Official Title: “A Phase II Randomized Trial Comparing Standard and Low Dose Rituximab: Initial Treatment of Progressive Chronic Lymphocytic Leukemia in Elderly Patients Using Alemtuzumab, and Rituximab”

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

PURPOSE: This randomized phase II trial is studying two different doses of rituximab to compare how well they work when given together with alemtuzumab in treating older patients with progressive chronic lymphocytic leukemia.

Study Type: Interventional

Study Design: Treatment, Randomized

Study Primary Completion Date: February 2012

OBJECTIVES:

Primary - To compare the rate of complete and overall response in elderly patients with progressive chronic lymphocytic leukemia (CLL) treated with one of two doses of rituximab combined with alemtuzumab to determine if the use of modified-dose rituximab significantly affects outcome.

Secondary - To monitor and assess toxicity of these regimens. - To determine the overall and progression-free survival, time to clinical response, time to next treatment, and duration of response in patients treated with these regimens - To assess the correlation between risk stratification prognostic markers (i.e., CD38, ZAP-70, FISH, and IgVH mutation) and clinical outcome. - To assess response to these regimens using both the NCI-WG 96 criteria and an expanded definition of response for patients in complete remission, including immunohistochemical examination of the bone marrow and sensitive flow cytometry (4-6 color) of blood for minimal residual disease and CT scans for residual adenopathy. - To determine the mechanism of action of rituximab and alemtuzumab and to detail the in vivo effect of this regimen on critical aspects of the immune system in select patients with CLL.

OUTLINE: This is a multicenter study. Patients are stratified according to FISH risk (low [13q14-] vs intermediate [12+, no abnormality, all other abnormalities] vs high [17p13-,11q22-]). Patients are randomized to 1 of 2 treatment arms. - Arm I: Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab IV on days 8, 15, 22, and 29 in course 1. In courses 2 and 3, patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. - Arm II: Patients receive alemtuzumab as in arm I. Patients also receive low-dose rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in course 1 and on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in courses 2 and 3. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples are collected periodically for cytogenetic and biomarker analysis.

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

Intervention(s) in this Clinical Trial

• Biological: alemtuzumab
  • Given IV
• Biological: rituximab
  • Given IV

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Arm I
  • Patients receive alemtuzumab subcutaneously (SC) on days 1-3, 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 and standard-dose rituximab IV on days 8, 15, 22, and 29 in course 1. In courses 2 and 3, patients receive alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 and standard-dose rituximab IV on days 3, 10, 17, and 24. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
• Experimental: Arm II
  • Patients receive alemtuzumab as in arm I. Patients also receive low-dose rituximab IV on days 6, 8, 10, 13, 15, 17, 20, 22, 24, 27, 29, and 31 in course 1 and on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 in courses 2 and 3. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.

Primary Measures

• Rate of complete and overall response
  • Safety Issue?: No

Secondary Measures

• Toxicity as assessed by NCI CTC v3.0 criteria
  • Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:
• Minimum threshold peripheral lymphocyte count of 5 x 10^9/L (CLL variant) OR palpable adenopathy > 1 cm or palpable splenomegaly (SLL variant)
• Immunophenotypic demonstrations of a population of B-lymphocytes (as defined by CD19+) that are monoclonal (by light-chain exclusion) AND have ≥ 3 of the following characteristics:
• CD5+
• CD23+
• Dim surface light chain expression
• Dim surface CD20 expression
• FISH analysis is negative for IGH/CCND1 and/or immunostaining is negative for cyclin D1 expression (to exclude mantle cell lymphoma)
• Has progressive, symptomatic CLL, defined by at least one of the following:
• Weight loss > 10% within the past 6 months attributable to progressive CLL (grade 2 or higher)
• Extreme fatigue attributable to progressive CLL (grade 3 or higher)
• Fevers > 100.5° F for 2 weeks without evidence of infection (grade 1 or higher)
• Night sweats without evidence of infection (drenching)
• Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10^9/L
• Rapidly progressive lymphadenopathy for which the largest node is ≤ 5 cm in any dimension
• Largest lymph nodes involved in the neck, axilla, and groin need to be measured and followed for response
• No massive splenomegaly > 6 cm below left costal margin, at rest, on clinical examination
• No lymphadenopathy > 5 cm in any diameter

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3
• Creatinine ≤ 2 times upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 times ULN
• AST ≤ 3.0 times ULN (unless due to CLL involvement of the liver)
• Not pregnant or nursing
• Fertile patients must use effective contraception during and for 12 months after completion of study therapy
• None of the following comorbid conditions:
• New York Heart Association class III or IV heart disease
• Recent myocardial infarction (within the past month)
• Uncontrolled infection
• HIV/AIDS
• Serological evidence of active hepatitis B infection (HBsAg or HBeAg positive)
• Positive hepatitis C serology
• No active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia
• No other active primary malignancy requiring treatment or that limits survival to ≤ 2 years, except for in situ carcinoma of the cervix or breast or non-metastatic basal cell or squamous cell carcinoma of the skin

PRIOR CONCURRENT THERAPY:

• No prior treatment for CLL
• More than 4 weeks since prior major surgery
• No concurrent continuous systemic corticosteroids
• Prior corticosteroids are allowed but not at time of pre-registration to the study

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 70 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Eastern Cooperative Oncology Group

Overall Clinical Trial Officials and Contacts

Clive S. Zent, MD Study Chair Mayo Clinic  

Information obtained from ClinicalTrials.gov on February 08, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01013961

Study ID Number: CDR0000659098

ClinicalTrials.gov Identifier: NCT01013961

Health Authority: Unspecified

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