Dasatinib Holiday for Improved Tolerability

Myeloid Leukemia, Chronic Clinical Trial

— DasaHIT  

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 Details — Status: Completed

Administrative data

• NCT number: NCT02890784
• Other study ID #: DasaHIT
• Status: Completed
• Phase: Phase 3
• Start date: August 2016
• Est. completion date: March 31, 2023

Study information

• Verified date: May 2023
• Source: University of Jena
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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))

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 291
• Est. completion date: March 31, 2023
• Est. primary completion date: March 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Myeloid Leukemia, Chronic

Intervention

Drug:
• dasatinib (SPRYCEL®)
Treatment optimization for patients with chronic myeloid leukemia (CML)

Locations

Country	Name	City	State
Germany	Uniklinik der RWTH Aachen	Aachen
Germany	Gesundheitszentrum St. Marien GmbH	Amberg
Germany	Gemeinschaftspraxis Dres. Klausmann	Aschaffenburg
Germany	OnkoBer	Berlin
Germany	Evangelisches Klinikum Bethel gGmbH	Bielefeld
Germany	Universitätsklinikum Bonn	Bonn
Germany	Klinikum Bremen-Mitte gGmbH	Bremen
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Gemeinschaftspraxis Mohm/Prange-Krex	Dresden
Germany	Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden	Dresden
Germany	Helios St. Johannes Klinik Duisburg	Duisburg
Germany	Gemeinschaftspraxis Erlangen	Erlangen
Germany	Universitätsklinikum Essen	Essen
Germany	Universitätsklinikum Frankfurt	Frankfurt
Germany	Universitätsklinikum Freiburg	Freiburg
Germany	Katholisches Karl-Leisner Klinikum	Goch
Germany	MVZ Onkologische Kooperation Harz	Goslar
Germany	ConMed GmbH	Göttingen
Germany	Hämato-Onkologische Gemeinschaftspraxis Halberstadt	Halberstadt
Germany	Universitätsklinikum Halle/S.	Halle
Germany	Asklepios MVZ Onkologie	Hamburg
Germany	MediProjekt GbR	Hannover
Germany	St. Bernward Krankenhaus Hildesheim	Hildesheim
Germany	Universitätsklinikum Jena	Jena
Germany	Institut für med. Dokumentation, Gutachtenstellung, Gesundheitsförderung und Qualitätssicherung GbR	Kaiserslautern
Germany	St. Vincentius-Kliniken Karlsruhe	Karlsruhe
Germany	Städtisches Klinikum Karlsruhe gGmbH	Karlsruhe
Germany	Klinikum Kassel	Kassel
Germany	Onkologische Gemeinschaftspraxis	Kassel
Germany	Städtisches Krankenhaus Kiel GmbH	Kiel
Germany	Universitätsklinikum Schleswig-Holstein	Kiel
Germany	InVo Institut für Versorgungsforschung	Koblenz
Germany	MVZ Hämatologie und Onkologie	Krefeld
Germany	Onkologische Schwerpunktpraxis	Kronach
Germany	Onkologisches Zentrum	Lebach
Germany	Studienzentrum UnterEms	Leer
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Universitätsmedizin Mannheim	Mannheim
Germany	Universitätsklinikum Gießen und Marburg GmbH	Marburg
Germany	Gemeinschaftspraxis Hämatologie/ Onkologie	München
Germany	Rotkreuzklinikum München	München
Germany	Universitätsklinikum Münster	Münster
Germany	Stauferklinikum Schwäbisch Gmünd	Mutlangen
Germany	Hämatologisch-onkologische Schwerpunktpraxis	Neustadt Am Rübenberge
Germany	Klinikum Passau	Passau
Germany	Kreiskliniken Reutlingen GmbH	Reutlingen
Germany	Klinikum Südstadt Rostock	Rostock
Germany	Universitätsmedizin Rostock	Rostock
Germany	Hämatologie-Onkologie Stolberg	Stolberg
Germany	Klinikum Mutterhaus der	Trier
Germany	Universitätsklinikum Ulm	Ulm
Germany	Schwarzwald-Baar Klinikum Villingen-Schwenningen GmbH	Villingen-Schwenningen
Germany	Rems-Murr-Klinik Winnenden	Winnenden

Sponsors (1)

Lead Sponsor	Collaborator
University of Jena

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	cumulative toxicity score	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)	month 24
Primary	Rate of molecular Response	The co-primary endpoint of the study is: rate of major molecular response (MMR) as assessed by BCR-ABL (IS [International Score] in %) -monitoring by 24 months to safeguard non-inferiority of the test cohort.	month 24
Secondary	Quality of life assessment	Quality of life assessment via Patient-Questionnaire.	month 24
Secondary	Rate of molecular Response	Rate of molecular response (MMR)as assessed by BCR-ABL (IS [International Score] in %) at 6 and 12 months.	6 and 12 months