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Fludarabine and Cyclophosphamide With or Without Rituximab in Patients With Previously Untreated Chronic B-Cell Lymphocytic Leukemia (CLL-8)

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ClinicalTrials.gov Identifier: NCT00281918
Recruitment Status : Completed
First Posted : January 25, 2006
Results First Posted : March 29, 2011
Last Update Posted : September 19, 2013
Sponsor:
Collaborator:
German CLL Study Group
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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Brief Summary:
This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared to fludarabine and cyclophosphamide in treating patients with B-cell chronic lymphocytic leukemia.

Condition or disease Intervention/treatment Phase
Leukemia Drug: Rituximab Drug: Cyclophosphamide Drug: Fludarabine Phosphate Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 817 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase III Trial of Combined Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) Versus Chemotherapy With Fludarabine and Cyclophosphamide (FC) Alone in Patients With Previously Untreated Chronic Lymphocytic Leukaemia
Study Start Date : July 2003
Actual Primary Completion Date : July 2007
Actual Study Completion Date : October 2011

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Fludarabine+Cyclophosphamide+Rituximab (FCR) Drug: Rituximab
Intravenous repeating dose

Drug: Cyclophosphamide
Intravenous repeating dose

Drug: Fludarabine Phosphate
Intravenous repeating dose
Active Comparator: Fludarabine+Cyclophosphamide (FC) Drug: Cyclophosphamide
Intravenous repeating dose

Drug: Fludarabine Phosphate
Intravenous repeating dose


Outcome Measures
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Primary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Median observation time at time of analysis was approximately 21 months ]
    Progression-free survival (PFS) was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.

  2. Final Analysis: Time to Progression-free Survival Event [ Time Frame: Median observation time was approximately 66.4 months ]
    Progression-free survival was defined as the time between randomization and the date of first documented disease progression, relapse or death by any cause, whichever came first.


Secondary Outcome Measures :
  1. Event-free Survival (EFS) [ Time Frame: Median observation time at time of analysis was approximately 21 months ]
    Event-free survival (EFS) was defined as the time between randomization and the date of disease progression, relapse, start of new CLL treatment or death by any cause.

  2. Overall Survival (OS) [ Time Frame: Median observation time at time of analysis was approximately 21 months ]
    Overall survival (OS) was defined as the time between randomization and the date of death due to any cause. Median OS was not reached.

  3. Disease-free Survival (DFS) of Patients With Confirmed Complete Response (CR). [ Time Frame: Median observation time at time of analysis was approximately 21 months ]
    CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death. Median DFS was not reached.

  4. Final Analysis: Time to Overall Survival Event [ Time Frame: Median observation time was approximately 66.4 months ]
    Overall survival (OS) was defined as the time between randomization and the date of death due to any cause.

  5. Final Analysis: Time to Event-free Survival Event [ Time Frame: Median observation time was approximately 66.4 months ]
    Event-free survival was defined as the time between randomization and the date of disease progression, relapse, start of new Chronic Lymphocytic Leukemia treatment or death by any cause.

  6. Final Analysis: Time to Disease-free Survival (DFS) Event in Participants With Complete Response (CR) [ Time Frame: Median observation time was approximately 66.4 months ]
    CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. DFS was calculated from time of CR to relapse or death

  7. Final Analysis: Duration of Response [ Time Frame: Median observation time was approximately 66.4 months ]
    Duration of response was defined as the time from the first documented Complete Response, Partial Response to disease progression or death by any cause.

  8. Final Analysis: Percentage of Participants With Complete Response (CR) and Partial Response [ Time Frame: Median observation time was approximately 66.4 months ]
    CR is defined by at least 8 weeks of: 1)Absence of lymphadenopathy 2)No hepatomegaly or splenomegaly 3)Absence of B-symptoms 4)Normal blood count 5)Bone marrow aspirate and biopsy 8 weeks after the clinical and laboratory results demonstrated that a CR was achieved. A marrow sample had to be normocellular for age with less than 30% lymphocytes. Lymphoid nodules had to be absent. If marrow was hypocellular,a repeat biopsy was taken 4 weeks later and samples were re-reviewed in conjunction with the prior pathology. Partial response is defined as a decrease in the size of a tumor, or in the extent of cancer in the body, in response to treatment.

  9. Final Analysis: Time to New Treatment for Chronic Lymphocytic Leukemia(CLL) [ Time Frame: Median observation time was approximately 66.4 months ]
    The time from randomization to the start of a new treatment.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

DISEASE CHARACTERISTICS:

  • Diagnosed B-cell chronic lymphocytic leukemia (CLL) defined by the National Cancer Institute (NCI) Working Group criteria

  • Meets 1 of the following criteria:

    • Binet stage C disease

    • Binet stage B disease AND ≥ 1 of the following signs or symptoms*:

      • B symptoms (night sweats, weight loss ≥ 10% within the previous 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection), or constitutional symptoms (fatigue)
      • Continuous progression (doubling of peripheral lymphocyte count within the past 6 months and absolute lymphocyte count > 50 G/I)
      • Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia
      • Massive, progressive or painful splenomegaly or hypersplenism
      • Massive lymph nodes or lymph node clusters (> 10 cm in longest diameter), danger of organ complications through large lymphoma (e.g., vascular compression or tracheal narrowing), or progressive lymphadenopathy
      • Occurrence of symptomatic hyperviscosity problems at leukocyte counts > 200 G/I (symptomatic leukostasis) NOTE: * Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for eligibility
  • No Binet stage A disease
  • No transformation to an aggressive B-cell malignancy (e.g., diffuse large cell lymphoma, Richter's syndrome, or prolymphocytic leukemia)

PATIENT CHARACTERISTICS:

  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Cumulative Illness Rating Scale (CIRS) score > 6
  • Life expectancy > 6 months
  • Bilirubin ≤ 2 times upper limit of normal (ULN)
  • Alkaline phosphatase and transaminases ≤ 2 times ULN
  • Creatinine clearance ≥ 70 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 2 months after study treatment
  • No known hypersensitivity with anaphylactic reaction to humanized monoclonal antibodies or any of the study drugs
  • No cerebral dysfunction that precludes chemotherapy
  • No active bacterial, viral, or fungal infection
  • No clinically significant autoimmune cytopenia or Coombs-positive hemolytic anemia
  • No other active malignancy requiring concurrent treatment except basal cell carcinoma or tumors treated curatively by surgery
  • No medical or psychological condition that would preclude study therapy
  • No concurrent disease that requires prolonged (> 1 month) therapy involving glucocorticoids

PRIOR CONCURRENT THERAPY:

  • No previous treatment of CLL by chemotherapy, radiotherapy, or immunotherapy
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00281918


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
German CLL Study Group
Investigators
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Study Chair: Michael Hallek, MD Medizinische Universitaetsklinik I at the University of Cologne
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00281918    
Other Study ID Numbers: CDR0000454560
GCLLSG-CLL-8
EU-20560
ML17102
First Posted: January 25, 2006    Key Record Dates
Results First Posted: March 29, 2011
Last Update Posted: September 19, 2013
Last Verified: September 2013
Keywords provided by Hoffmann-La Roche:
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
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Hematologic Diseases
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Chronic Disease
Disease Attributes
Pathologic Processes
Cyclophosphamide
 Rituximab
Fludarabine
Fludarabine phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Antimetabolites, Antineoplastic
Antimetabolites