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Clinical Trials (PDQ®)

Phase II Study of Pentostatin and Rituximab With or Without Cyclophosphamide in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Pentostatin and Rituximab With or Without Cyclophosphamide in Treating Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IITreatmentClosed18 and overNCIMAYO-MC0183
NCT00201721

Objectives

Primary

  1. Determine the complete and overall response rate in patients with previously untreated B-cell chronic lymphocytic leukemia (CLL) treated with pentostatin and rituximab with or without cyclophosphamide (Group 1).
  2. Determine the toxicity of these regimens in these patients.

Secondary

  1. Determine the overall and progression-free survival of patients treated with these regimens.
  2. Correlate the angiogenic profile of CLL B-cell clones prior to and during study treatment with clinical outcome in patients treated with pentostatin, rituximab, and cyclophosphamide (PCR) (Group 1).
  3. Correlate gene expression patterns prior to study entry with clinical outcome using gene array analysis in patients treated with PCR (Group 1).
  4. Determine the CLL B-cell genetic defects at baseline using CLL fluorescence in situ hybridization (FISH) panels to characterize the CLL clone in patients treated with PCR (Group 1).
  5. Correlate the VH gene mutation status of the CLL B-cell clones prior to study entry with clinical outcome in patients treated with PCR (Group 1).
  6. Determine the in vivo consequences of administering rituximab to these patients and if favorable modulation of mcl-1, XIAP, and signaling in vivo is predictive of complete response (Group 1).
  7. Correlate the p53 functional status of CLL B cell at study entry with clinical outcome in patients treated with PCR (Group 1).
  8. Determine the response rate for hematopathologically-based complete remission, flow-based complete remission, and molecular-based complete remission.
  9. Correlate the Ig VH gene mutation, CD38, ZAP-70, and FISH status of the CLL B-cell clones obtained prior to study entry with clinical outcome in patients treated with pentostatin and rituximab (PR) (Group 2).
  10. Conduct simultaneous conventional cytogenetic and interphase and metaphase FISH testing in patients treated with PR (Group 2).
  11. Assess the ability of patients to reconstitute their immune system by serial evaluation of the blood natural killer- and T-cell subsets, including CD3, CD4, CD8, and T-cell repertoire, in responding patients.

Entry Criteria

Disease Characteristics:

  • Diagnosis of B-cell chronic lymphocytic leukemia (CLL), manifested by all of the following:
    • Minimum threshold peripheral blood lymphocyte count > 5,000/mm3
    • Small to moderate peripheral blood lymphocytes with ≤ 55% prolymphocytes
    • Bone marrow aspirate containing ≥ 30% lymphoid cells
    • Demonstrates monoclonality of B lymphocytes by immunophenotypic evaluation of peripheral blood lymphocytes, as evidenced by all of the following:
      • B-cell markers with CD5 antigen in the absence of other pan-T-cell markers (e.g., CD3 or CD2)
      • CD19 and/or CD20
      • Expression of CD23 on the CLL cells OR dim B-cell expression of kappa or lambda light chains

  • Active disease, meeting any of the following criteria*:
    • At least 1 of the following disease-related symptoms:
      • Weight loss ≥ 10% within the past 6 months
      • Fever > 100.5°F for ≥ 2 weeks without evidence of infection
      • Night sweats without evidence of infection
    • Evidence of progressive marrow failure as manifested by the development or worsening of anemia (i.e., hemoglobin ≤ 11 g/dL) and/or thrombocytopenia (i.e., platelet count < 100,000/mm3)
    • Stage III or IV disease
    • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly
    • Progressive lymphocytosis (not due to the effects of corticosteroids) with an increase of > 50% over a 2-month period or an anticipated doubling time < 6 months

     [Note: *Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for study entry]

  • Previously untreated disease

Prior/Concurrent Therapy:

  • More than 4 weeks since prior radiotherapy or major surgery
  • Prior corticosteroids allowed

Patient Characteristics:

  • ECOG performance status 0-3
  • Creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 times ULN
  • SGOT ≤ 3.0 times ULN (unless due to hemolysis or CLL)
  • Hemoglobin ≥ 9.0 g/dL
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • No comorbid conditions, including any of the following:
    • New York Heart Association class III or IV heart disease
    • Myocardial infarction within the past month
    • Uncontrolled infection
    • Active infection due to HIV or AIDS
  • No other active primary malignancy requiring treatment or that limits survival to ≤ 2 years

Expected Enrollment

98

A total of 98 patients will be accrued for this study.

Outcomes

Primary Outcome(s)

Proportion of clinical complete response

Secondary Outcome(s)

Treatment response
Time to event analysis, in terms of time to response, duration of response, survival, and time to disease progression
Toxicity as measured by NCI CTC version 2.0
Ig VH gene mutation, CD38, ZAP-70, and fluorescence in situ hybridization (FISH) status of the chronic lymphocytic leukemia (CLL) B-cell clones at pretreatment
Correlation of gene expression profiles at baseline with leukemic cell Ig mutation status, CLL FISH panel defects, p53 mutation status, and ATM with clinical stage at presentation and clinical outcome (Group 1)
Correlation of angiogenic profile of CLL B-cell by quantification of both pro- and anti-angiogenic factor production with membrane vascular receptors on the clonal B-cells (Group 1)
Extent of rituximab-based therapy modulation of critical apoptotic factors in relation to spontaneous apoptosis of CLL B-cells (Group 1)
Microarray data analysis, in terms of the genes that best discriminate between SM and GL status, or any genes of interest (Group 1)
Conventional cytogenetic and interphase and metaphase FISH evaluation (Group 2)

Outline

This is a multicenter study. Patients are assigned to 1 of 2 treatment groups.

  • Group 1 (pentostatin, rituximab, and cyclophosphamide): Patients receive rituximab IV over 1-4 hours on days 1, 3, and 5 during course 1 and on day 1 only during all subsequent courses. They also receive pentostatin IV over 30 minutes on day 1, cyclophosphamide IV over 30 minutes on day 1, and filgrastim (G-CSF) subcutaneously (SC) on days 3-7.

  • Group 2 (pentostatin and rituximab): Patients receive rituximab IV over 1-4 hours on days 1, 3, and 5 during course 1 and on day 1 only during all subsequent courses. They also receive pentostatin IV over 30 minutes on day 1 and G-CSF SC on days 3-7.

In both groups, treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

All patients undergo blood collection at baseline and periodically during study for biomarker correlative studies. Patients in group 1 also undergo urine collection at baseline and periodically during study.

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

Published Results

Browning RL, Geyer SM, Johnson AJ, et al.: Expression of TCL-1 as a potential prognostic factor for treatment outcome in B-cell chronic lymphocytic leukemia. Leuk Res 31 (12): 1737-40, 2007.[PUBMED Abstract]

Kay NE, Geyer SM, Call TG, et al.: Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 109 (2): 405-11, 2007.[PUBMED Abstract]

Shanafelt TD, Lin T, Geyer SM, et al.: Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 109 (11): 2291-8, 2007.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Neil Kay, MD, Protocol chair
Ph: 507-538-7623
Email: cancerclinicaltrials@mayo.edu
John Byrd, MD, Protocol co-chair
Ph: 614-293-9869
Email: john.byrd@osumc.edu
Michael Grever, MD, Protocol co-chair
Ph: 614-293-8724
Email: michael.grever@osumc.edu
Thomas Lin, MD, PhD, Protocol co-chair
Ph: 614-293-5655
Email: thomas.lin@osumc.edu
Pierluigi Porcu, MD, Protocol co-chair
Ph: 614-293-9273
Email: pierluigi.porcu@sumc.edu
Timothy Call, MD, Protocol co-chair
Ph: 507-538-7623
Email: cancerclinicaltrials@mayo.edu
Robert Phyliky, MD, Protocol co-chair
Ph: 507-538-7623
Email: cancerclinicaltrials@mayo.edu

Registry Information
Official Title Phase II Trial of Pentostatin, and Rituximab With and Without Cyclophosphamide For Previously Untreated B-Chronic Lymphocytic Leukemia (CLL)
Trial Start Date 2002-03-01
Trial Completion Date 2008-12-31 (estimated)
Registered in ClinicalTrials.gov NCT00201721
Date Submitted to PDQ 2006-12-22
Information Last Verified 2007-09-30
NCI Grant/Contract Number CA15083

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

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