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Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) With Pentostatin, Alemtuzumab, and Low Dose Rituximab: A Phase II Clinical Trial


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Leukemia, Lymphoma

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Trial Information

Treatment of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL) With Pentostatin, Alemtuzumab, and Low Dose Rituximab: A Phase II Clinical Trial


OBJECTIVES:

Primary

- 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.

- 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.

- To monitor and assess toxicity of this treatment regimen.

Secondary

- To determine the overall and progression-free survival, duration of response, and time
to next treatment.

- 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

- Measure the effect of monoclonal antibody concentration on the complement
fixation-antibody dependent cellular cytotoxicity interaction.

- 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.

- Detail the in vivo effect of this treatment regimen on critical aspects of the immune
system in these patients.

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.

Inclusion 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 10^9/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 10^9/L

- Massive and progressive splenomegaly (> 6 cm below left costal margin)

- Massive (> 10 cm) or rapidly progressive lymphadenopathy

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

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

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of complete responses

Safety Issue:

No

Principal Investigator

Clive S. Zent, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mayo Clinic

Authority:

United States: Food and Drug Administration

Study ID:

LS0881

NCT ID:

NCT00669318

Start Date:

July 2008

Completion Date:

Related Keywords:

  • Leukemia
  • Lymphoma
  • refractory chronic lymphocytic leukemia
  • recurrent small lymphocytic lymphoma
  • B-cell chronic lymphocytic leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma

Name

Location

Mayo ClinicRochester, Minnesota  55905
Holden Comprehensive Cancer Center at University of IowaIowa City, Iowa  52242-1002
University of Virginia Cancer CenterCharlottesville, Virginia  22908