Activity & Safety Study of Lenalidomide & Rituximab as Non-chemotherapy Based Therapy on Chronic Lymphocytic Leukemia (LLC-LENAR-08)

Activity & Safety Study of Lenalidomide & Rituximab as Non-chemotherapy Based Therapy on Chronic Lymphocytic Leukemia

Phase I Study of the Activity and Safety of Lenalidomide and Rituximab as Non-chemotherapy Therapy for Patients With Recurrent and Refractory Chronic Lymphocytic Leukemia

The rationale for combining lenalidomide with rituximab derives from preclinical observations suggesting that lenalidomide may enhance the ADCC (antigen-dependent cellular cytotoxicity) triggered by monoclonal antibodies such as rituximab. Lenalidomide augments NK cytotoxicity by increasing CD56dimCD3 subset, in addition to inducing IL-2 in T cells. These results provide the cellular and molecular basis for the use of lenalidomide as an adjuvant in immunotherapeutic strategies of monoclonal antibodies (mAb)-based therapies. The combination lenalidomide-rituximab was tested in lymphoma cell lines but not specifically on CLL cell lines. However the observed synergism was attributed to NK cells expansion, thus lending support to the notion that this synergism may operate in other B-cell lymphoproliferative malignancies. The objective was to develop a non-cytotoxic and effective treatment for CLL that would fulfill an unmet medical need, as a significant proportion of CLL patients are elderly and frail. These patients experience an excess in chemotherapy induced toxicity, often preventing the completion of the planned treatment.

Phase I: Lenalidomide will be administered from day 1 to 21 of 28 days cycles, escalating doses (from 2,5mg to 25 mg).Rituximab dose will be administered at the standard (375 mg/m2 in the first cycle and 500 mg/m2 in successive cycles).

Lenalidomide: Oral use. It will be administered from day 1 to 21 of 28 days cycles in a total of 6 cycles. Rituximab, intravenous use. The dose will be administered at the standard (375 mg/m2 in the first cycle and 500 mg/m2 in successive cycles). In the first cycle Rituximab will be administered in two divided doses:100mg/m2 total on day 1 and the rest up to 375mg/m2 on day 2. If lenalidomide treatment starts on day 1, Rituximab will be administered, in this first cycle, on days -2 (100 mg/m2) and -1 (275 mg/m2). In the second and subsequent cycles, 500 mg/m2 of Rituximab will be administered on day -1.

Phase I: To determine Starting Recommended Dose for the first cycle and the subsequent cycles (Maximal Tolerated Dose)in relapsed B-cell CLL patients.

6 treatment cycles followed by an evaluation visit (between 60-90 days after last dosing) and quarterly follow up visits, until disease progression. Module I: patients on every cohort will have the same dose during treatment, except if they experiment DLT, in which case dose will be decreased (unless they are on the first dose level).

Phase II: patients will be followed during 6 cycles, safety assessment visit and quarterly follow up visits

Phase II: patients will be followed during 6 cycles, safety assessment visit and quarterly follow up visits

Phase II: patients will be followed during 6 cycles, safety assessment visit and quarterly follow up visits

6 treatment cycles followed by an evaluation visit (between 60-90 days after last dosing) and quarterly follow up visits, until disease progression

Inclusion Criteria: Recurrent and refractory CLL patients that have received at least one previous treatment with purine analogs. Adequate liver function and renal function. ECOG performance status ≤ 2. Signed informed consent Male and female patients who are fertile agree to use an effective barrier method of birth control to avoid pregnancy. Exclusion Criteria: Positive serological markers for hepatitis B with the exception of HBsAc in previously vaccinated patients Pregnant patients HIV infection Concurrent chemotherapy or immunotherapy Other malignancy within the last 2 years, except for localized cutaneous carcinoma Neurological impairment precluding understanding of protocol and the entailed visits and procedures. Patients with Renal insufficiency that requires dialysis.