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Lymphoblastic Leukemia, Acute, ChildhoodPhase 1NCT01411267

AC220 for Children With Relapsed/Refractory ALL or AML

A Phase 1 study testing AC220, Cytarabine and Etoposide in people with Lymphoblastic Leukemia, Acute, Childhood and Myelogenous Leukemia, Acute, Childhood, run by Therapeutic Advances in Childhood Leukemia Consortium at 11 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 1 month to 21 years
What is being tested?
AC220, Cytarabine and Etoposide
Could I receive a placebo?
No, everyone receives an active treatment
How many people
24 participants
Where
11 sitesUnited States
Study dates
1 Sep 2011to 12 Sep 2013
Phase
Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 month to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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.
Show all 26Show fewer
  • 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.

Who cannot join

  • 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).
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  • 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

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

United States11 sites

  • Children's Healthcare of Atlanta, Emory University

    Atlanta, Georgia, 30322

  • The Children's Hospital, University of Colorado

    Aurora, Colorado, 80045

  • Johns Hopkins University

    Baltimore, Maryland, 21231

  • Dana Farber

    Boston, Massachusetts, 02215

  • Levine Children's Hospital at Carolinas Medical Center

    Charlotte, North Carolina, 28203

  • Children's Mercy Hospitals and Clinics

    Kansas City, Missouri, 64108

  • Childrens Hospital Los Angeles

    Los Angeles, California, 90027

  • Children's Hospital Central California

    Madera, California, 93636

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • UCSF School of Medicine

    San Francisco, California, 94143-0106

  • Seattle Children's Hospital

    Seattle, Washington, 98105

Other trials in United States

About this study

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

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).

Read the 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.

Being tested
AC220, Cytarabine, Etoposide, Methotrexate
Keywords
Relapse, Lymphoblastic, Leukemia, AC220, Refractory, Myelogenous, Acute, Childhood, Pediatric, ALL, AML
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Myeloid, Recurrence, Leukemia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AC220Drug

    Also called Quizartinib

    Dose assigned at study entry. AC220 will be given orally once daily on days 7-28.

  • CytarabineDrug

    Also called Cytosine Arabinoside, Ara-C, Cytosar®-U, Arabinosylcytosine

    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

  • EtoposideDrug

    Also called VePesid®, Etopophos, VP-16, Toposar®

    150 mg/m2/day IV on days 1 through 5.

  • MethotrexateDrug

    Also called MTX, Amethopterin, Otrexup™, Rasuvo®

    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
Study groups in NCT01411267
Study groupRoleWhat they receive
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide; Drug: Methotrexate
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide; Drug: Methotrexate
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide; Drug: Methotrexate
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide; Drug: Methotrexate
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide; Drug: Methotrexate
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide
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.
Receives: Drug: AC220; Drug: Cytarabine; Drug: Etoposide

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 4 weeks from therapy start

Secondary outcomes (2)

  1. 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

    Measured: 10 weeks

  2. 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.

    Measured: 4 weeks from therapy start

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted8 Aug 2011 (estimated)
  2. Study start1 Sep 2011
  3. Primary completion12 Sep 2013
  4. Study completion12 Sep 2013

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
24 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01411267
Sponsor's protocol ID
T2009-004
Status last verified
Mar 2022
First submitted
1 Aug 2011
Last updated
4 Apr 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • 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.

    PubMed 26920889

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing AC220, Cytarabine and Etoposide in people with Lymphoblastic Leukemia, Acute, Childhood and Myelogenous Leukemia, Acute, Childhood, run by Therapeutic Advances in Childhood Leukemia Consortium at 11 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 26 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 4 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Feb 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The Dose of AC220 That is Safe and Biologically Active When Given in Sequential Combination With Ara-C/Etoposide (time frame: 4 weeks from therapy start). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01411267, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Apr 2022.

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