Clinical trial NCT00634881: Alemtuzumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukemia
Keywords: 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
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
First posted: 2008-03-13
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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

Primary outcomes:
measure: Dose-limiting toxicity
timeFrame: 28 days after the last dose of study medication
measure: Maximum tolerated dose
timeFrame: 28 days after the last dose of study medication
Secondary outcomes:
measure: Rate of complete minimal residual disease response
timeFrame: 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
measure: Rate of immunophenotypic remission using 4-color flow cytometry
timeFrame: will be tested repeatedly, first time 3 months after the last dose of study medication,
measure: Rate of infections (especially CMV infections and reactivations)
timeFrame: upt to 24 months after last dose of study medication (end of study)
measure: Rate of severe hematologic and non-hematologic side effects
timeFrame: 28 days after the last dose of study medication
measure: Pharmacokinetics of alemtuzumab (after IV and subcutaneous administration)
timeFrame: up to 8 weeks during the alemtuzumab treatment
measure: Progression-free survival
timeFrame: upt to 24 months after last dose of study medication (end of study)
measure: Overall survival
timeFrame: upt to 24 months after last dose of study medication (end of study)
measure: Complete remission rate
timeFrame: 28 days after the last dose of study medication
Other outcomes:
Locations:
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I at the University of Cologne
city: Eberswalde
country: Germany
facility: Klinikum Barnim GmbH, Werner Forssmann Krankenhaus
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Lemgo
country: Germany
facility: Klinikum Lippe - Lemgo
city: Mannheim
country: Germany
facility: III Medizinische Klinik Mannheim
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brueder Regensburg
Study officials:
affiliation: Medizinische Universitaetsklinik I at the University of Cologne
name: Michael Hallek, MD
role: STUDY_CHAIR
References:
citation: Al-Sawaf O, Fischer K, Herling CD, Ritgen M, Bottcher S, Bahlo J, Elter T, Stilgenbauer S, Eichhorst BF, Busch R, Elberskirch U, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Alemtuzumab consolidation in chronic lymphocytic leukaemia: a phase I/II multicentre trial. Eur J Haematol. 2017 Mar;98(3):254-262. doi: 10.1111/ejh.12825. Epub 2016 Dec 1.