AC220 for Children With Relapsed/Refractory ALL or AML
A Phase I Study of AC220 for Children With Relapsed or Refractory ALL or AML
1 other identifier
interventional
24
1 country
11
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).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P25-P50 for phase_1
Started Sep 2011
Typical duration for phase_1
11 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 1, 2011
CompletedFirst Posted
Study publicly available on registry
August 8, 2011
CompletedStudy Start
First participant enrolled
September 1, 2011
CompletedPrimary Completion
Last participant's last visit for primary outcome
September 12, 2013
CompletedStudy Completion
Last participant's last visit for all outcomes
September 12, 2013
CompletedResults Posted
Study results publicly available
February 20, 2020
CompletedApril 4, 2022
March 1, 2022
2 years
August 1, 2011
October 3, 2018
March 24, 2022
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
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 Outcomes (2)
Disease Response
10 weeks
Count of Participants According to Inhibition of FLT3 Phosphorylation
4 weeks from therapy start
Study Arms (10)
ALL AC220 @ 25mg/m2/day (Dose Level 1)
EXPERIMENTALThe 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.
AML AC220 @ 25mg/m2/day (Dose Level 1)
EXPERIMENTALThe 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.
ALL AC220 @ 40mg/m2/day (Dose Level 2)
EXPERIMENTALDose 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.
ALL AC220 @ 60mg/m2/day (Dose Level 3)
EXPERIMENTALDose 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.
ALL AC220 @ 90mg/m2/day (Dose Level 4)
EXPERIMENTALIf 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.
ALL AC220 @ 130 mg/m2/day (Dose Level 5)
EXPERIMENTALIf 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.
AML AC220 @ 40mg/m2/day (Dose Level 2)
EXPERIMENTALDose 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.
AML AC220 @ 60mg/m2/day (Dose Level 3)
EXPERIMENTALDose 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.
AML AC220 @ 90mg/m2/day (Dose Level 4)
EXPERIMENTALIf 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.
AML AC220 @ 130mg/m2/day (Dose Level 5)
EXPERIMENTALIf 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
Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.
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
150 mg/m2/day IV on days 1 through 5.
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
Eligibility Criteria
You may qualify if:
- 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.
- +11 more criteria
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (11)
Childrens Hospital Los Angeles
Los Angeles, California, 90027, United States
Children's Hospital Central California
Madera, California, 93636, United States
UCSF School of Medicine
San Francisco, California, 94143-0106, United States
The Children's Hospital, University of Colorado
Aurora, Colorado, 80045, United States
Children's Healthcare of Atlanta, Emory University
Atlanta, Georgia, 30322, United States
Johns Hopkins University
Baltimore, Maryland, 21231, United States
Dana Farber
Boston, Massachusetts, 02215, United States
Children's Mercy Hospitals and Clinics
Kansas City, Missouri, 64108, United States
Levine Children's Hospital at Carolinas Medical Center
Charlotte, North Carolina, 28203, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
Seattle Children's Hospital
Seattle, Washington, 98105, United States
Related Publications (1)
Cooper TM, Cassar J, Eckroth E, Malvar J, Sposto R, Gaynon P, Chang BH, Gore L, August K, Pollard JA, DuBois SG, Silverman LB, Oesterheld J, Gammon G, Magoon D, Annesley C, Brown PA. A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Clin Cancer Res. 2016 Aug 15;22(16):4014-22. doi: 10.1158/1078-0432.CCR-15-1998. Epub 2016 Feb 26.
PMID: 26920889RESULT
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Peggy Romano, BA, CCRP
- Organization
- Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) / Children's Hospital Los Angeles
Study Officials
- STUDY CHAIR
Todd Cooper, MD
Children's Healthcare of Atlanta, Emory University
Publication Agreements
- PI is Sponsor Employee
- No
- Restriction Type
- GT60
- Restrictive Agreement
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
August 1, 2011
First Posted
August 8, 2011
Study Start
September 1, 2011
Primary Completion
September 12, 2013
Study Completion
September 12, 2013
Last Updated
April 4, 2022
Results First Posted
February 20, 2020
Record last verified: 2022-03