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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01051115
Recruitment Status : Unknown
Verified August 2011 by A.P. Kater, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA).
Recruitment status was:  Recruiting
First Posted : January 18, 2010
Last Update Posted : August 31, 2011
Information provided by (Responsible Party):
A.P. Kater, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Brief Summary:

Patients with chemo refractory CLL have a poor prognosis. 2 independent mechanisms are attributed to the development of chemoresistance in CLL. The first is a shift in the balance between pro- and anti-apoptotic regulators. The second mechanism is based on acquired mutations resulting in a dysfunctional p53 response. Recent studies indicate that the tyrosine kinase inhibitor dasatinib acts synergistically with both purine analogies and alkylating agents. Also, dasatinib has the potency to restore the apoptotic balance of CLL cells.

Hypothesis: Dasatinib will be clinically active in chemo-refractory CLL patients and will act synergistically with the purine-analogue fludarabine.

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia Drug: Dasatinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Dasatinib Combination for Chronic Lymphocytic Leukemia Patients With Chemo Refractory Disease
Study Start Date : October 2008
Estimated Primary Completion Date : January 2013
Estimated Study Completion Date : January 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Dasatinib

Arm Intervention/treatment
Experimental: Dasatinib
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.
Drug: Dasatinib
Chemo-refractory CLL patients will be treated with dasatinib monotherapy 100mg daily.Patients with less than a partial response at 4 weeks will receive fludarabine (orally 40mg/daily for 3 days q28) in addition to dasatinib for a maximum of 6 cycles. Patients with at least a partial response will continue dasatinib monotherapy. Patients that receive monotherapy after the initial 28 days and that develop progressive disease will 'cross-over' to the combination treatment.
Other Names:
  • Sprycel
  • BMS-354825

Primary Outcome Measures :
  1. response rate and response quality [ Time Frame: At 32 weeks of either dasatinib monotherapy or after 6 cycles of fludarabine and dasatinib combination ]

Secondary Outcome Measures :
  1. overall safety profile of these treatment approaches, event free survival, progression free survival, relapse or death, disease free survival [ Time Frame: 3 years ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 transplantation;
  • 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 antibodies)
  • 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 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;
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01051115

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Contact: Arnon P Kater, MD, PhD +31-20-5669111
Contact: Marjolein Spiering, Ms +31-20-5669111

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Maastricht university medical center Not yet recruiting
Maastricht, Limburg, Netherlands, 6229 HX
Contact: Michel van Gelder, MD, PhD    +31-43 - 387 6543   
Academic Medical Center Recruiting
Amsterdam, NH, Netherlands, 1105 AZ
Contact: Marjolein Spiering, Ms    +31-20-5669111   
Contact: Arnon P Kater, MD, PhD    +31-20-5669111   
Erasmus MC-Daniel den Hoed Cancer Center Recruiting
Rotterdam, ZH, Netherlands, 3015 CE
Contact: Jeanette K Doorduijn, MD, PhD    +31-10 7040704   
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: Simon MG Daenen, MD, PhD    +31-50 3616161   
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
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Principal Investigator: Arnon P kater, MD, PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Principal Investigator: Marinus HJ van Oers, MD, PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Additional Information:
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Responsible Party: A.P. Kater, A.P. Kater, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) Identifier: NCT01051115    
Other Study ID Numbers: D'Accord study
First Posted: January 18, 2010    Key Record Dates
Last Update Posted: August 31, 2011
Last Verified: August 2011
Keywords provided by A.P. Kater, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Additional relevant MeSH terms:
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Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action