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Protocol in Acute Myeloid Leukemia With FLT3-ITD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01477606
Recruitment Status : Completed
First Posted : November 22, 2011
Last Update Posted : June 4, 2020
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Prof. Dr. Hartmut Doehner, University of Ulm

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

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Midostaurin Drug: Cytarabine Drug: Daunorubicin Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 451 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2012
Actual Primary Completion Date : February 26, 2020
Actual Study Completion Date : February 26, 2020

Arm Intervention/treatment
Experimental: Midostaurin 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)

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. Rate of complete remission (CR) [ Time Frame: Two months ]
  2. Relapse-free survival [ Time Frame: 8 years ]
  3. overall survival [ Time Frame: 8 years ]
  4. Cumulative incidence of relapse [ Time Frame: 8 years ]
  5. cumulative incidence of death in CR [ Time Frame: 8 years ]
  6. Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity [ Time Frame: 8 years ]
    Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin

  7. 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.

  8. Rate of early deaths and hypoplastic deaths (ED/HD) [ Time Frame: two months ]
  9. Death in CR [ Time Frame: 8 years ]
  10. 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

  11. Impact of allogeneic HSCT [ Time Frame: 8 years ]
    Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01477606

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Sponsors and Collaborators
University of Ulm
Novartis Pharmaceuticals
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Principal Investigator: Hartmut Doehner, MD University Hospital of Ulm
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Prof. Dr. Hartmut Doehner, University of Ulm Identifier: NCT01477606    
Other Study ID Numbers: AMLSG 16-10
2011-003168-63 ( EudraCT Number )
First Posted: November 22, 2011    Key Record Dates
Last Update Posted: June 4, 2020
Last Verified: June 2020
Keywords provided by Prof. Dr. Hartmut Doehner, University of Ulm:
Acute myeloid leukemia
midostaurin (PKC412)
Additional relevant MeSH terms:
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Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors