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

• Status: Unknown status
• Trial end date: 2016-01-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Treatments: Dasatinib; Fludarabine

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