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Trial record 19 of 202 for:    "Leukemia" | "Sargramostim"

Rituximab, Alemtuzumab, and GM-CSF As First-Line Therapy in Treating Patients With Early-Stage Chronic Lymphocytic Leukemia

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ClinicalTrials.gov Identifier: NCT00562328
Recruitment Status : Completed
First Posted : November 22, 2007
Results First Posted : May 8, 2012
Last Update Posted : June 16, 2017
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Tracking Information
First Submitted Date  ICMJE November 21, 2007
First Posted Date  ICMJE November 22, 2007
Results First Submitted Date  ICMJE April 11, 2012
Results First Posted Date  ICMJE May 8, 2012
Last Update Posted Date June 16, 2017
Actual Study Start Date  ICMJE January 2008
Actual Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2012)
Proportion of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months [ Time Frame: 6 months ]
Response, as defined by the National Cancer Institute Working Group (NCIWG), requires 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
  • 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, >100,000/μL platelets, >11.0 g/dL hemoglobin or 50% improvement for these parameters without transfusions
Original Primary Outcome Measures  ICMJE
 (submitted: November 21, 2007)
  • Proportion of Confirmed Responses (Complete or Partial Response Noted as the Objective Status for a Duration of at Least 2 Months) at 6 Months
  • Time to disease progression
Change History Complete list of historical versions of study NCT00562328 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2012)
  • Time to Disease Progression [ Time Frame: Time from registration to progression (up to 5 years) ]
    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 OS with 95% confidence interval (CI) was estimated using the Kaplan Meier method.
  • Time to Response [ Time Frame: time from registration to first documentation of response (up to 5 years) ]
    Time to response (TTR) is defined as the time from registration to first documentation of response (CR or PR). In participants who do not achieve a response, time will be censored at the participants last evaluation (for disease) date. The median TTR with 95% CI was estimated using the Kaplan Meier method.
  • Duration of Response [ Time Frame: time from start of response to progression (up to 5 years) ]
    Duration of response (DOR) is defined as the time from documentation of response (CR or PR) to disease progression. The median DOR with 95% CI was estimated using the Kaplan Meier method.
  • Overall Survival [ Time Frame: Time from registration to death (up to 5 years) ]
    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 Subsequent Therapy [ Time Frame: time from end of protocol treatment to subsequent treatment (up to 5 years) ]
    Time to subsequent treatment (TTS) was defined as the time from end of active (protocol) treatment to the start of subsequent treatment. The median TTS with 95% CI was estimated using the Kaplan Meier method.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2007)
  • Complete response rate
  • Time to Response
  • Duration of Response
  • Survival time
  • Time to Subsequent Therapy
  • Correlation of in vitro response of chronic lymphocytic cells with clinical outcome
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Rituximab, Alemtuzumab, and GM-CSF As First-Line Therapy in Treating Patients With Early-Stage Chronic Lymphocytic Leukemia
Official Title  ICMJE Antibody Therapy With Alemtuzumab, Rituximab and GM-CSF for Initial Treatment of High Risk Chronic Lymphocytic Leukemia
Brief Summary

RATIONALE: Monoclonal antibodies, such as rituximab and alemtuzumab, 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. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Giving monoclonal antibody therapy together with GM-CSF may be an effective treatment for early-stage chronic lymphocytic leukemia.

PURPOSE: This phase II trial is studying the side effects of giving rituximab and alemtuzumab together with GM-CSF and to see how well it works in treating patients with early-stage chronic lymphocytic leukemia.

Detailed Description

OBJECTIVES:

Primary

  • To assess the rate of complete and overall response in patients with high-risk, early-stage, chronic lymphocytic leukemia (CLL) treated with alemtuzumab, rituximab, and sargramostim (GM-CSF).
  • To monitor and assess toxicity of this regimen in these patients through clinical evaluation and serial monitoring of cytomegalovirus antigenemia by polymerase chain reaction (PCR).

Secondary

  • To determine the overall and progression-free survival, time to response, time to next treatment, and duration of response in patients treated with this regimen.
  • To assess the correlation between individual prognostic markers (i.e., 17p-, 11q-, unmutated VH gene, use of VH3-21, ZAP70+, CD38+) and clinical outcome.

Correlative Studies

  • To assess response in these patients using an expanded definition of response, including minimal residual disease (MRD) by sensitive flow cytometry in patients in complete clinical remission.
  • To assess MRD status of responding patients using sensitive flow cytometry and molecular assays (i.e., spectral karyotype analysis of CLL cells) before treatment and at relapse to identify subpopulations that could contribute to disease resistance and relapse.
  • To detail the in vivo effect of this regimen on critical aspects of the immune system in CLL.
  • To determine if GM-CSF, β-glucan, and CpG7909 can increase antibody dependent cellular cytotoxicity to improve efficacy against CLL cells and clinical response to treatment.

OUTLINE: Patients receive rituximab IV over 30 minutes on day 3 of weeks 2-5, alemtuzumab subcutaneously (SC) on days 3, 4, and 5 in week 1 and on days 1, 3, and 5 in weeks 2-5, and sargramostim SC on days 1, 3, and 5 in weeks 1-6. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection for measurement of serum cytomegalovirus DNA copy number by polymerase chain reaction at baseline, weekly during treatment, and monthly for the 6 months after completion of treatment. Patients also undergo bone marrow biopsy and aspirate at two months and then again at 12 months (if in complete remission). Blood samples are collected periodically during study for evaluation of prognostic biomarkers (i.e., 11q-, 17p-, unmutated IgVH gene, VH3-21 gene segment use, and CD38 and ZAP-70 expression) by fluorescent in situ hybridization (FISH) and for immunophenotyping by flow cytometry. Blood samples are collected from patients at the Mayo Clinic Rochester site at baseline and periodically during study for immunological and other correlative studies, including minimal residual disease (in responding patients only).

After completion of study therapy, patients are followed periodically for up to 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Leukemia
Intervention  ICMJE
  • Biological: Alemtuzumab

    Week 1 (dose escalation):

    Day 3: 3mg subcutaneously; Day 4: 10mg subcutaneously; Day 5 30mg subcutaneously

    Weeks 2-5:

    30mg subcutaneously three times a week.

  • Biological: Rituximab

    Weeks 2-5:

    375 mg/m^2 by IV once weekly

  • Biological: Sargramostim

    Week 1-6:

    250 mcg subcutaneously three time as week

    Other Name: GM-CSF
Study Arms  ICMJE Experimental: Alemtuzumab + Rituximab + GM-CSF
Alemtuzumab + Rituximab + GM-CSF
Interventions:
  • Biological: Alemtuzumab
  • Biological: Rituximab
  • Biological: Sargramostim
Publications * Zent CS, Wu W, Bowen DA, Hanson CA, Pettinger AM, Shanafelt TD, Kay NE, Leis JF, Call TG. Addition of granulocyte macrophage colony stimulating factor does not improve response to early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Leuk Lymphoma. 2013 Mar;54(3):476-82. doi: 10.3109/10428194.2012.717276. Epub 2012 Aug 22.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 14, 2008)
33
Original Enrollment  ICMJE
 (submitted: November 21, 2007)
30
Actual Study Completion Date  ICMJE December 18, 2014
Actual Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

DISEASE CHARACTERISTICS:

  • Diagnosis of chronic lymphocytic leukemia (CLL) meeting the following criteria:

    • Minimum threshold peripheral blood lymphocyte count 5 x 10^9/L
    • Monoclonality (light chain exclusion) of B lymphocytes detected by immunophenotyping (CD19-positive), demonstrating ≥ 3 of the following characteristics:

      • CD5-positive
      • CD23-positive
      • Dim surface light chain expression
      • Dim surface CD20 expression
    • Negative for IGH/CCND1 translocation AND/OR immunostaining is negative for cyclin D1 expression by fluorescent in-situ hybridization (FISH) analysis
    • Rai stage 0, I, or II disease that does not meet standard NCI-Working Group criteria for treatment of CLL
  • Poor prognosis as defined by ≥ 1 of the following factors:

    • Unmutated IgVH mutation status AND CD38 expression (i.e., ≥ 30% cells positive on flow cytometry)
    • Unmutated IgVH mutation status AND ZAP-70 expression (i.e., ≥ 20% cells positive on flow cytometry)
    • VH3-21 gene segment use irrespective of mutation status AND CD38 expression (≥ 30% cells positive on flow cytometry)
    • VH3-21 gene segment use irrespective of mutation status AND ZAP-70 expression (≥ 20% cells positive on flow cytometry)
    • 11q-negative*
    • 17p-negative* NOTE: *Determination of IgVH mutation status is not required in patients whose eligibility is based on 17p13- or 11q22- deletions

PATIENT CHARACTERISTICS:

  • ECOG performance status 0- 2
  • Creatinine ≤ 1.5 times upper limit of normal (ULN)
  • Total bilirubin ≤ 3.0 times ULN OR direct bilirubin ≤ 1.5 ULN
  • AST ≤ 3.0 times ULN (unless due to hemolysis or CLL)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must practice effective contraception
  • Willing to provide mandatory blood samples (for patients at the Mayo Clinic in Rochester only) for research studies as required by the protocol
  • No comorbid conditions, including any of the following:

    • New York Heart Association Class III or IV heart disease
    • Myocardial infarction within the past month
    • Uncontrolled infection
    • HIV infection or AIDS
    • Serological evidence of active hepatitis B infection (i.e., serum antigen or e-antigen positivity) or positive hepatitis C serology
  • No other active primary malignancy requiring treatment or limiting survival to ≤ 2 years
  • No active autoimmune hemolytic anemia, immune thrombocytopenia, or pure red blood cell aplasia

PRIOR CONCURRENT THERAPY:

  • More than 4 weeks since prior major surgery
  • No prior chemotherapy or monoclonal antibody treatment for CLL
  • No concurrent corticosteroids
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 120 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00562328
Other Study ID Numbers  ICMJE CDR0000574754
P30CA015083 ( U.S. NIH Grant/Contract )
MC0785 ( Other Identifier: Mayo Clinic Cancer Center )
U4449s ( Other Identifier: Genentech )
001.0888 ( Other Identifier: Bayer )
07-002087 ( Other Identifier: Mayo Clinic IRB )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Study Chair: Clive S. Zent, MD Mayo Clinic
PRS Account Mayo Clinic
Verification Date May 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP