AC220 for Children With Relapsed/Refractory ALL or AML

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I Study of AC220 for Children With Relapsed or Refractory ALL or AML

Conditions
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Lymphoblastic Leukemia, Acute, Childhood, Myelogenous Leukemia, Acute, Childhood

Intervention / Treatment
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* Drug: AC220
* Drug: Cytarabine
* Drug: Etoposide
* Drug: Methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be greater than 1 month and ≤ 21 years of age at study entry. Patients must have a diagnosis of relapsed/refractory AML, ALL or acute leukemia of ambiguous lineage and meet the following criteria: Patients with AML or leukemia with ambiguous lineage must have greater than or equal to 5% blasts in the bone marrow. Patients with ALL must have an M3 marrow (marrow blasts >25%). Patients with ALL must have MLL gene rearrangement or hyperdiploid >50 chromosomes. Patients with treatment related AML (t-AML) are eligible, provided they meet all other eligibility criteria. Karnofsky > 50% for patients >16 years of age and Lansky >50% for patients ≤16 years of age. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Myelosuppressive chemotherapy: Patients with ALL who relapse during standard maintenance therapy are eligible at time of relapse. For patients with ALL and AML who relapse while they are receiving cytotoxic therapy, at least 14 days must have elapsed since the completion of cytotoxic therapy. Cytoreduction with hydroxyurea can be initiated and continued for up to 24 hours prior to the start of AC220. Patients who have received other FLT3 inhibitors (ex. lestaurtinib, sorafenib) are eligible for this study. Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair. XRT: 2 wks must have elapsed since local palliative XRT for CNS chloromas; No washout period is necessary for other chloromas; at least 3 months must have elapsed if prior TBI, craniospinal XRT. Hematopoetic Stem Cell Transplant: At least 90 days must have elapsed since hematopoietic stem cell transplant (HSCT) and patients must not have active GVHD. Patient must have adequate renal and hepatic functions as indicated by the following laboratory values: Patients must have a calculated creatinine clearance or radioisotope GFR ≥70mL/min/1.73m2 or a normal serum creatinine based on age/gender. Total bilirubin <1.5 x ULN for age or normal conjugated bilirubin. Alanine transaminase (ALT) <5 × ULN (unless related to leukemic involvement). Patient must have a shortening fraction of ≥ 27% by echocardiogram, OR an ejection fraction of ≥ 50% by radionuclide angiogram. Reproductive Function Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment. Female patients with infants must agree not to breastfeed their infants while on this study. Male and female patients of child-bearing potential must agree to use an effective method of contraception approved by the investigator during the study and for a minimum of 6 months after study treatment. Exclusion Criteria: Patients will be excluded if they have CNS 3 disease. Patients will be excluded if they have uncontrolled or significant cardiovascular disease, including: A myocardial infarction within 12 months. Uncontrolled angina within 6 months. Diagnosed or suspected congenital long QT syndrome or any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes [TdP]); any history of arrhythmia will be discussed with the Sponsor's Medical Monitor prior to patient's entry into the study. Prolonged QTcF interval on pre-entry ECG (≥450 ms). Any history of second or third degree heart block (may be eligible if the patient currently has a pacemaker). Heart rate < 50/minute on pre-entry ECG. Uncontrolled hypertension. Complete left bundle branch block. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or TdP. Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours. Patient is receiving or plans to receive concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol. Any significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results. Patients who are concurrently receiving CYP3A4 and 5 inhibitors and inducers

Ages Eligible for Study
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Minimum Age: 1 Month
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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALL AC220 @ 25mg/m2/day (Dose Level 1)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;Drug: Methotrexate<br>* 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<br>* Other names: Methotrexate Sodium;|
| Experimental: AML AC220 @ 25mg/m2/day (Dose Level 1)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;|
| Experimental: ALL AC220 @ 40mg/m2/day (Dose Level 2)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;Drug: Methotrexate<br>* 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<br>* Other names: Methotrexate Sodium;|
| Experimental: ALL AC220 @ 60mg/m2/day (Dose Level 3)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;Drug: Methotrexate<br>* 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<br>* Other names: Methotrexate Sodium;|
| Experimental: ALL AC220 @ 90mg/m2/day (Dose Level 4)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;Drug: Methotrexate<br>* 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<br>* Other names: Methotrexate Sodium;|
| Experimental: ALL AC220 @ 130 mg/m2/day (Dose Level 5)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;Drug: Methotrexate<br>* 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<br>* Other names: Methotrexate Sodium;|
| Experimental: AML AC220 @ 40mg/m2/day (Dose Level 2)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;|
| Experimental: AML AC220 @ 60mg/m2/day (Dose Level 3)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;|
| Experimental: AML AC220 @ 90mg/m2/day (Dose Level 4)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;|
| Experimental: AML AC220 @ 130mg/m2/day (Dose Level 5)<br>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. | Drug: AC220<br>* Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.<br>* Other names: Quizartinib;Drug: Cytarabine<br>* 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<br>* Other names: Arabinosylcytosine;Drug: Etoposide<br>* 150 mg/m2/day IV on days 1 through 5.<br>* Other names: Etoposide phosphate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Dose of AC220 That is Safe and Biologically Active When Given in Sequential Combination With Ara-C/Etoposide | The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy. Plasma inhibitor activity (PIA) will be measured Pre-treatment and on Days 7, 14, 21 and 28 of Course 1. For the MTD to be considered biologically active, we will require that 7 of 9 patients achieve PIA of > 90% at 3 of 4 trough time points. | 4 weeks from therapy start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Response | Possible outcomes are: Complete Remission (CR), Complete Remission without Platelet Recovery (CRp), complete response with incomplete hematologic recovery (CRi), Stable Disease, Progressive Disease, Induction Death, or Relapse | 10 weeks | 
| Count of Participants According to Inhibition of FLT3 Phosphorylation | PIA samples will be collected pre-treatment and on Days 7, 14, 21 and 28 of Course 1. | 4 weeks from therapy start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Refractory, Myelogenous, Acute, Childhood, Pediatric, ALL, AML, Relapse, Lymphoblastic, Leukemia, AC220