Conditions: Lymphoblastic Leukemia, Acute, Childhood Myelogenous Leukemia, Acute, Childhood
Keywords: Relapse Lymphoblastic Leukemia AC220 Refractory Myelogenous Acute Childhood Pediatric ALL AML
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 24
Healthy volunteers: no

Brief summary:
This is a phase I study of the investigational drug AC220 combined with cytarabine and etoposide in pediatric patients with relapsed acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML).

Detailed description:
This is a study for pediatric patients with relapsed acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). Some people diagnosed with leukemia have changes in a receptor located on the surface of white blood cells called FLT3. This is known as a FLT3 mutation. FLT3 plays an important role in the way cells grow and divide. In normal cells, the FLT3 receptor is switched off most of the time and only switches on when it gets a chemical signal from outside. But cells with the FLT3 mutation have the grow signal permanently switched on. This means leukemia cells with the FLT3 mutation are growing and dividing all the time. Doctors have found that people with leukemia cells that carry FLT3 mutations are less likely to go into remission with chemotherapy and have a higher risk of the leukemia coming back after treatment.

This is a study of an investigational drug called AC220. AC220 is considered investigational because it has not been approved in the United States by the Food and Drug Administration (FDA). AC220 is a drug which is able to "turn off" the FLT3 grow signal. AC220 will be given with cytarabine and etoposide to treat the relapsed leukemia. This is a phase I study, which means that the study is being done to find the highest dose of AC220 that can be given safely with the drugs cytarabine and etoposide to children and young adults.

Arms:
arm 1: The starting dose is Dose Level 1 at 25 mg/m2/day. Dose escalation will proceed from level 1 to 2 to 3, and so on, assuming the maximum tolerated dose is not exceeded. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT Methotrexate will be given to patients with ALL on Day 0, dose assigned by age. arm 2: The starting dose is Dose Level 1 at 25 mg/m2/day. Dose escalation will proceed from level 1 to 2 to 3, and so on, assuming the maximum tolerated dose is not exceeded. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT cytarabine will be given to patients with AML on Day 0, dose assigned by age. arm 3: Dose escalation will proceed from level 1 to level 2 for AC220 at 40mg/m2/day, assuming the maximum tolerated dose is not exceeded. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT Methotrexate will be given to patients with ALL on Day 0, dose assigned by age. arm 4: Dose escalation will proceed from level 2 to 3 for AC220 at 60mg/m2/day, assuming the maximum tolerated dose is not exceeded. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT Methotrexate will be given to patients with ALL on Day 0, dose assigned by age. If toxicity at Dose Level 3 would allow further escalation, but demonstrated sufficient AC220 activity, no further dose escalation will be required. arm 5: If the study dose of 60 mg/m2/day at Dose Level 3 is well tolerated but does not show sufficient AC220 activity, the study may proceed to Dose Level 4 at 90 mg/m2/day. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT Methotrexate will be given to patients with ALL on Day 0, dose assigned by age. If toxicity at Dose Level 4 would allow further escalation, but demonstrated sufficient AC220 activity, no further dose escalation will be required. arm 6: If the study dose of 90 mg/m2/day at Dose Level 4 is well tolerated but does not show sufficient AC220 activity, the study may proceed to Dose Level 5 at 130 mg/m2/day. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT Methotrexate will be given to patients with ALL on Day 0, dose assigned by age. Dose Level 5 is the highest dose for this study. arm 7: Dose escalation will proceed from level 1 to level 2 for AC220 at 40mg/m2/day, assuming the maximum tolerated dose is not exceeded. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT cytarabine will be given to patients with AML on Day 0, dose assigned by age. arm 8: Dose escalation will proceed from level 2 to 3 for AC220 at 60mg/m2/day, assuming the maximum tolerated dose is not exceeded. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT cytarabine will be given to patients with AML on Day 0, dose assigned by age. If toxicity at Dose Level 3 would allow further escalation, but demonstrated sufficient AC220 activity, no further dose escalation will be required. arm 9: If the study dose of 60 mg/m2/day at Dose Level 3 is well tolerated but does not show sufficient AC220 activity, the study may proceed to Dose Level 4 at 90 mg/m2/day. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT cytarabine will be given to patients with AML on Day 0, dose assigned by age. If toxicity at Dose Level 4 would allow further escalation, but demonstrated sufficient AC220 activity, no further dose escalation will be required. arm 10: If the study dose of 90 mg/m2/day at Dose Level 4 is well tolerated but does not show sufficient AC220 activity, the study may proceed to Dose Level 5 at 130 mg/m2/day. Patients will received etoposide and cytarabine on Days 1-5, and AC220 on Day 7 through 28. IT cytarabine will be given to patients with AML on Day 0, dose assigned by age. Dose Level 5 is the highest dose for this study.

Interventions: intervention 1: AC220 intervention 2: Cytarabine intervention 3: Etoposide intervention 4: Methotrexate
Intervention descriptions: intervention 1: Dose assigned at study entry. AC220 will be given orally once daily on days 7-28. intervention 2: All patients receive 1000 mg/m2/day IV given every 12 hours on days 1 through 5. Additionally, AML patients and patients with ambiguous leukemia receive cytarabine intrathecally on day "1" of course 1 and 2. Dose defined by age:

* 20 mg for patients age \<1 yr
* 30 mg for patients age 1-1.99 years of age
* 50 mg for patients age 2-2.99 years of age
* 70 mg for patients \>3 years of age intervention 3: 150 mg/m2/day IV on days 1 through 5. intervention 4: IT methotrexate given intrathecally to patients with ALL on day "0" of course 1 and 2. Dose defined by age

* 6 mg for patients age \< 1yr
* 8 mg for patients age 1-1.99
* 10 mg for patients age 2-2.99
* 12 mg for patients 3-8.99 years of age
* 15 mg for patients \>9 years of age

Protocol document: