Pentostatin, Cyclophosphamide, Rituximab, and Mitoxantrone in Treating Patients With Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Cancer

Lymphoma Clinical Trial

Official title:

A Phase I-II Study of Pentostatin, Cyclophosphamide, Rituximab, and Mitoxantrone in Previously Treated Patients With Chronic Lymphocytic Leukemia and Other Low Grade B-Cell Neoplasms

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00546377
• Other study ID #: 05-077
• Secondary ID: MSKCC-05077
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: October 17, 2007
• Last updated: May 7, 2014
• Start date: July 2005
• Est. completion date: May 2014

Study information

• Verified date: May 2014
• Source: Memorial Sloan Kettering Cancer Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

RATIONALE: Pentostatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cyclophosphamide and mitoxantrone, 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 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 combination chemotherapy and rituximab may kill more cancer cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of mitoxantrone when given together with pentostatin, cyclophosphamide, and rituximab and to see how well it works in treating patients with chronic lymphocytic leukemia or other low-grade B-cell cancer.

Description:

OBJECTIVES:

• To determine the dose of mitoxantrone hydrochloride that can be safely administered with pentostatin, cyclophosphamide, and rituximab in patients with previously treated chronic lymphocytic leukemia or other low-grade B-cell malignancies.

• To characterize the toxicity of this regimen in these patients.

• To determine the response rate in patients treated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of mitoxantrone hydrochloride followed by a phase II study.

• Phase I: Patients receive pentostatin IV, cyclophosphamide IV, and mitoxantrone hydrochloride IV on day 1. Patients also receive rituximab IV on day 1 beginning in course 2. Treatment repeats every 4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

• Phase II: Patients receive pentostatin, cyclophosphamide, rituximab, and mitoxantrone hydrochloride (at the maximum tolerated dose determined in phase I) as in phase I.

All patients receive either pegfilgrastim subcutaneously (SC) on days 1-4 following each course or filgrastim or sargramostim SC beginning 2 days after each course until blood counts recover.

Patients undergo blood collection and bone marrow biopsy periodically for assessment of therapy response by biomarker and laboratory studies. Samples are analyzed for molecular genetics for IgH arrangement by PCR and for response by immunoelectrophoresis. Some samples are analyzed for response by flow cytometry or fluorescence in situ hybridization (FISH).

After completion of study treatment, patients are followed every 3 months for 1 year.

PROJECTED ACCRUAL: A total of 63 patients (18 patients for phase I and 45 patients for phase II) will be accrued for this study.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: May 2014
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

DISEASE CHARACTERISTICS:

• Diagnosis of 1 of the following diseases confirmed by a Memorial Sloan-Kettering Cancer Center (MSKCC) pathologist:

• Chronic lymphocytic leukemia meeting the following risk criteria as defined by the three-stage Rai system:

• Intermediate-risk disease meeting the following criteria for active disease as defined by the NCI Working Group:

• Weight loss

• Fatigue

• Fevers

• Evidence of progressive marrow failure

• Splenomegaly

• Progressive lymphadenopathy

• Progressive lymphocytosis with a rapid doubling time, defined as doubling time less than 6 months and absolute lymphocyte count > 30,000/µL

• High-risk disease

• Other low grade B-cell neoplasms, including any of the following:

• Small lymphocytic lymphoma

• Follicular lymphoma

• Waldenstrom macroglobulinemia

• Marginal zone lymphomas

• Mantle cell lymphomas

• Transformed lymphoma

• Previously treated disease

• Must have received prior cytotoxic therapy

• Malignant lymphocytes must demonstrate B-cells via immunophenotypic or immunohistochemical analysis NOTE: A new classification scheme for adult non-Hodgkin's lymphoma has been adopted by PDQ. The terminology of "indolent" or "aggressive" lymphoma will replace the former terminology of "low", "intermediate", or "high" grade lymphoma. However, this protocol uses the former terminology.

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%

• Life expectancy > 8 weeks

• Total bilirubin = 2.0 mg/dL (patients with Gilbert disease or autoimmune hemolytic anemia should have an evaluation for other causes of hyperbilirubinemia, but if none are found, may be enrolled regardless of serum bilirubin)

• Total creatinine = 2.0 mg/dL OR creatinine clearance > 50 mL/min

• Not pregnant or nursing

• Fertile patients must use effective contraception

• Normal cardiac ejection fraction = 50% (increased ejection fraction [at least 5% over rest]) required for study eligibility

• Borderline (40-50%) ejection fraction must undergo a stress echocardiogram or MUGA scan

• Patients with autoimmune hemolytic anemia or autoimmune thrombocytopenia are eligible for treatment

• Must have undergone consultation with the primary investigator or his/her designee prior to study entry

• No significant active infections

• No ongoing hepatitis B infection, specifically hepatitis B antigen or surface antigen positivity

• Hepatitis B antibody-positive patients are eligible

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• The following concurrent medications are allowed:

• Intravenous immunoglobulin (IVIG)

• Erythropoietin, darbepoetin, filgrastim, or sargramostim

• Cyclosporine (only for patients with cellular immune cytopenias [i.e., pure red cell aplasia]), with required consultation of the principle investigator or designee

• Concurrent prednisone allowed provided it is used as brief courses (= 7 days) for inflammatory conditions unrelated to CLL

• No concurrent chemotherapy or radiotherapy

Study Design

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:
• filgrastim

• pegfilgrastim

• rituximab

• sargramostim

Drug:
• cyclophosphamide

• mitoxantrone hydrochloride

• pentostatin

Genetic:
• fluorescence in situ hybridization

• gene rearrangement analysis

• polymerase chain reaction

• protein expression analysis

Other:
• flow cytometry

Procedure:
• biopsy

Locations

Country	Name	City	State
United States	Memorial Sloan-Kettering Cancer Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Memorial Sloan Kettering Cancer Center	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall response including complete response, clinical complete response, nodular response, and partial response		Prior to cycle 4 and after completion of all therapy	No
Primary	Maximum tolerated dose		After each cycle	Yes
Primary	Toxicity		After each cycle	Yes