the time from study inclusion until first event of disease progression or death and was estimated using Kaplan-Meier analysis.

3. Percentage of Participants Who Died [Up to 5 years (from Baseline until death)]

   Participants were followed for survival throughout the study. The percentage of participants who died of any cause during the study was calculated.

4. Overall Survival (OS) [Up to 5 years (from Baseline until death)]

   Participants were followed for survival throughout the study. OS was defined as the time from study inclusion until death from any cause and was estimated using Kaplan-Meier analysis

5. Percentage of Participants With Complete Response (CR), Nodular Partial Response (nPR), or Partial Response (PR) [Up to 4 years (assessed every 3 months during 6-month treatment period, every 2 months during 6-month safety follow-up, then every 3 months during 3-year safety follow-up)]

   Treatment response was monitored throughout the study and assessed using standardized criteria. CR was defined as hemoglobin ≥11 grams per deciliter (g/dL), lymphocytes less than (<) 4000 cells per cubic millimeter (cells/mm^3), neutrophils greater than (>) 1500 cells/mm^3, platelets >100,000 cells/mm^3, bone marrow (BM) biopsy with <30% lymphocytes with no lymphocytic infiltrates, no evidence of lymphoid nodules on physical exam, and performance status of 0. PR was defined as >50% decrease in size of enlarged lymph nodes, hepatomegaly, and splenomegaly, with peripheral counts meeting the same criteria as CR or ≥50% improvement from pre-treatment values. Participants with lymphoid nodules on BM biopsy who otherwise met CR criteria were considered nPR. The percentage of participants with each level of best overall response was calculated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult participants greater than or equal to (≥) 18 years of age

• B-cell CLL

• No previous treatment for leukemia

Exclusion Criteria:

• History of other malignancies within 2 years before study entry, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, prostate cancer, or breast cancer

• Comorbid condition requiring long-term (greater than [>] 1 month) systemic corticosteroids during study treatment

• Known infection with hepatitis B or C virus or with human immunodeficiency virus (HIV)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Buenos Aires		Argentina	1406
2		Buenos Aires		Argentina	C1114AAN
3		Buenos Aires		Argentina	C1280AEB
4		Buenos Aires		Argentina	C1431FWO
5		Córdoba		Argentina	5016
6		La Plata		Argentina	B1897GOL
7		Pilar		Argentina	B1629ODT
8		Rosario		Argentina	S2000DSV
9		Caracas		Venezuela	2122

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT02533401
• Other Study ID Numbers: ML18429
• First Posted: Aug 26, 2015
• Last Update Posted: May 2, 2016
• Last Verified: Mar 1, 2016

• 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 with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via intravenous (IV) infusion as 375 milligrams per meter-squared (mg/m^2) on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Period Title: Overall Study
STARTED	34
COMPLETED	23
NOT COMPLETED	11

Baseline Characteristics

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Overall Participants	34
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.3 (8.8)
Sex: Female, Male (Count of Participants)
Female	5 14.7%
Male	29 85.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Death or Disease Progression
Description	Treatment response was monitored throughout the study and assessed using standardized criteria. Disease progression was defined as the occurrence of at least one of the following: greater than or equal to (≥) 50 percent (%) increase in the longest diameter of at least two enlarged lymph nodes, increase in spleen and/or liver size by at least 2 centimeters (cm) from Baseline as determined by measurement below the costal margin, or ≥50% increase in the number of circulating lymphocytes. The percentage of participants with death or documented disease progression at any time during the study was calculated.
Time Frame	Up to 5 years (from Baseline until disease progression or death, whichever occurred first)

Outcome Measure Data

Analysis Population Description

All Participants Enrolled.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Measure Participants	34
Number [percentage of participants]	24 70.6%

2. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	Treatment response was monitored throughout the study and assessed using standardized criteria. Disease progression was defined as the occurrence of at least one of the following: ≥50% increase in the longest diameter of at least two enlarged lymph nodes, increase in spleen and/or liver size by at least 2 cm from Baseline as determined by measurement below the costal margin, or ≥50% increase in the number of circulating lymphocytes. PFS was defined as the time from study inclusion until first event of disease progression or death and was estimated using Kaplan-Meier analysis.
Time Frame	Up to 5 years (from Baseline until disease progression or death, whichever occurred first)

Outcome Measure Data

Analysis Population Description

All Participants Enrolled.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Measure Participants	34
Mean (95% Confidence Interval) [months]	47.2

3. Primary Outcome

Title	Percentage of Participants Who Died
Description	Participants were followed for survival throughout the study. The percentage of participants who died of any cause during the study was calculated.
Time Frame	Up to 5 years (from Baseline until death)

Outcome Measure Data

Analysis Population Description

All Participants Enrolled.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Measure Participants	34
Number [percentage of participants]	14 41.2%

4. Primary Outcome

Title	Overall Survival (OS)
Description	Participants were followed for survival throughout the study. OS was defined as the time from study inclusion until death from any cause and was estimated using Kaplan-Meier analysis
Time Frame	Up to 5 years (from Baseline until death)

Outcome Measure Data

Analysis Population Description

All Participants Enrolled.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Measure Participants	34
Mean (95% Confidence Interval) [months]	49.5

5. Primary Outcome

Title	Percentage of Participants With Complete Response (CR), Nodular Partial Response (nPR), or Partial Response (PR)
Description	Treatment response was monitored throughout the study and assessed using standardized criteria. CR was defined as hemoglobin ≥11 grams per deciliter (g/dL), lymphocytes less than (<) 4000 cells per cubic millimeter (cells/mm^3), neutrophils greater than (>) 1500 cells/mm^3, platelets >100,000 cells/mm^3, bone marrow (BM) biopsy with <30% lymphocytes with no lymphocytic infiltrates, no evidence of lymphoid nodules on physical exam, and performance status of 0. PR was defined as >50% decrease in size of enlarged lymph nodes, hepatomegaly, and splenomegaly, with peripheral counts meeting the same criteria as CR or ≥50% improvement from pre-treatment values. Participants with lymphoid nodules on BM biopsy who otherwise met CR criteria were considered nPR. The percentage of participants with each level of best overall response was calculated.
Time Frame	Up to 4 years (assessed every 3 months during 6-month treatment period, every 2 months during 6-month safety follow-up, then every 3 months during 3-year safety follow-up)

Outcome Measure Data

Analysis Population Description

All Participants Enrolled.

Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
Measure Participants	34
CR	71 208.8%
nPR	9 26.5%
PR	18 52.9%

Adverse Events

Time Frame	Up to 4 years (assessed every 4 weeks during 6-month treatment period, every 2 months during 6-month safety follow-up, then every 3 months during 3-year safety follow-up
Arm/Group Title	Rituximab + Fludarabine + Cyclophosphamide
Arm/Group Description	Participants with CLL received 6 treatment cycles of chemotherapy. Rituximab was administered via IV infusion as 375 mg/m^2 on Day 1 of Cycle 1 and as 500 mg/m^2 on Day 1 of Cycles 2 to 6. Fludarabine was given as 25 mg/m^2 daily and cyclophosphamide as 250 mg/m^2 daily, each via IV infusion on Days 2 to 4 during Cycle 1 and on Days 1 to 3 during Cycles 2 to 6. The length of each cycle was 28 days.
All Cause Mortality
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	15/34 (44.1%)
Blood and lymphatic system disorders
Anemia	1/34 (2.9%)
Neutropenia	5/34 (14.7%)
Gastrointestinal disorders
Abdominal pain	1/34 (2.9%)
General disorders
Death	1/34 (2.9%)
Fever	3/34 (8.8%)
Infusion related reaction	1/34 (2.9%)
Infections and infestations
Febrile neutropenia	7/34 (20.6%)
Bronchial infection	1/34 (2.9%)
Sepsis	1/34 (2.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm (colon)	1/34 (2.9%)
Nervous system disorders
Seizure	1/34 (2.9%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/34 (2.9%)
Surgical and medical procedures
Surgical and medical procedures (gallbladder)	1/34 (2.9%)
Other (Not Including Serious) Adverse Events
	Rituximab + Fludarabine + Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	18/34 (52.9%)
Blood and lymphatic system disorders
Anemia	8/34 (23.5%)
Leukopenia	6/34 (17.6%)
Low platelets	10/34 (29.4%)
Hypogammaglobulinemia	6/34 (17.6%)
Infections and infestations
Skin infection	7/34 (20.6%)

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.