Dasatinib Holiday for Improved Tolerability

Last updated: May 9, 2023
Sponsor: University of Jena
Overall Status: Completed

Phase

3

Condition

Leukemia

Treatment

dasatinib (SPRYCEL®)

Clinical Study ID

NCT02890784
DasaHIT
  • Ages > 18
  • All Genders

Study Summary

Treatment optimization for patients with chronic myeloid leukemia (CML) with treatment naïve disease (1st line) and patients with resistance or intolerance against alternative Abl-Kinase Inhibitors (≥2nd line) (DasaHIT Trial (Dasatinib Holiday for Improved Tolerability))

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Male or female patients with diagnosis of CP-CML with cytogenetic confirmation of Ph+chromosome [t(9;22)(q34;q11)].
  • Ph negative cases or patients with variant translocations who are BCR-ABL positive inmultiplex PCR4 will be also considered eligible.
  • ECOG performance status ≤2.
  • Age ≥ 18 years old (no upper age limit is given)
  • Serum levels of potassium, magnesium and total calcium within the normal limits (≥LLN [lower limit of normal] and ≤ULN [upper limit of normal]). Correction of electrolytes'levels with supplements to meet enrolment criteria is allowed.
  • AST and ALT ≤2.5 x ULN or 5.0 x ULN if considered due to leukemia
  • Alkaline phosphatase ≤2.5 x ULN unless considered due to leukemia
  • Total bilirubin ≤1.5 x ULN, except known Gilbert disease
  • Serum creatinine ≤2 x ULN
  • Written informed consent prior to any study procedures being performed. For 1st-line patients:

• Pre-treatment with hydroxyurea up to 6 months and imatinib or dasatinib for duration ofup to 4 weeks is permitted. For ≥ 2nd-line patients:

• Patients with treatment failure according to the 2013 ELN Recommendations criteria3 ortreatment intolerance as assessed by the investigator after prior treatment with TKIs otherthan dasatinib (imatinib, nilotinib, bosutinib, ponatinib).

Exclusion

Exclusion Criteria:

  • Previous allogeneic stem cell transplantation (AlloSCT)
  • Known impaired cardiac function, including any of the following:
  • Congenital long QT syndrome
  • History of or presence of clinically significant ventricular or atrialtachyarrhythmia
  • QTc >450 msec on screening ECG
  • Myocardial infarction within 6 months prior to starting therapy
  • Other clinical significant heart disease (e.g. unstable angina pectoris, congestiveheart failure)
  • Acute or chronic viral hepatitis with moderate or severe hepatic impairment (Child-Pugh scores >6), even if controlled
  • Other concurrent uncontrolled medical conditions (e.g., active or uncontrolledinfections, acute or chronic liver and renal disease) that could cause unacceptablesafety risks or compromise compliance with the protocol
  • Impaired gastrointestinal function or disease that may alter the absorption of studydrug (e.g., ulcerative disease, uncontrolled nausea, vomiting and diarrhea,malabsorption syndrome, small bowel resection or gastric by-pass surgery)
  • Concomitant medications known to be strong inducers or inhibitors of the CYP450isoenzyme CYP3A4
  • Patients who have undergone major surgery ≤2 weeks prior to starting study drug or whohave not recovered from side effects of such therapy
  • Patients who are pregnant or breastfeeding or women of reproductive potential notemploying an effective method of birth control. Women of childbearing potential musthave a negative serum pregnancy test within 14 days prior to administration ofdasatinib. Post-menopausal women must be amenorrheic for at least 12 months in orderto be considered of non-childbearing potential. Male and female patients must agree toemploy an effective method of birth control throughout the study and for up to 3months following discontinuation of study drug
  • Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is notmandatory)
  • Active autoimmune disorder, including autoimmune hepatitis
  • Known serious hypersensitivity reactions to dasatinib
  • Patients with a history of another primary malignancy that is currently clinicallysignificant or currently requires active intervention
  • Patients unwilling or unable to comply with the protocol.

Study Design

Total Participants: 291
Treatment Group(s): 1
Primary Treatment: dasatinib (SPRYCEL®)
Phase: 3
Study Start date:
August 01, 2016
Estimated Completion Date:
March 31, 2023

Study Description

Dasatinib is indicated in Europe for:

  • Treatment of adult patients with newly diagnosed Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase

  • Chronic, accelerated or blast phase CML with resistance or intolerance to prior therapy including imatinib

  • Ph+ acute lymphoblastic leukemia (ALL) and lymphoid blast CML with resistance or intolerance to prior therapy Compared to imatinib, dasatinib in CML achieves faster and better responses. Dasatinib is known for its selected toxicities (fluid retention, edema, pleural effusion, and hematological toxicity) requiring dose reductions or treatment interruptions; these toxicities are more frequent in the first two years of treatment. A randomized dose optimization trial for QD dosing vs. BID dosing has demonstrated non-inferiority with regards to efficacy with an improved toxicity profile. In a pilot study, analyzing patients with dasatinib toxicity, a fixed dasatinib weekend holiday allowed safe toxicity management without impairing efficacy. Furthermore the alternated schedule was also able to improve response parameters in patients that had never achieved an acceptable response prior to the onset of dasatinib holiday dosing schedule. The biological rationale for a holiday dosing schedule is that dasatinib has shown an improved cell death of CML cells even after short exposure times; this improved cell death exceeds the killing rate observed with imatinib in vitro. In summary, the reported preclinical and clinical evidence indicates that efficacy seems to require adequate dasatinib Cmax, while low Cmin (five half-lives between doses) does not impair efficacy nor induces drug resistance. It is speculated that a weekend holiday, allowing a better tolerability, would improve patients' drug adherence. The Investigators hypothesize that a dasatinib holiday schedule (5x100mg+2x0mg weekly) compared to a regular dose (7x100mg weekly) will reduce the rate of clinically significant toxicity (e.g., fluid retention, hematological toxicity, musculoskeletal pain) by 20% observed within the first two years of treatment. The Investigators also hypothesize that the dasatinib holiday schedule is non-inferior to dasatinib regular dose in achieving the European LeukemiaNet (ELN) recommended levels of response within the first 24 months.

Connect with a study center

  • Uniklinik der RWTH Aachen

    Aachen, 52074
    Germany

    Site Not Available

  • Gesundheitszentrum St. Marien GmbH

    Amberg, 92224
    Germany

    Site Not Available

  • Gemeinschaftspraxis Dres. Klausmann

    Aschaffenburg, 63739
    Germany

    Site Not Available

  • OnkoBer

    Berlin, 10115
    Germany

    Site Not Available

  • Evangelisches Klinikum Bethel gGmbH

    Bielefeld, 33611
    Germany

    Site Not Available

  • Universitätsklinikum Bonn

    Bonn, 53111
    Germany

    Site Not Available

  • Klinikum Bremen-Mitte gGmbH

    Bremen, 28177
    Germany

    Site Not Available

  • Klinikum Chemnitz gGmbH

    Chemnitz, 09113
    Germany

    Site Not Available

  • Gemeinschaftspraxis Mohm/Prange-Krex

    Dresden, 01307
    Germany

    Site Not Available

  • Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden

    Dresden, 01307
    Germany

    Site Not Available

  • Helios St. Johannes Klinik Duisburg

    Duisburg, 47166
    Germany

    Site Not Available

  • Gemeinschaftspraxis Erlangen

    Erlangen, 91052
    Germany

    Site Not Available

  • Universitätsklinikum Essen

    Essen, 45147
    Germany

    Site Not Available

  • Universitätsklinikum Frankfurt

    Frankfurt, 60590
    Germany

    Site Not Available

  • Universitätsklinikum Freiburg

    Freiburg, 79106
    Germany

    Site Not Available

  • Katholisches Karl-Leisner Klinikum

    Goch, 47574
    Germany

    Site Not Available

  • MVZ Onkologische Kooperation Harz

    Goslar, 38642
    Germany

    Site Not Available

  • ConMed GmbH

    Göttingen, 37073
    Germany

    Site Not Available

  • Hämato-Onkologische Gemeinschaftspraxis Halberstadt

    Halberstadt, 38820
    Germany

    Site Not Available

  • Universitätsklinikum Halle/S.

    Halle, 06120
    Germany

    Site Not Available

  • Asklepios MVZ Onkologie

    Hamburg, 22417
    Germany

    Site Not Available

  • MediProjekt GbR

    Hannover, 30171
    Germany

    Site Not Available

  • St. Bernward Krankenhaus Hildesheim

    Hildesheim, 31134
    Germany

    Site Not Available

  • Universitätsklinikum Jena

    Jena, 07740
    Germany

    Site Not Available

  • Institut für med. Dokumentation, Gutachtenstellung, Gesundheitsförderung und Qualitätssicherung GbR

    Kaiserslautern, 67655
    Germany

    Site Not Available

  • St. Vincentius-Kliniken Karlsruhe

    Karlsruhe, 76137
    Germany

    Site Not Available

  • Städtisches Klinikum Karlsruhe gGmbH

    Karlsruhe, 76133
    Germany

    Site Not Available

  • Klinikum Kassel

    Kassel, 34125
    Germany

    Site Not Available

  • Onkologische Gemeinschaftspraxis

    Kassel, 34119
    Germany

    Site Not Available

  • Städtisches Krankenhaus Kiel GmbH

    Kiel, 24116
    Germany

    Site Not Available

  • Universitätsklinikum Schleswig-Holstein

    Kiel, 24116
    Germany

    Site Not Available

  • InVo Institut für Versorgungsforschung

    Koblenz, 56068
    Germany

    Site Not Available

  • MVZ Hämatologie und Onkologie

    Krefeld, 47805
    Germany

    Site Not Available

  • Onkologische Schwerpunktpraxis

    Kronach, 96317
    Germany

    Site Not Available

  • Onkologisches Zentrum

    Lebach,
    Germany

    Site Not Available

  • Studienzentrum UnterEms

    Leer, 26789
    Germany

    Site Not Available

  • Universitätsklinikum Leipzig

    Leipzig, 04103
    Germany

    Site Not Available

  • Universitätsmedizin Mannheim

    Mannheim, 68169
    Germany

    Site Not Available

  • Universitätsklinikum Gießen und Marburg GmbH

    Marburg, 35043
    Germany

    Site Not Available

  • Stauferklinikum Schwäbisch Gmünd

    Mutlangen, 73557
    Germany

    Site Not Available

  • Gemeinschaftspraxis Hämatologie/ Onkologie

    München, 81241
    Germany

    Site Not Available

  • Rotkreuzklinikum München

    München, 80634
    Germany

    Site Not Available

  • Universitätsklinikum Münster

    Münster, 48149
    Germany

    Site Not Available

  • Hämatologisch-onkologische Schwerpunktpraxis

    Neustadt Am Rübenberge, 31535
    Germany

    Site Not Available

  • Klinikum Passau

    Passau, 94032
    Germany

    Site Not Available

  • Kreiskliniken Reutlingen GmbH

    Reutlingen, 72764
    Germany

    Site Not Available

  • Klinikum Südstadt Rostock

    Rostock, 18059
    Germany

    Site Not Available

  • Universitätsmedizin Rostock

    Rostock, 18057
    Germany

    Site Not Available

  • Hämatologie-Onkologie Stolberg

    Stolberg, 52222
    Germany

    Site Not Available

  • Klinikum Mutterhaus der

    Trier, 54290
    Germany

    Site Not Available

  • Universitätsklinikum Ulm

    Ulm, 89081
    Germany

    Site Not Available

  • Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH

    Villingen-Schwenningen, 78052
    Germany

    Site Not Available

  • Rems-Murr-Klinik Winnenden

    Winnenden, 71364
    Germany

    Site Not Available

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