Phase 2 Fludarabine, Cytoxan and FCCAM <Alemtuzumab> in Untreated B-Cell Chronic Lymphocytic Leukemia

Sponsor
Steven E. Coutre (Other)
Overall Status
Completed
CT.gov ID
NCT00230282
Collaborator
Bayer (Industry)
25
Enrollment
1
Location
1
Arm
87
Duration (Months)
0.3
Patients Per Site Per Month

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.

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

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Multi-Center Phase 2 Efficacy and Pharmacokinetic Study Evaluating Fludarabine, Cyclophosphamide, and Subcutaneous Campath (FCCam, Alemtuzumab) for Previously Untreated B-Cell Chronic Lymphocytic Leukemia
Study Start Date :
Jul 1, 2004
Actual Primary Completion Date :
Dec 1, 2010
Actual Study Completion Date :
Oct 1, 2011

Arms and Interventions

ArmIntervention/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:
  • Campath
  • MabCampath
  • Campath-1H
  • Lemtrada
  • FCCam
  • Drug: Fludarabine
    [(2R,3R,4S,5R)-5-(6-amino-2-fluoro-purin-9-yl)- 3,4-dihydroxy-oxolan-2-yl]methoxyphosphonic acid
    Other Names:
  • Fludara
  • Drug: Cytoxan
    (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
    Other Names:
  • Cyclophosphamide
  • cytophosphane
  • Endoxan
  • Neosar
  • Procytox
  • Revimmune
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. Duration of Response [105 months]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Stanford University School of MedicineStanfordCaliforniaUnited States94305

    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.
    Responsible Party:
    Steven E. Coutre, Associate Professor of Medicine, Stanford University
    ClinicalTrials.gov Identifier:
    NCT00230282
    Other Study ID Numbers:
    • IRB-13053
    • 31185
    • 80071
    • HEMCLL0001
    First Posted:
    Sep 30, 2005
    Last Update Posted:
    Oct 6, 2014
    Last Verified:
    Sep 1, 2014

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleFludarabine and Cyclophosphamide, Followed by Alemtuzumab
    Arm/Group DescriptionFludarabine 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
    STARTED25
    COMPLETED17
    NOT COMPLETED8
    Period Title: Fludarabine + Cyclophosphamide
    STARTED17
    COMPLETED17
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleFludarabine and Cyclophosphamide, Followed by Alemtuzumab
    Arm/Group DescriptionFludarabine 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 Participants25
    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

    1. Primary Outcome
    TitleNumber of Subjects Maintaining Partial Response (PR) or Complete Response (CR)
    DescriptionResponse 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 Frame24 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFludarabine and Cyclophosphamide, Followed by Alemtuzumab
    Arm/Group DescriptionFludarabine 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 Participants25
    Number [participants]
    17
    68%
    2. Secondary Outcome
    TitleDuration of Response
    Description
    Time Frame105 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFludarabine and Cyclophosphamide, Followed by Alemtuzumab
    Arm/Group DescriptionFludarabine 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 Participants17
    Median (Full Range) [months]
    38

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group TitleFludarabine, Cytoxan, Then Alemtuzumab
    Arm/Group DescriptionFludarabine 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
    Total5/25 (20%)
    Blood and lymphatic system disorders
    febrile neutropenia1/25 (4%)
    anemia1/25 (4%)
    hemolysis1/25 (4%)
    Infections and infestations
    lung infection1/25 (4%)
    Respiratory, thoracic and mediastinal disorders
    pneumonitis1/25 (4%)
    Other (Not Including Serious) Adverse Events
    Fludarabine, Cytoxan, Then Alemtuzumab
    Affected / at Risk (%)# Events
    Total2/25 (8%)
    Blood and lymphatic system disorders
    anemia1/25 (4%)
    Gastrointestinal disorders
    mucositis1/25 (4%)

    Limitations/Caveats

    [Not Specified]

    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/TitleSteven E. Coutre, Associate Professor of Medicine
    OrganizationStanford University
    Phone650-723-6661
    Emailcoutre@stanford.edu
    Responsible Party:
    Steven E. Coutre, Associate Professor of Medicine, Stanford University
    ClinicalTrials.gov Identifier:
    NCT00230282
    Other Study ID Numbers:
    • IRB-13053
    • 31185
    • 80071
    • HEMCLL0001
    First Posted:
    Sep 30, 2005
    Last Update Posted:
    Oct 6, 2014
    Last Verified:
    Sep 1, 2014