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A Phase I/II Study of Fludarabine, Rituximab, and Lenalidomide in Minimally Treated and Untreated Patients With Chronic Lymphocytic Leukemia

Phase 1/Phase 2
18 Years
Open (Enrolling)
Chronic Lymphocytic Leukemia

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Trial Information

A Phase I/II Study of Fludarabine, Rituximab, and Lenalidomide in Minimally Treated and Untreated Patients With Chronic Lymphocytic Leukemia

Primary (Phase I) Portion:

1. To determine the overall safety and tolerability of this regimen and to define the
optimal phase II dosing schedule.

2. To determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of
lenalidomide when combined with a 3 day course of fludarabine and monthly rituximab.

Primary (Phase II) Portion:

1. To determine the complete response (CR) rate.

2. To determine minimal residual disease by flow cytometry in patients who otherwise meet
CR criteria and correlate with progression free and overall survival.

Secondary (Phase II) Portion:

1. To determine partial remission and overall response rate.

2. To measure progression free survival, overall survival, and response duration.

3. To correlate responses with: RAI stage, degree of white blood cell count elevation, CD
38 expression levels, FISH for 11q deletion, 17p deletion, 13q deletion, and trisomy
12, and beta-2 microglobulin.

4. To determine the effects of therapy on the patient's absolute CD4 count and IgG, IgA,
and IgM levels 2 months post-treatment and 1 year after the completion of therapy
compared to baseline levels.

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 the NCI 1996 guidelines, which are as follows:

- A minimum of any one of the following disease-related symptoms must be present:
Weight loss >= 10% within the previous 6 months, Extreme fatigue (ECOG PS <= 2),
Fevers of greater than 100.5° F for >= 2 weeks without evidence of infection, Night
sweats without evidence of infection, Evidence of progressive marrow failure as
manifested by the development or worsening of anemia and/or thrombocytopenia,
Autoimmune anemia and/or thrombocytopenia (must be controlled prior to study entry),
Massive (i.e., > 6 cm below the left costal margin) or progressive splenomegaly,
Massive nodes or clusters (i.e., > 10 cm in longest diameter) or progressive
lymphadenopathy, Progressive lymphocytosis with an increase of > 50% over a 2 month
period, or an anticipated doubling time of less than 6 months

- 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

- 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.

- Prior chemotherapy for CLL of any type (purine analogues, alkylating agents) or
radiation therapy. Prior monoclonal antibodies except for rituximab, which is
allowed in the Phase I cohort only.

- 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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety and tolerability

Outcome Time Frame:

24 months

Safety Issue:


Principal Investigator

Ian W. Flinn, M.D.

Investigator Role:

Study Chair

Investigator Affiliation:

Sarah Cannon Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

January 2008

Completion Date:

June 2014

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Chronic Lymphocytic Leukemia
  • untreated
  • minimally treated
  • fludarabine
  • rituximab
  • lenalidomide
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



Florida Hospital Cancer Institute Orlando, Florida  32804
Florida Cancer Specialists Fort Myers, Florida  33901
South Carolina Oncology Associates, PA Columbia, South Carolina  29210
Center for Cancer and Blood Disorders Bethesda, Maryland  20817
Tennessee Oncology, PLLC Clarksville, Tennessee  37043
National Capital Clinical Research Consortium Bethesda, Maryland  20817