A phase 3, multicenter, open-label, randomized, 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 (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations eligible for intensive chemotherapy

• 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) for MDS. ESA 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
o Serum total bilirubin <= 2.5 × upper limit of normal (ULN) unless considered
due to leukemic involvement following written approval by the (co) Principal
Investigator
o 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:
o 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)
o 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 the requirements of the CTFG Guidance document *Recommendations
related to contraception and pregnancy testing in clinical trials*, September
2014 (and any updates thereof) during the protocol defined period.
o 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.
o 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

• 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
• Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any
excipients
• 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:
o Basal or squamous cell carcinoma of the skin;
o Carcinoma in situ of the cervix;
o Carcinoma in situ of the breast;
o Incidental histologic finding of prostate cancer
• Significant active cardiac disease within 6 months prior to the start of
study treatment, including:
o New York Heart Association (NYHA) Class III or IV congestive heart failure;
o Myocardial infarction;
o Unstable angina and/or stroke;
o 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 before registration (defined
as values below LLN) Note: electrolyte suppletion is allowed to correct LLN
values before registration.
• 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