Crenolanib in Combination With Sorafenib in Patients With Refractory or Relapsed Hematologic Malignancies

Inclusion Criteria - Initial Enrollment:

* Participant has a relapsed or refractory hematologic malignancy (with any measurable disease) with FLT3-ITD or TKD mutations and one of the following diagnoses:

  * Acute myeloid leukemia (AML)
  * AML with prior myelodysplastic syndrome (MDS)
  * Myeloperoxidase (MPO)-positive mixed phenotype acute leukemia
* Participant's disease has relapsed after, is refractory to induction and/or salvage therapy, or has relapsed after hematopoietic stem cell transplant (HSCT).
* Participant disease tested positive for FLT3-ITD or -TKD within 60-day screening period.
* Participant's age is 1 to 25 years, inclusive (St. Jude participants must be aged 1 to 25 years, inclusive).
* Karnofsky or Lansky performance score is \> 60%. The Lansky performance score should be used for participants \< 16 years and the Karnofsky performance score for participants ≥ 16 years.
* Adequate organ function defined as:

  * Bilirubin ≤1.5 x upper limit of normal (ULN)
  * ALT ≤ 3 x ULN and AST ≤ 3 x ULN
  * Serum creatinine ≤1.5 x ULN
* Participant must have recovered from the acute side effects of all prior anti-cancer therapy, and:

  * At least 2 weeks have elapsed since prior systemic cytotoxic chemotherapy (except intrathecal chemotherapy, hydroxyurea, low-dose cytarabine, and/or low dose maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids), and
  * If the participant received a prior allogeneic HSCT, at least 30 days have elapsed and there is no evidence of clinically significant graft versus host disease requiring treatment and/or have \> grade 2 persistent non-hematologic toxicity related to a transplant

Exclusion Criteria - Initial Enrollment:

* Concurrent chemotherapy, or targeted anti-cancer agents, other than hydroxyurea, low-dose cytarabine, intrathecal therapy and/or low dose maintenance therapy such as vincristine, mercaptopurine, methotrexate or glucocorticoids.
* Patient with concurrent severe and/or uncontrolled medical conditions that, in the opinion of the investigator, may impair participation in the study or the evaluation of safety and/or efficacy.
* Known HIV infection or active hepatitis B (defined as hepatitis B surface antigen-positive) or C (defined as hepatitis C antibody-positive).
* Prior crenolanib treatment for a non-leukemic indication.
* Major surgical procedures within 14 days of Day 1 administration of crenolanib.
* Pregnant or lactating (female participant of childbearing potential must have negative serum or urine pregnancy test required within 7 days prior to start of treatment).
* Male or female participant of reproductive potential must agree to use appropriate methods of contraception for the duration of study treatment and for at least 30 days after last dose of protocol treatment
* Inability or unwillingness or research participant or legal guardian/representative to give written informed consent.

Inclusion Criteria - Maintenance Therapy After HSCT:

* Patient must have received crenolanib on this protocol prior to HSCT to continue on to maintenance.
* Patient must be within 30 - 120 days after hematopoietic stem cell transplant (HSCT).
* Response to previous treatment on this protocol: at least resistant disease with clinical benefit or better response.
* Patient is off or on a stable dose of immunosuppressive drugs for management or prophylaxis of graft-versus-host-disease (GVHD) (defined as no escalation of therapy for GVHD) within 14 days prior to starting crenolanib.
* Patient must have recovered from acute side effects of HSCT, defined as having \<Grade 2 non-hematological toxicity related to the transplant (exceptions are alopecia and other non-acute toxicities).
* Adequate hematopoietic recovery (ANC \>500/mm\^3 and platelet count \>50,000/mm\^3)
* Research participant or legal guardian/representative is able and willing to give written informed consent.