Relapsed/Refractory FLT3-mutated AML
Conditions
Brief summary
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.
Interventions
DRUGCrenolanib
66.7 mg/m2 three times a day (TID)
DRUGFludarabine
30 mg/m2/day, intravenous infusions over 30 mins.
DRUGCytarabine
2000 mg/m2/day, intravenous infusions over 1-3 hours.
Sponsors
Arog Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 21 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 60 days | Number of patients who died within 60 days of start of therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | 4 years | 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. |
| Relapse-free survival (RFS) | 4 years | RFS is defined as the time from the date of remission to date of relapse or death. |
| Overall survival (OS) | 4 years | OS is defined as the time from the date of start of treatment until death. |
Outcome results
None listed