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

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

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.

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.

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.