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Dasatinib Combination for Chronic Lymphocytic Leukemia Patients With Chemo Refractory Disease

Phase 2
18 Years
80 Years
Open (Enrolling)
Chronic Lymphocytic Leukemia

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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:


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


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

- 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.

Inclusion Criteria:

- CLL confirmed according to the IWCLL Working Group criteria;

- Binet stages A or B with indication for treatment according to IWCLL guidelines,
Binet C AND

- Fludarabine refractory, defined as relapse (any sign of disease recurrence or
progression with or without indication for treatment ≤ 6 months following fludarabine
containing chemo(immuno)therapy;

- Age 18-80 years inclusive;

- WHO performance status ≤ 2;

- No possibility for rapid reduced intensity allogeneic hematopoietic stem cell

- At least 4 weeks without any treatment before study entry;

- Negative pregnancy test;

- Written informed consent;

Exclusion Criteria:

- Richter's transformation;

- Suspected or documented CNS involvement by CLL;

- Grade 3 cytopenia not due to bone marrow infiltration

- Concurrent medical condition which may increase the risk of toxicity, including:

- Pleural or pericardial effusion of any grade

- Cardiac Symptoms, including:

- Uncontrolled angina, congestive heart failure or MI within (6 months)

- Diagnosed congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation, or Torsades de pointes)

- prolonged QTc interval on pre-entry electrocardiogram (> 450 msec)

- Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to
dasatinib administration;

- Severe pulmonary dysfunction (CTCAE grade III-IV);

- Active hepatitis B infection;

- History of significant bleeding disorder unrelated to the CLL, including:

- Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)

- Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII

- Ongoing or recent (within 3 months) significant gastrointestinal bleeding

- Known HIV positivity

- Clinically significant auto-immune hemolytic anemia (AIHA)

- Severe neurological or psychiatric disease;

- Significant hepatic dysfunction (Total bilirubin < 2.0 times ULN; Hepatic enzymes
(AST, ALT ) ≤ 2.5 times ULN) except when caused by leukemic infiltration;

- Significant renal dysfunction (serum creatinine more than 150 uM/L after

- History of active malignancy during the past 5 years with the exception of basal
carcinoma of the skin or stage 0 cervical carcinoma;

- Concurrent use of CYP3A4 inducers or inhibitors, or QTc-prolonging agents*;

- Active, uncontrolled infections;

- Any psychological, familial, sociological and geographical condition potentially
hampering compliance with the study protocol and follow-up schedule;

- Female patients of reproductive potential who are not using effective contraception;

- The following medications should be considered for exclusion:

1. Category I drugs that are generally accepted to have a risk of causing Torsades
de Pointes including: (Patients must discontinue drug 7 days prior to starting
dasatinib) quinidine, procainamide, disopyramide amiodarone, sotalol, ibutilide,
dofetilide erythromycin, clarithromycin chlorpromazine, haloperidol,
mesoridazine, thioridazine, pimozide, zyprasidone, cisapride, bepridil,
droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine,
levomethadyl, pentamidine, sparfloxacin, lidoflazine.

2. The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is
not recommended. The use of antacids should be considered in place of H2
blockers or proton pump inhibitors in patients receiving dasatinib therapy. If
antacid therapy is needed, the antacid dose should be administered at least 2
hours prior to or 2 hours after the dose of dasatinib. Patient may not be
receiving any prohibited CYP3A4

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

response rate and response quality

Outcome Time Frame:

At 32 weeks of either dasatinib monotherapy or after 6 cycles of fludarabine and dasatinib combination

Safety Issue:


Principal Investigator

Arnon P kater, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Academic medical Center, Amsterdam, the Netherlands


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:

D'Accord study



Start Date:

October 2008

Completion Date:

January 2016

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • CLL
  • refractory
  • dasatinib
  • fludarabine
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid