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Protocol in Acute Myeloid Leukemia With FLT3-ITD

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by University of Ulm
Sponsor:
Collaborator:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Dr. Richard Schlenk, University of Ulm
ClinicalTrials.gov Identifier:
NCT01477606
First received: November 17, 2011
Last updated: October 13, 2014
Last verified: October 2014
  Purpose

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: 284 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: 48 months


Condition Intervention Phase
Acute Myeloid Leukemia
Drug: Midostaurin
Drug: Cytarabine
Drug: Daunorubicin
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by University of Ulm:

Primary Outcome Measures:
  • Event-free Survival [ Time Frame: Four years ] [ Designated as safety issue: Yes ]
    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:
  • Rate of complete remission (CR) [ Time Frame: Two months ] [ Designated as safety issue: No ]
  • Relapse-free survival [ Time Frame: four years ] [ Designated as safety issue: No ]
  • overall survival [ Time Frame: four years ] [ Designated as safety issue: Yes ]
  • Cumulative incidence of relapse [ Time Frame: four years ] [ Designated as safety issue: No ]
  • cumulative incidence of death in CR [ Time Frame: four years ] [ Designated as safety issue: Yes ]
  • Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity [ Time Frame: four years ] [ Designated as safety issue: No ]
    Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin

  • Quality of life [ Time Frame: 5 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: Yes ]
  • Death in CR [ Time Frame: four years ] [ Designated as safety issue: Yes ]
  • Toxicities [ Time Frame: between 18 and 24 months ] [ Designated as safety issue: Yes ]
    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: Four years ] [ Designated as safety issue: No ]
    Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints.


Estimated Enrollment: 284
Study Start Date: May 2012
Estimated Study Completion Date: December 2019
Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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)


  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 3 month 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 3 month 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01477606

Contacts
Contact: Peter Paschka, MD +49-731-500-0 peter.paschka@uniklinik-ulm.de

  Show 50 Study Locations
Sponsors and Collaborators
University of Ulm
Novartis Pharmaceuticals
Investigators
Principal Investigator: Richard F Schlenk, MD University Hospital of Ulm
  More Information

No publications provided

Responsible Party: Dr. Richard Schlenk, PD Dr. Richard Schlenk, University of Ulm
ClinicalTrials.gov Identifier: NCT01477606     History of Changes
Other Study ID Numbers: AMLSG 16-10, 2011-003168-63
Study First Received: November 17, 2011
Last Updated: October 13, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by University of Ulm:
Acute myeloid leukemia
FLT3-ITD
midostaurin (PKC412)

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms
Neoplasms by Histologic Type
4'-N-benzoylstaurosporine
Daunorubicin
Antibiotics, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Topoisomerase II Inhibitors
Topoisomerase Inhibitors

ClinicalTrials.gov processed this record on November 19, 2014