Clinical trial NCT00436904: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia
Keywords: stage 0 chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
B-cell chronic lymphocytic leukemia
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-02-19
Enrollment: 30
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 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Confirmed Response, Defined as Objective Complete Remission or Partial Remission for a Duration of at Least 2 Months
timeFrame: Up to 6 months
measure: Number of Participants With Treatment Related Adverse Events
timeFrame: Weekly for first 6 weeks, then monthly for 6 months, then at 9 and 12 months post registration
Secondary outcomes:
measure: Time to Response
timeFrame: Registration to first response (up to 5 years)
measure: Duration of Response
timeFrame: Up to 5 years
measure: Survival
timeFrame: Death or last follow-up (up to 5 years)
measure: Time to Disease Progression
timeFrame: Time from registration to progression (up to 5 years)
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Clive S. Zent, MD
role: STUDY_CHAIR
References:
citation: Zent CS, Call TG, Shanafelt TD, Tschumper RC, Jelinek DF, Bowen DA, Secreto CR, Laplant BR, Kabat BF, Kay NE. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer. 2008 Oct 15;113(8):2110-8. doi: 10.1002/cncr.23824.
citation: Zent CS, Secreto CR, LaPlant BR, Bone ND, Call TG, Shanafelt TD, Jelinek DF, Tschumper RC, Kay NE. Direct and complement dependent cytotoxicity in CLL cells from patients with high-risk early-intermediate stage chronic lymphocytic leukemia (CLL) treated with alemtuzumab and rituximab. Leuk Res. 2008 Dec;32(12):1849-56. doi: 10.1016/j.leukres.2008.05.014. Epub 2008 Jun 27.