Clinical trial NCT00546377: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: 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
Lead sponsor: Memorial Sloan Kettering Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2007-10-18
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Overall Response
timeFrame: 3 years
measure: Maximum Tolerated Dose (MTD) of Mitoxantrone
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Renier Brentjens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Andrew D. Zelenetz, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: