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

Inclusion Criteria:

• Age ≥18 years

• Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHOcriteria (appendix A), with centrally documented FLT3 gene mutation (either TKD orITD or both). AML may be secondary to prior hematological disorders, including MDS,and/or therapy-related. Patients may have had previous treatment with erythropoiesisstimulating agents (ESA) or hypomethylating agents (HMAs) for an antecedent phase ofMDS. 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-TKDmutation. 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 dueto leukemic involvement following written approval by the (co) PrincipalInvestigator

• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkalinephosphatase (ALP) ≤ 3.0 × ULN, unless considered due to leukemic involvementfollowing written approval by the (co) Principal Investigator

• Adequate renal function as defined by creatinine clearance > 40 mL/min based on theCockroft-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 toscreening, or

• Documented surgically sterile or status posthysterectomy (at least 1 monthprior to screening)

• Or, if of childbearing potential,

• Agree not to try to become pregnant during the study and for 6 monthsafter 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 barriermethod starting at screening and throughout the study period and for 6months after the final study drug administration.

• Highly effective forms of birth control include:

• Consistent and correct usage of established hormonal contraceptivesthat inhibit ovulation,

• Established intrauterine device (IUD) or intrauterine system (IUS),

• Bilateral tubal occlusion,

• Vasectomy (A vasectomy is a highly effective contraception methodprovided the absence of sperm has been confirmed. If not, anadditional 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 ifdefined as refraining from heterosexual activity during the entireperiod of risk associated with the study drug. The reliability ofsexual abstinence needs to be evaluated in relation to the durationof the clinical study and the preferred and usual lifestyle of thepatient.

• (*)List is not all inclusive. Prior to enrollment, the investigator isresponsible for confirming patient will utilize highly effective forms ofbirth control per the requirements of the CTFG Guidance document 'Recommendations related to contraception and pregnancy testing inclinical trials', September 2014 (and any updates thereof) during theprotocol defined period.

• Female patient must agree not to breastfeed starting at screening andthroughout the study period, and for 2 months and 1 week after the final studydrug administration.

• Female patient must not donate ova starting at screening and throughout thestudy period, and for 6 months after the final study drug administration.

• Male patient and their female partners who are of childbearing potential must beusing highly effective contraception per locally accepted standards in addition to abarrier method starting at screening and continue throughout the study period andfor 4 months and 1 week after the final study drug administration.

• Male patient must not donate sperm starting at screening and throughout the studyperiod 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 withhypomethylating agents. Hydroxyurea is allowed for the control of peripheralleukemic 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 pathognomonicvariant fusion genes/chromosome translocations

• Blast crisis after CML

• Known or suspected hypersensitivity to midostaurin or gilteritinib and/or anyexcipients

• Patient requires treatment with concomitant drugs that are strong inducers ofcytochrome P450 (CYP) 3A

• Breast feeding at start of study treatment

• Active infection, including hepatitis B or C or HIV infection that is uncontrolledat randomization. An infection controlled with an approved or closely monitoredantibiotic/antiviral/antifungal treatment is allowed.

• Patients with a currently active second malignancy. Patients are not considered tohave a currently active malignancy if they have completed therapy and are consideredby 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 studytreatment, 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 obtainedwithin 28 days prior to the start of study treatment

• QTc interval using Fridericia's formula (QTcF) ≥ 450 msec (average of triplicatedeterminations) or other factors that increase the risk of QT prolongation orarrhythmic events (e.g., heart failure, family history of long QT intervalsyndrome). Prolonged QTc interval associated with bundle branch block or pacemakingis permitted with written approval of the (co) Principal Investigator.

• Patient with hypokalemia and/or hypomagnesemia before registration (defined asvalues below LLN) Note: electrolyte suppletion is allowed to correct LLN valuesbefore registration.

• Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit theingestion or gastrointestinal absorption of orally administered drugs

• Clinical symptoms suggestive of active central nervous system (CNS) leukemia orknown CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is onlyrequired if there is a clinical suspicion of CNS involvement by leukemia duringscreening

• Immediate life-threatening, severe complications of leukemia such as uncontrolledbleeding and/or disseminated intravascular coagulation

• Any other medical or psychological condition deemed by the Investigator to be likelyto interfere with a patient's ability to give informed consent or participate in thestudy

• Any psychological, familial, sociological or geographical condition potentiallyhampering compliance with the study protocol and follow-up schedule