Clinical Trials /

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

NCT02013648

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

Related Conditions:
  • Core Binding Factor Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Randomized Phase III Study of Intensive Chemotherapy With or Without Dasatinib (Sprycel™)
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: AMLSG 21-13
  • NCT ID: NCT02013648

Conditions

  • Acute Myeloid Leukemia (AML)

Interventions

DrugSynonymsArms
DasatinibSprycelInvestigational arm
CytarabineARA-cellStandard arm
DaunorubicinDaunoblastinStandard arm

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Standard armActive ComparatorInduction therapy: Patients will receive induction therapy (one or two cycles) with daunorubicin 60 mg/m2/day administered on days 1-3 and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. No dose reduction is planned in elderly (>60 years) patients. Optional second induction cycle: Patients achieving PR only at the end of cycle 1 will receive a second induction cycle with daunorubicin 50 mg/m2/day administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion daily on days 1-5. Consolidation therapy: 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.
  • Cytarabine
  • Daunorubicin
Investigational armExperimentalInduction therapy: Patients will receive induction therapy (one or two cycles) with daunorubicin 60 mg/m2/day administered on days 1-3 and cytarabine 200 mg/m2/day administered by continuous IV infusion on days 1-7. Patients will receive dasatinib 100 mg once daily (QD) on days 8-21. Opt. 2nd induction cycle: Patients achieving PR only at the end of cycle 1 will receive a 2nd induction cycle with daunorubicin 50 mg/m2/day administered on days 1-3 and cytarabine 200 mg/m2/day administered by cont. IV infusion on days 1-5. Patients will receive dasatinib 100 mg QD on days 6-21. Consolidation therapy: Patients will receive 4 consolidation cycles. Treatment consists of high-dose cytarabine 3 g/m2 (>60 years: 1 g/m2) q12h, days 1-3 administered 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).
  • Dasatinib
  • Cytarabine
  • Daunorubicin

Eligibility Criteria

        Inclusion Criteria:

          -  Core-binding factor (CBF) AML with molecular diagnosis of RUNX1-RUNX1T1 fusion
             transcript resulting from t(8;21)(q22;q22) (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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free Survival
Time Frame:4 years
Safety Issue:
Description: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

Secondary Outcome Measures

Measure:Cumulative incidence of relapse (CIR)
Time Frame:4 years
Safety Issue:
Description:
Measure:Cumulative incidence of death (CID)
Time Frame:4 years
Safety Issue:
Description:
Measure:overall survival
Time Frame:4 years
Safety Issue:
Description:
Measure:relapse-free survival
Time Frame:4 years
Safety Issue:
Description:
Measure:PIA analysis
Time Frame:4 years
Safety Issue:
Description:Pharmacodynamic inhibition of KIT as assessed by the KIT plasma inhibitory assay (PIA)
Measure:toxicity
Time Frame:7 months (standard arm) / 19 months (investigational arm)
Safety Issue:
Description: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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Ulm

Trial Keywords

  • AML
  • Dasatinib
  • Core Binding Factor (CBF)

Last Updated