Fludarabine (Fludara®) Plus Alemtuzumab (CAMPATH®, MabCampath®) vs Fludarabine Alone in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients
Condition: B-Cell Chronic Lymphocytic Leukemia
MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell
Intervention: FluCAM [Fludara + Campath]; fludarabine phosphate
Intervention description: Phase A: Escalating Doses of alemtuzumab (Campath) Alone
Day 1: alemtuzumab 3 mg intravenously (IV) over 2 hours.
Day 2: alemtuzumab 10 mg IV over 2 hours if 3 mg was tolerated, else repeat 3 mg daily until tolerated.
Day 3: alemtuzumab 30 mg IV over 2 hours if 10 mg was tolerated, else repeat 10 mg daily until tolerated.
Participants were allowed 3-14 days to escalate to 30 mg. Once 30 mg was tolerated, the participant had to begin Phase B within 7 days.
Phase B: FluCAM
Cycle 1: Days 1,2,3 fludarabine phosphate administered at 30 mg/m^2 over 30 minutes IV, followed within 1 hour by alemtuzumab 30 mg IV over 2 hours. A similar schedule is set for Cycles 2 through 6; duration of alemtuzumab infusions vary from 2-6 hours. Each 28-day period is 1 cycle. Fludarabine phosphate dosage is based on participants' body surface area at the beginning of each cycle. FluCAM administered up to a maximum of 6 cycles, based upon participants' response to therapy and toxicity.; Fludarabine phosphate (Fludara) is administered at a dose of 25 mg/m^2 IV over 15 to 30 minutes daily for 5 consecutive days (days 1 through 5) every 28 days (per package instructions). Each 28-day period is 1 cycle. The dose of fludarabine phosphate will be based on the participant's body surface area as calculated at the beginning of each cycle. Participants treated with fludarabine phosphate up to a maximum of 6 cycles, based upon their response to therapy and toxicity.
Intervention MeSH terms: Vidarabine; Fludarabine; Fludarabine phosphate; Alemtuzumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 335.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a Phase 3, prospective, multicenter, open-label, randomized, controlled study to
      evaluate and compare the efficacy and safety of fludarabine plus alemtuzumab versus
      fludarabine alone as second-line therapy for patients with relapsed or refractory B-cell
      chronic lymphocytic leukemia (B-CLL). Patients who meet all eligibility criteria and sign the
      informed consent document may be entered on the study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A diagnosis of B-cell chronic lymphocytic leukemia (B-CLL); according to the National
             Cancer Institute Working Group (NCI WG) criteria.

          -  Relapsed or refractory disease after 1 prior regimen except patients who were
             refractory to (i.e., progressed on) fludarabine or alemtuzumab therapy. Patients who
             previously responded (complete response or partial response) to fludarabine or
             alemtuzumab therapy, but who have relapsed at the time of study entry, may be eligible
             but response to fludarabine or alemtuzumab therapy must have lasted >12 months (i.e.,
             >12 months from a documented response to a documented relapse).

          -  Binet stage A, stage B, or stage C or Rai Stage I through IV disease with evidence of
             progression as evidenced by the presence of one or more of the following:

        I. Evidence of progressive marrow failure as manifested by: 1) a decrease in hemoglobin to
        <11g/dL, or 2) a decrease in platelet count to <100 x 10^9/L within the previous 6 months,
        or 3) a decrease in absolute neutrophil count (ANC) to <1.0 X 10^9/L.

        II. Progressive splenomegaly to >2 cm below the left costal margin or other organomegaly.

        III. Progressive lymphadenopathy.

        IV. Progressive lymphocytosis with an increase of 50% over a 2-month period, or an
        anticipated doubling time of less than 6 months.

          -  World Health Organization (WHO) performance status (PS) of 0 or 1.

          -  Life expectancy >12 weeks.

          -  Anti-cancer therapy, major surgery, or irradiation was completed >3 weeks before
             randomization in this study. Patient must have recovered from the acute side effects
             incurred as a result of previous therapy.

          -  Serum creatinine less than or equal to 2.0 x institutional upper limits of normal
             (ULN) and calculated creatinine clearance (CrCl) greater than or equal to 30mL/min
             using the Cockroft and Gault formula.

          -  Adequate liver function as indicated by a total bilirubin, AST, and ALT less than or
             equal to 2 x the institutional ULN value, unless directly attributable to the
             patient's tumor.

          -  Female patients with childbearing potential must have a negative serum pregnancy test
             with 2 weeks of first dose of study drug(s). Male and female patients must agree to
             use an effective contraceptive method while on study treatment, if appropriate, and
             for a minimum of 6 months following study therapy.

          -  Signed, written informed consent.

        Exclusion Criteria:

          -  Previously treated with >1 prior regimen for B-CLL.

          -  Previously treated with a fludarabine plus alemtuzumab (FluCAM) regimen for B-CLL.

          -  Positive Coombs test and actively hemolyzing.

          -  Absolute neutrophil count (ANC) <1.5 x 10^9/L or platelet count <75 x 10^9/L, unless
             due to bone marrow involvement.

          -  Medical condition requiring chronic use of pharmacologic doses of oral
             corticosteroids, i.e. anything other than replacement dose levels.

          -  History of anaphylaxis following exposure to monoclonal antibodies.

          -  Use of investigational agents within 6 weeks prior to study randomization.

          -  Active infection or history of severe infection (grade 4) within 3 months prior to
             study randomization.

          -  Known to be human immunodeficiency virus (HIV) positive.

          -  Autoimmune thrombocytopenia.

          -  Active second malignancy.

          -  Known central nervous system (CNS) involvement with B-CLL.

          -  Other severe, concurrent diseases, including tuberculosis, mental disorders, serious
             cardiac functional capacity (Class III or IV as defined by the New York Heart
             Association Classification), severe diabetes, severe hypertension, pulmonary disease
             (chronic obstructive pulmonary disease [COPD] with hypoxemia), or major organ
             malfunction (liver, kidney) that could interfere with the patient's ability to
             participate in the study.

          -  Pregnant or nursing women.

          -  Patients that have progressed with more aggressive B-cell cancers such as Richter's
             syndrome.

          -  Active hepatitis or a history of prior viral hepatitis B or hepatitis C, or positive
             hepatitis B serologies without prior immunization.