Rituximab, Pentostatin, Cyclophosphamide, and Lenalidomide in Treating Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00602836
First received: January 12, 2008
Last updated: May 12, 2014
Last verified: May 2014
  Purpose

RATIONALE: 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. Drugs used in chemotherapy, such as pentostatin and cyclophosphamide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Lenalidomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving rituximab together with combination chemotherapy and lenalidomide may kill more cancer cells.

PURPOSE: This phase II trial is studying how well giving rituximab together with pentostatin, cyclophosphamide, and lenalidomide works in treating patients with previously untreated B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma.


Condition Intervention Phase
Leukemia
Lymphoma
Biological: Rituximab
Drug: Cyclophosphamide
Drug: Lenalidomide
Drug: Pentostatin
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial of Pentostatin, Cyclophosphamide, and Rituximab Followed by Consolidation With Lenalidomide for Previously Untreated B-Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL)

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Number of Participants With Complete Response (CR) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    A complete response, as defined by the National Cancer Institute Working Group (NCIWG), requires all of the following for a period of at least 2 months:

    - CR: no lymphadenopathy, hepatomegaly, splenomegaly or constitutional symptoms; normal complete blood count; confirmed by bone marrow (BM) aspirate & biopsy



Secondary Outcome Measures:
  • Number of Participants Who Convert From a Nodular Partial Response (nPR), Partial Response (PR), or Stable Disease (SD) After Pentostatin, Cyclophosphamide, and Rituximab (PCR) to a Complete Response (CR) After 6 Courses of Consolidation With Lenalidomide [ Time Frame: 12 months ] [ Designated as safety issue: No ]

    According to the NCIWG criteria, response is defined as follows:

    nPR: Meets all criteria for CR, as described above, except the presence of residual clonal nodules in the bone marrow PR: 50% decrease in peripheral blood lymphocytes, lymphadenopathy, liver/spleen size, presence/absence of constitutional symptoms; plus ≥1 of the following: ≥1500/μL polymorphonuclear leukocytes, >100000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions SD: participant who does not meet any of the criteria described above


  • Number of Participants Who Convert From a CR With Minimal Residual Disease (MRD) Positive Status After PCR to a CR With MRD-negative Status After 6 Courses of Consolidation With Lenalidomide [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    MRD refers to small number of leukemic cells that remain in the participant during treatment or after treatment when the participant has achieved CR. For all participants who achieved CR, the follow-up bone marrow sample was tested for malignant B cells to determine if there was any MRD.

  • Number of Participants Who Convert From a CR With MRD or nPR, PR, or Stable Disease With Residual Disease After PCR to a CR With MRD-negative Status After 6 Courses of Consolidation With Lenalidomide [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  • Number of Participants With a Response (CR, nPR, PR) [ Time Frame: During treatment (up to 5 years) ] [ Designated as safety issue: No ]
    Response criteria described in above outcomes

  • Overall Survival (OS) [ Time Frame: time from registration to death (up to 5 years) ] [ Designated as safety issue: No ]
    Overall Survival (OS) was defined as the time from registration to death of any cause. Participants were followed for a maximum of 5 years from registration. The median OS with 95% CI was estimated using the Kaplan Meier method.

  • Time to Disease Progression (TTP) [ Time Frame: time from registration to progression (up to 5 years) ] [ Designated as safety issue: No ]
    Time to disease progression (TTP) was defined as the time from registration to the earliest date documentation of disease progression. Participants were followed for a maximum of 5 years from registration. The median TTP with 95% CI was estimated using the Kaplan Meier method.

  • Number of Participants With IgVH Testing at Baseline Who Also Had a Clinical Response (CR, nPR, or PR). [ Time Frame: During treatment (up to 5 years) ] [ Designated as safety issue: No ]
    Response categories described in above outcome measures. IgVH mutation status describe in baseline characteristics section.

  • Number of Participants With CD38 Testing at Baseline Who Also Had a Clinical Response (CR, nPR, or PR). [ Time Frame: During treatment (up to 5 years) ] [ Designated as safety issue: No ]
    Response categories described in above outcome measures. CD38 status described in baseline characteristics section.

  • Number of Participants With ZAP-70 Testing at Baseline Who Also Had a Clinical Response (CR, nPR, or PR). [ Time Frame: During treatment (up to 5 years) ] [ Designated as safety issue: No ]
    Response categories described in above outcome measures. ZAP-70 status describe in baseline characteristics section.

  • Number of Participants With FISH Testing at Baseline Who Also Had a Clinical Response (CR, nPR, or PR). [ Time Frame: During treatment (up to 5 years) ] [ Designated as safety issue: No ]
    Response categories described in above outcome measures. FISH status describe in baseline characteristics section.


Enrollment: 45
Study Start Date: February 2008
Estimated Study Completion Date: December 2014
Primary Completion Date: December 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: PCR-Lenalidomide
Pentostatin, Cyclophosphamide, Rituximab + Lenalidomide
Biological: Rituximab
Cycle 1: 100 mg by IV on day 1, 375 mg/m^2 by IV on day 2 Cycle 2-6: 375 mg/m^2 by IV on day 1 (every 21 days)
Drug: Cyclophosphamide
600 mg/m^2 by IV on day 1 of cycles 1-6 (every 21 days)
Drug: Lenalidomide
Cycle 7: 5 mg orally daily on days 1-28 Cycle 8: 10 mg orally daily on days 1-28 as tolerability permits Cycle 9 and beyond: 10 mg orally daily on days 1-28
Drug: Pentostatin
2 mg/m^2 by IV on day 1 of cycles 1-6 (every 21 days)

Detailed Description:

OBJECTIVES:

Primary

  • To assess the rate of complete and overall response using pentostatin, cyclophosphamide, and rituximab (PCR) followed by consolidation with lenalidomide in patients with previously untreated B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma.

Secondary

  • To assess the proportion of patients who convert from a nodular partial response (nPR), PR, or stable disease after completing PCR to a complete response (CR) after 6 cycles of consolidation with lenalidomide.
  • To assess the proportion of patients who convert from a CR with detectable minimal residual disease (MRD) after PCR to a CR with MRD negative state after 6 courses of consolidation with lenalidomide.
  • To assess the proportion of patients who convert from a CR with detectable MRD, nPR, PR, or stable disease with residual disease after PCR to a CR with MRD negative state after 6 cycles of consolidation with lenalidomide.
  • To monitor and assess toxicity of this regimen.
  • To determine if molecular prognostic parameters (e.g., ZAP-70, CD38, cytogenetic abnormalities identified by FISH, IgVH mutation status) relate to response to PCR-lenalidomide therapy.
  • To use evaluation of MRD to determine the duration of lenalidomide therapy.
  • To determine the progression-free survival in CLL patients using this treatment regimen.

OUTLINE: This is a multicenter study.

  • Induction therapy: Patients receive rituximab IV over 4 hours on days 1 and 2 of course 1, and over 1 hour on day 1 of each subsequent course. Patients also receive pentostatin IV over 30 minutes and cyclophosphamide IV over 30 minutes on day 1, and pegfilgrastim subcutaneously on day 2. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
  • Consolidation therapy: Beginning 2 months after completion of induction therapy, patients receive oral lenalidomide once daily on days 1-28. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
  • Continuation therapy: Patients with residual disease continue to receive lenalidomide as in consolidation therapy until they achieve a minimal residual disease-negative status or complete remission. Patients who achieve complete response with no detectable disease discontinue therapy and enter the observation phase.

Blood samples are collected periodically during treatment for translational and pharmacologic studies. Samples are analyzed for immunoglobulin heavy chain gene mutational status, ZAP-70 status, and levels of VEGF, bFGF, thrombospondin, and TGF-beta by ELISA; and for the effects of therapy on immune function. Samples are also stored for future research. Bone marrow aspirate samples are analyzed for minimal residual disease by flow cytometry.

After completion of study treatment, patients are followed every 90 days for 3 years.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), meeting the following criteria:

    • Biopsy-proven SLL according to WHO criteria
    • CLL diagnosis* according to NCI working group criteria as evidenced by all of the following:

      • Peripheral blood lymphocyte count of > 5,000/mm³
      • Small to moderate peripheral blood lymphocyte with < 55% prolymphocytes
      • Immunophenotyping consistent with CLL defined as:

        • B-cell markers with CD5 antigen in the absence of other pan-T-cell markers (e.g., CD3, CD2)
        • CD19, CD20, or CD23
        • Dim surface immunoglobulin expression
        • Exclusively kappa or lambda light chains
      • Diagnosis of mantle cell lymphoma must be excluded by negative FISH analysis for t(11;14)(IgH/CCND1) on peripheral blood or tissue biopsy or negative immunohistochemical stains for cyclin D1 on involved tissue biopsy NOTE: *Splenomegaly, hepatomegaly, or lymphadenopathy are not required for the diagnosis of CLL
  • Previously untreated disease and meets ≥ 1 of the following criteria*:

    • At least 1 or more of the following disease-related symptoms:

      • Weight loss > 10% within the previous 6 months
      • Extreme fatigue attributed to CLL
      • Fevers > 100.5º F for 2 weeks without evidence of infection
      • Night sweats without evidence of infection
    • Evidence of progressive marrow failure as manifested by the development of or worsening anemia (i.e., hemoglobin ≤ 11 g/dL) and/or thrombocytopenia (i.e., platelet count ≤ 100,000/mm³) not due to autoimmune disease
    • Symptomatic or progressive lymphadenopathy, splenomegaly, or hepatomegaly
    • Progressive lymphocytosis due to CLL with an increase of > 50% over a 2-month period or an anticipated doubling time < 6 months NOTE: *Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease are not sufficient for protocol therapy

PATIENT CHARACTERISTICS:

  • ECOG performance status 0-3
  • Serum creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Total bilirubin ≤ 3.0 times ULN (unless due to Gilbert disease)

    • Direct bilirubin < 1.5 mg/dL for Gilbert disease to be diagnosed if total bilirubin > 3.0 times ULN
  • AST and ALT ≤ 3.0 times ULN (unless due to hemolysis or CLL)
  • Willing to provide blood samples
  • Able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Female patients must use effective double-method contraception beginning 1 month prior to, during, and for 4 weeks after completion of study treatment
  • Male patients must use effective contraception during and for 4 weeks after completion of study treatment
  • No comorbid conditions, including any of the following:

    • New York Heart Association class III or IV heart disease
    • Recent myocardial infarction (< 1 month)
    • Uncontrolled infection
    • Infection with HIV/AIDS
  • No other active primary malignancy requiring treatment or that limits survival to ≤ 2 years
  • No history of deep venous thrombosis or pulmonary embolism ≤ 12 months prior to study registration
  • No active hemolytic anemia requiring immunosuppressive or other pharmacologic therapy

PRIOR CONCURRENT THERAPY:

  • See Disease Characteristics
  • No prior chemotherapy or monoclonal antibody-based therapy for treatment of CLL
  • Nutraceutical treatments with no established benefit in CLL (e.g., epigallocatechin gallate or other herbal treatments) are not considered prior therapy
  • More than 4 weeks since prior radiotherapy
  • At least 4 weeks since prior major surgery
  • No concurrent corticosteroids

    • Concurrent low doses of steroids (e.g., < 10 mg of prednisone or equivalent dose of other steroid) used for treatment of non-hematologic medical conditions allowed
    • Prior use of corticosteroids allowed
  • No prior thalidomide or lenalidomide
  • No concurrent therapeutic doses of coumadin-derivative anticoagulants (e.g., warfarin)

    • Doses of ≤ 2 mg daily allowed for thrombosis prophylaxis
    • Prophylactic doses of low molecular weight heparin allowed
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00602836

Locations
United States, Arizona
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States, 85259-5499
United States, Florida
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States, 32224
United States, Minnesota
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
Investigators
Study Chair: Tait D. Shanafelt, MD Mayo Clinic
Principal Investigator: Han Win Tun, MD Mayo Clinic
Principal Investigator: Jose F. Leis, MD, PhD Mayo Clinic
  More Information

Additional Information:
No publications provided

Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT00602836     History of Changes
Other Study ID Numbers: CDR0000582676, P30CA015083, MC0784, 07-002156, RV-CLL-PI-146, NCI-2009-01281
Study First Received: January 12, 2008
Results First Received: March 15, 2012
Last Updated: May 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Mayo Clinic:
B-cell chronic lymphocytic leukemia
stage I chronic lymphocytic leukemia
stage II chronic lymphocytic leukemia
stage III chronic lymphocytic leukemia
stage IV chronic lymphocytic leukemia
contiguous stage II small lymphocytic lymphoma
noncontiguous stage II small lymphocytic lymphoma
stage I small lymphocytic lymphoma
stage III small lymphocytic lymphoma
stage IV small lymphocytic lymphoma

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, B-Cell
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Thalidomide
Rituximab
Lenalidomide
Pentostatin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Adenosine Deaminase Inhibitors
Enzyme Inhibitors
Leprostatic Agents

ClinicalTrials.gov processed this record on July 23, 2014