A Study of Crenolanib With Fludarabine and Cytarabine in Pediatric Patients With Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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.

Official Title
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A Phase II Study of Crenolanib With Fludarabine and Cytarabine in Pediatric Patients With Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia

Conditions
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Relapsed/Refractory FLT3-mutated AML

Intervention / Treatment
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* Drug: Crenolanib
* Drug: Fludarabine
* Drug: Cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 1 years and ≤ 21 years Confirmed diagnosis of AML according to World Health Organization (WHO) 2016 classification Definitive evidence of a FLT3-ITD and/or FLT3-TKD (D835/I836) mutation at the time of enrollment Patients must have histologically or molecularly confirmed relapsed or refractory AML Karnofsky or Lansky performance score ≥ 50. Use Karnofsky for patients > 16 years old and Lansky for patients ≤ 16 years of age. Adequate renal function, defined as: Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m2 or Normal serum creatinine based on age/gender 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: 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) Patients who are refractory to first line (induction and re-induction) and a second line (1st salvage) treatment for AML. Patients who have received more than 1 prior allogeneic HSCT 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. Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period. Known severe liver disease (e.g. cirrhosis, non-alcoholic steatohepatitis, sclerosing cholangitis or hyperbilirubinemia) Known, active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) Currently receiving prophylactic treatment of hepatitis B with anti-viral therapy Known infection with human immunodeficiency virus (HIV)

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crenolanib<br> | Drug: Crenolanib<br>* 66.7 mg/m2 three times a day (TID)<br>* Other names: Crenolanib besylate;Drug: Fludarabine<br>* 30 mg/m2/day, intravenous infusions over 30 mins.<br>Drug: Cytarabine<br>* 2000 mg/m2/day, intravenous infusions over 1-3 hours.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients experiencing ≥ Grade 3 adverse events as assessed by CTCAE v4.0 |  | From study entry to 30 days post-treatment | 
| Number of patients experiencing Grade 4 adverse events related to crenolanib as assessed by CTCAE v4.0 |  | 60 days | 
| Rate of early mortality | Number of patients who died within 60 days of start of therapy | 60 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | EFS is defined as the time from the date of start of treatment to the date of failure to achieve a remission, relapse, or death from any cause. | 4 years | 
| Relapse-free survival (RFS) | RFS is defined as the time from the date of remission to date of relapse or death. | 4 years | 
| Overall survival (OS) | OS is defined as the time from the date of start of treatment until death. | 4 years |