Primary:To determine the response rate and response quality of dasatinib monotherapy or dasatinib/fludarabine combination in fludarabine refractory CLL patientsSecundaryTo asses the overall safety profile of this treatment approachTo asses event…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Clinical response rate and quality ( CR, PR) at 28 weeks according to the
IWCLL Working Group criteria
In case of complete responses: minimal residual disease status as assessed by
flow cytometry
Secondary outcome
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.
Background summary
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.
Study objective
Primary:
To determine the response rate and response quality of dasatinib monotherapy or
dasatinib/fludarabine combination in fludarabine refractory CLL patients
Secundary
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 by in vitro analysis whether dasatinib acts synergistically with
other immuno-chemotherapeutic agents by co-culture experiments.
Study design
Prospective, one center clinical trial
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.
Study burden and risks
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 trombocytes 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.
Meibergdreef 9
1105 AZ Amsterdam
NL
Meibergdreef 9
1105 AZ Amsterdam
NL
Listed location countries
Age
Inclusion criteria
- CLL confirmed according to the IWCLL Working Group criteria;
- Binet stages A or B with indication for treatment according to IWCLL guidelines, or Binet C AND
- Fludarabine refractory, defined as relapse within 6 months following fludarabine containing chemo(immuno)therapy;
- Age 18-80 years inclusive;
- WHO performance status * 2;
Exclusion criteria
- Richter*s transformation;
- Suspected or documented CNS involvement by CLL;
- Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure, symptomatic ischemic heart disease or prolonged QT interval);
- Severe pulmonary dysfunction (CTCAE grade III-IV);
- Severe neurological or psychiatric disease;
- Significant hepatic dysfunction (serum bilirubin or transaminases * 3 times normal level) except when caused by leukemic infiltration;
- Significant renal dysfunction (creatinine clearance < 30 ml/min after rehydration);
- 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;
- Female patients of reproductive potential who are not using effective contraception;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-002236-15-NL |
| CCMO | NL22407.018.08 |