Multi-center Trial of Revlimid® and Rituximab, for First-Line Treatment of Chronic Lymphocytic Leukemia (CLL)

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IITreatment18 and over2008-0385
NCI-2009-01510, Celgene # RV-CLL-PI-0223, NCT00628238

Trial Description

Summary

The study is a two-arm, multi-center trial of Revlimid® and Rituximab, for the frontline

treatment of patients with Chronic Lymphocytic Leukemia (CLL) designed and conducted by the

CLL Research Consortium (CRC). The purpose 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, and the significance of the tumor flare reaction.

All patients will have assessment of known prognostic factors for CLL as well as novel

prognostic factors will be evaluated for predicting response to treatment. Biologic

corollary studies are designed to evaluate the mechanism of Revlimid® in CLL and the

combination of Revlimid® and Rituximab.

Further Study Information

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.

Eligibility Criteria

Inclusion Criteria:

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

Guidelines

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

excluded.

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

Exclusion Criteria:

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

Guidelines

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

excluded.

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

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

M D Anderson Cancer Center

  • Celgene Corporation
William George Wierda, Principal Investigator

Trial Sites

U.S.A.

New York
New Hyde Park

Long Island Jewish Medical Center

Kanti R. Rai
Ph: 516)470-7000
Email: rai@lij.edu

Kanti R. Rai
Principal Investigator

Ohio
Columbus

Ohio State University Comprehensive Cancer Center

Michael Rhodes Grever
Ph: 614-293-4976
Email: Michael.Grever@osumc.edu

Michael Rhodes Grever
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00628238

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.