Pentostatin, Cyclophosphamide, and Rituximab Followed By Alemtuzumab in Treating Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia

Official Title: “Phase II Trial of Pentostatin, Cyclophosphamide and Rituximab (PCR) Followed by Campath-1H for Previously Treated Relapsed or Refractory Patients With Chronic Lymphocytic Leukemia”

RATIONALE: Drugs used in chemotherapy, such as pentostatin and cyclophosphamide, work in different ways to stop cancer cells from dividing so they stop growing or die. Monoclonal antibodies, such as rituximab and alemtuzumab, can locate cancer cells and either kill them or deliver cancer-killing substances to them without harming normal cells. Combining chemotherapy with monoclonal antibody therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well pentostatin, cyclophosphamide, rituximab, and alemtuzumab work in treating patients with relapsed or refractory B-cell chronic lymphocytic leukemia.

OBJECTIVES:

Primary - Determine the objective response rate (complete remission, partial remission [PR], or nodular PR) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL) treated with pentostatin, cyclophosphamide, and rituximab (PCR) followed by alemtuzumab. - Determine the presence of minimal residual disease in patients treated with this regimen.

Secondary - Determine the toxicity of this regimen in these patients. - Determine the overall and progression-free survival of patients treated with this regimen. - Determine the number of patients who, after PCR, only achieve PR, stable disease, or progressive disease and subsequently convert to a higher response category after alemtuzumab. - Correlate V_H gene mutation status and CD38 expression of the CLL B-cell clones with clinical outcome in patients treated with this regimen. - Correlate the differential expression of genes in the leukemic cells with clinical outcome in patients treated with this regimen. - Correlate surface phenotype and genetic defects of the CLL B-cell clones with clinical outcome and gene expression patterns in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Pentostatin, cyclophosphamide, and rituximab (PCR)* therapy: Patients receive pentostatin IV over 10-30 minutes, cyclophosphamide IV over 30-60 minutes, and rituximab** IV on day 1.

Patients also receive filgrastim (G-CSF) or pegfilgrastim subcutaneously (SC) beginning on day 3 and continuing until blood counts recover. Treatment repeats every 28 days for a total of 6 courses in the absence of unacceptable toxicity.

NOTE: *Patients demonstrating progression while receiving PCR must have completed 2 courses of PCR prior to proceeding to alemtuzumab therapy

NOTE: **Patients receive rituximab IV on days 1, 3, and 5 for course 1 only; for courses 2-6, patients receive rituximab on day 1 only

Alemtuzumab therapy: Twelve weeks after completion of PCR therapy, patients receive alemtuzumab SC on days 1, 3, and 5. In the absence of disease progression or unacceptable toxicity, treatment repeats weekly for 4 weeks for patients with complete remission or nodular partial remission (PR) after PCR OR for 18 weeks for patients with PR, stable disease, or progressive disease after PCR.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 26-110 patients will be accrued for this study within 1.5 years.

Intervention(s) in this Clinical Trial

• Biological: alemtuzumab
• Biological: filgrastim
• Biological: pegfilgrastim
• Biological: rituximab
• Drug: cyclophosphamide
• Drug: pentostatin

Primary Measures

• Objective response rate as measured by percentage after pentostatin, cyclophosphamide, and rituximab (PCR) and Campath at 6 months and 12 months
  • Safety Issue?: No
• Level of residual disease as measured by bone marrow and imaging studies at 6 months and 12 months
  • Safety Issue?: No

Secondary Measures

• Toxicity as measured by CTCAE criteria every month
  • Safety Issue?: Yes
• Overall survival and progression-free survival as measured by Kaplan-Meier method during study treatment
  • Safety Issue?: No
• Conversion rate of complete remission after Campath therapy in partial remission patients as measured by the percent improvement rate after Campath
  • Safety Issue?: No

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting the following criteria:
• Peripheral blood absolute lymphocyte count greater than 5,000/mm^3
• Lymphocytosis must comprise small to moderate size lymphocytes with no greater than 55% prolymphocytes, atypical lymphocytes, or lymphoblasts morphologically
• Phenotypically characterized CLL defined by the following:
• Predominant population of cells share B-cell antigens with CD5 in the absence of other pan-T-cell markers (CD3 or CD2)
• B cell expresses either kappa or lambda light chains
• Surface immunoglobulin with low cell surface density expression
• Requires chemotherapy, as indicated by any of the following:
• Disease-related symptoms
• Weight loss of 10% or more within the past 6 months
• Extreme fatigue
• Fevers greater than 100.5°F for 2 weeks without evidence of infection
• Night sweats without evidence of infection
• Evidence of progressive marrow failure manifested by the development of or worsening anemia (hemoglobin no greater than 10 g/dL) and/or thrombocytopenia (platelet count no greater than 100,000/mm^3)
• Massive (i.e., greater than 6 cm below left costal margin) or progressive splenomegaly
• Massive nodes or clusters (i.e., greater than 10 cm in longest diameter) or progressive adenopathy
• Progressive lymphocytosis with an increase of greater than 50% over a 2-month period OR an anticipated doubling time of less than 6 months
• Demonstrated progression after at least 1 course of either an alkylating agent-based or purine nucleoside-based (e.g., fludarabine) regimen OR failed to achieve a meaningful response OR relapsed after prior therapy
• Patients who have relapsed after a pentostatin-based regimen are eligible provided the response was greater than 12 months prior to study entry
• No bone marrow dysplasia related to prior therapy

PATIENT CHARACTERISTICS:

• Age
• 18 and over
• Performance status
• ECOG 0-2
• Life expectancy
• Not specified
• Hematopoietic
• See Disease Characteristics
• Hepatic
• Bilirubin no greater than 2 mg/dL (unless secondary to tumor, hemolysis, or Gilbert's syndrome)
• Renal
• Creatinine no greater than 2.0 mg/dL OR
• Creatinine clearance ≥ 30 mL/min
• Cardiovascular
• No New York Heart Association class III or IV heart failure
• Other
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No other malignancy within the past 2 years except squamous cell or basal cell skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

• Biologic therapy
• See Chemotherapy
• No prior alemtuzumab
• At least 8 weeks since prior rituximab
• Chemotherapy
• See Disease Characteristics
• At least 6 weeks since prior chemotherapy
• At least 1 year since prior pentostatin, cyclophosphamide, and rituximab (PCR) therapy
• PCR therapy at least 1 year prior to study entry allowed
• Endocrine therapy
• Not specified
• Radiotherapy
• Not specified
• Surgery
• Not specified
• Other
• No concurrent oral or IV antibiotics for active infection

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: Eastern Cooperative Oncology Group Other

Overall Clinical Trial Officials and Contacts

Sanford J. Kempin, MD Study Chair St. Vincent's Comprehensive Cancer Center - Manhattan  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00074282

Study ID Number: CDR0000343796

ClinicalTrials.gov Identifier: NCT00074282

Health Authority: Unspecified

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