Dose Escalation Study of Revlimid With Fludarabine-Rituximab for CLL/SLL

A Phase I Dose Escalation Study of Lenalidomide (Revlimid) in Combination With Fludarabine-Rituximab (Rituxan) for Previously Untreated CLL/SLL

Brigham and Women's Hospital, Massachusetts General Hospital, Beth Israel Deaconess Medical Center, Celgene Corporation

The purpose of this study is to determine the safety of lenalidomide (revlimid) in combination with fludarabine and rituximab and to determine the highest dose of lenalidomide that can safely be given in that combination. Lenalidomide is a drug that alters the immune system and may also interfere with the the development of tiny blood vessels that help support tumor growth. Lenalidomide is approved by the FDA for the treatment of two different blood cancers called myelodysplastic syndrome and multiple myeloma. Lenalidomide has also been studied in subjects with relapsed CLL. In this research study we are adding lenalidomide to a well-established initial therapy for CLL/SLL.

Participants will be treated in groups (cohorts) of three to six subjects per cohort. The dose of lenalidomide or fludarabine will be increased from one cohort to the next. Regardless of the treatment cohort, participants will receive treatment in cycles lasting 28 days. For the first 3-5 days (depending on the group), participants will be treated on an outpatient basis in the infusion room at the Dana-Farber Clinic, with fludarabine and rituximab. Fludarabine is given intravenously for 3-5 days. Rituximab is given intravenously on day 1 of each 28-day cycle. Lenalidomide is given orally once per day for 3 weeks, followed by 1 week of rest. Participants will be monitored very closely during the study treatment. During the first 28 day period (cycle 1), a physical exam and routine blood tests will be performed weekly. All participants in a group must finish the first 28-day treatment period before we proceed with the next group. Once started on study treatment, participants will continue for six cycles (a cycle is 28 days) of combination therapy with all three drugs. During that period they will have a physical exam and routine blood tests on day 1 of each treatment cycle, and additional blood tests on day 15 of each cycle. When participants complete 6 cycles of combination therapy, they will proceed with two additional months of the lenalidomide alone, for 21 out of 28 days. Disease response will be evaluated after 2, 6, and 8 months of study treatment. The following tests and procedures will be performed: Physical exam; blood tests; CT scans to evaluate lymph nodes; skin testing; and bone marrow biopsy if all other tests show no evidence of any remaining CLL and if the baseline bone marrow biopsy was positive Participants will have a physical exam and lab work every 3 months as long as their disease remains in remission.

Lenalidomide-Dose level will depend upon time the participant enrolls on the study: Given orally once a day for 3 weeks followed by a one week rest period fludarabine- Dose level will vary depending upon when participant enters the trial: Given intravenously for 3-5 days Rituximab- Given intravenously on Day 1 of each 28 day cycle

Dose level will depend upon time the participant enrolls on the study: Given orally once a day for 3 weeks followed by a one week rest period

Dose level will vary depending upon when participant enters the trial: Given intravenously for 3-5 days

To evaluate the safety of lenalidomide in combination with fludarabine-rituximab (FR) and to determine the maximum tolerated dose in subjects with previously untreated CLL/SLL.

To determine the objective response rate and progression-free survival following lenalidomide/FR in this patient population

To determine the improvement in ORR following two months of consolidation lenalidomide after completion of combination therapy

To assess effects on immune function as measured by cytokine levels, T and NK cell subsets, T cell activation during therapy and DTH vaccine responses.

Inclusion Criteria: 18 years of age or older Diagnosed with B-CLL/SLL based on the standard histologic and immunophenotypic criteria described in the WHO classification No prior systemic therapy for CLL/SLL, including chemotherapy or antibody therapy Currently needs therapy based on 1996 NCI-WG criteria Measurable disease ECOG Performance Status of 0-2 Laboratory test results within parameters outlined in protocol Able to take aspirin daily as prophylactic anticoagulation Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent document Pregnant or breast-feeding females Any condition, including the presence of abnormal laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study Use of any other experimental drug or therapy within 28 days of baseline Known hypersensitivity to thalidomide Development of erythema nodosum characterized by a desquamating rash while taking thalidomide or similar drugs Prior use of lenalidomide Concurrent use of other anti-cancer agents or treatments Known positive for HIV Chronic active Hep B patients not on prophylactic lamivudine Diagnosis of Mantle Cell Lymphoma