A Study of MabThera/Rituxan (Rituximab) in Combination With Fludarabine And Cyclophosphamide as Primary Therapy in Elderly Patients With Chronic Lymphocytic Leukemia

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01263704
• Collaborator: (none)
• Enrollment: 42
• Locations: 12
• Arm: 1
• Actual Duration (Months): 68.6
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This single arm, open-label study will assess the safety and efficacy of low dose fludarabine and cyclophosphamide in combination with standard dose MabThera/Rituxan (rituximab) as primary therapy in elderly patients (>/= 65 years) with chronic lymphocytic leukemia. Patients will receive six 28-day cycles of treatment with Mabthera/Rituxan (375 mg/m2 intravenously [iv] Day 0 of cycle 1, 500 mg/m2 iv Day 1 of cycles 2-6), fludarabine (12.5 mg/m2/d iv Days 1-3, cycles 1-6) and cyclophosphamide (150 mg/m2/d iv Days 1-3, cycles 1-6). Anticipated time on study treatment is 6 months, with a 30-month follow-up period.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Multicenter, Single Arm Study to Determine the Efficacy and Safety of Low Dose Fludarabine and Cyclophosphamide Combined With Standard Dose Rituximab as Primary Therapy in Elderly Untreated Patients (>/=65 Years Old) With Chronic Lymphocytic Leukemia
• Actual Study Start Date: Jul 17, 2011
• Actual Primary Completion Date: Apr 3, 2017
• Actual Study Completion Date: Apr 3, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Rituximab plus Fludarabine and Cyclophosphamide Elderly participants with chronic lymphocytic leukemia (CLL) will receive combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment is followed by a follow up period of 36 months.	Drug: Cyclophosphamide; 150 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1-3 of each 28-day cycle for 6 cycles; Drug: Fludarabine; 12.5 mg/m^2 IV on Days 1-3 of every 28-day cycle for 6 cycles; Drug: Rituximab; 375 mg/m^2 IV Day 0 of Cycle 1, 500 mg/m^2 IV Day 1 of Cycles 2-6. Each cycle was 28 days.; Other Names: MabThera/Rituxan

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [Up to 42 months]

   Overall response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) according to National Cancer Institute - Working Group [NCI-WG] guidelines. CR: no clonal B lymphocytes in peripheral blood, no significant lymphadenopathy, liver and spleen normal size, no disease symptoms, blood counts: absolute neutrophil count (ANC) >1,500/microliter (mcL), platelets > 100,000/mcL, hemoglobin > 11.0 grams/deciliter (g/dL), normocellular bone marrow. PR: >/= 50% decrease in clonal B lymphocyte count, >/= 50% reduction in lymphadenopathy, >/= 50% reduction of liver or spleen enlargement and ANC >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 11.0 g/dL OR >/= 50% increase in ANC, platelets or hemoglobin.

Secondary Outcome Measures

1. Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Up to 53 months]

   An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Preexisting conditions which worsen during a study are also considered as adverse events. An SAE is any experience that suggests a significant hazard, contraindication, side effect, or precaution, and fulfills any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.

2. Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations [Up to 53 months]

3. Hospitalization Days [Up to 53 months]

4. Progression-free Survival (PFS) [Up to 53 months]

   PFS was defined as the interval from the first study drug treatment day to the first sign of disease progression according to NCI-WG guidelines. Progressive disease (PD): Any new lesion, any disease symptoms, >/=50% increase in lymphadenopathy, splenomegaly, hepatomegaly, >/= 50% increase in the number of circulating clonal B lymphocytes, decrease of hemoglobin levels by > 2.0 g/dL, >/= 50% decrease of platelet counts, increase of lymphocytes in bone marrow to more than 30% from normal.

5. Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire [[Visit 1 (Screening, Week 0), at Visits 11 (Week 45) and 14 (Week 80) and at the end of the study (Month 42)]]

   The FACIT-F questionnaire consists of 13 questions with a total score range of 0 to 52 with 0 indicating a better outcome and 52 indicating a worse outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 65 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients, >/= 65 years of age

• Previously untreated B-cell chronic lymphocytic leukemia (CLL)

• Binet stage C or active Binet stage A and B disease

Exclusion Criteria:

• Prior treatment for CLL

• CLL with transformation (Richter's syndrome)

• Suspected or known central nervous system (CNS) involvement of CLL

• Impaired renal or hepatic function

• Human Immunodeficiency Virus (HIV) positivity, active hepatitis B/C or Hepatitis B Virus (HBV) surface antigen positive, or any active or uncontrolled infections

• Patients with anti-HBV core antibodies (past infection with HBV) but who are negative for Hepatitis B Virus Surface Antigen (HBVsAg) (either anti-HBS Ab positive or negative) and are positive for HBV- Deoxyribonucleic acid (DNA) by Polymerase chain reaction (PCR) analysis

• Concomitant diseases requiring chronic steroid administration

• Active second malignancy within the 2 years prior to study (except for non-melanoma skin cancer and in situ cervix or breast or prostate carcinoma)

• Eastern Cooperative Oncology Group (ECOG) performance status >/= 3

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Haemek Medical Center; Hematology Department	Afula		Israel	18101
2	Soroka Medical Center; Hematology Deptartment	Beer Sheva		Israel	8410101
3	Rambam Medical Center; Heamatology & Bone Marrow Transplantation	Haifa		Israel	3109601
4	Bnei-Zion Medical Center; Hematology Dept	Haifa		Israel	3339419
5	Shaare Zedek Medical Center; Hematology Dept.	Jerusalem		Israel	9103102
6	Hadassah Ein Karem Hospital; Haematology	Jerusalem		Israel	9112001
7	Meir Medical Center; Internal Dept A	Kfar Saba		Israel	44281
8	Western Galilee Hospital - Nahariya	Nahariya		Israel	22100
9	Beilinson Medical Center; Haematology	Petach Tikva		Israel	49100
10	Kaplan Medical Center	Rehovot		Israel	7661041
11	ASSAF Harofe; Department of Hematology	Rishon Lezion		Israel	70300
12	Ichilov Sourasky Medical Center; Heamatology	Tel Aviv		Israel	6423906

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 7, 2014

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01263704
• Other Study ID Numbers: ML25464
• First Posted: Dec 21, 2010
• Last Update Posted: Apr 23, 2018
• Last Verified: Apr 1, 2018

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

Study Results

Participant Flow

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Period Title: Overall Study
STARTED	42
COMPLETED	13
NOT COMPLETED	29

Baseline Characteristics

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Overall Participants	42
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	72.9 (5.0)
Sex: Female, Male (Count of Participants)
Female	13 31%
Male	29 69%
Race and Ethnicity Not Collected (Count of Participants)

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	Overall response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) according to National Cancer Institute - Working Group [NCI-WG] guidelines. CR: no clonal B lymphocytes in peripheral blood, no significant lymphadenopathy, liver and spleen normal size, no disease symptoms, blood counts: absolute neutrophil count (ANC) >1,500/microliter (mcL), platelets > 100,000/mcL, hemoglobin > 11.0 grams/deciliter (g/dL), normocellular bone marrow. PR: >/= 50% decrease in clonal B lymphocyte count, >/= 50% reduction in lymphadenopathy, >/= 50% reduction of liver or spleen enlargement and ANC >1,500/mcL, platelets > 100,000/mcL, hemoglobin > 11.0 g/dL OR >/= 50% increase in ANC, platelets or hemoglobin.
Time Frame	Up to 42 months

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all participants who received rituximab during the study.

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Measure Participants	40
Number (95% Confidence Interval) [percentage of participants]	67.5 160.7%

2. Secondary Outcome

Title	Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. Preexisting conditions which worsen during a study are also considered as adverse events. An SAE is any experience that suggests a significant hazard, contraindication, side effect, or precaution, and fulfills any of the following criteria: fatal (resulted in death), life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was medically significant or required intervention to prevent any of the other outcomes listed here.
Time Frame	Up to 53 months

Outcome Measure Data

Analysis Population Description

The safety population included all enrolled participants.

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Measure Participants	42
AEs	97.6 232.4%
SAEs	45.2 107.6%

3. Secondary Outcome

Title	Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations
Time Frame	Up to 53 months

Outcome Measure Data

Analysis Population Description

The safety population included all enrolled participants.

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Measure Participants	42
Infection	47.6 113.3%
Neutropenic fever	14.3 34%
≥ Grade 3 drug-related neutropenia	47.6 113.3%
≥ Grade 3 drug-related thrombocytopenia	11.9 28.3%
Hospitalization	19.1 45.5%

4. Secondary Outcome

Title	Hospitalization Days
Time Frame	Up to 53 months

Outcome Measure Data

Analysis Population Description

The safety population included all enrolled participants.

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Measure Participants	42
Median (Full Range) [days]	8

5. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	PFS was defined as the interval from the first study drug treatment day to the first sign of disease progression according to NCI-WG guidelines. Progressive disease (PD): Any new lesion, any disease symptoms, >/=50% increase in lymphadenopathy, splenomegaly, hepatomegaly, >/= 50% increase in the number of circulating clonal B lymphocytes, decrease of hemoglobin levels by > 2.0 g/dL, >/= 50% decrease of platelet counts, increase of lymphocytes in bone marrow to more than 30% from normal.
Time Frame	Up to 53 months

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all participants who received rituximab during the study.

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Measure Participants	40
Median (95% Confidence Interval) [months]	36.1

6. Secondary Outcome

Title	Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire
Description	The FACIT-F questionnaire consists of 13 questions with a total score range of 0 to 52 with 0 indicating a better outcome and 52 indicating a worse outcome.
Time Frame	[Visit 1 (Screening, Week 0), at Visits 11 (Week 45) and 14 (Week 80) and at the end of the study (Month 42)]

Outcome Measure Data

Analysis Population Description

Efficacy analysis population included all participants who received rituximab during the study. Participants from the efficacy analysis population, who completed the FACIT-F questionnaire at any time point during the study, were analyzed as indicated at each time point.

Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
Measure Participants	40
Visit 1 (Screening, Week 0)	36.1 (11.1)
Visit 11 (Week 45)	39.4 (9.2)
Visit 14 (Week 80)	40.2 (10.1)
End of the Study (Month 42)	47.0 (1.0)

Adverse Events

Time Frame	Up to 53 months
Adverse Event Reporting Description	The safety population included all enrolled participants.
Arm/Group Title	Rituximab Plus Fludarabine and Cyclophosphamide
Arm/Group Description	Elderly participants with chronic lymphocytic leukemia (CLL) received combination treatment with low-dose fludarabine and cyclophosphamide combined with standard-dose of rituximab for 6 months. Treatment was followed by a follow up period of 36 months.
All Cause Mortality
	Rituximab Plus Fludarabine and Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	2/42 (4.8%)
Serious Adverse Events
	Rituximab Plus Fludarabine and Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	19/42 (45.2%)
Blood and lymphatic system disorders
Febrile neutropenia	6/42 (14.3%)
Leukopenia	1/42 (2.4%)
Thrombocytopenia	1/42 (2.4%)
Endocrine disorders
Diabetes mellitus	1/42 (2.4%)
Gastrointestinal disorders
Pancreatitis acute	1/42 (2.4%)
General disorders
Chills	1/42 (2.4%)
Pyrexia	3/42 (7.1%)
Infections and infestations
Herpes zoster	1/42 (2.4%)
Pneumonia	3/42 (7.1%)
Pneumonia bacterial	1/42 (2.4%)
Sepsis	1/42 (2.4%)
Subacute endocarditis	1/42 (2.4%)
Urinary tract infection	1/42 (2.4%)
Injury, poisoning and procedural complications
Compression fracture	1/42 (2.4%)
Femoral neck fracture	1/42 (2.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma	1/42 (2.4%)
Psychiatric disorders
Delirium	1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/42 (2.4%)
Dyspnoea	1/42 (2.4%)
Hypoxia	1/42 (2.4%)
Respiratory failure	1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	Rituximab Plus Fludarabine and Cyclophosphamide
	Affected / at Risk (%)	# Events
Total	41/42 (97.6%)
Blood and lymphatic system disorders
Anemia	14/42 (33.3%)
Leukopenia	4/42 (9.5%)
Neutropenia	22/42 (52.4%)
Thrombocytopenia	10/42 (23.8%)
Gastrointestinal disorders
Constipation	7/42 (16.7%)
Diarrhea	7/42 (16.7%)
Nausea	7/42 (16.7%)
General disorders
Asthenia	8/42 (19%)
Chills	4/42 (9.5%)
Fatigue	4/42 (9.5%)
Infusion related reaction	5/42 (11.9%)
Edema peripheral	3/42 (7.1%)
Pyrexia	4/42 (9.5%)
Infections and infestations
Pneumonia	5/42 (11.9%)
Urinary tract infection	5/42 (11.9%)
Investigations
Neutrophil count decreased	3/42 (7.1%)
Musculoskeletal and connective tissue disorders
Back pain	4/42 (9.5%)
Musculoskeletal pain	3/42 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough	10/42 (23.8%)
Dyspnea	3/42 (7.1%)
Skin and subcutaneous tissue disorders
Pruritus	4/42 (9.5%)
Rash	6/42 (14.3%)

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.