Alemtuzumab in Treating Patients With B-Cell Chronic Lymphocytic Leukemia

German CLL Study Group

Status and phase: Completed; Phase 2; Phase 1

Conditions: Chronic Lymphocytic Leukemia

Treatments: Biological: Alemtuzumab s.c.; Biological: Alemtuzumab i.v.

Study type: Interventional

Funder types: Other

Identifiers

NCT00634881

CLL2i

CDR0000587746 (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 13 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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13 participants in 2 patient groups

Cohort A: Alemtuzumab i.v.

Experimental group

Description:

Intravenous administration of alemtuzumab according to the 3 + 3 dose escalation design.

Treatment:

Biological: Alemtuzumab i.v.

Cohort B: Alemtuzumab s.c.

Experimental group

Description:

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.

Treatment:

Biological: Alemtuzumab s.c.