Fludarabine (Fludara®) Plus Alemtuzumab (CAMPATH®, MabCampath®) vs Fludarabine Alone in B-Cell Chronic Lymphocytic Leukemia (B-CLL) Patients

Official Title: “Phase III Randomized Trial to Evaluate the Efficacy and Safety of Second-Line Therapy With Fludara Plus Alemtuzumab (Campath, MabCampath) Versus Fludara Alone in Patients With B-Cell Chronic Lymphocytic Leukemia”

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.

Intervention(s) in this Clinical Trial

• Biological: FluCAM [Fludara + Campath]
  • 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.
• Biological: fludarabine phosphate
  • 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.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Combination Arm (FluCAM)
• Active Comparator: Fludarabine Alone

Primary Measures

• Kaplan-Meier Estimates for Progression-free Survival (PFS) Based on Independent Response Review Panel (IRRP) Assessment
  • Time Frame: Up to 6 years
    Safety Issue?: No

Secondary Measures

• Participant Best Response to Treatment Assessed by the Independent Response Review Panel (IRRP)
  • Time Frame: Up to 9 months
    Safety Issue?: No
• Kaplan-Meier Estimates of Overall Survival Time
  • Time Frame: Up to 6 years
    Safety Issue?: No
• Kaplan Meier Estimates for Time to Disease Progression Assessed by the Independent Response Review Panel (IRRP)
  • Time Frame: Up to 6 years
    Safety Issue?: No
• Kaplan-Meier Estimates for Duration of Response Assessed by the Independent Response Review Panel (IRRP)
  • Time Frame: Up to 6 years
    Safety Issue?: No
• Kaplan-Meier Estimates for Time to Alternative Therapy
  • Time Frame: Up to 6 years
    Safety Issue?: No
• Mean EQ-5D™ Index Scores to Measure Quality of Life at Baseline
  • Time Frame: Day 0 (baseline)
    Safety Issue?: No
• Mean EQ-5D™ Index Scores to Measure Quality of Life at End of Treatment
  • Time Frame: up to month 6 (end of treatment)
    Safety Issue?: No
• Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at Baseline
  • Time Frame: Day 0 (baseline)
    Safety Issue?: No
• Mean EuroQol Visual Analogue Scale (EQ-VAS) Scores to Measure Quality of Life at End of Treatment
  • Time Frame: up to month 6 (end of treatment)
    Safety Issue?: No
• Summary of Participants With Adverse Experiences (AEs)
  • Time Frame: Up to 6 years
    Safety Issue?: Yes
• Mean Systemic Clearance (CL) of Fludarabine
  • Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
    Safety Issue?: No
• Total Volume of Distribution (Vss) of Fludarabine
  • Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
    Safety Issue?: No
• Area Under the Curve (AUC) of Fludarabine From (AUC 0-tau)
  • Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
    Safety Issue?: No
• Maximum Plasma Concentration (Cmax) of Fludarabine
  • Time Frame: month 4 (cycle 4): first day of dosing (pre-dose, 0.5 hr end of infusion), second day of dosing (pre-dose, 0.5 hr end of infusion), third day of dosing (pre-dose, 0.25 hr, 0.5 hr end of infusion, 1,2,3,4,6,24,48,72 hr after start of fludarabine infusion)
    Safety Issue?: No
• Participants With Minimal Residual Disease (MRD)
  • Time Frame: up to 9 months
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Genzyme Industry

Overall Clinical Trial Officials and Contacts

Medical Monitor Study Director Genzyme  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00086580

Study ID Number: CAM314

ClinicalTrials.gov Identifier: NCT00086580

Health Authority: United States: Food and Drug Administration