Lymphocytic Leukemia, Chronic
Conditions
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.
Interventions
DRUGCyclophosphamide
150 milligrams per square meter (mg/m\^2) intravenously (IV) on Days 1-3 of each 28-day cycle for 6 cycles
DRUGFludarabine
12.5 mg/m\^2 IV on Days 1-3 of every 28-day cycle for 6 cycles
DRUGRituximab
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.
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) | 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. |
| 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. |
Countries
Israel
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide 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. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Colon metastases | 1 |
| Overall Study | Death | 2 |
| Overall Study | Eligibility criteria not fulfilled | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Patient withdrew consent | 2 |
| Overall Study | Principal Investigator (PI) decision | 1 |
| Overall Study | Progressive disease | 18 |
Baseline characteristics
| Characteristic | Rituximab Plus Fludarabine and Cyclophosphamide | — |
|---|---|---|
| Age, Continuous | 72.9 years STANDARD_DEVIATION 5 | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Sex: Female, Male Female | 13 Participants | — |
| Sex: Female, Male Male | 29 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 42 |
| other Total, other adverse events | 41 / 42 |
| serious Total, serious adverse events | 19 / 42 |
Outcome results
Primary
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.
Time frame: Up to 42 months
Population: Efficacy analysis population included all participants who received rituximab during the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide | Overall Response Rate | 67.5 percentage of participants |
Secondary
Hospitalization Days
Time frame: Up to 53 months
Population: The safety population included all enrolled participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide | Hospitalization Days | 8 days |
Secondary
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.
Time frame: Up to 53 months
Population: The safety population included all enrolled participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 97.6 percentage of participants |
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 45.2 percentage of participants |
Secondary
Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations
Time frame: Up to 53 months
Population: The safety population included all enrolled participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | Infection | 47.6 percentage of participants |
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | Neutropenic fever | 14.3 percentage of participants |
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | ≥ Grade 3 drug-related neutropenia | 47.6 percentage of participants |
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | ≥ Grade 3 drug-related thrombocytopenia | 11.9 percentage of participants |
| Rituximab Plus Fludarabine and Cyclophosphamide | Percentage of Participants With Neutropenic Fever, Infection, >/= Grade 3 Drug-Related Neutropenia, >/= Grade 3 Drug-Related Thrombocytopenia, Hospitalizations | Hospitalization | 19.1 percentage of participants |
Secondary
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.
Time frame: Up to 53 months
Population: Efficacy analysis population included all participants who received rituximab during the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide | Progression-free Survival (PFS) | 36.1 months |
Secondary
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.
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)]
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab Plus Fludarabine and Cyclophosphamide | Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | Visit 1 (Screening, Week 0) | 36.1 score on a scale | Standard Deviation 11.1 |
| Rituximab Plus Fludarabine and Cyclophosphamide | Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | Visit 11 (Week 45) | 39.4 score on a scale | Standard Deviation 9.2 |
| Rituximab Plus Fludarabine and Cyclophosphamide | Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | Visit 14 (Week 80) | 40.2 score on a scale | Standard Deviation 10.1 |
| Rituximab Plus Fludarabine and Cyclophosphamide | Quality of Life (QoL): Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) Questionnaire | End of the Study (Month 42) | 47.0 score on a scale | Standard Deviation 1 |