Alemtuzumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia
RATIONALE: Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them.
PURPOSE: This phase I/II trial is studying the side effects and best dose of alemtuzumab in treating patients with B-cell chronic lymphocytic leukemia.
|Chronic Lymphocytic Leukemia||Biological: Alemtuzumab i.v. Biological: Alemtuzumab s.c.||Phase 1 Phase 2|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Consolidation Therapy With Alemtuzumab (MabCampath®) in Patients With Chronic Lymphocytic Leukemia Who Are in Complete or Partial 2nd Remission After Cytoreduction With Fludarabine or Fludarabine Plus Cyclophosphamide or Fludarabine Plus Cyclophosphamide Plus Rituximab or Bendamustine or Bendamustine Plus Rituximab - a Phase I/II Study|
- Dose-limiting toxicity [ Time Frame: 28 days after the last dose of study medication ]• Dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) DLT is defined as a) all grade III/IV non-hematologic toxicity and b) all grade IV hematologic toxicity lasting for more than 2 weeks (excluding lymphopenia) occuring during or within 4 weeks after end of consolidation therapy.
- Maximum tolerated dose [ Time Frame: 28 days after the last dose of study medication ]• Dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) DLT is defined as a) all grade III/IV non-hematologic toxicity and b) all grade IV hematologic toxicity lasting for more than 2 weeks (excluding lymphopenia) occuring during or within 4 weeks after end of consolidation therapy.
- Rate of complete minimal residual disease response [ Time Frame: will be tested repeatedly, first time 3 months after the last dose of study medication, last time point 24 months after last dose of study medication ]• Rate of molecular responses (defined by negativity of 4- colour- cytometry in BOTH peripheral blood AND bone marrow in patients in clinical CR) The approved laboratory diagnostics for detection of MRD response is 4-colour flow cytometry. Collaterally, it is possible to take samples for potential PCR- analysis for confirmation if available.
- Rate of immunophenotypic remission using 4-color flow cytometry [ Time Frame: will be tested repeatedly, first time 3 months after the last dose of study medication, ]
- Rate of infections (especially CMV infections and reactivations) [ Time Frame: upt to 24 months after last dose of study medication (end of study) ]
- Rate of severe hematologic and non-hematologic side effects [ Time Frame: 28 days after the last dose of study medication ]
- Pharmacokinetics of alemtuzumab (after IV and subcutaneous administration) [ Time Frame: up to 8 weeks during the alemtuzumab treatment ]Pharmacokinetic samples will be taken at week 4 and 8 during alemtuzumab treatment at the following time points: 0, 4, 8, 24, 48, 96, 168 h
- Progression-free survival [ Time Frame: upt to 24 months after last dose of study medication (end of study) ]
- Overall survival [ Time Frame: upt to 24 months after last dose of study medication (end of study) ]
- Complete remission rate [ Time Frame: 28 days after the last dose of study medication ]
|Study Start Date:||November 2003|
|Study Completion Date:||January 2010|
|Primary Completion Date:||January 2010 (Final data collection date for primary outcome measure)|
Experimental: Cohort A: Alemtuzumab i.v.
Intravenous administration of alemtuzumab according to the 3 + 3 dose escalation design.
Biological: Alemtuzumab i.v.
Alemtuzumab will be administered once per week as a 2 h infusion
Experimental: Cohort B: Alemtuzumab s.c.
After i.v. MTD (maximum tolerable dosage) has been determined, subcutaneous dose escalation is performed according to the same escalation rules as for cohort A, starting with the recommended dose level of i.v. application.
Biological: Alemtuzumab s.c.
Alemtuzumab will be administered once per week subcutaneously
- To determine the safest dose of alemtuzumab as consolidation therapy in patients in second remission after fludarabine phosphate alone; fludarabine phosphate and cyclophosphamide; fludarabine phosphate, cyclophosphamide, and rituximab; bendamustine hydrochloride alone; or bendamustine hydrochloride and rituximab.
- To determine the frequency of cytomegalovirus reactivations or infections during or after alemtuzumab treatment.
- To determine which dose of alemtuzumab is efficient to eliminate minimal residual disease in peripheral blood and bone marrow (i.e., to turn a clinical partial remission into a clinical complete remission [CR], to turn a flow cytometry-positive CR into a flow cytometry-negative CR, or to turn a PCR-positive CR into a PCR-negative CR).
- To determine the pharmacokinetic profile of alemtuzumab.
- To compare the pharmacokinetic profile between intravenous versus subcutaneous administration of alemtuzumab.
OUTLINE: This is a multicenter, dose-escalation study of alemtuzumab.
- Group 1: Patients receive escalating doses of alemtuzumab IV over 2 hours once weekly for 8 weeks until the maximum tolerated dose (MTD) is determined.
- Group 2: Patients receive escalating doses of alemtuzumab subcutaneously once weekly for 8 weeks, beginning with the MTD determined in group 1 until a second MTD is determined.
Patients undergo bone marrow and blood sample collection periodically for laboratory and pharmacokinetic studies. Samples are analyzed for minimal residual disease and T-cell subsets (i.e., CD4 and CD8) via quantitative-PCR analysis and flow cytometry and cytomegalovirus antigens via PCR.
After completion of study treatment, patients are followed at 3, 6, 9, 12, 18, and 24 months.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00634881
|Medizinische Universitaetsklinik I at the University of Cologne|
|Cologne, Germany, D-50924|
|Klinikum Barnim GmbH, Werner Forssmann Krankenhaus|
|Eberswalde, Germany, 16225|
|Heidelberg, Germany, D-69115|
|Klinikum Lippe - Lemgo|
|Lemgo, Germany, D-32657|
|III Medizinische Klinik Mannheim|
|Mannheim, Germany, D-68305|
|Krankenhaus Barmherzige Brueder Regensburg|
|Regensburg, Germany, D-93049|
|Study Chair:||Michael Hallek, MD||Medizinische Universitaetsklinik I at the University of Cologne|