Trial Information

Dasatinib Combination for Chronic Lymphocytic Leukemia Patients With Chemo 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.