A Study of Gilteritinib Versus Midostaurin in Combination With Induction and Consolidation Therapy Followed by One-year Maintenance in Patients With Newly Diagnosed Acute Myeloid Leukemia or Myelodysplastic Syndromes With Excess Blasts-2 With FLT3 Mutations Eligible for Intensive Chemotherapy

  • End date
    Sep 23, 2032
  • participants needed
  • sponsor
    Stichting Hemato-Oncologie voor Volwassenen Nederland
Updated on 23 January 2021
myelodysplastic syndromes
hematologic disorder
consolidation therapy
serum bilirubin level
flt3 internal tandem duplication
consolidation chemotherapies
blast cells


Activating mutations in the fms like tyrosine kinase 3 (FLT3) gene are observed in approximately 30% of patients with newly diagnosed acute myeloid leukemia (AML). Addition of the multitargeted kinase inhibitor midostaurin to standard chemotherapy prolongs event-free survival (EFS) and overall survival (OS) in patients with a FLT3 mutation. Gilteritinib is a more potent and more specific inhibitor of mutant FLT3 in comparison to midostaurin and has shown promising clinical activity in AML.


AML and MDS-EB2 are malignant diseases of the bone marrow. The standard treatment for these diseases is chemotherapy. A subgroup of these diseases is characterized by a specific error in the DNA of the leukemic cells. This is the FLT3 mutation, which leads to a change of a certain protein (FLT3) on the blasts. This altered protein plays an important role in the development of leukemia and the survival of leukemic cells.

FLT3 can be inhibited by the drug midostaurin. Adding midostaurin to chemotherapy leads to better treatment results in patients with AML. Therefore, the standard treatment for AML or MDS-EB2 with a FLT3 mutation (FLT3-AML) is a combination of chemotherapy and midostaurin.

Gilteritinib is also a drug that inhibits FLT3. In laboratory studies, gilteritinib was found to be significantly more specific and potent than midostaurin in inhibiting FLT3.

Gilteritinib has subsequently been studied in patients with AML, who relapsed after previous treatment with chemotherapy. This resulted in a much larger number of complete remissions than previously seen when comparable patients were treated with midostaurin.

Condition Acute myeloid leukemia, Acute Myelogenous Leukemia (AML), Myelodysplastic Syndrome With Excess Blasts-2, Myelodysplastic Syndrome With Excess Blasts-2, acute myelogenous leukemia, anll, acute myeloblastic leukemia, Myelodysplastic Syndrome With Excess Blasts-2
Treatment Gilteritinib, Midostaurin
Clinical Study IdentifierNCT04027309
SponsorStichting Hemato-Oncologie voor Volwassenen Nederland
Last Modified on23 January 2021


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Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Acute myeloid leukemia or Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome With Excess Blasts-2?
Do you have any of these conditions: Myelodysplastic Syndrome With Excess Blasts-2 or acute myeloblastic leukemia or anll or Acute Myelogenous Leukemia (AML) or acute myelogenous leukemia...?
Age 18 years
Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or ITD or both). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related. Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase of MDS. ESA and HMAs have to be stopped at least four weeks before registration
FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of 0.05 (5%)
Considered to be eligible for intensive chemotherapy
Patient is suitable for oral administration of study drug
WHO/ECOG performance status 2
Adequate hepatic function as evidenced by
Serum total bilirubin 2.5 upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) 3.0 ULN, unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
Adequate renal function as defined by creatinine clearance > 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
Written informed consent
Patient is capable of giving informed consent
Female patient must either
Be of nonchildbearing potential
Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
Or, if of childbearing potential
Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
And have a negative urine or serum pregnancy test at screening
And, if heterosexually active, agree to consistently use highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration
Highly effective forms of birth control include
Consistent and correct usage of established hormonal contraceptives that inhibit ovulation
Established intrauterine device (IUD) or intrauterine system (IUS)
Bilateral tubal occlusion
Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)
Male is sterile due to a bilateral orchiectomy
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient
()List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per locally accepted standards during the protocol defined period
Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration
Female patient must not donate ova starting at screening and throughout the study period, and for 6 months after the final study drug administration
Male patient and their female partners who are of childbearing potential must be using highly effective contraception per locally accepted standards in addition to a barrier method starting at screening and continue throughout the study period and for 4 months and 1 week after the final study drug administration
Male patient must not donate sperm starting at screening and throughout the study period and for 4 months and 1 week after the final study drug administration
Patient agrees not to participate in another interventional study while on treatment

Exclusion Criteria

Prior chemotherapy for AML or MDS-EB2, including prior treatment with hypomethylating agents. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 30 x 10^9/L)
Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
Blast crisis after CML
Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
Breast feeding at start of study treatment
Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed
Patients with a currently active second malignancy. 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. However, patients with the following history/concurrent conditions are allowed
Basal or squamous cell carcinoma of the skin
Carcinoma in situ of the cervix
Carcinoma in situ of the breast
Incidental histologic finding of prostate cancer
Significant active cardiac disease within 6 months prior to the start of study treatment, including
New York Heart Association (NYHA) Class III or IV congestive heart failure
Myocardial infarction
Unstable angina and/or stroke
Left ventricular ejection fraction (LVEF) < 40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment
QTc interval using Fridericia's formula (QTcF) 450 msec (average of triplicate determinations) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the (co) Principal Investigator
Patient with hypokalemia and/or hypomagnesemia at screening (defined as values below LLN) Note: electrolyte suppletion is allowed to correct LLN values before screening
Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening
Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient's ability to give informed consent or participate in the study
Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
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