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A Two-Arm, Multi-center Trial of Revlimid® and Rituximab, for First-Line Treatment in Patients With B-cell Chronic Lymphocytic Leukemia (CLL)

Phase 2
Open (Enrolling)
Chronic Lymphocytic Leukemia, CLL, Untreated, Front-line, First-Line, Initial Therapy

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Trial Information

A Two-Arm, Multi-center Trial of Revlimid® and Rituximab, for First-Line Treatment in Patients With B-cell Chronic Lymphocytic Leukemia (CLL)

The CLL Research Consortium (CRC) is conducting a two-arm, multi-center phase II trial of
Revlimid® and rituximab for the first-line treatment of patients with CLL.

Revlimid® (lenalidomide) a derivative of thalidomide with immune-modulating properties.
Revlimid® is FDA approved for treatment of relapsed multiple myeloma and 5q-
myelodysplastic syndrome. Revlimid® has promising clinical activity in relapsed CLL in two
early clinical trials. However, the mechanism(s) whereby Revlimid® is active in CLL is
unknown. Rituximab (Rituxan®) is a protein that binds to CD20 expressed on normal and
leukemia B cells. Rituximab is FDA approved for the treatment of lymphoma and is used
commonly for the treatment of CLL. The purposes of this study are to evaluate the safety
and activity of the combination of Revlimid® and rituximab in CLL, elucidate the mechanism
of Revlimid® in CLL, and to assess whether prognostic factors might predict those patients
likely to benefit from this therapy in the future.

As older patients are commonly under-represented in CLL clinical trials and are less
tolerable of frontline therapy that utilizes combinations of fludarabine and
cyclophosphamide the trial has two arms; one to specifically assess for the tolerability of
the regimen in older subjects.

The primary objective of this study is to determine the response rate of the combination of
Revlimid® and Rituximab in previously untreated CLL patients in two arms- those aged 65
years and above and those younger than 65. Secondary objectives will evaluate the safety of
the combination of Revlimid® and Rituximab, response duration, improvement in hematologic
parameters, activity of the combination in high-risk CLL subsets, and the significance of
the tumor flare reaction.

All patients will have baseline assessment of known CLL prognostic factors including:
immunoglobulin variable heavy chain (IgVH) gene mutational status, interphase cytogenetics,
intracellular ZAP-70 expression, and CD38 expression through the CRC tissue core. These
known prognostic features in CLL together with novel prognostic factors will be evaluated
for the ability to predict response to treatment with Revlimid® and the combination of
Revlimid® and Rituximab. Extensive biologic corollary studies are designed to evaluate the
mechanism of Revlimid® in CLL, the impact of Revlimid® on the CLL microenvironment, and
Revlimid®'s impact on and rituximab mediated cytotoxicity.

All patients will receive the same treatment. Revlimid® will be started at a low dose and
slowly escalated based on patient tolerability. Rituximab will be administered following 21
days of Revlimid® monotherapy. Patients will continue treatment for up to 7 cycles unless
there is toxicity or progressive disease. There are three planned response assessments for
the subjects: a single agent Revlimid® response assessment prior to the addition of
rituximab, after 3 cycles of treatment, and following all the therapy.

Inclusion Criteria:

1. Diagnosis of chronic lymphocytic leukemia with no history of previous treatments with
monoclonal antibodies or chemotherapy.

2. Subjects must have an indication for treatment as defined by the NCI Working Group

3. Understand and voluntarily sign an informed consent form.

4. Age ≥18 years at the time of signing the informed consent form.

5. Able to adhere to the study visit schedule and other protocol requirements.

6. ECOG performance status of ≤ 2 at study entry (see Appendix A).

7. Laboratory test results within these ranges: Absolute neutrophil count ≥ 1.0 x 109/L,
Platelet count ≥ 50 x 109/L, Serum creatinine ≤ 1.5 mg/dL, Total bilirubin ≤ 1.5
mg/dL, AST & ALT ≤ 2 x ULN

8. 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 had a successful vasectomy. All
patients must be counseled at a minimum of every 28 days about pregnancy precautions
and risks of fetal exposure.

9. Disease free of prior malignancies for ≥ 2 years with exception of currently treated
basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix
or breast

Exclusion Criteria:

1. Previous treatment for CLL with chemotherapy or monoclonal antibodies

2. Known Hepatitis B Ag positive, Hepatitis C positive patients

3. Known HIV positive patients

4. Patients with uncontrolled Autoimmune Hemolytic Anemia (AIHA) or autoimmune
thrombocytopenia (ITP).

5. Inability to provide informed consent.

6. Concurrent malignancy (excluding basal and squamous cell skin cancers).

7. Active fungal, bacterial, and/or viral infection.

8. Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

9. Pregnant or breast-feeding females. (Lactating females must agree not to breast feed
while taking lenalidomide).

10. Any condition, including the presence of laboratory abnormalities, which places the
subject at unacceptable risk if he/she were to participate in the study or confounds
the ability to interpret data from the study.

11. Use of any other experimental drug or therapy within 28 days of baseline.

12. Known hypersensitivity to thalidomide.

13. The development of erythema nodosum if characterized by a desquamating rash while
taking thalidomide or similar drugs.

14. Any prior use of lenalidomide.

15. Concurrent use of other anti-cancer agents or treatments.

16. Patients with history of deep venous thrombus or pulmonary embolism. Patients who are
at increased risk of thrombosis during treatment with lenalidomide including those
taking concurrent erythropoietin, darbepoetin or high-dose corticosteroids are also

17. Patients with a history of embolic events (e.g. TIA) from arrhythmia or peripheral
arterial disease or of recent MI whether or not treated with anti-platelet drugs

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Efficacy to be assessed by clinical response rate following 3 cycles of treatment and the NCI-CLL working group response rate assessed after completion of all treatment.

Outcome Time Frame:

clinical response assessment after 3 cycles of therapy and 3 months following completion of all therapy for NCI-CLL working group response assessment

Safety Issue:


Principal Investigator

Thomas J Kipps, M.D., Ph.D

Investigator Role:

Study Director

Investigator Affiliation:

Director of the CLL Research Consortium and University of California San Diego


United States: Food and Drug Administration

Study ID:




Start Date:

February 2008

Completion Date:

July 2011

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • CLL
  • Untreated
  • Front-line
  • First-Line
  • Initial Therapy
  • Chronic Lymphocytic Leukemia Research Consortium
  • Chronic lymphocytic leukemia
  • CLL
  • CLL Research Consortium
  • CRC
  • Revlimid
  • lenalidomide
  • Rituximab
  • Rituxan
  • First-line
  • therapy
  • untreated
  • Frontline
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Columbus, Ohio  43210-1240
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute Boston, Massachusetts  02115
Long Island Jewish Medical Center New Hyde Park, New York  11040
M. D. Anderson Cancer Center at University of Texas Houston, Texas  77030-4009
University of California San Diego La Jolla, California  92093