Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations

Inclusion Criteria:

1. Patients with confirmed diagnosis of AML either refractory to induction therapy orrelapsed after first line treatment including chemotherapy, autologous and allogeneicHCT
2. refractory to induction therapy is defined as no CR, CRi, PR (according tostandard criteria, 28) after one intensive induction therapy including at least 7days of cytarabine 100-200mg/m² continuously or an equivalent regimen withcytarabine with total dose not less than 700mg/m² per cycle and 3 days of ananthracycline (e.g. daunorubicin, idarubicin)
3. relapsed after first line therapy is defined as relapsed AML (according tostandard criteria, 28) after a first line therapy including at least oneintensive induction and consolidation therapy
4. Presence of FLT3-activating mutation at the time of refractory disease or relapseassessed in the central AMLSG reference laboratory within AMLSG BiO study (ClinicalTrials.gov Identifier: NCT01252485); positivity of FLT3-ITD and FLT3-TKD isdefined based on genescan analysis with a mutant to wild-type ratio equal or above 5%
5. Patients considered eligible for intensive chemotherapy
6. ECOG performance status of ≤ 2
7. Age ≥ 18 years with the capacity to give written informed consent
8. Non-pregnant and non-nursing women of childbearing potential (WOCBP) must have anegative serum or urine pregnancy test within a sensitivity of at least 25 mIU/mLwithin 72 hours prior to registration ("Women of childbearing potential" is defined asa sexually active mature woman who has not undergone a hysterectomy or who has hadmenses at any time in the preceding 24 consecutive months).
9. Female patients of reproductive age must agree to avoid getting pregnant while ontherapy and for 3 months after the last dose of crenolanib.
10. Women of child-bearing potential must either commit to continued abstinence fromheterosexual intercourse or begin one acceptable method of birth control (IUD, tuballigation, or partner's vasectomy). Hormonal contraception is an inadequate method ofbirth control.
11. Men must use a latex condom during any sexual contact with women of childbearingpotential, even if they have undergone a successful vasectomy and must agree to avoidto father a child (while on therapy and for 3 month after the last dose ofcrenolanib).
12. Willing to adhere to protocol specific requirements
13. Following receipt of verbal and written information about the study, the patient mustprovide signed informed consent before any study related activity is carried out.

Exclusion Criteria: The presence of any of the following will exclude a patient from study enrollment:

1. Known or suspected hypersensitivity to the study drugs and/or any excipients
2. ECOG performance status >2
3. Inadequate cardiac, hepatic and/or renal function at the Screening Visit defined as:

• ejection fraction < 45% confirmed by echocardiography
• creatinine >1.5x upper normal serum level
• total bilirubin > upper normal serum level
• AST or ALT >2x upper normal serum level

4. Active central nervous system involvement
5. Any clinically significant, advanced or unstable disease or history of that mayinterfere with primary or secondary variable evaluations or put the patient at specialrisk, such as:

• Myocardial infarction, unstable angina within 3 months before screening
• Heart failure NYHA III/IV
• Severe obstructive or restrictive ventilation disorder
• Uncontrolled infection

6. Severe neurological or psychiatric disorder interfering with ability of giving aninformed consent
7. Currently receiving a therapy not permitted during the study, as defined in Section 10.6.5
8. Active Graft-versus-Host Disease (GvHD) under immunosuppressive therapy different fromsteroids
9. Patients with a "currently active" second malignancy other than non-melanoma skincancers. Patients are not considered to have a "currently active" malignancy if theyhave completed therapy and are considered by their physician to be at less than 30%risk of relapse within one year.
10. Pre-existing liver disease (e.g.,. cirrhosis, chronic hepatitis B or C, nonalcoholicsteatohepatitis, sclerosing cholangitis)
11. Known history of positive test for hepatitis B surface antigen (HsbAg) or hepatitis Cantibody or history of positive test for Human Immunodeficiency Virus (HIV)
12. Hematologic disorder independent of leukemia
13. No consent for registration, storage and processing of the individual diseasecharacteristics and course as well as information of the family physician and/or otherphysicians involved in the treatment of the patient about study participation
14. No consent for biobanking
15. Current participation in any other interventional clinical study within 30 days beforethe first administration of the investigational product or at any time during thestudy
16. Patients known or suspected of not being able to comply with this trial protocol
17. Breast feeding women or women with a positive pregnancy test at Screening visit
18. Patients of childbearing potential not willing to use adequate contraception duringstudy and 3 months after last dose of crenolanib.