Study of Crenolanib Combined With Chemotherapy in FLT3-mutated Acute Myeloid Leukemia Patients

Phase I-II Study of Crenolanib Combined With Standard Salvage Chemotherapy, and Crenolanib Combined With 5-Azacitidine in Acute Myeloid Leukemia Patients With FLT3 Activating Mutations

This is an open label, two-arm, Phase I-II trial, non-randomized. Arm 1: crenolanib with standard chemotherapy (Idarubicin/Cytarabine, MEC;Mitoxantrone/Etoposide/Cytarabine, FLAG-Ida: Fludarabine/Cytarabine/G-CSF/Idarubicin) Arm 2: crenolanib with 5-azacitidine

For each arm:

The phase I with dose-limiting toxicity (DLT) determination will use 3+3 design.

Phase II total of 52 patients (26 per arm) will be treated at established phase I dose.

Enrollment to be simultaneous to each arm.

Inclusion Criteria:

1. Confirmed diagnosis of refractory/relapsed AML or high-risk MDS

   • Arm 1: Subjects must have received at least one prior therapy and a maximum of three prior therapies
   • Arm 2: Subjects must have received at least one prior therapy and a maximum of three prior therapies. No prior treatment with 5-Azacitidine is allowed in this arm.

2. FLT3 mutation positive (ITD, TKD or other)

3. ECOG PS 0-2

4. Adequate liver and renal function

5. Negative pregnancy test

6. Extramedullary leukemia allowed except CNS disease

Exclusion Criteria:

• Arm 1 and 2 Exclusion:

  1. <5% blasts in marrow or blood at time of screening
  2. Active HIV, hepatitis B or C
  3. CNS leukemia
  4. Clinically significant GVHD or organ dysfunction where chemotherapy specified by protocol cannot be given
  5. Patient with AML-M3 (APL)
  6. Pre-existing liver diseases (i.e. cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, sclerosing cholangitis)