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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2011 by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor:
Information provided by (Responsible Party):
A.P. Kater, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier:
NCT01051115
First received: January 15, 2010
Last updated: August 29, 2011
Last verified: August 2011
  Purpose

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 Intervention Phase
Chronic Lymphocytic Leukemia
Drug: Dasatinib
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Dasatinib Combination for Chronic Lymphocytic Leukemia Patients With Chemo Refractory Disease

Resource links provided by NLM:


Further study details as provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):

Primary Outcome Measures:
  • response rate and response quality [ Time Frame: At 32 weeks of either dasatinib monotherapy or after 6 cycles of fludarabine and dasatinib combination ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • overall safety profile of these treatment approaches, event free survival, progression free survival, relapse or death, disease free survival [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 35
Study Start Date: October 2008
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: January 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01051115

Contacts
Contact: Arnon P Kater, MD, PhD +31-20-5669111 a.p.kater@amc.nl
Contact: Marjolein Spiering, Ms +31-20-5669111 m.spiering@amc.nl

Locations
Netherlands
Maastricht university medical center Not yet recruiting
Maastricht, Limburg, Netherlands, 6229 HX
Contact: Michel van Gelder, MD, PhD    +31-43 - 387 6543    m.van.gelder@mumc.nl   
Academic Medical Center Recruiting
Amsterdam, NH, Netherlands, 1105 AZ
Contact: Marjolein Spiering, Ms    +31-20-5669111    m.spiering@amc.nl   
Contact: Arnon P Kater, MD, PhD    +31-20-5669111    a.p.kater@amc.nl   
Erasmus MC-Daniel den Hoed Cancer Center Recruiting
Rotterdam, ZH, Netherlands, 3015 CE
Contact: Jeanette K Doorduijn, MD, PhD    +31-10 7040704    j.doorduijn@erasmusmc.nl   
University Medical Center Groningen Recruiting
Groningen, Netherlands, 9713 GZ
Contact: Simon MG Daenen, MD, PhD    +31-50 3616161    s.m.g.j.daenen@int.umcg.nl   
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Investigators
Principal Investigator: Arnon P kater, MD, PhD Academic medical Center, Amsterdam, the Netherlands
Principal Investigator: Marinus HJ van Oers, MD, PhD Academic Medical Center, Amsterdam, the Netherlands
  More Information

Additional Information:
No publications provided

Responsible Party: A.P. Kater, A.P. Kater, MD, PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01051115     History of Changes
Other Study ID Numbers: D'Accord study
Study First Received: January 15, 2010
Last Updated: August 29, 2011
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
CLL
refractory
dasatinib
fludarabine

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Immune System Diseases
Immunoproliferative Disorders
Leukemia, B-Cell
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Dasatinib
Fludarabine
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014