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Alemtuzumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
German CLL Study Group
ClinicalTrials.gov Identifier:
NCT00634881
First received: March 12, 2008
Last updated: November 22, 2016
Last verified: September 2016
  Purpose

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.


Condition Intervention Phase
Chronic Lymphocytic Leukemia
Biological: Alemtuzumab i.v.
Biological: Alemtuzumab s.c.
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
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

Resource links provided by NLM:


Further study details as provided by German CLL Study Group:

Primary Outcome Measures:
  • Dose-limiting toxicity [ Time Frame: 28 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
    • 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 ] [ Designated as safety issue: Yes ]
    • 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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    • 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, ] [ Designated as safety issue: No ]
  • Rate of infections (especially CMV infections and reactivations) [ Time Frame: upt to 24 months after last dose of study medication (end of study) ] [ Designated as safety issue: Yes ]
  • Rate of severe hematologic and non-hematologic side effects [ Time Frame: 28 days after the last dose of study medication ] [ Designated as safety issue: Yes ]
  • Pharmacokinetics of alemtuzumab (after IV and subcutaneous administration) [ Time Frame: up to 8 weeks during the alemtuzumab treatment ] [ Designated as safety issue: No ]
    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) ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: upt to 24 months after last dose of study medication (end of study) ] [ Designated as safety issue: Yes ]
  • Complete remission rate [ Time Frame: 28 days after the last dose of study medication ] [ Designated as safety issue: No ]

Enrollment: 13
Study Start Date: November 2003
Study Completion Date: January 2010
Primary Completion Date: January 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  • Dose level I: 10mg once weekly (start with dose escalation : 3 mg on day 1, 10mg on day 2) Duration
  • Dose level II: 20mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 20mg on day 3)
  • Dose level III: 30mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 30mg on day 3)
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

  • Dose level I: 10mg once weekly (start with dose escalation : 3 mg on day 1, 10mg on day 2) Duration
  • Dose level II: 20mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 20mg on day 3)
  • Dose level III: 30mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 30mg on day 3)

Detailed Description:

OBJECTIVES:

  • 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

Inclusion criteria:

  • Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL)
  • Disease in complete or partial remission after completion of 4-6 courses of second-line cytoreductive therapy no less than 90 days and no more than 150 days ago

    • Second-line cytoreductive therapy must comprise 1 of the following regimens:

      • Fludarabine phosphate alone (F)
      • Fludarabine phosphate and cyclophosphamide (FC)
      • Fludarabine phosphate, cyclophosphamide, and rituximab (FCR)
      • Bendamustine hydrochloride alone (B)
      • Bendamustine hydrochloride and rituximab chemotherapy (BR)
  • Complete minimal residual disease response defined by the following:

    • At least negativity of 4-color-cytometry and/or even PCR-amplifiable clonal CDR III rearrangement of the IgV_H

      • For PCR analysis, blood sample need to be taken at beginning or during second-line cytoreductive therapy before achievement of a clinical complete remission
  • Disease not refractory to first-line F/FC/FCR/B/BR if received such therapy

Exclusion criteria:

  • Presence of bulky lymph nodes (> 5 cm) after second-line F/FC/FCR/B/BR
  • Clinically apparent autoimmune cytopenia (i.e., autoimmune hemolytic anemia, autoimmune thrombocytopenia, or pure red cell aplasia)
  • CNS involvement with B-CLL

PATIENT CHARACTERISTICS:

Inclusion criteria:

  • ECOG performance status 0-1
  • ANC ≥ 1,500/µL
  • Platelets ≥ 50,000/µL
  • Creatinine ≤ 1.5 times the upper normal limit (ULN)
  • Conjugated bilirubin ≤ 2 times ULN
  • Thyroid function normal
  • Not pregnant or nursing
  • Fertile patients must use effective contraception

Exclusion criteria:

  • Severe infection during second-line treatment with F/FC/FCR/B/BR, meeting any 1 of the following criteria:

    • Any episode of NCI grade 4 infection
    • More than 1 episode of NCI grade 3 infection
  • Medical condition requiring long-term use of oral corticosteroids for more than 1 month
  • Active bacterial, viral, or fungal infection
  • HIV, hepatitis B virus, and/or hepatitis C virus-positive serum status
  • Concurrent severe diseases that exclude the administration of protocol therapy, including any of the following:

    • NYHA class III-IV heart insufficiency
    • Severe chronic obstructive lung disease with hypoxemia
    • Severe ischemic cardiac disease
  • Active secondary malignancy other than B-CLL prior to the study
  • Known hypersensitivity or anaphylactic reaction against murine proteins or one of the drug components

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No more than 2 prior chemotherapies, including F/FC/FCR/B/BR therapy
  • No more than 1 pretreatment (before second-line therapy) with chlorambucil or F/FC/FCR/B/BR
  • No chemotherapy or radiotherapy for any neoplastic disease other than B-CLL prior to the study
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00634881

Locations
Germany
Medizinische Universitaetsklinik I at the University of Cologne
Cologne, Germany, D-50924
Klinikum Barnim GmbH, Werner Forssmann Krankenhaus
Eberswalde, Germany, 16225
Universitatsklinikum Heidelberg
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
Sponsors and Collaborators
German CLL Study Group
Investigators
Study Chair: Michael Hallek, MD Medizinische Universitaetsklinik I at the University of Cologne
  More Information

Additional Information:
Publications:
Responsible Party: German CLL Study Group
ClinicalTrials.gov Identifier: NCT00634881     History of Changes
Other Study ID Numbers: CLL2i  CDR0000587746 
Study First Received: March 12, 2008
Last Updated: November 22, 2016
Health Authority: Germany: Paul-Ehrlich-Institut
Individual Participant Data  
Plan to Share IPD: No

Keywords provided by German CLL Study Group:
B-cell chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Alemtuzumab
Antineoplastic Agents

ClinicalTrials.gov processed this record on December 02, 2016