Fludarabine and Rituximab Followed By Alemtuzumab in Treating Patients With Chronic Lymphocytic Leukemia

Official Title: “A Phase II Study Of Fludarabine + Rituximab Induction Followed By Alemtuzumab (Compath-1H, NSC # 715969, IND # 10864) Administered Subcutaneously As Consolidation In Untreated Patients With B-Cell Chronic Lymphocytic Leukemia”

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 can find cancer cells and help kill them or carry cancer-killing substances to them. Drugs used in chemotherapy, such as fludarabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving fludarabine together with rituximab followed by alemtuzumab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving fludarabine together with rituximab followed by alemtuzumab works in treating patients with chronic lymphocytic leukemia.

OBJECTIVES:

Primary - Determine the rate of complete response in patients with previously untreated B-cell chronic lymphocytic leukemia (CLL) treated with induction therapy comprising fludarabine and rituximab followed by consolidation therapy comprising alemtuzumab. - Determine the toxicity of this regimen in these patients. - Determine whether alemtuzumab improves the complete response rate with acceptable toxicity in patients treated with this regimen. - Determine the progression-free and overall survival of high-risk and low-risk patients treated with this regimen. - Determine the frequency of molecular remission in patients treated with this regimen.

Secondary - Determine the clinical and molecular features that predict poor response to this regimen in these patients. - Determine the frequency of patients who remain at high risk for progression of CLL despite treatment with this regimen. - Determine the pharmacokinetics and ideal schedule of administration for a subsequent maintenance therapy approach with rituximab in these patients.

OUTLINE: This is a multicenter study.

Patients receive induction therapy comprising rituximab IV over 4 hours on days 1, 3, and 5 of course 1 and day 1 of all subsequent courses and fludarabine IV over 30 minutes on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression.

Approximately 4 months after completion of induction therapy, patients achieving a partial response, nodular partial response, or stable disease receive consolidation therapy comprising alemtuzumab subcutaneously on days 1-3. Treatment repeats weekly for up to 6 courses in the absence of disease progression.

Patients are followed at 2 months, every 3 months for 1 year, and then every 6 months for 7 years from study entry.

PROJECTED ACCRUAL: A total of 100 patients will be accrued for this study within 2 years.

Intervention(s) in this Clinical Trial

• Biological: alemtuzumab
  • 30 mg subQ for 6 weeks beginning at approx study week 36
• Biological: rituximab
  • d.1: 50mg/sq m IV infusion over 4 hrs; d.3: 325 mg/sq m IV 50 mg/hr; d.5: 375 mg/sq m IV 100 mg/hr and d.1 wks 5,9,13,17,21: 375 mg/sq m IV
• Drug: fludarabine phosphate
  • 25 mg/sq m/d IV infusion over 30 min on days 1-5 wks 1,5,9,13,17,21

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Alemtuzumab consolidation
  • Alemtuzumab consolidation following fludarabine and rituximab induction in pts with B-cell CLL

Primary Measures

• Complete response
  • Time Frame: 13.5 mon post tx onset
    Safety Issue?: No

Secondary Measures

• Molecular remission rates
  • Time Frame: After induction and after consolidation
    Safety Issue?: No
• Time to disease progression
  • Time Frame: After 2 induction cycles then up to 8 yrs post study entry
    Safety Issue?: No
• Overall survival
  • Time Frame: 8 years post study entry
    Safety Issue?: No
• Toxicity
  • Time Frame: 6 weeks beginning at study week 36
    Safety Issue?: Yes

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL)
• Absolute lymphocyte count > 5,000/mm^3
• Lymphocytes must appear mature with < 55% prolymphocytes
• Bone marrow aspirate smear with > 30% of all nucleated cells shown to be lymphoid OR bone marrow core biopsy showing lymphoid infiltrates compatible with marrow involvement by CLL
• Overall cellularity must be normocellular or hypercellular
• Lymphocyte phenotype revealing predominant B-cell monoclonal population sharing a B-cell marker (CD19, CD20, or CD23) with the CD5 antigen in the absence of other pan-T-cell markers
• B-cells must be monoclonal with regard to expression of either kappa or lambda and have surface immunoglobulin expression of low density
• Patients with bright surface immunoglobulin levels must have CD23 coexpression
• Intermediate- or high-risk disease
• Stage I, II, III, or IV disease
• Patients with intermediate-risk disease must have evidence of active disease as evidenced by meeting at least 1 of the following criteria:
• Massive or progressive splenomegaly, hepatomegaly, and/or lymphadenopathy
• Weight loss > 10% within the past 6 months
• Grade 2 or 3 fatigue
• Fevers > 100.5°F or night sweats for more than 2 weeks without evidence of infection
• Progressive lymphocytosis with an increase of > 50% over 2 months OR an anticipated doubling time of < 6 months
• High-risk disease defined as 1 of the following:
• Hemoglobin < 11 g/dL
• Platelet count < 100,000/mm^3

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Performance status
• 0-2
• Life expectancy
• Not specified
• Hematopoietic
• See Disease Characteristics
• Hepatic
• See Disease Characteristics
• Renal
• Creatinine ≤ 1.5 times upper limit of normal
• Other
• Not pregnant
• No nursing during and for ≥ 3 months after study participation
• Fertile patients must use effective contraception during and for ≥ 6 months after study participation
• HIV negative
• Coombs' test negative

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• Not specified
• Chemotherapy
• No other concurrent chemotherapy
• Endocrine therapy
• No prior corticosteroids for autoimmune complications that have developed since initial diagnosis of CLL
• No concurrent hormonal therapy except for the following:
• Hypersensitivity reactions
• Steroids for new adrenal failure
• Hormones administered for non-disease-related conditions (e.g., insulin for diabetes)
• No concurrent chronic oral corticosteroids
• No concurrent dexamethasone or other corticosteroids as antiemetic prophylaxis
• Radiotherapy
• No concurrent palliative radiotherapy
• Surgery
• Not specified
• Other
• No prior therapy for CLL

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: Cancer and Leukemia Group B Other

Overall Clinical Trial Officials and Contacts

Thomas S. Lin, MD, PhD Study Chair Arthur G. James Cancer Hospital & Richard J. Solove Research Institute  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00098670

Study ID Number: CDR0000398139

ClinicalTrials.gov Identifier: NCT00098670

Health Authority: United States: Food and Drug Administration

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