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

Dose-Finding Run-in Phase I Followed by a Phase III, Multicenter, Randomized, Double-Blind, Placebo-controlled Study of Crenolanib in Combination With Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia and Activating FLT3 Mutations

The main trial is a double-blinded, placebo-controlled, randomized, phase III, multi-center trial in adult patients with relapsed or refractory AML harboring an activating FLT3 mutation as defined in the inclusion /exclusion criteria.

An initial open label dose-finding run-in phase I of the study will be performed administering the study drug crenolanib with salvage chemotherapy consisting of mitoxantrone and cytarabine (MC) in 18 patients according to the experimental arm of the study. After completion of this dose-finding run-in phase I, toxicity and response data will be provided to the external Data and Safety Monitoring Board (DSMB) and the Trial Committee by the Coordinating Investigator. The Trial Committee will decide on the basis of these data and the recommendation of the DSMB on dose modification and the further conduct of the study with regard to the double-blinded, placebo-controlled, randomized phase of the study.

The double-blinded, placebo-controlled randomized portion will start after the completion of the dose-finding run-in phase I and positive opinion of the Trial Committee.

Crenolanib starts on day 7 of MC and is given continuously until 48 hours prior to the next chemotherapy; if receiving allogeneic HCT, crenolanib is held 48 hours prior to conditioning and restarts no sooner than 30 days and not later than day 100 after transplant.

Sample size randomized phase: 276 patients

Primary objective: To evaluate the impact of crenolanib given in combination with salvage chemotherapy and consolidation including allogeneic hematopoietic cell transplantation and ongoing single agent maintenance therapy with crenolanib on event-free (EFS) and overall survival (OS) in adult patients with relapsed or refractory AML harboring FLT3 activating mutations.

Inclusion Criteria:

1. Patients with confirmed diagnosis of AML either refractory to induction therapy or relapsed after first line treatment including chemotherapy, autologous and allogeneic HCT

   1. refractory to induction therapy is defined as no CR, CRi, PR (according to standard criteria, 28) after one intensive induction therapy including at least 7 days of cytarabine 100-200mg/m² continuously or an equivalent regimen with cytarabine with total dose not less than 700mg/m² per cycle and 3 days of an anthracycline (e.g. daunorubicin, idarubicin)
   2. relapsed after first line therapy is defined as relapsed AML (according to standard criteria, 28) after a first line therapy including at least one intensive induction and consolidation therapy

2. Presence of FLT3-activating mutation at the time of refractory disease or relapse assessed in the central AMLSG reference laboratory within AMLSG BiO study (ClinicalTrials.gov Identifier: NCT01252485); positivity of FLT3-ITD and FLT3-TKD is defined based on genescan analysis with a mutant to wild-type ratio equal or above 5%

3. Patients considered eligible for intensive chemotherapy

4. ECOG performance status of ≤ 2

5. Age ≥ 18 years with the capacity to give written informed consent

6. 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).

7. Female patients of reproductive age must agree to avoid getting pregnant while on therapy and for 3 months after the last dose of crenolanib.

8. 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.

9. Men must use a latex condom during any sexual contact with women of childbearing potential, even if they have undergone a successful vasectomy and must agree to avoid to father a child (while on therapy and for 3 month after the last dose of crenolanib).

10. Willing to adhere to protocol specific requirements

11. Following receipt of verbal and written information about the study, the patient must provide 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 may interfere with primary or secondary variable evaluations or put the patient at special risk, 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 an informed 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 from steroids

9. 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.

10. Pre-existing liver disease (e.g.,. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)

11. Known history of positive test for hepatitis B surface antigen (HsbAg) or hepatitis C antibody 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 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

14. No consent for biobanking

15. Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study

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 during study and 3 months after last dose of crenolanib.