Withdrawn: Study halted prior to enrollment of first participant

This is a phase II, multicenter, single-arm study to assess the safety and feasibility of combining crenolanib with fludarabine and cytarabine chemotherapy in pediatric patients with relapsed/refractory FLT3-mutated AML. Patients will receive up to two courses of salvage chemotherapy with fludarabine, cytarabine, and crenolanib. Response will be assessed between day 29-43 of each course.

Inclusion Criteria:

1. Age ≥ 1 years and ≤ 21 years

2. Confirmed diagnosis of AML according to World Health Organization (WHO) 2016 classification

3. Definitive evidence of a FLT3-ITD and/or FLT3-TKD (D835/I836) mutation at the time of enrollment

4. Patients must have histologically or molecularly confirmed relapsed or refractory AML

5. Karnofsky or Lansky performance score ≥ 50. Use Karnofsky for patients > 16 years old and Lansky for patients ≤ 16 years of age.

6. Adequate renal function, defined as:

   • Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or
   • Normal serum creatinine based on age/gender

7. Adequate liver function, defined as:

   • Serum total bilirubin ≤ 1.5x ULN for age,
   • Serum aspartate aminotransferase (AST) ≤ 3.0x ULN for age, and
   • Serum alanine aminotransferase (ALT) ≤ 3.0x ULN for age.

Exclusion Criteria:

1. Patients with any of the following current or previous diagnoses:

   • Acute promyelocytic leukemia (APL)
   • Down syndrome
   • DNA fragility or bone marrow failure syndromes (such as Fanconi anemia, Bloom syndrome, Kostmann syndrome, or Shwachman syndrome)
   • AML secondary to prior MDS/MPN, including chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia
   • Blastic plasmacytoid dendritic cell neoplasm
   • Acute leukemia of ambiguous lineage
   • B-lymphoblastic leukemia/lymphoma
   • T-lymphoblastic leukemia/lymphoma, including early T-cell precursor lymphoblastic leukemia (ETP-ALL)

2. Patients who are refractory to first line (induction and re-induction) and a second line (1st salvage) treatment for AML.

3. Patients who have received more than 1 prior allogeneic HSCT

4. Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection of which they exhibit ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment.

5. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.

6. Known severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis or hyperbilirubinemia)

7. Known, active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV)

8. Currently receiving prophylactic treatment of hepatitis B with anti-viral therapy

9. Known infection with human immunodeficiency virus (HIV)