A Phase II Study of Fludarabine + Rituximab Induction Followed by Alemtuzumab (Campath-1H, NSC #715969, IND #10864) Administered Subcutaneously as Consolidation in Untreated Patients With B-Cell Chronic Lymphocytic Leukemia
Overview
- Phase
- Phase 2
- Intervention
- alemtuzumab
- Conditions
- B-cell Chronic Lymphocytic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 102
- Locations
- 2
- Primary Endpoint
- Number of Participants With a Complete Response After Treatment With Fludarabine & Rituximab Followed by Alemtuzumab
- Status
- Completed
- Last Updated
- 11 years ago
Overview
Brief Summary
This phase II trial is studying how well giving fludarabine together with rituximab followed by alemtuzumab works in treating patients with chronic lymphocytic leukemia. Monoclonal antibodies, such as rituximab and alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others can find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving fludarabine together with rituximab followed by alemtuzumab may kill more cancer cells.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the rate of complete response and toxicity of concurrent treatment with fludarabine and rituximab followed by consolidative alemtuzumab in patients with previously untreated, but symptomatic, CLL. II. To determine if alemtuzumab improves the CR rate with acceptable toxicity when administered as consolidation therapy following induction therapy with fludarabine and rituximab. III. To estimate the progression-free and overall survival of high risk (VH gene unmutated and those with p53 dysfunction) and low-risk (others) patients following therapy with fludarabine and rituximab induction and consolidative alemtuzumab. IV. To determine the frequency of molecular (PCR) remission following fludarabine and rituximab induction therapy and alemtuzumab consolidation therapy and if this serves as a surrogate marker for prolonged progression-free and overall survival. SECONDARY OBJECTIVES: I. To determine the effect of concurrent treatment with fludarabine and rituximab followed by consolidative alemtuzumab on recovery of T-cells, NK cells, and serum immunoglobulin levels. II. To determine clinical and molecular features that predict for poor response to fludarabine and rituximab induction and subsequent alemtuzumab consolidation therapy. III. To assess preliminarily the molecular features of CLL at relapse in patients responding to chemoimmunotherapy for CLL. IV. To determine the frequency of patients who remain at high risk for progression of CLL despite this therapy and who are thus eligible for nonmyeloablative stem cell transplantation studies such as CALGB 109901. V. To perform limited rituximab pharmacokinetics to determine the ideal schedule of administration for a subsequent rituximab maintenance treatment approach following induction therapy with fludarabine and rituximab. OUTLINE: Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression. Patients are followed at 2 months, every 3 months for 1 year, and then every 6 months for 7 years from study entry.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Specific Diagnosis of B-Cell CLL
- •An absolute lymphocytosis of \> 5,000/μL
- •Morphologically, the lymphocytes must appear mature with \< 55% prolymphocytes
- •Bone marrow examination must include at least a unilateral aspirate and biopsy; the aspirate smear must show \> 30% of all nucleated cells to be lymphoid or the bone marrow core biopsy must show lymphoid infiltrates compatible with marrow involvement by CLL; the overall cellularity must be normocellular or hypercellular
- •Local institution lymphocyte phenotype must reveal a predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, CD23) with the CD5 antigen, in the absence of other pan-T-cell markers; additionally, the B-cells must be monoclonal with regard to expression of either κ or λ and have surface immunoglobulin expression of low density; patients with bright surface immunoglobulin levels must have CD23 co-expression
- •Patients must be in the intermediate- or high-risk categories of the modified three-stage Rai staging system (i.e., stages I, II, III, or IV)
- •Patients in the intermediate-risk group must have evidence of active disease as demonstrated by at least one of the following criteria:
- •Massive or progressive splenomegaly, hepatomegaly and/or lymphadenopathy;
- •Presence of weight loss \> 10% over the preceding 6 month period;
- •Grade 2 or 3 fatigue;
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (alemtuzumab, rituximab, fludarabine phosphate)
Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression.
Intervention: alemtuzumab
Treatment (alemtuzumab, rituximab, fludarabine phosphate)
Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression.
Intervention: rituximab
Treatment (alemtuzumab, rituximab, fludarabine phosphate)
Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression. Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression.
Intervention: fludarabine phosphate
Outcomes
Primary Outcomes
Number of Participants With a Complete Response After Treatment With Fludarabine & Rituximab Followed by Alemtuzumab
Time Frame: Duration of treatment (up to 13.5 months)
A complete response, as defined by the National Cancer Institute Working Group (NCIWG): - CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate \& biopsy
Secondary Outcomes
- 2 Year Progression Free Survival(2 years from registration)
- Number of Participants With Severe Non-Hematologic Adverse Events During Treatment With Alemtuzumab(6 weeks beginning at study week 36)
- Number of Participants With a Complete or Partial Response After Induction Therapy With Fludarabine & Rituximab(Up to 9 months)
- 2 Year Survival(2 years from registration)