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

• ClinicalTrials.gov Identifier: NCT00546377
• Recruitment Status: Completed
• First Posted: October 18, 2007
• Results First Posted: May 12, 2016
• Last Update Posted: May 12, 2016
• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Memorial Sloan Kettering Cancer Center

Tracking Information

• First Submitted Date: October 17, 2007
• First Posted Date: October 18, 2007
• Results First Submitted Date: December 17, 2015
• Results First Posted Date: May 12, 2016
• Last Update Posted Date: May 12, 2016
• Study Start Date: July 2005
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 7, 2016)

• Overall Response [ Time Frame: 3 years ]
  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 [ Time Frame: 2 years ]
  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.

Original Primary Outcome Measures (submitted: October 17, 2007)

• Overall response including complete response, clinical complete response, nodular response, and partial response
• Maximum tolerated dose
• Toxicity

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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

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.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Leukemia
• Lymphoma

Intervention

• Biological: filgrastim
• Biological: pegfilgrastim
• Biological: rituximab
• Biological: sargramostim
• Drug: cyclophosphamide
• Drug: mitoxantrone hydrochloride
• Drug: pentostatin
• Genetic: fluorescence in situ hybridization
• Genetic: gene rearrangement analysis
• Genetic: polymerase chain reaction
• Genetic: protein expression analysis
• Other: flow cytometry
• Procedure: biopsy

Study Arms

Experimental: Mitoxantrone

Interventions:

• Biological: filgrastim
• Biological: pegfilgrastim
• Biological: rituximab
• Biological: sargramostim
• Drug: cyclophosphamide
• Drug: mitoxantrone hydrochloride
• Drug: pentostatin
• Genetic: fluorescence in situ hybridization
• Genetic: gene rearrangement analysis
• Genetic: polymerase chain reaction
• Genetic: protein expression analysis
• Other: flow cytometry
• Procedure: biopsy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 7, 2014): 50
• Original Enrollment (submitted: October 17, 2007): 63
• Actual Study Completion Date: May 2014
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00546377
• Other Study ID Numbers: 05-077; MSKCC-05077
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Memorial Sloan Kettering Cancer Center
• Original Responsible Party: Not Provided
• Current Study Sponsor: Memorial Sloan Kettering Cancer Center
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Renier Brentjens, MD, PhD; Memorial Sloan Kettering Cancer Center
• Principal Investigator: Andrew D. Zelenetz, MD, PhD; Memorial Sloan Kettering Cancer Center

• PRS Account: Memorial Sloan Kettering Cancer Center
• Verification Date: April 2016