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

Primary Purpose

Leukemia, Lymphoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
filgrastim
pegfilgrastim
rituximab
sargramostim
cyclophosphamide
mitoxantrone hydrochloride
pentostatin
fluorescence in situ hybridization
gene rearrangement analysis
polymerase chain reaction
protein expression analysis
flow cytometry
biopsy
Sponsored by
Memorial Sloan Kettering Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia focused on measuring B-cell chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, recurrent mantle cell lymphoma, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, recurrent marginal zone lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma

Eligibility Criteria

18 Years - 120 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Memorial Sloan-Kettering Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Mitoxantrone

Arm Description

Outcomes

Primary Outcome Measures

Overall Response
Complete response (CR): Absence of lymphadenopathy, hepatomegaly or splenomegaly by physical examination and appropriate radiographic techniques (if abnormal pre-treatment): it is recognized that some patients with lymphoid malignancies who achieve a CR may have mild persistent abnormalities on CT Scan. Such abnormalities if stable on subsequent scanning will not be viewed as persistent disease in patients who otherwise meet the criteria for CR. Response will be assessed on an ongoing basis, but at a minimum of prior to cycle four and following completion of all therapy. Patients who are removed from study early will have response status determined at time of removal from study. The major criteria for determination of response to therapy in patients with CLL include physical examination and examination of the peripheral blood and bone marrow. Radiographic studies are not required but those that were abnormal pre-treatment, will be repeated to document the degree of maximal response.
Maximum Tolerated Dose (MTD) of Mitoxantrone
The MTD is defined as the highest dose studied for which the incidence of DLT is less than 33%. In the phase I portion of the trial, cohorts of 3-6 pts will receive pentostatin, cyclophosphamide and rituximab along with one of three potential dose levels of mitoxantrone. The following dose escalation scheme will be followed: If none of the initial three pts in a cohort experience a dose-limiting toxicity (grade 4 infection, or grade ≥ 3 non-hematologic toxicity that persists for 7 days or more) then a new cohort of three pts will be treated at the next higher dose level. If one of the three pts in a cohort experiences DLT, then up to three additional pts will be treated at the same dose level. If two or more pts in a cohort experience DLT, then the maximum tolerated dose (MTD) will have been exceeded, and no further dose escalation will occur. The previous dose level will be considered as the MTD.

Secondary Outcome Measures

Full Information

First Posted
October 17, 2007
Last Updated
April 7, 2016
Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00546377
Brief Title
Pentostatin, Cyclophosphamide, Rituximab, and Mitoxantrone in Treating Patients With Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Cancer
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
Study Type
Interventional

2. Study Status

Record Verification Date
April 2016
Overall Recruitment Status
Completed
Study Start Date
July 2005 (undefined)
Primary Completion Date
May 2014 (Actual)
Study Completion Date
May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Memorial Sloan Kettering Cancer Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Lymphoma
Keywords
B-cell chronic lymphocytic leukemia, Waldenstrom macroglobulinemia, recurrent mantle cell lymphoma, recurrent small lymphocytic lymphoma, refractory chronic lymphocytic leukemia, recurrent marginal zone lymphoma, recurrent grade 1 follicular lymphoma, recurrent grade 2 follicular lymphoma, recurrent grade 3 follicular lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mitoxantrone
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
filgrastim
Intervention Type
Biological
Intervention Name(s)
pegfilgrastim
Intervention Type
Biological
Intervention Name(s)
rituximab
Intervention Type
Biological
Intervention Name(s)
sargramostim
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Intervention Type
Drug
Intervention Name(s)
mitoxantrone hydrochloride
Intervention Type
Drug
Intervention Name(s)
pentostatin
Intervention Type
Genetic
Intervention Name(s)
fluorescence in situ hybridization
Intervention Type
Genetic
Intervention Name(s)
gene rearrangement analysis
Intervention Type
Genetic
Intervention Name(s)
polymerase chain reaction
Intervention Type
Genetic
Intervention Name(s)
protein expression analysis
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Type
Procedure
Intervention Name(s)
biopsy
Primary Outcome Measure Information:
Title
Overall Response
Description
Complete response (CR): Absence of lymphadenopathy, hepatomegaly or splenomegaly by physical examination and appropriate radiographic techniques (if abnormal pre-treatment): it is recognized that some patients with lymphoid malignancies who achieve a CR may have mild persistent abnormalities on CT Scan. Such abnormalities if stable on subsequent scanning will not be viewed as persistent disease in patients who otherwise meet the criteria for CR. Response will be assessed on an ongoing basis, but at a minimum of prior to cycle four and following completion of all therapy. Patients who are removed from study early will have response status determined at time of removal from study. The major criteria for determination of response to therapy in patients with CLL include physical examination and examination of the peripheral blood and bone marrow. Radiographic studies are not required but those that were abnormal pre-treatment, will be repeated to document the degree of maximal response.
Time Frame
3 years
Title
Maximum Tolerated Dose (MTD) of Mitoxantrone
Description
The MTD is defined as the highest dose studied for which the incidence of DLT is less than 33%. In the phase I portion of the trial, cohorts of 3-6 pts will receive pentostatin, cyclophosphamide and rituximab along with one of three potential dose levels of mitoxantrone. The following dose escalation scheme will be followed: If none of the initial three pts in a cohort experience a dose-limiting toxicity (grade 4 infection, or grade ≥ 3 non-hematologic toxicity that persists for 7 days or more) then a new cohort of three pts will be treated at the next higher dose level. If one of the three pts in a cohort experiences DLT, then up to three additional pts will be treated at the same dose level. If two or more pts in a cohort experience DLT, then the maximum tolerated dose (MTD) will have been exceeded, and no further dose escalation will occur. The previous dose level will be considered as the MTD.
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Renier Brentjens, MD, PhD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Andrew D. Zelenetz, MD, PhD
Organizational Affiliation
Memorial Sloan Kettering Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Memorial Sloan-Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Learn more about this trial

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

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