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Fludarabine, Rituximab, and Lenalidomide in Minimally Treated/Untreated Patients With Chronic Lymphocytic Leukemia (CLL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00536341
Recruitment Status : Completed
First Posted : September 27, 2007
Results First Posted : May 4, 2016
Last Update Posted : January 16, 2017
Celgene Corporation
Genentech, Inc.
Information provided by (Responsible Party):
SCRI Development Innovations, LLC

Brief Summary:
This phase I/II trial will combine fludarabine, rituximab, and lenalidomide in untreated or minimally treated (Phase I only) CLL patients, employing fixed doses of fludarabine and rituximab, using a schedule similar to that examined by investigators at MD Anderson (J Clin Oncol 23(18):4079-88, 2005). Given that the optimal dose and schedule is not currently known, this trial will perform a phase I component followed by a phase II examination to further explore this regimen's activity.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: lenalidomide Drug: Rituximab Drug: Fludarabine Phase 1 Phase 2

Detailed Description:
While progress has been made in treating CLL patients over the last decade, a cure remains elusive for many patients treated with standard therapies. The combination of fludarabine, a purine analog, and rituximab, a monoclonal antibody, is an effective and frequently used therapy for CLL. However, this drug combination is associated with increased toxicity. Lenalidomide has been shown to be less toxic and has been used to treat hematologic malignancies including CLL. We propose this Phase I/Phase II study to examine the combination of lenalidomide with a rituximab/fludarabine backbone.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Fludarabine, Rituximab, and Lenalidomide in Minimally Treated and Untreated Patients With Chronic Lymphocytic Leukemia
Study Start Date : January 2008
Actual Primary Completion Date : April 2013
Actual Study Completion Date : November 2016

Arm Intervention/treatment
Experimental: lenalidomide, fludarabine, rituximab

Phase I Non-stratified, dose-escalation: >=3 patients per dose level. Safety and tolerability will be evaluated every 2 weeks during the active treatment. Doses of lenalidomide will be escalated, while the fludarabine and rituximab doses remain fixed.

Phase II The Phase II regimen will be chosen following a review of the Phase I data. Following selection of the Phase II schedule, 40 treatment naive patients will be enrolled and treated with the Phase II regimen every 28 days for up to 6 courses. For those patients achieving a CR after 3 cycles, one additional cycle of treatment will be administered beyond CR confirmation.

Drug: lenalidomide
2.5 mg orally (PO) daily, Days 8-28, Cycle 1; 5.0 mg PO daily, Days 8-28 Cycles 2-6
Other Name: Revlimid

Drug: Rituximab
375 mg/m2 Cycle 1 (split over Day 1 & Day 2); 500 mg/m2 Day 1 of Cycles 2-6
Other Name: Rituxan

Drug: Fludarabine
25 mg/m2 on Days 1, 2, and 3
Other Name: Fludara

Primary Outcome Measures :
  1. Number of Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 63 months ]
    Recorded from first treatment until 30 days after last treatment and assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

  2. Complete Response Rate [ Time Frame: At 12 weeks during treatment and 2 months post-treatment until disease progression, projected 8 months ]
    An improvement in complete response to at least 60% following treatment, assessed using CT scans, clinical/lab examinations, and bone marrow aspirations, as defined by National Cancer Institute Working Group Response Criteria.

Secondary Outcome Measures :
  1. Progression-Free Survival [ Time Frame: Every 3 months during treatment until disease progression and every 6 months thereafter, up to 5 years ]
    Measured from first treatment to disease progression and assessed using Kaplan-Meier methods.

  2. Overall Survival [ Time Frame: Every 3 months until treatment discontinuation, expected average of 6 months and then every 6 months thereafter up to 5 years ]
    Defined as the time from Day 1 of treatment administration to date of death from any cause, estimated using Kaplan-Meier methods.

Information from the National Library of Medicine

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

Inclusion Criteria:

  • Understand and voluntarily sign an informed consent form.
  • Able to adhere to the study visit schedule and other protocol requirements.
  • Age >=18 years at the time of signing the informed consent form.
  • Patient must have histopathologically confirmed B-cell CLL
  • For Phase I only: Untreated or minimally treated patients (patients who have received only prior single agent rituximab) are eligible. For those patients who have had rituximab monotherapy, last dose must be greater than 90 days prior to beginning study treatment.
  • For Phase II only: Untreated B-cell CLL patients only.
  • Rai staging, will be employed. Patients must have Rai stage III/IV disease (irrespective of symptoms) OR symptomatic Rai stage 0-II disease, requiring therapy as defined by NCI 1996 guidelines.
  • Platelets must be > 75,000/mm3 and absolute neutrophil count must be > 1000/mm3 within 14 days of starting protocol treatment unless treating physicians deems the neutropenia is related to marrow involvement and then ANC > 750/mm3 is allowed.
  • Serum creatinine <=2.0 mg/dl obtained within 14 days of starting protocol treatment. Creatinine clearance as determined by the Cockroft-Gault formula, using ideal body weight, must be > 30 mL/minute.
  • AST or ALT must be < 3 x the upper limit of normal within 14 days of starting treatment.
  • ECOG performance of 0, 1 or 2.
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
  • Disease free of prior malignancies for >= 2 years (including carcinoma in situ of the cervix or breast) treated with curative intent and anticipated 5 year disease-free survival is greater than 90%. Any basal cell or squamous cell carcinoma of the skin treated with curative intent is permitted.
  • Able to take aspirin (325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use low molecular weight heparin).

Exclusion Criteria:

  • Major surgery less than 28 days prior to study treatment.
  • Any prior use of lenalidomide or thalidomide.
  • Concurrent use of other anti-cancer therapies.
  • Pregnant or breast feeding females. (Lactating females may be considered if they agree not to breast feed while receiving study treatment and until 12 months following last dose of rituximab).
  • History of pulmonary embolus or deep vein thrombosis.
  • Clinically significant heart dysfunction, defined as New York Heart Association class III or IV, at the time of screening, or history of myocardial infarction or heart failure within 6 months preceding the first study treatment (cardiac ejection fraction must be >= 50% within 8 weeks of beginning study treatment for any patient with a history of clinically significant heart dysfunction).
  • Known positive for HIV, hepatitis B surface Ag, hepatitis B core antibody, or hepatitis C. Mandatory testing is not required, but should be considered in patients deemed high risk or suspicious.
  • Active infection requiring oral or intravenous antibiotics at study entry. After infection resolves patient may be evaluated for enrollment.
  • Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenia purpura.
  • Richter's transformation.
  • CNS involvement.
  • Other severe, acute, or chronic medical or psychiatric condition, laboratory abnormality, or difficulty complying with protocol requirements that may increase the risk associated with study participation or study drug administration or may interfere with interpretation of study results that in the judgment of the investigator would make the patient inappropriate for this study or that would prevent the patient from signing the informed consent form.
  • Use of any other biologic agent or disease-modifying anti-rheumatic drugs (DMARDS).
  • Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component of rituximab.
  • Evidence of laboratory TLS by Cairo-Bishop criteria (subjects may be enrolled upon correction of electrolyte abnormalities).

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 identifier (NCT number): NCT00536341

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United States, Florida
Florida Cancer Specialists
Fort Myers, Florida, United States, 33901
Florida Hospital Cancer Institute
Orlando, Florida, United States, 32804
United States, Maryland
Center for Cancer and Blood Disorders
Bethesda, Maryland, United States, 20817
National Capital Clinical Research Consortium
Bethesda, Maryland, United States, 20817
United States, South Carolina
South Carolina Oncology Associates, PA
Columbia, South Carolina, United States, 29210
United States, Tennessee
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37023
Sponsors and Collaborators
SCRI Development Innovations, LLC
Celgene Corporation
Genentech, Inc.
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Study Chair: Ian W. Flinn, M.D. SCRI Development Innovations, LLC

Additional Information:
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Responsible Party: SCRI Development Innovations, LLC Identifier: NCT00536341    
Other Study ID Numbers: SCRI CLL 02
First Posted: September 27, 2007    Key Record Dates
Results First Posted: May 4, 2016
Last Update Posted: January 16, 2017
Last Verified: November 2016
Keywords provided by SCRI Development Innovations, LLC:
Chronic Lymphocytic Leukemia
minimally treated
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Fludarabine phosphate
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Antiviral Agents
Anti-Infective Agents