Dasatinib Combination for Chronic Lymphocytic Leukemia(CLL) With Refractory Disease

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. The disease mostly affects the elderly. At present no curative therapy is available. Although the majority of patients initially do respond to chemotherapy, most patients eventually develop drug resistance. The prognosis for patients with chemotherapy resistant disease is very poor wit an overall survival of approximately 10 months. Standard therapy for these patients currently does not exist. Treatment with the monoclonal antibody alemtuzumab could be tried, however toxicity of this drug is high especially following multiple cycles of chemotherapy. Allogeneic stem cell transplantation is still considered experimental in this setting and is only available for a minority of patients.

The development of chemoresistant disease is highly correlated with a disturbed balance of apoptosis regulating molecules, resulting in a decrease in sensitivity to apoptotic stimuli. The tyrosine kinase inhibitor dasatinib (Sprycel®) is successfully being used in the treatment of chronic myeloid leukemia (CML). This form of chronic leukemia is also characterized by a disturbed balance between apoptosis regulating genes, which can be restored by tyrosine kinase inhibitors. Recent studies indicate that also in CLL, dasatinib has the potential to restore the apoptotic balance. In this clinical study we will investigate whether dasatinib is an effective drug in the treatment of chemoresistant CLL and whether treatment with dasatinib restores the sensitivity to chemotherapeutic agents.

Objective of the study:

Primary:

To determine the response rate and response quality of dasatinib monotherapy or dasatinib/fludarabine combination in fludarabine refractory CLL patients

Secondary To asses the overall safety profile of this treatment approach To asses event free survival (i.e. time from registration to induction failure, progression, relapse or death whichever occurs first), progression free survival (i.e. time from registration to disease progression, relapse or death due to CLL whichever occurs first) and disease free survival (i.e. time from CR to relapse) To asses influence of dasatinib on the expression profile of apoptosis regulatory genes.

To determine whether dasatinib acts synergistically with other immuno-chemotherapeutic agents by co-culture experiments.

Study design:

Prospective, multi center clinical trial

Study population:

Patients with CLL in need of treatment AND fludarabine refractory, age 18-80 year inclusive

Intervention:

Patients will be treated with dasatinib monotherapy 100mg daily. At four weeks patients will be re-evaluated. Patients with less than a partial response will receive fludarabine (orally 40mg/daily for 3 days q28) in addition to dasatinib. After two cycles of fludarabine, responses will be evaluated. In case of progressive disease following 2 cycles of fludarabine in combination with dasatinib, patients will go off study. All other patients will be treated with four more cycles of fludarabine in combination with daily dasatinib treatment. Patients that receive monotherapy after the initial 28 days and that develop progressive disease will 'cross-over' to the combination treatment.

Primary study parameters/outcome of the study:

-- Clinical response rate and quality ( CR, PR) at 32 weeks

-In case of complete responses: minimal residual disease status

Secondary :

• Overall safety profile as determined by the incidence of clinically significant adverse events.
• Event free survival (i.e. time from registration to induction failure, progression, relapse or death whichever occurs first), progression free survival (i.e. time from registration to disease progression, relapse or death due to CLL whichever occurs first) and disease free survival (i.e. time from CR to relapse)

Extensive (functional) In vitro studies of dasatinib treated cells will be performed:

• Expression profile of apoptosis regulatory genes at the mRNA level (MLPA) and protein level (western blot)
• Study in vitro synergy of dasatinib treatment with different chemotherapeutic and immunotherapeutic drugs

Nature and extent of the burden and risks associated with participation, benefit and group relatedness (if applicable):

The monitoring of the patients during treatment and follow-up are according to the standard procedures in the treatment of patients with CLL. This means physical examination at a regular frequency (7 times from registration until the end of treatment; every 3 months during follow-up), blood sample analysis (9 times from registration until the end of treatment; every 3 months during follow-up), bone marrow analysis (2 times from registration until the end of treatment) and CT-scan (4 times from registration until the end of treatment). In addition, an ECG will be performed at entry of the study.

Hematological side-effects of dasatinib are cytopenias. Especially a drop in leukocytes and thrombocytes has been reported. In most cases, cytopenias can be controlled by dose adjustment. A temporarily inflammation of the liver can occur (< 3% of patients) and is in most cases reversible by dose adjustment. Most other reported side-effects are nausea, muscle cramps, painful joints, headache, fluid retention (including pleural effusion) and gain of weight. Most of the side-effects can successfully be managed by dose-adjustment.

Side-effects of fludarabine in the dose just in this study are temporarily cytopenias, nausea, emesis, diarrhea, mucositis, liver function abnormalities, fever, rash, conjunctivitis and dizziness.