Protocol in Acute Myeloid Leukemia With FLT3-ITD

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Midostaurin
* Drug: Cytarabine
* Drug: Daunorubicin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midostaurin<br> | Drug: Midostaurin<br>* 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.<br>* Other names: PKC412;Drug: Cytarabine<br>* 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).<br>Drug: Daunorubicin<br>* Induction therapy: 60 mg/m², by 1-hour i.v. infusion, day 1-3 (total dose 180 mg/m²)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | 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. | 8years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of complete remission (CR) |  | Two months | 
| Relapse-free survival |  | 8 years | 
| overall survival |  | 8 years | 
| Cumulative incidence of relapse |  | 8 years | 
| cumulative incidence of death in CR |  | 8 years | 
| Target (FLT3) inhibition by measuring the FLT3 plasma inhibitory activity | Evaluation of target (FLT3) inhibition by continuous dosing of midostaurin | 8 years | 
| Quality of life | 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. | 5 years | 
| Rate of early deaths and hypoplastic deaths (ED/HD) |  | two months | 
| Death in CR |  | 8 years | 
| Toxicities | 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 | between 18 and 24 months | 
| Impact of allogeneic HSCT | Assessment of the relative impact of allogeneic HSCT analyzed as time-dependent variable on survival endpoints. | 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, FLT3-ITD, midostaurin (PKC412)