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

Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00669318
• Other study ID #: LS0881
• Secondary ID: LS088108-000673
• Status: Completed
• Phase: Phase 2
• First received: April 29, 2008
• Last updated: June 20, 2014
• Start date: July 2008
• Est. completion date: May 2014

Study information

• Verified date: June 2014
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Drugs used in chemotherapy, such as pentostatin, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as alemtuzumab and rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving pentostatin together with alemtuzumab and rituximab may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving pentostatin together with alemtuzumab and rituximab works in treating patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma.

Description:

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 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: May 2014
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma

Intervention

Biological:
• alemtuzumab

• rituximab

Drug:
• pentostatin

• sargramostim

Locations

Country	Name	City	State
United States	University of Virginia Cancer Center	Charlottesville	Virginia
United States	Holden Comprehensive Cancer Center at University of Iowa	Iowa City	Iowa
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Complete Response Rate	A Complete Response (CR) requires the disappearance of all nodes, a non-palpable liver and spleen, no constitutional symptoms, absolute neutrophil counts >1500/uL, platelets >100000/uL, Hemoglobin >11.0 g/dL, and lymphocytes <4000/uL. In addition, a bone marrow biopsy with evidence of <30% lymphocytes and no nodules.; Here we report the rate of complete response as the number of patients attaining a CR status divided by the total number of evaluable patients. The 95% CI is estimated using the binomial distribution.	Up to 3 cycles of treatment and 2 cycles of observation (up to 5 months total)	No
Secondary	Overall Response Rate (Complete and Partial Response)	A Complete Response (CR) requires the disappearance of all nodes, a non-palpable liver and spleen, no constitutional symptoms, absolute neutrophil counts >1500/uL, platelets >100000/uL, Hemoglobin >11.0 g/dL, and lymphocytes <4000/uL. A bone marrow biopsy with evidence of <30% lymphocytes and no nodules.; Patients who fulfill all criteria for a CR but have a persistent anemia, thrombocytopenia, or neutropenia related to drug toxicity will be classified as CR with incomplete marrow recovery (CRi).; A Partial Response (PR) requires a 50% reduction in nodes and liver/spleen measurements and at least two of the following: absolute neutrophil counts >1500/uL, platelets >100000/uL, Hemoglobin >11.0 g/dL, or a >50% reduction in lymphocytes.; Here we report the rate of overall response as the number of patients attaining a CR, PR, or CRi status divided by the total number of evaluable patients. The 95% CI is estimated using the binomial distribution.	Up to 3 cycles of treatment and 2 cycles of observation (up to 5 months total)	No
Secondary	Overall Survival	Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.	Follow-up status and retreatment information will be collected up to 5 years from registration	No
Secondary	Progression-free Survival	The progression-free survival (PFS) time is defined as the time from registration to progression or death due to any cause. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier.	Follow-up status and retreatment information will be collected up to 5 years from registration	No
Secondary	Time to Retreatment	Time to subsequent therapy is defined to be the time from the registration to the date subsequent therapy is initiated. The distribution of time to subsequent therapy will be estimated using the method of Kaplan-Meier	Follow-up status and retreatment information will be collected up to 5 years from registration	No