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

Alternate Title

Pentostatin, Alemtuzumab, and Rituximab in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Basic Trial Information

Special Category: SPORE trial

Objectives

Primary

1. To assess the rate of complete and overall response in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma treated with pentostatin, alemtuzumab, and low-dose rituximab.
2. To assess response to this treatment regimen using an expanded definition of response, including CT scans of chest-abdomen-pelvis, immunohistochemical analysis for residual disease in the bone marrow, and sensitive flow cytometry for minimal residual disease in patients who achieve a complete clinical remission.
3. To monitor and assess toxicity of this treatment regimen.

Secondary

1. To determine the overall and progression-free survival, duration of response, and time to next treatment.
2. To assess the correlation between individual prognostic markers (17p-, 11q-, unmutated VH gene, VH3-21, ZAP-70+, CD38+, CD49d, and β2 microglobulin, miRNA profiles, angiogenesis status, and karyotypes of CpG stimulated cells) and clinical outcome.

Tertiary

1. Measure the effect of monoclonal antibody concentration on the complement fixation-antibody dependent cellular cytotoxicity interaction.
2. Assess minimal residual disease status in responding patients using sensitive flow cytometry and correlate with overall and progression-free survival, duration of response, and time to next treatment.
3. Detail the in vivo effect of this treatment regimen on critical aspects of the immune system in these patients.

Entry Criteria

Disease Characteristics:

• Histologically or cytologically confirmed chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) meeting the following criteria:
  • Minimum threshold peripheral blood lymphocyte count of 5 x 10⁹/L (CLL variant) OR 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

• Must have progressive disease as indicated by any of the following characteristics (based on standard criteria for treatment):
  • Symptomatic CLL characterized by any of the following:
    • Weight loss > 10% within the past 6 months
    • Extreme fatigue
    • Fevers > 38.5° C (not due to infection)
    • Drenching night sweats without evidence of infection
  • Evidence of progressive bone marrow failure with hemoglobin < 11 g/dL or platelet count < 100 x 10⁹/L
  • Massive and progressive splenomegaly (> 6 cm below left costal margin)
  • Massive (> 10 cm) or rapidly progressive lymphadenopathy

Prior/Concurrent Therapy:

• No more than 3 prior treatment regimens for CLL that included purine analogue drugs (e.g., fludarabine, pentostatin, or cladribine) OR previously untreated CLL in patients with high-risk disease due to 17p13 deletion on FISH analysis
• More than 4 weeks since prior major surgery
• More than 2 months since prior alemtuzumab
• Prior corticosteroids allowed
• No concurrent continuous systemic corticosteroids

Patient Characteristics:

• ECOG performance status 0-3
• Creatinine ≤ 2 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)
• Willing to provide mandatory blood samples for research studies
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for up to 12 months after completion of study treatment
• No other active primary malignancy that requires treatment or limits survival to ≤ 2 years
• No active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia
• No New York Heart Association class III or IV heart disease
• No myocardial infarction within the past month
• No uncontrolled infection
• No HIV infection or AIDS
• No active hepatitis B infection (i.e., HBsAg or HBeAg positivity) or hepatitis C infection by serology
• No other comorbid condition

Expected Enrollment

Outcomes

Proportion of complete responses

Overall response rate (complete and partial response)
Overall survival
Progression-free survival
Duration of response
Time to subsequent therapy
IgVh gene mutation, CD38, ZAP-70, CD49d, and FISH status of chronic lymphocytic leukemia clones

Outline

This is a multicenter study.

• Course 1: Patients receive pentostatin IV on days 8 and 22; alemtuzumab subcutaneously (SC) on days 3-5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; and sargramostim (GM-CSF) SC on days 10-14 and 24-28. Patients then proceed to course 2.

• Courses 2 and 3: Patients receive pentostatin IV on days 1 and 15; alemtuzumab SC and rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26; and GM-CSF SC on days 3-7 and 17-21. After completion of course 2, patients with a complete response proceed to observation. Patients with a partial response or stable disease receive another course of therapy (course 3).

Treatment continues in the absence of disease progression or unacceptable toxicity.

Blood is collected on days 1, 3, 8, and 10 of course 1 for monoclonal antibody studies. Samples are analyzed for serum concentration of alemtuzumab and rituximab by ELISA and PCR; CH50 assay; complement activation and cytokine levels by ELISA; NK cell activation; and NK cell phenotype by immunofluorescent staining and flow cytometry.

After completion of study treatment, patients are followed up monthly for 6 months, every 3 months for 6 months, and then every 6-12 months for up to 5 years.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Clive Zent, MD, Protocol chair		Ph: 507-266-1154
Thomas Witzig, MD, Protocol co-chair		Ph: 507-266-9276 Email: witzig.thomas@mayo.edu
George Weiner, MD, Protocol co-chair		Ph: 319-353-8620 Email: george-weiner@uiowa.edu
John Densmore, MD, Protocol co-chair		Ph: 434-924-9637; 800-223-9173 Email: jjd2q@hscmail.mcc.virginia.edu

U.S.A.
Iowa
	Iowa City
	Holden Comprehensive Cancer Center at University of Iowa
		Cancer Information Service	Ph:  800-237-1225
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Virginia
	Charlottesville
	University of Virginia Cancer Center
		Ronald Taylor, MD	Ph:  434-924-9333 800-223-9173

Registry Information
Official Title		Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) with Pentostatin, Alemtuzumab, and Low Dose Rituximab: A Phase II Clinical Trial
Trial Start Date		2008-07-01
Trial Completion Date		2010-09-01 (estimated)
Registered in ClinicalTrials.gov		NCT00669318
Date Submitted to PDQ		2008-04-21
Information Last Verified		2010-01-04
NCI Grant/Contract Number		CA15083

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