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

Primary Purpose

Leukemia, Lymphoma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

alemtuzumab

rituximab

pentostatin

sargramostim

About this trial

This is an interventional treatment trial for Leukemia focused on measuring refractory chronic lymphocytic leukemia, recurrent small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Holden Comprehensive Cancer Center at University of Iowa
Mayo Clinic
University of Virginia Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (Pentostatin, Alemtuzumab, Rituximab)

Arm Description

Course 1: Patients receive: 2 mg/m^2 pentostatin IV on days 8 and 22; 3 mg alemtuzumab subcutaneously (SC) on day 3; 10 mg alemtuzumab SC on day 4; 30 mg alemtuzumab SC on days 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; 20 mg/m^2 rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, and 33; 6 mg Sargramostim (GM-CSF) SC on days 10-14. Patients then proceed to course 2. Courses 2 and 3: Patients receive: 2 mg/m^2 pentostatin IV on days 1 and 15; 30 mg alemtuzumab SC on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26; 20 mg/m^2 rituximab IV on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26; 6 mg GM-CSF SC on days 3-7. 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).

Outcomes

Primary Outcome Measures

Complete Response Rate

Secondary Outcome Measures

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.

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.

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.

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

Full Information

NCT ID

NCT00669318

First Posted

April 29, 2008

Last Updated

June 20, 2014

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT00669318

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2014

Overall Recruitment Status

Completed

Study Start Date

July 2008 (undefined)

Primary Completion Date

May 2013 (Actual)

Study Completion Date

May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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.

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukemia, Lymphoma

Keywords

refractory chronic lymphocytic leukemia, recurrent small lymphocytic lymphoma, B-cell chronic lymphocytic leukemia

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

41 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (Pentostatin, Alemtuzumab, Rituximab)

Arm Type

Experimental

Arm Description

Intervention Type

Biological

Intervention Name(s)

alemtuzumab

Intervention Type

Biological

Intervention Name(s)

rituximab

Intervention Type

Drug

Intervention Name(s)

pentostatin

Intervention Type

Drug

Intervention Name(s)

sargramostim

Other Intervention Name(s)

GM-CSF

Primary Outcome Measure Information:

Title

Complete Response Rate

Description

Time Frame

Up to 3 cycles of treatment and 2 cycles of observation (up to 5 months total)

Secondary Outcome Measure Information:

Title

Overall Response Rate (Complete and Partial Response)

Description

Time Frame

Up to 3 cycles of treatment and 2 cycles of observation (up to 5 months total)

Title

Overall Survival

Description

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.

Time Frame

Follow-up status and retreatment information will be collected up to 5 years from registration

Title

Progression-free Survival

Description

Time Frame

Follow-up status and retreatment information will be collected up to 5 years from registration

Title

Time to Retreatment

Description

Time Frame

Follow-up status and retreatment information will be collected up to 5 years from registration

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Clive S. Zent, MD

Organizational Affiliation

Mayo Clinic

Official's Role

Study Chair

Facility Information:

Facility Name

Holden Comprehensive Cancer Center at University of Iowa

City

Iowa City

State/Province

Iowa

ZIP/Postal Code

52242-1002

Country

United States

Facility Name

Mayo Clinic

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Facility Name

University of Virginia Cancer Center

City

Charlottesville

State/Province

Virginia

ZIP/Postal Code

22908

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24723493

Citation

Zent CS, Taylor RP, Lindorfer MA, Beum PV, LaPlant B, Wu W, Call TG, Bowen DA, Conte MJ, Frederick LA, Link BK, Blackwell SE, Veeramani S, Baig NA, Viswanatha DS, Weiner GJ, Witzig TE. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells. Am J Hematol. 2014 Jul;89(7):757-65. doi: 10.1002/ajh.23737. Epub 2014 Apr 26.

Results Reference

derived

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

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