Phase 2 Fludarabine, Cytoxan and FCCAM <Alemtuzumab> in Untreated B-Cell Chronic Lymphocytic Leukemia
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Fludarabine, cytoxan, then alemtuzumab Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed. |
Drug: Alemtuzumab
3 to 30 mg, IV
Other Names:
Drug: Fludarabine
[(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid
Other Names:
Drug: Cytoxan
(RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- Duration of Response [105 months]
Eligibility Criteria
Criteria
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:
-
Weight loss ≥ 10% body weight within the previous 6 months
-
Extreme fatigue
-
Fever greater than 100.5° F for ≥ 2 weeks without evidence of infection
-
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.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Stanford University School of Medicine | Stanford | California | United States | 94305 |
Sponsors and Collaborators
- Steven E. Coutre
- Bayer
Investigators
- Principal Investigator: Steven Edward Coutre, Stanford University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- IRB-13053
- 31185
- 80071
- HEMCLL0001
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Fludarabine and Cyclophosphamide, Followed by Alemtuzumab |
---|---|
Arm/Group Description | 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). |
Period Title: Fludarabine + Cyclophosphamide | |
STARTED | 25 |
COMPLETED | 17 |
NOT COMPLETED | 8 |
Period Title: Fludarabine + Cyclophosphamide | |
STARTED | 17 |
COMPLETED | 17 |
NOT COMPLETED | 0 |
Baseline Characteristics
Arm/Group Title | Fludarabine and Cyclophosphamide, Followed by Alemtuzumab |
---|---|
Arm/Group Description | 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). |
Overall Participants | 25 |
Age (Count of Participants) | |
<=18 years |
0
0%
|
Between 18 and 65 years |
13
52%
|
>=65 years |
12
48%
|
Sex: Female, Male (Count of Participants) | |
Female |
11
44%
|
Male |
14
56%
|
Outcome Measures
Title | Number of Subjects Maintaining Partial Response (PR) or Complete Response (CR) |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Fludarabine and Cyclophosphamide, Followed by Alemtuzumab |
---|---|
Arm/Group Description | 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). |
Measure Participants | 25 |
Number [participants] |
17
68%
|
Title | Duration of Response |
---|---|
Description | |
Time Frame | 105 months |
Outcome Measure Data
Analysis Population Description |
---|
[Not Specified] |
Arm/Group Title | Fludarabine and Cyclophosphamide, Followed by Alemtuzumab |
---|---|
Arm/Group Description | 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). |
Measure Participants | 17 |
Median (Full Range) [months] |
38
|
Adverse Events
Time Frame | ||
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Fludarabine, Cytoxan, Then Alemtuzumab | |
Arm/Group Description | Fludarabine and cyclophosphamide days 1 to 3 for six 28-day cycles. Minimal residual disease positive responders continued on-treatment to receive alemtuzumab 30 mg weekly. MRD negative responders were observed. Alemtuzumab: 3 to 30 mg, IV Fludarabine: [(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid Cytoxan: (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide | |
All Cause Mortality |
||
Fludarabine, Cytoxan, Then Alemtuzumab | ||
Affected / at Risk (%) | # Events | |
Total | / (NaN) | |
Serious Adverse Events |
||
Fludarabine, Cytoxan, Then Alemtuzumab | ||
Affected / at Risk (%) | # Events | |
Total | 5/25 (20%) | |
Blood and lymphatic system disorders | ||
febrile neutropenia | 1/25 (4%) | |
anemia | 1/25 (4%) | |
hemolysis | 1/25 (4%) | |
Infections and infestations | ||
lung infection | 1/25 (4%) | |
Respiratory, thoracic and mediastinal disorders | ||
pneumonitis | 1/25 (4%) | |
Other (Not Including Serious) Adverse Events |
||
Fludarabine, Cytoxan, Then Alemtuzumab | ||
Affected / at Risk (%) | # Events | |
Total | 2/25 (8%) | |
Blood and lymphatic system disorders | ||
anemia | 1/25 (4%) | |
Gastrointestinal disorders | ||
mucositis | 1/25 (4%) |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Steven E. Coutre, Associate Professor of Medicine |
---|---|
Organization | Stanford University |
Phone | 650-723-6661 |
coutre@stanford.edu |
- IRB-13053
- 31185
- 80071
- HEMCLL0001