B-cell Leukemia, Chronic Leukemia, Chronic Lymphocytic Leukemia (CLL), Leukemia
Conditions
Brief summary
The primary objective of this study was to evaluate the safety and efficacy of the combination of fludarabine and cyclophosphamide in previously untreated CLL patients. Participants will receive fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles.
Detailed description
This single-arm study evaluated the safety and efficacy of the combination of fludarabine 25 mg/m2/d IV and cyclophosphamide 250 mg/m2/d SC in previously untreated CLL patients. Participants received fludarabine and cyclophosphamide on days 1, 2, and 3 of six 28-day cycles, followed by a no-treatment rest period (observation) for 3 to 12 weeks. Responders entered a no-treatment rest period (observation) for 3 to 8 weeks, then depending on status, continued on follow-up or on-study to receive Campath stating at 3 mg/day with the dose adjusted to the maximum tolerated dose.
Interventions
DRUGAlemtuzumab
3 to 30 mg, IV
DRUGFludarabine
\[(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl\]methoxyphosphonic acid
DRUGCytoxan
(RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
Sponsors
Bayer
Steven E. Coutre
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ≥ age 18 * Karnofsky performance status 60% or above * Confirmed immunohistological diagnosis of Chronic Lymphocytic Leukemia (CLL) * Rai Stage I to IV as follows: * Advanced stage disease (Rai Stage III or IV, or modified Rai High Risk) * OR * Patients with Rai Stage I - II or (Modified Rai Intermediate-Risk) disease must have an indication for therapy based on 1996 NCI revised criteria for active disease as follows: * Any one of the following disease-related symptoms: 1. Weight loss ≥ 10% body weight within the previous 6 months 2. Extreme fatigue 3. Fever greater than 100.5° F for ≥ 2 weeks without evidence of infection 4. Night sweats without evidence of infection * Evidence of progressive marrow failure based on the development of worsening of anemia or thrombocytopenia * Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroid therapy * Massive (\> 6 cm below the left costal margin) or progressive splenomegaly * Bulky (\>10 cm in cluster) or progressive lymphadenopathy * Progressive lymphocytosis \> 50% increase over 2 months, or anticipated doubling time \< 6 months * Patients with immunoglobulin VH gene in unmutated nucleotide sequence configuration, as defined by ≥ 98% homology with the nearest germline counterpart * Serum creatinine ≤ 2x the upper limit of normal * Total serum bilirubin ≤ 2x the upper limit of normal. * AST ≤ 2x the upper limit of normal. * ALT ≤ 2x the upper limit of normal. * Signed written informed consent
Exclusion criteria
* Prior pharmacological treatment for CLL * Past history of anaphylaxis following exposure to monoclonal antibodies * Active secondary malignancy or a history of malignant disease (other than CLL or non-melanoma skin cancer) within the preceding 5 years * Any medical condition requiring systemic corticosteroids * Active systemic infection * Major systemic or other illness (including Coombs positivity and active hemolysis) that would, in the opinion of the investigator, interfere with the patient's ability to comply with the protocol, compromise patient safety, or interfere with the interpretation of study results * HIV positive by serologic testing * Pregnant or nursing female * Unwilling/unable to practice an acceptable form of contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR) | 24 weeks | Response criteria as per the NCI-WG Revised Guidelines for B-CLL Complete remission: No lymphadenopathy by physical exam No hepatomegaly or splenomegaly Absence of constitutional symptoms Polymorphonuclear leukocytes \> 1,500/uL, Platelets \> 100,000/uL, Hemoglobin \> 11.0 g/dL Bone marrow aspirate and biopsy normocellular with \< 30% lymphocytes Absent lymphoid nodules Partial remission: * 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value * 50% reduction in lymphadenopathy and/or ≥ 50% reduction in the size of the liver and/or spleen AND one or more of the following Polymorphonuclear leukocytes \> 1,500/uL or 50% improvement over baseline Platelets \> 100,000/uL or 50% improvement over baseline Hemoglobin \> 11.0 g/dL or 50% improvement over baseline |
Secondary
| Measure | Time frame |
|---|---|
| Duration of Response | 105 months |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fludarabine and Cyclophosphamide, Followed by Alemtuzumab Fludarabine 25 mg/m2/d IV and cyclophosphamide 250 mg/m2/d SC on days 1 to 3 for each of six 28-day cycles, when the assessment for Primary Completion occurred. Responders entered a no-treatment rest period (observation) for 3 to 8 weeks, then depending on status, continued on follow-up or on-study to receive alemtuzumab IV starting at 3 mg/day with the dose adjusted to the maximum tolerated dose (up to 30 mg). | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Fludarabine + Cyclophosphamide | Change in diagnosis | 1 |
| Fludarabine + Cyclophosphamide | Lost to Follow-up | 4 |
| Fludarabine + Cyclophosphamide | Richters transformation (progression) | 2 |
| Fludarabine + Cyclophosphamide | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Fludarabine and Cyclophosphamide, Followed by Alemtuzumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 12 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 25 |
| serious Total, serious adverse events | 5 / 25 |
Outcome results
Primary
Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR)
Response criteria as per the NCI-WG Revised Guidelines for B-CLL Complete remission: No lymphadenopathy by physical exam No hepatomegaly or splenomegaly Absence of constitutional symptoms Polymorphonuclear leukocytes \> 1,500/uL, Platelets \> 100,000/uL, Hemoglobin \> 11.0 g/dL Bone marrow aspirate and biopsy normocellular with \< 30% lymphocytes Absent lymphoid nodules Partial remission: * 50% decrease in peripheral blood lymphocyte count from the pretreatment baseline value * 50% reduction in lymphadenopathy and/or ≥ 50% reduction in the size of the liver and/or spleen AND one or more of the following Polymorphonuclear leukocytes \> 1,500/uL or 50% improvement over baseline Platelets \> 100,000/uL or 50% improvement over baseline Hemoglobin \> 11.0 g/dL or 50% improvement over baseline
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fludarabine and Cyclophosphamide, Followed by Alemtuzumab | Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR) | 17 participants |
Secondary
Duration of Response
Time frame: 105 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Fludarabine and Cyclophosphamide, Followed by Alemtuzumab | Duration of Response | 38 months |