Alemtuzumab and Rituximab in Treating Patients With High-Risk, Early-Stage Chronic Lymphocytic Leukemia

Official Title: “Antibody Therapy With Alemtuzumab and Rituximab for Initial Treatment of High Risk Chronic Lymphocytic Leukemia”

RATIONALE: Monoclonal antibodies, such as alemtuzumab and rituximab, 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. Giving alemtuzumab together with rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying the side effects and how well giving alemtuzumab together with rituximab works in treating patients with high-risk, early-stage chronic lymphocytic leukemia.

OBJECTIVES:

Primary - Determine the rate of complete and overall response to alemtuzumab and rituximab in patients with high-risk, early-stage chronic lymphocytic leukemia. - Determine the toxicity of this regimen in these patients. Secondary - Determine the overall survival and time to progression of patients treated with this regimen. - Determine time to response and duration of response in patients treated with this regimen. - Correlate prognostic markers 11q-, 17p-, unmutated VH gene, and CD38+ with clinical outcome. - Determine response to this regimen using an expanded definition of response that includes minimal residual disease detected by sensitive flow cytometry in patients in complete clinical remission and single rearranged IgVH gene detected by polymerase chain reaction in patients with no monoclonal population on flow cytometry. - Correlate in vitro response with clinical outcome in patients treated with this regimen. - Determine if alemtuzumab and rituximab are synergistic in vitro. - Determine the mechanism of action of this regimen in vitro. - Determine the effect of this regimen on immune function. - Monitor T-lymphocyte, natural killer cell, and monocyte number during and after treatment in these patients. - Serially evaluate T-lymphocyte immunophenotype and function in patients treated with this regimen. - Monitor recovery of humoral immunity by serial serum protein electrophoresis, immunofixation electrophoresis, and immunoglobulin quantification.

OUTLINE: - Dose-escalation (week 1): Patients receive rituximab IV on day 1 and escalating doses of alemtuzumab subcutaneously (SC) on days 3-5 in week 1. - Treatment (weeks 2-5): Patients receive alemtuzumab SC on days 1-3 (at the highest dose administered during week 1) and rituximab IV on day 3 in weeks 2-5 in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection at baseline and periodically during study treatment for pharmacokinetic and prognostic biomarker (11q-, 17p-, unmutated IgVH, and CD38 expression by flow cytometry and fluorescent in-situ hybridization) studies. Immune function (CDR3 T-cell receptor by reverse transcriptase-polymerase chain reaction) and in vitro and in vivo response are also examined.

After completion of study therapy, patients are followed periodically for 5 years.

PROJECTED ACCRUAL: A total of 33 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: Alemtuzumab
  • 30 mg Monday, Wednesday, and Friday x 5 weeks
• Drug: Rituximab
  • 375mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Alemtuzumab + Rituximab
  • Alemtuzumab 30mg Monday, Wednesday, and Friday x 5 weeks, Rituximab 375/mg/m2 IV weekly (Wednesday) x 4 weeks (weeks 2-5)

Primary Measures

• Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months
  • Time Frame: Up to 6 months
    Safety Issue?: No
• Number of Participants With Treatment Related Adverse Events
  • Time Frame: Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration
    Safety Issue?: Yes

Secondary Measures

• Time to Response
  • Time Frame: Registration to first response (up to 5 years)
    Safety Issue?: No
• Duration of Response
  • Time Frame: Up to 5 years
    Safety Issue?: No
• Survival
  • Time Frame: Death or last follow-up (up to 5 years)
    Safety Issue?: No
• Time to Disease Progression
  • Time Frame: Time from registration to progression (up to 5 years)
    Safety Issue?: No

DISEASE CHARACTERISTICS:

• * Diagnosis of B-cell chronic lymphocytic leukemia (CLL)
• Early-stage, biologically high-risk disease defined by the following criteria:
• Rai stage 0-II (does not meet standard NCI-sponsored Working Group criteria for treatment)
• Clinical and phenotypic features manifested in the peripheral blood, including the following:
• Minimum threshold peripheral blood lymphocyte count of > 5,000/mm³
• Small-to-moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes
• Monoclonality of B lymphocytes by immunophenotypic evaluation, demonstrating co-expression of CD19, CD5, and CD23 antigens, surface expression of CD20 and CD52, and B-cell monoclonal population defined by light-chain exclusions
• Poor prognosis demonstrated by ≥ 1 of the following high-risk parameters:
• Unmutated human immunoglobulin variable region heavy chain (IgVH) gene and CD38 expression (≥ 30% cells positive on flow cytometry) OR unmutated IgVH ZAP-70 expression (≥ 20% cells positive on flow cytometry) = 11q- = 17p-

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Creatinine ≤ 1.5 times upper limit of normal (ULN)
• Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 times ULN
• AST ≤ 3.0 times ULN (unless due to hemolysis or CLL)
• Hemoglobin ≥ 9.0 g/dL
• No New York Heart Association class III-IV heart disease
• No myocardial infarction within the past month
• No uncontrolled infection
• No active HIV infection
• No evidence of autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia
• No other active primary malignancy requiring treatment or limiting survival to less than 2 years

PRIOR CONCURRENT THERAPY:

• No prior treatment for CLL
• Prior corticosteroids allowed
• No prior radiotherapy
• More than 4 weeks since prior major surgery

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Mayo Clinic Other

Overall Clinical Trial Officials and Contacts

Clive S. Zent, MD Study Chair Mayo Clinic  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00436904

Study ID Number: CDR0000529809

ClinicalTrials.gov Identifier: NCT00436904

Health Authority: United States: Food and Drug Administration

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