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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Lymphocytic Leukemia, Chronic

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Fludarabine
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab plus Fludarabine and Cyclophosphamide<br>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<br>* 150 milligrams per square meter (mg/m^2) intravenously (IV) on Days 1-3 of each 28-day cycle for 6 cycles<br>Drug: Fludarabine<br>* 12.5 mg/m^2 IV on Days 1-3 of every 28-day cycle for 6 cycles<br>Drug: Rituximab<br>* 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.<br>* Other names: MabThera/Rituxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | 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. | Up to 42 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Up to 53 months | 
| Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations |  | Up to 53 months | 
| Hospitalization Days |  | Up to 53 months | 
| Progression-free Survival (PFS) | 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. | Up to 53 months | 
| Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | 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. | [Visit 1 (Screening, Week 0), at Visits 11 (Week 45) and 14 (Week 80) and at the end of the study (Month 42)] |