Dasatinib With Fludarabine and Rituximab in Relapsed and Refractory CLL and SLL

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL) are similar diseases of the white blood cells and are typically treated the same way. Recent research shows that a key enzyme in CLL cells is responsible for cell survival. This enzyme is called LYN kinase. Laboratory studies show that inhibition of LYN kinase in CLL cells results in the death of CLL cells. Dasatinib has the ability to inhibit LYN kinase and, therefore, should have some effect on CLL cells. The purpose of this study is to see of the study drug dasatinib, in combination with fludarabine and rituximab, is safe and effective to use for people with relapsed or refractory CLL/SLL.

* Since the purpose of the study is to determine the response rate of the 3 drug regimen, everyone who participates will receive the same dose of the study drug, dasatinib and the 2 standard drugs, fludarabine and rituximab.
* Participants will receive the drugs dasatinib, fludarabine, and rituximab at the following time points through each cycle of treatment. A cycle of study treatment is 28 days. Dasatinib pills will be taken orally each day for the first 2 weeks of each cycle. Fludarabine will be give intravenously on three days of each cycle (Days 3-5 in the first cycle, days 1-3 after that). Rituximab will be given intravenously with a total dose of 375 mg/m2 each cycle (split on Days 3+4 in the first cycle and at the discretion of the treating physician after that on Days 1-3).
* The following procedures will be repeated throughout the study: medical history review; physical exam; performance status test; blood tests and EKG. They will occur daily during the first week of treatment, then weekly for the rest of cycle 1. After cycle 1 these procedures will be done once a week for 4 weeks then once a month for 6 months.
* Tumor assessments will be repeated once every 2 months for the first six months of the study, and then once every 6 months after that.
* Blood samples will be obtained in the first 5 days of treatment for pharmacokinetic studies and pharmacodynamic studies.
* Participants that are benefiting from the study treatment after the first cycle can continue to receive an additional 6 cycles of study treatment.

Eligibility Criteria:
Inclusion Criteria:

* CLL/SLL with cells positive by flow cytometry (or immunostaining) for CD19, CD23, and CD5. Patients may be CD23 negative as long as they are also cyclin D1 negative or t(11;14) negative.
* Participants must have received at least 1 prior regimen containing a purine analogue or have received at least 2 chemotherapy regimens not containing a purine analogue. Patients may be refractory to single-agent purine analogue treatment, but patients may not be refractory to a combination of purine analogue with rituximab. Patients may have received rituximab.
* 18 years of age or older
* Able to take oral medications
* ECOG Performance Status of 2 or better
* Adequate organ function to tolerate chemotherapy
* Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study drug administration and agree to use and utilize an adequate method of contraception throughout treatment and for at least 4 weeks after study is stopped.
* Require treatment based on 1996 NCI-WG criteria updated in 2008 by the IWCLL
* Patient agrees to discontinue St. John's Wort while receiving dasatinib therapy and stop at least 5 days before starting dasatinib.
* Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib

Exclusion Criteria:

* Pregnant or breastfeeding women
* Uncontrolled angina, congestive heart failure, or MI within 6 months
* Diagnosed or suspected congenital long QT syndrome
* Any history of clinically significant ventricular arrhythmias
* Prolonged QTc interval on pre-entry ECG
* Uncontrolled hypertension
* Hypokalemia or hypomagnesemia that is not corrected prior to dasatinib administration
* Patients should not be taking drugs that are generally accepted to have a risk of causing Torsades de Pointes
* Known HIV positive
* Known significant bleeding disorder unrelated to CLL
* Any significant pleural or pericardial effusion
* Patients may not have another malignancy that is uncontrolled or requires treatment within a year of starting this study.