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Protocol in Acute Myeloid Leukemia With FLT3-ITD

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ClinicalTrials.gov Identifier: NCT01477606
Recruitment Status : Active, not recruiting
First Posted : November 22, 2011
Last Update Posted : May 17, 2019
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Prof. Dr. Hartmut Doehner, University of Ulm

Tracking Information
First Submitted Date  ICMJE November 17, 2011
First Posted Date  ICMJE November 22, 2011
Last Update Posted Date May 17, 2019
Study Start Date  ICMJE May 2012
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 7, 2017)
Event-free Survival [ Time Frame: 8years ]
To perform two predefined subgroup analyses in the age-groups 18-60 years and 61-70 years evaluating the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.
Original Primary Outcome Measures  ICMJE
 (submitted: November 21, 2011)
Event-free Survival [ Time Frame: Two years ]
To evaluate the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.
Change History Complete list of historical versions of study NCT01477606 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 7, 2017)
  • Rate of complete remission (CR) [ Time Frame: Two months ]
  • Relapse-free survival [ Time Frame: 8 years ]
  • overall survival [ Time Frame: 8 years ]
  • Cumulative incidence of relapse [ Time Frame: 8 years ]
  • cumulative incidence of death in CR [ Time Frame: 8 years ]
  • Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity [ Time Frame: 8 years ]
    Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin
  • Quality of life [ Time Frame: 5 years ]
    Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics initially, in first CR, after one year,3 and 5 years after initial diagnosis.
  • Rate of early deaths and hypoplastic deaths (ED/HD) [ Time Frame: two months ]
  • Death in CR [ Time Frame: 8 years ]
  • Toxicities [ Time Frame: between 18 and 24 months ]
    Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0), timing and relatedness of hematological and non-hematological toxicities observed during the different treatment cycles
  • Impact of allogeneic HSCT [ Time Frame: 8 years ]
    Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 21, 2011)
  • Rate of complete remission (CR) [ Time Frame: Two months ]
  • Relapse-free survival [ Time Frame: four years ]
  • overall survival [ Time Frame: four years ]
  • Cumulative incidence of relapse [ Time Frame: four years ]
  • cumulative incidence of death in CR [ Time Frame: four years ]
  • Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity [ Time Frame: four years ]
    Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin
  • Quality of life [ Time Frame: 5 years ]
    Quality of life assessed by the EORTC Quality of Life Core Questionnaire (QLQ-C30), supplemented by information on self-assessed concomitant diseases, late treatment effects, and demographics initially, in first CR, after one year,3 and 5 years after initial diagnosis.
  • Rate of early deaths and hypoplastic deaths (ED/HD) [ Time Frame: two months ]
  • Death in CR [ Time Frame: four years ]
  • Toxicities [ Time Frame: between 18 and 24 months ]
    Type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 3.0), timing and relatedness of hematological and non-hematological toxicities observed during the different treatment cycles
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Protocol in Acute Myeloid Leukemia With FLT3-ITD
Official Title  ICMJE Phase-II Study Evaluating Midostaurin in Induction, Consolidation and Maintenance Therapy Also After Allogeneic Blood Stem Cell Transplantation in Patients With Newly Diagnosed Acute Myeloid Leukemia Exhibiting a FLT3 Internal Tandem Duplication
Brief Summary

This is a phase II, single-arm, open-label, multi-center study in adult patients with Acute Myeloid Leukemia (AML) and FLT3-ITD as defined in inclusion/exclusion criteria.

The primary efficacy object is to evaluate the impact of midostaurin given in combination with intensive induction, consolidation including allogeneic hematopoietic stem cell transplantation and single agent maintenance therapy on event-free survival (EFS) in adult patients with AML exhibiting a FLT3-ITD.

Sample size: 440 patients

The treatment duration of an individual patient is between 18 and 24 months. Duration of the study for an individual patient including treatment (induction, consolidation [chemotherapy or allogeneic SCT], maintenance and follow-up period: Maximum 8 years

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Acute Myeloid Leukemia
Intervention  ICMJE
  • Drug: Midostaurin

    Induction therapy: 50 mg, oral, twice daily, starting on day 8, thereafter continuous dosing until 48h before start of subsequent chemotherapy cycle.

    Consolidation therapy: 50 mg, oral twice daily, starting on day 6, thereafter continuous dosing until 48h before start of conditioning therapy for allogeneic HSCT or 48h before start of subsequent consolidation chemotherapy.

    Maintenance therapy:

    50 mg oral twice daily over one year.

    Other Name: PKC412
  • Drug: Cytarabine

    Induction therapy:

    200 mg/m2/day by continuous i.v. infusion on days 1-7 (total dose 1400 mg/m²)

    Consolidation therapy:

    Younger adult patients (18 to 65 yrs): 3 g/m2 by i.v infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 18 g/m2).

    Older patients (>65 yrs): 1 g/m2 by i.v. infusion over 3 hours every 12 hours on days 1, 3, and 5 (total dose 6 g/m2).

  • Drug: Daunorubicin

    Induction therapy:

    60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²)

Study Arms  ICMJE Experimental: Midostaurin
Interventions:
  • Drug: Midostaurin
  • Drug: Cytarabine
  • Drug: Daunorubicin
Publications * Schlenk RF, Weber D, Fiedler W, Salih HR, Wulf G, Salwender H, Schroeder T, Kindler T, Lübbert M, Wolf D, Westermann J, Kraemer D, Götze KS, Horst HA, Krauter J, Girschikofsky M, Ringhoffer M, Südhoff T, Held G, Derigs HG, Schroers R, Greil R, Grießhammer M, Lange E, Burchardt A, Martens U, Hertenstein B, Marretta L, Heuser M, Thol F, Gaidzik VI, Herr W, Krzykalla J, Benner A, Döhner K, Ganser A, Paschka P, Döhner H; German-Austrian AML Study Group. Midostaurin added to chemotherapy and continued single-agent maintenance therapy in acute myeloid leukemia with FLT3-ITD. Blood. 2019 Feb 21;133(8):840-851. doi: 10.1182/blood-2018-08-869453. Epub 2018 Dec 18.

*   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 Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 9, 2016)
440
Original Estimated Enrollment  ICMJE
 (submitted: November 21, 2011)
142
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with suspected diagnosis of AML or related precursor neoplasm, or acute leukemia of ambiguous lineage (classified according to the World Health Organization (WHO) 2008 classification)
  • Presence of FLT3-ITD assessed in the central AMLSG reference laboratories
  • Patients considered eligible for intensive chemotherapy
  • WHO performance status of ≤ 2
  • Age ≥ 18 years and ≤ 70 years
  • No prior chemotherapy for leukemia except hydroxyurea to control hyperleukocytosis (≤ 7 days)
  • Non-pregnant and non-nursing. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mL within 72 hours prior to registration ("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)
  • Female patients in the reproductive age and male patients must agree to avoid getting pregnant or to father a child while on therapy and for 5 months after the last dose of chemotherapy
  • Women of child-bearing potential must either commit to continued abstinence from heterosexual intercourse or begin one acceptable method of birth control (IUD, tubal ligation, or partner's vasectomy). Hormonal contraception is an inadequate method of birth control
  • Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy (while on therapy and for 5 months after the last dose of chemotherapy)
  • Signed written informed consent.

Exclusion Criteria:

•AML with the following recurrent genetic abnormalities (according to WHO 2008): AML with t(8;21)(q22;q22); RUNX1-RUNX1T1 AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 AML with t(15;17)(q22;q12); PML-RARA (or variant translocations with other RARA gene fusions)

  • Performance status WHO >2
  • Patients with ejection fraction < 50% by MUGA or ECHO scan within 14 days of day 1
  • Organ insufficiency (creatinine >1.5x upper normal serum level; bilirubin, AST or ALP >2.5x upper normal serum level, not attributable to AML; heart failure NYHA III/IV; severe obstructive or restrictive ventilation disorder)
  • Uncontrolled infection
  • Severe neurological or psychiatric disorder interfering with ability of giving an informed consent
  • 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
  • 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 to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Austria,   Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01477606
Other Study ID Numbers  ICMJE AMLSG 16-10
2011-003168-63 ( EudraCT Number )
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 Novartis Pharmaceuticals
Investigators  ICMJE
Principal Investigator: Hartmut Doehner, MD University Hospital of Ulm
PRS Account University of Ulm
Verification Date May 2019

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