CRC022: Revlimid® and Rituximab, for Relapse/Refaractory Patients with B-cell Chronic Lymphocytic Leukemia (CLL)
CRC 022: A Two-Arm, Multi-center trial of Revlimid® and Rituximab, for Relapse/Refaractory Patients with B-cell Chronic Lymphocytic Leukemia (CLL)
The Chronic Lymphocytic Leukemia Research Consortium (CRC) is conducting a two-arm, multi-center phase II trial of Revlimid® and Rituximab for the treatment of patients with relapsed or refractory 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 therapy(ies) that utilizes combinations of fludarabine and cyclophosphamide the trial has two arms- those aged 65 years and above and those younger than 65.
All patients will have baseline assessments 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.
A dual-arm, multi-center phase II trial of Revlimid® and rituximab for the treatment of patients with B-cell CLL who have previously received therapy. The trial will have two arms; one to include those under the age of 65 and the second to include patients 65 years and older. In addition to age and performance status additional assessments will be performed on those who enroll into arm B of the study (those age 65 or older) - including assessing activities of independent daily living (IADL), nutrition, and comorbidities as outlined in Appendix P. At baseline all patients will have assessment of immunoglobulin variable heavy chain (IgVH) gene mutational status, interphase cytogenetics, and intracellular ZAP-70 expression.
All patients will begin treatment with Revlimid® at a dose of 5mg (except those patients with creatinine clearance < 60 ml/min who will begin treatment with Revlimid 2.5mg or if the investigator's discretion favors a 2.5mg starting dose). Revlimid® may be dose escalated at 5 mg increments (or from 2.5 mg to 5 mg) at the start of each cycle, if no grade II or greater toxicity is present and no toxicity requiring holding of dose occurred during the previous cycle as outlined in section 6.5.7. At any point Revlimid dose escalation can occur only at the discretion of the investigator. Each cycle Revlimid® will be administered for only 21 days. Revlimid® will be given for a maximum of 13 cycles. Cycles 8-13 will be considered consolidation with Revlimid administered to patients who chose to have additional therapy after a response assessment and documentation of residual disease. Revlimid® dose reduction for toxicity is outlined in section 6.5.7. Revlimid® dose can be escalated by one dose level daily on days 1-21 followed by 7 days rest during cycles 2-13 per guidelines in section 6.5.8. Dose reduction and escalation rules for Revlimid® are listed in Section 6.5. The first dose of rituximab will be administered as a split dose during week 4 of cycle 1 (day 29 and 31) with a second full dose of rituximab administered on day 33. Rituximab will be administered on a weekly basis for four weeks beginning on day 1 of cycle 2, followed by rituximab 375 mg/m2 monthly starting with cycle 3 through cycle 7.
Additional consolidation treatment with single agent Revlimid® (cycles 8-13): Patients with residual disease, but without evidence of significant toxicity or progressive disease may stay on study for up to 6 additional cycles of Revlimid® orally on days 1 - 21 followed by 7 days rest (28 day cycle). During this additional treatment with Revlimid® the previous tolerated dose of Revlimid should be continued and dose escalation and reduction rules apply as during the initial seven cycles of therapy. Full response assessment will then occur two months following completion of all therapy.
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