Clinical Trials /

Dasatinib Holiday for Improved Tolerability

NCT02890784

Description:

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))

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Dasatinib Holiday for Improved Tolerability
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: DasaHIT
  • NCT ID: NCT02890784

Conditions

  • Myeloid Leukemia, Chronic

Interventions

DrugSynonymsArms
dasatinib (SPRYCEL®)A. Standard arm

Purpose

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))

Detailed 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.
    

Trial Arms

NameTypeDescriptionInterventions
A. Standard armActive Comparator100mg dasatinib (SPRYCEL®) daily dose (QD) (7x100) (Standard therapy)
  • dasatinib (SPRYCEL®)
B. Study armExperimental100mg dasatinib (SPRYCEL®) (QD) weekdays (1-5) only (5x100+2x0) (overall dose reduction per week)
  • dasatinib (SPRYCEL®)

Eligibility Criteria

        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 in
             multiplex 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 of
        up to 4 weeks is permitted.

        For ≥ 2nd-line patients:

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

        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 atrial
                  tachyarrhythmia

               -  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, congestive
             heart 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 uncontrolled
             infections, acute or chronic liver and renal disease) that could cause unacceptable
             safety risks or compromise compliance with the protocol

          -  Impaired gastrointestinal function or disease that may alter the absorption of study
             drug (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 CYP450
             isoenzyme CYP3A4

          -  Patients who have undergone major surgery ≤2 weeks prior to starting study drug or who
             have not recovered from side effects of such therapy

          -  Patients who are pregnant or breastfeeding or women of reproductive potential not
             employing an effective method of birth control. Women of childbearing potential must
             have a negative serum pregnancy test within 14 days prior to administration of
             dasatinib. Post-menopausal women must be amenorrheic for at least 12 months in order
             to be considered of non-childbearing potential. Male and female patients must agree to
             employ an effective method of birth control throughout the study and for up to 3
             months following discontinuation of study drug

          -  Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not
             mandatory)

          -  Active autoimmune disorder, including autoimmune hepatitis

          -  Known serious hypersensitivity reactions to dasatinib

          -  Patients with a history of another primary malignancy that is currently clinically
             significant or currently requires active intervention

          -  Patients unwilling or unable to comply with the protocol.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:cumulative toxicity score
Time Frame:month 24
Safety Issue:
Description:The cumulative toxicity score after two years of dasatinib treatment. More specifically, toxicity will be assessed taking into account both the rate of grade 2-4 toxicities and the cumulative severity of adverse events of specific interest. The following AEs of specific interest will be used to compose the cumulative toxicity score: Pleural effusion Fluid retention, other (edema, pericardial effusion, pulmonary arterial hypertension, congestive heart failure, pulmonary edema) Hematological toxicity (neutropenia, thrombocytopenia, anemia) Others (Musculoskeletal pain, skin toxicity (rash), gastrointestinal toxicity (nausea, diarrhea, abdominal pain, vomiting)

Secondary Outcome Measures

Measure:Quality of life assessment
Time Frame:month 24
Safety Issue:
Description:Quality of life assessment via Patient-Questionnaire.
Measure:Rate of molecular Response
Time Frame:6 and 12 months
Safety Issue:
Description:Rate of molecular response (MMR)as assessed by BCR-ABL (IS [International Score] in %) at 6 and 12 months.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Prof. Dr. med. Andreas Hochhaus

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