Alemtuzumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia

Condition(s) targeted: Cancer-Related Problem/Condition; Leukemia

Intervention: alemtuzumab (Biological); polymerase chain reaction (Genetic); flow cytometry (Other); laboratory biomarker analysis (Other); pharmacological study (Other)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: German CLL Study Group

Official(s) and/or principal investigator(s):
Michael Hallek, MD, Study Chair, Affiliation: Medizinische Universitaetsklinik I at the University of Cologne

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.

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 design: Treatment, Open Label

Primary outcome:

Dose-limiting toxicity

Maximum tolerated dose

Secondary outcome:

Rate of complete minimal residual disease response

Rate of immunophenotypic remission using 4-color flow cytometry

Rate of infections (especially CMV infections and reactivations)

Rate of severe hematologic and non-hematologic side effects

Pharmacokinetics of alemtuzumab (after IV and subcutaneous administration)

Progression-free survival

Overall survival

Complete remission rate

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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

III Medizinische Klinik Mannheim, Mannheim D-68305, Germany; Recruiting
Contact Person, Phone: 49-621-383-4152, Email: nicolai.haertel@med3.ma.uni-heidelberg.de

Klinikum Barnim GmbH, Werner Forssmann Krankenhaus, Eberswalde 16225, Germany; Recruiting
Contact Person, Phone: 49-89-595-191, Email: abenhardt@t-online.de

Klinikum Lippe - Lemgo, Lemgo D-32657, Germany; Recruiting
Contact Person, Phone: 49-526-126-4129, Email: karin.heinisch@klinikum-lippe.de

Krankenhaus Barmherzige Brueder Regensburg, Regensburg D-93049, Germany; Recruiting
Contact Person, Phone: 49-941-264-129

Medizinische Universitaetsklinik I at the University of Cologne, Cologne D-50924, Germany; Recruiting
Michael Hallek, MD, Phone: 49-221-478-4400

Universitatsklinikum Heidelberg, Heidelberg D-69115, Germany; Recruiting
Contact Person, Phone: 49-622-156-8023, Email: manfred.hensel@med.uni-heidelberg.de

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: November 2003
Last updated: February 6, 2009