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Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)

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ClinicalTrials.gov Identifier: NCT02013648
Recruitment Status : Recruiting
First Posted : December 17, 2013
Last Update Posted : June 4, 2020
Sponsor:
Information provided by (Responsible Party):
Prof. Dr. Hartmut Doehner, University of Ulm

Tracking Information
First Submitted Date  ICMJE December 11, 2013
First Posted Date  ICMJE December 17, 2013
Last Update Posted Date June 4, 2020
Study Start Date  ICMJE July 2014
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 11, 2013)
Event-free Survival [ Time Frame: 4 years ]
To assess event-free survival (EFS) after intensive induction (daunorubicin and cytarabine) and consolidation (high-dose cytarabine) chemotherapy with or without dasatinib in patients with CBF-AML
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 7, 2014)
  • Cumulative incidence of relapse (CIR) [ Time Frame: 4 years ]
  • Cumulative incidence of death (CID) [ Time Frame: 4 years ]
  • overall survival [ Time Frame: 4 years ]
  • relapse-free survival [ Time Frame: 4 years ]
  • PIA analysis [ Time Frame: 4 years ]
    Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA)
  • toxicity [ Time Frame: 7 months (standard arm) / 19 months (investigational arm) ]
    Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03), timing and relatedness of non-hematologic toxicity observed during different treatment cycles.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 11, 2013)
  • Cumulative incidence of relapse (CIR) [ Time Frame: 4 years ]
  • Cumulative incidence of death (CID) [ Time Frame: 4 years ]
  • overall survival [ Time Frame: 4 years ]
  • relapse-free survival [ Time Frame: 4 years ]
  • PIA analysis [ Time Frame: 4 years ]
    Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA)
  • toxicity [ Time Frame: 7 months (standard arm) / 19 months (investigational arm) ]
    Type, frequency, severity (graded using the National Cancer Institute Common Terminology Crite-ria for Adverse Events [NCI CTCAE] version 4.03), timing and relatedness of non-hematologic toxicity observed during different treatment cycles.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)
Official Title  ICMJE Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™) in Adult Patients With Newly Diagnosed Core-Binding Factor Acute Myeloid Leukemia (CBF-AML)
Brief Summary This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML
Detailed Description

This is a randomized phase III open-label, multicenter trial evaluating standard induction therapy (daunorubicin [DNR] and cytarabine [Ara-C]) and consolidation therapy (high-dose cytarabine [HDAC]) with or without dasatinib in adult patients with newly diagnosed CBF-AML; in the investigational arm, consolidation therapy is followed by a one-year maintenance therapy with dasatinib. Patients with molecular disease persistence or molecular relapse as assessed by quantitative RQ-PCR for the CBF fusion transcripts will be eligible for hematopoietic stem cell transplantation before overt hematologic relapse occurs. Primary endpoint is event-free survival.

AML patients will be assessed for the CBF fusion genes in one of two AMLSG central laboratories within 48 hours of diagnosis, and only patients with CBF-AML will be enrolled.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia (AML)
Intervention  ICMJE
  • Drug: Dasatinib
    Other Name: Sprycel
  • Drug: Cytarabine
    Other Name: ARA-cell
  • Drug: Daunorubicin
    Other Name: Daunoblastin
  • Drug: Idarubicin
Study Arms  ICMJE
  • Active Comparator: Standard arm

    Patients will receive induction therapy with daunorubicin 60 mg/m2/day administered on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7.

    Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5.

    Patients will receive 4 cycles of consolidation therapy. Consolidation therapy consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered intravenously over three hours.

    Follow-up period: There is no maintenance therapy in the standard arm. Patients will be closely followed, in particular for molecular disease persistence or molecular relapse.

    Interventions:
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Idarubicin
  • Experimental: Investigational arm

    Patients will receive induction therapy with daunorubicin 60 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 12mg²/day on days 1,3,5) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-7. Patients will receive dasatinib 100 mg QD on days 8-21. Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day on days 1-3 (when daunorubicin is not available due to supply shortage: Idarubicin 10 mg²/day on days 1 and 3) and cytarabine 200 mg/m2/day by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21.

    Consolidation therapy (4 cycles). Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 iv over 3 hours. Patients will receive dasatinib 100 mg QD on days 4-21. Maintenance therapy: Patients completing consolidation therapy will continue to receive single agent dasatinib 100 mg QD for one year (or until relapse).

    Interventions:
    • Drug: Dasatinib
    • Drug: Cytarabine
    • Drug: Daunorubicin
    • Drug: Idarubicin
Publications * Paschka P, Schlenk RF, Weber D, Benner A, Bullinger L, Heuser M, Gaidzik VI, Thol F, Agrawal M, Teleanu V, Lübbert M, Fiedler W, Radsak M, Krauter J, Horst HA, Greil R, Mayer K, Kündgen A, Martens U, Heil G, Salih HR, Hertenstein B, Schwänen C, Wulf G, Lange E, Pfreundschuh M, Ringhoffer M, Girschikofsky M, Heinicke T, Kraemer D, Göhring G, Ganser A, Döhner K, Döhner H. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia. 2018 Jul;32(7):1621-1630. doi: 10.1038/s41375-018-0129-6. Epub 2018 Apr 17.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 3, 2019)
203
Original Estimated Enrollment  ICMJE
 (submitted: December 11, 2013)
277
Estimated Study Completion Date  ICMJE February 2024
Estimated Primary Completion Date February 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion transcript resulting from t(8;21)(q22;q22.1) (or a variant form) or of CBFB-MYH11 fusion transcript resulting from inv(16)(p13.1q22)/t(16;16)(p13.1;q22) as assessed in one of the central AMLSG reference laboratories (Ulm, Hannover)
  • Age ≥ 18; there is no upper age limit
  • No prior chemotherapy for leukemia except hydroxyurea for up to 5 days during the diagnostic screening phase
  • Non-pregnant and non-nursing. Due to the unknown teratogenic potential of dasatinib in humans, pregnant or nursing patients may not be enrolled. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL with-in 72 hours prior to registration. Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control - one highly effective method (e.g., IUD, hormonal, tubal ligation, or partner's vasectomy), and one additional effective method (e.g., latex condom, diaphragm, or cervical cap) - AT THE SAME TIME, at least four weeks before she begins dasatinib therapy. "Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months.
  • Men must agree not to father a child and must use a latex condom during any sexual contact with women of childbearing potential while taking dasatinib and for 3 months after therapy is stopped, even if they have undergone a successful vasectomy.
  • Signed written informed consent.

Exclusion Criteria:

  • Performance status WHO >2
  • Pulmonary edema and/or pleural/pericardial effusion within 14 days of day 1. If edema/effusion resolves to CTC Grade ≤1, patients can be treated with dasatinib.
  • Patients with ejection fraction <50% by echocardiography within 14 days of day 1
  • Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or AP >2.5x upper normal serum level; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
  • Uncontrolled infection
  • Patients with a "currently active" second malignancy other than non-melanoma skin cancers. Patients are not considered to have a "currently active" malignancy, if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year.
  • Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
  • Known positive for HIV, active HBV, HCV, or Hepatitis A infection
  • Bleeding disorder independent of leukemia
  • No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician and/or other physicians involved in the treatment of the patient about study participation.
  • No consent for biobanking.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Hartmut Doehner, Prof. Dr. 0049-731-500- ext 45501 hartmut.doehner@uniklinik-ulm.de
Contact: Peter Paschka, Dr. 0049-731-500 ext 45746 peter.paschka@uniklinik-ulm.de
Listed Location Countries  ICMJE Austria,   Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02013648
Other Study ID Numbers  ICMJE AMLSG 21-13
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Prof. Dr. Hartmut Doehner, University of Ulm
Study Sponsor  ICMJE University of Ulm
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Hartmut Doehner, Prof. Dr. University of Ulm
PRS Account University of Ulm
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP