Lenalidomide, Fludarabine & Cyclophosphamide in Advanced Chronic Lymphocytic Leukemia Not Responding to Therapy

This is a phase I - II multicenter, non-comparative, open label study in patients with previously treated CLL aimed at defining the MTD of Lenalidomide given in combination with Fludarabine, Cyclophosphamide and at evaluating the (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL).

OBJECTIVES:

Primary

* To define the maximum tolerated dose (MTD) of Lenalidomide given in combination with FC.(Phase I)
* To evaluate the complete remission (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL). (Phase II)

Secondary

* To define the toxicity and the infection rate of patients treated with FCL and the median number of delivered courses of FCL, overall response rate and the progression-free survival and the relationship between the response and the baseline biologic factors (IgVH, FISH, ZAP-70, CD38).
* To evaluate the overall response rate (complete and partial responses).
* To evaluate the progression-free survival.

OUTLINE: This is a phase I - II multicenter, non-comparative, open label study in patients with previously treated CLL aimed at defining the MTD of Lenalidomide given in combination with Fludarabine, Cyclophosphamide and at evaluating the (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL).

All patients will receive six monthly courses of FCL schedule consisting of three days of Fludarabine and Cyclophosphamide administration (d1-d3) combined with 14 days of Lenalidomide administration (d1-d14).

After completion of study treatment, patients are followed periodically for up to 18 months.

Eligibility Criteria:
Inclusion criteria:

* Age \>=18 years.
* Able to adhere to the study visit schedule and other protocol requirements.
* Patients with advanced stage or progressive CLL (NCI criteria) and relapsed or refractory disease.
* No more than 2 previous different treatment lines.
* No treatment with Campath-1H in the previous 6 months.
* Disease-free of prior malignancies for \>=5 years, with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
* All previous cancer therapy, including chemotherapy, immunotherapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study.
* ECOG performance status of \<=2 at study entry.
* Laboratory test results within these ranges:

  * Serum creatinine \<=1.5 mg/dL and creatinine clearance ≥60mL/min
  * Total bilirubin \<=1.5 mg/dL
  * AST (SGOT) and ALT (SGPT) \<=1.5 x ULN
* Able to take low molecular weight heparin or in alternative, low- fixed-dose warfarin or, in alternative, low-dose aspirin.
* Able to understand and voluntarily sign the informed consent form.
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 10 - 14 days prior to therapy and repeated within 24 hours of starting study. FCBP must agree to use two reliable forms of contraception for at least 28 days before starting study drug; while participating in the study; and for at least 4 weeks after discontinuation from the study.
* Females must agree to abstain from breastfeeding during study participation and for at least 28 days after discontinuation from the study.
* Males must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 4 weeks following discontinuation.
* (Other details regarding pregnancy tests and contraception are reported in the chapter "Eligibility Criteria" within the study protocol).

Exclusion criteria:

* Treatment with Campath-1H during the previous 6 months.
* Concurrent use of other anti-cancer agents.
* Positive DAT with clinical and laboratory signs of hemolysis, autoimmune thrombocytopenia.
* Known positivity for HIV or active infectious hepatitis.
* Active bacterial, viral, or fungal infection requiring systemic anti-viral, antibiotic or anti-fungal therapy.
* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
* Pregnant or breast feeding females (lactating females must agree not to breast feed while taking Lenalidomide).
* 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.
* Prior history or presence of thrombosis, thromboembolism, hearth failure or arrhythmia, neurologic disease and renal insufficiency.
* Use of any other experimental drug or therapy within 28 days of baseline.
* Known hypersensitivity to thalidomide.
* The development of erythema nodosum, desquamating rash while taking thalidomide or similar drugs.
* Any prior use of Lenalidomide
* Lactose intolerance