Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04293562 |
| Other study ID # |
AAML1831 |
| Secondary ID |
NCI-2020-00546AA |
| Status |
Active, not recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
July 21, 2020 |
| Est. completion date |
September 30, 2027 |
Study information
| Verified date |
April 2024 |
| Source |
Children's Oncology Group |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This phase III trial compares standard chemotherapy to therapy with liposome-encapsulated
daunorubicin-cytarabine (CPX-351) and/or gilteritinib for patients with newly diagnosed acute
myeloid leukemia with or without FLT3 mutations. Drugs used in chemotherapy, such as
daunorubicin, cytarabine, and gemtuzumab ozogamicin, work in different ways to stop the
growth of cancer cells, either by killing the cells, by stopping them from dividing, or by
stopping them from spreading. CPX-351 is made up of daunorubicin and cytarabine and is made
in a way that makes the drugs stay in the bone marrow longer and could be less likely to
cause heart problems than traditional anthracycline drugs, a common class of chemotherapy
drug. Some acute myeloid leukemia patients have an abnormality in the structure of a gene
called FLT3. Genes are pieces of DNA (molecules that carry instructions for development,
functioning, growth and reproduction) inside each cell that tell the cell what to do and when
to grow and divide. FLT3 plays an important role in the normal making of blood cells. This
gene can have permanent changes that cause it to function abnormally by making cancer cells
grow. Gilteritinib may block the abnormal function of the FLT3 gene that makes cancer cells
grow. The overall goals of this study are, 1) to compare the effects, good and/or bad, of
CPX-351 with daunorubicin and cytarabine on people with newly diagnosed AML to find out which
is better, 2) to study the effects, good and/or bad, of adding gilteritinib to AML therapy
for patients with high amounts of FLT3/ITD or other FLT3 mutations and 3) to study changes in
heart function during and after treatment for AML. Giving CPX-351 and/or gilteritinib with
standard chemotherapy may work better in treating patients with acute myeloid leukemia
compared to standard chemotherapy alone.
Description:
PRIMARY OBJECTIVE:
I. To compare event-free survival (EFS) in children with de novo acute myeloid leukemia (AML)
without FLT3 mutations who are randomly assigned to standard induction therapy on Arm A with
daunorubicin, cytarabine (DA) and gemtuzumab ozogamicin (GO) (DA-GO) versus Arm B with
CPX-351 and GO.
SECONDARY OBJECTIVES:
I. To compare overall survival (OS) and rates of end of Induction 1 (EOI1) minimal residual
disease (MRD) in children with de novo AML without FLT3 mutations who are randomly assigned
to standard induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B).
II. To estimate the EFS and rate of EOI1 MRD in FLT3 internal tandem duplication mutation
positive patients (FLT3/ITD+; as defined by allelic ratio > 0.1) without favorable
cytomolecular characteristics (NPM1 and/or CEBPA) receiving gilteritinib fumarate
(gilteritinib) in combination with DA-GO (Arm AC).
III. To estimate the EFS and rate of EOI1 MRD in patients with non-ITD FLT3 activating
mutations who receive backbone therapy (DA-GO or CPX-351 and GO) with gilteritinib (Arms AD
and BD).
IV. To determine the feasibility of combining gilteritinib and DA-GO or CPX-351 and GO in
patients with FLT3/ITD and FLT3/TKD mutations (Arm AC/Arm BC/Arm AD/Arm BD).
V. To compare EOI1 MRD and EFS in patients with FLT3/ITD AML+ (allelic ratio [AR] > 0.1)
without favorable cytogenetic/molecular characteristics treated with DA-GO-gilteritinib
versus (vs) CPX-GO-gilteritinib (Arm AC vs Arm BC).
VI. To compare the incidence of significant left ventricular systolic dysfunction (LVSD) in
children with de novo AML without FLT3 mutations who are randomly assigned to standard
induction therapy (Arm A) with DA-GO versus CPX-351 and GO (Arm B).
VII. To compare the changes in echocardiography-derived measures of cardiac function,
including left ventricular ejection fraction (EF) and global longitudinal strain (GLS),
throughout AML therapy in patients with low and high risk AML without FLT3 mutations
receiving Arm A vs Arm B.
VIII. Determine if early changes in sensitive echocardiographic measures of cardiac function
(i.e., post-Induction 1 decline in GLS) and elevations in circulating cardiac biomarkers
(i.e., cardiac troponin T and N-terminal pro b-type natriuretic peptide) are associated with
subsequent declines in left ventricular ejection fraction in patients with non-FLT3 mutant
AML receiving therapy on Arms A or B.
IX. To compare longitudinal acute changes in neuropsychological functioning and
neurocognitive late effects between those with central nervous system (CNS) disease and those
without CNS disease and between those treated with hematopoietic stem cell transplant (HSCT)
and those treated with chemotherapy only for patients on Arms A and B.
X. To compare cardiotoxicity measures (EF, GLS, and cardiac biomarkers) in patients receiving
standard induction with dexrazoxane hydrochloride (dexrazoxane) vs. CPX-351 in the context of
gilteritinib therapy and explore whether the differential cardiotoxicity across arms varies
from that observed in non-FLT3 mutant AML without gilteritinib exposure.
EXPLORATORY OBJECTIVES:
I. To estimate the EFS and rate of EOI1 MRD in patients with high allelic ratio (HAR)
FLT3/ITD+ patients, as historically defined by an AR > 0.4, receiving gilteritinib in
combination with DA-GO (Arm AC with AR > 0.4).
II. To estimate the EFS, OS, and rate of EOI1 MRD in FLT3/ITD+ patients (as defined by
allelic ratio > 0.1) with NPM1 and/or bZIP CEBPA mutations receiving gilteritinib in
combination with DA-GO (Arm AC).
III. Compare the changes in high sensitivity troponin and natriuretic peptide elevations
throughout AML therapy, as measured at the end of each chemotherapy course, in patients with
low and high risk AML without FLT3 mutations receiving Arm A vs Arm B.
IV. Quantify the association of host factors (age, sex, body mass index [BMI], race),
treatment exposures (cumulative anthracycline dose, anthracycline arm, hematopoietic stem
cell transplant vs. chemotherapy alone), early declines in GLS, and elevations in cardiac
biomarkers (cTnT and NT-proBNP) with subsequent LVSD.
V. To describe the rates of CNS disease utilizing an updated strategy for diagnosing and
defining CNS disease in pediatric AML.
VI. To describe the rates of CNS relapse (both isolated CNS and combined bone marrow/CNS)
when utilizing this updated strategy as well as changing CNS prophylaxis and treatment to
include triple intrathecal chemotherapy.
VII. To describe the rate of bone marrow measurable residual disease, detected by
multi-dimensional flow cytometry, prior to hematopoietic stem cell transplant (HSCT).
VIII. To describe plasma metabolomics that may impact efficacy, toxicity, and/or
pharmacokinetics of allogeneic HSCT.
IX. To estimate the prevalence of non-risk stratifying cytogenetic/molecular variants and
assess their impact on outcome in childhood AML.
X. To describe the pharmacokinetic parameters of plasma cytarabine and daunorubicin after
CPX-351 administration to pediatric and young adult patients with new diagnosis of AML.
XI. To describe the pharmacokinetic parameters of orally administered gilteritinib when
administered to pediatric and young adult patients with new diagnosis of AML.
XII. To describe the pharmacodynamic parameters of gilteritinib using the FLT3 plasma
inhibitory activity assay (PIA) when administered to children and young adults with new
diagnosis of AML and FLT3 mutations.
XIII. To estimate OS in patients with FLT3/ITD+ AML (AR > 0.1) without favorable
cytogenetic/molecular characteristics treated with DA-GO-gilteritinib or
CPX-351-GO-gilteritinib (Separate analyses will be conducted for Arm AC vs Arm BC).
OUTLINE: Patients are randomized to either Arm A or B and assigned to Arm C or D based on
FLT3 testing results.
Risk group assignments are calculated based on cytogenetic, molecular and genomic findings
(details in protocol)
Risk groups include (Details in protocol):
1. Low Risk 1 (LR1)
2. Low Risk 2 (LR2)
3. High Risk (HR)
TREATMENT FOR PATIENTS WITHOUT FLT3 MUTATIONS:
ARM A LOW RISK GROUP 1:
INDUCTION 1: Patients receive cytarabine intravenously (IV) over 1-30 minutes every 12
hours (Q12H) on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over
1-15 minutes on days 1, 3, and 5, and gemtuzumab ozogamicin IV over 2 hours on day 6.
Patients with CNS1 receive methotrexate intrathecally (IT), therapeutic hydrocortisone
(hydrocortisone) IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT once weekly (QW) starting
on day 8 for 4-6 weeks (may continue into Induction 2) until the cerebral spinal fluid
(CSF) is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT,
hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue into
Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 5-15
minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and
etoposide IV over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1,
2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi intramuscularly
(IM) or IV over 1-2 hours or asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM B LOW RISK GROUP 1:
INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and
gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and
etoposide IV over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1,
2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours or asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM A LOW RISK GROUP 2:
INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10,
dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and
5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive
methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2,
CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear
of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 5-15
minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and
etoposide IV over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days
1-4 and dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone)
IV over 5-15 minutes on days 3-6.
INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1,
2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours or asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM B LOW RISK GROUP 2:
INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and
gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and
etoposide IV over 90-120 minutes on days 1-5.
INTENSIFICATION 2: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H on days
1-4 and dexrazoxane IV over 5-15 minutes and mitoxantrone hydrochloride (mitoxantrone)
IV over 5-15 minutes on days 3-6.
INTENSIFICATION 3: Patients receive high-dose cytarabine IV over 3 hours Q12H on days 1,
2, 8, and 9. Patients also receive asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours or asparaginase IM or IV over 30 minutes on days 2 and 9.
ARM A HIGH RISK GROUP:
INDUCTION 1: Patients receive cytarabine IV over 1-30 minutes Q12H on days 1-10,
dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and
5, and gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive
methotrexate IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2,
CNS3a, and CNS3b receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW
starting on day 8 for 4-6 weeks (may continue into Induction 2) until the CSF is clear
of blasts (CNS1 status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive cytarabine IV over 1-30 minutes Q12H on days 1-8 and dexrazoxane IV over 5-15
minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and
etoposide IV over 90-120 minutes on days 1-5.
HSCT: After completion of Intensification 1 and investigator assigned conditioning
regimen, patients undergo allogeneic HSCT.
ARM B HIGH RISK GROUP:
INDUCTION 1: Patients receive CPX-351 IV over 90 minutes on days 1, 3, and 5, and
gemtuzumab ozogamicin IV over 2 hours on day 6. Patients with CNS1 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2: Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 0. Patients with CNS2 receive methotrexate IT, hydrocortisone IT,
and cytarabine IT QW starting on day 0 until CNS1 status is reached. Patients also
receive CPX-351 IV over 90 minutes on days 1, 3, and 5.
INTENSIFICATION 1: Patients receive methotrexate IT, hydrocortisone IT, and cytarabine
IT on day 0. Patients also receive high-dose cytarabine IV over 1-3 hours Q12H and
etoposide IV over 90-120 minutes on days 1-5.
HSCT: After completion of Intensification 1 and investigator assigned conditioning
regimen, patients undergo allogeneic HSCT.
TREATMENT FOR PATIENTS WITH FLT3/ITD MUTATIONS (ITD AR > 0.1):
ARM AC LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30
minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over
1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and
gilteritinib orally (PO)/nasogastric (NG)/gastrostomy (G)-tube once daily (QD) on days
11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and cytarabine IT
on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT, hydrocortisone
IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue into Induction 2)
until the CSF is clear of blasts (CNS1 status). Patients with CNS3c receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6 weeks (may continue
into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8,
dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and
5, and gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib
PO/NG/G-tube QD on days 6-26.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15
minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3
hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours and asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib
PO/NG/G-tube QD on days 10-30.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube
QD on days 1-365.
ARM BC LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes
on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib
PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and
gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib
PO/NG/G-tube QD on days 6-26.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15
minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3
hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours and asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib
PO/NG/G-tube QD on days 10-30.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube
QD on days 1-365.
ARM AC HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30
minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over
1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and
gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8,
dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and
5, and gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib
PO/NG/G-tube QD on days 6-26.
HSCT: After completion of Intensification 1 and investigator assigned conditioning
regimen, patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT,
patients receive gilteritinib PO/NG/G-tube QD on days 1-365.
ARM BC HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes
on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib
PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and
gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib
PO/NG/G-tube QD on days 6-26.
HSCT: After completion of Intensification 1 and investigator assigned conditioning
regimen, patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT,
patients receive gilteritinib PO/NG/G-tube QD on days 1-365.
TREATMENT FOR NON-ITD FLT3 ACTIVATING MUTATIONS:
ARM AD LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30
minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over
1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and
gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8,
dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and
5, and gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib
PO/NG/G-tube QD on days 6-26.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15
minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3
hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours and asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib
PO/NG/G-tube QD on days 10-30.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube
QD on days 1-365.
ARM BD LOW RISK GROUP 2:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes
on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib
PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and
gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib
PO/NG/G-tube QD on days 6-26.
INTENSIFICATION 2 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H on days 1-4, dexrazoxane IV over 5-15 minutes and mitoxantrone IV over 5-15
minutes on days 3-6, and gilteritinib PO/NG/G-tube QD on days 7-27.
INTENSIFICATION 3 (WITH GILTERITINIB): Patients receive high-dose cytarabine IV over 3
hours Q12H on days 1, 2, 8, and 9, asparaginase Erwinia chrysanthemi IM or IV over 1-2
hours and asparaginase IM or IV over 30 minutes on days 2 and 9, and gilteritinib
PO/NG/G-tube QD on days 10-30.
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO/NG/G-tube
QD on days 1-365.
ARM AD HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive cytarabine IV over 1-30
minutes Q12H on days 1-10, dexrazoxane IV over 5-15 minutes and daunorubicin IV over
1-15 minutes on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and
gilteritinib PO/NG/G-tube QD on days 11-31. Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 8 for
4-6 weeks (may continue into Induction 2) until the CSF is clear of blasts (CNS1
status). Patients with CNS3c receive methotrexate IT, hydrocortisone IT, and cytarabine
IT QW starting on day 1 for 6 weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive cytarabine IV over 1-30 minutes Q12H on days 1-8,
dexrazoxane IV over 5-15 minutes and daunorubicin IV over 1-15 minutes on days 1, 3, and
5, and gilteritinib PO/NG/G-tube QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on
days 6-26.
HSCT: After completion of Intensification 1 and investigator assigned conditioning
regimen, patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT,
patients receive gilteritinib PO or NG or G tube QD on days 1-365.
ARM BD HIGH RISK GROUP:
CONTINUED INDUCTION 1 (WITH GILTERITINIB): Patients receive CPX-351 IV over 90 minutes
on days 1, 3, and 5, gemtuzumab ozogamicin IV over 2 hours on day 6, and gilteritinib PO
QD on days 11-31. Patients with CNS1 receive methotrexate IT, hydrocortisone IT, and
cytarabine IT on day 8. Patients with CNS2, CNS3a, and CNS3b receive methotrexate IT,
hydrocortisone IT, and cytarabine IT QW starting on day 8 for 4-6 weeks (may continue
into Induction 2) until the CSF is clear of blasts (CNS1 status). Patients with CNS3c
receive methotrexate IT, hydrocortisone IT, and cytarabine IT QW starting on day 1 for 6
weeks (may continue into Induction 2).
INDUCTION 2 (WITH GILTERITINIB): Patients with CNS1 receive methotrexate IT,
hydrocortisone IT, and cytarabine IT on day 0. Patients with CNS2 receive methotrexate
IT, hydrocortisone IT, and cytarabine IT QW starting on day 0 until CNS1 status is
reached. Patients also receive CPX-351 IV over 90 minutes on days 1, 3, and 5 and
gilteritinib PO QD on days 11-31.
INTENSIFICATION 1 (WITH GILTERITINIB): Patients receive methotrexate IT, hydrocortisone
IT, and cytarabine IT on day 0. Patients also receive high-dose cytarabine IV over 1-3
hours Q12H and etoposide IV over 90-120 minutes on days 1-5, and gilteritinib PO QD on
days 6-26.
HSCT: After completion of Intensification 1 and investigator assigned conditioning
regimen, patients undergo allogeneic HSCT.
POST-HSCT GILTERITINIB MAINTENANCE: Beginning 30-120 days after completion of HSCT,
patients receive gilteritinib PO or NG or G tube QD on days 1-365.
NOTE: During Induction 2 or Intensification 2, patients in Arms A and B with left
ventricular systolic dysfunction receive a replacement course of high-dose cytarabine IV
over 3 hours on days 1, 2, 8, and 9, and asparaginase Erwinia chrysanthemi IM or IV over
1-2 hours or asparaginase IM or IV over 30 minutes on days 2 and 9. Patients in Arms AC,
BC, AD, and BD receive treatment as in Arms A and B and also receive gilteritinib PO QD
on days 10-30 (Induction 2) or days 10-30 (Intensification 2).
All treatment continues in the absence of disease progression or unacceptable toxicity.
OPTIONAL NEUROCOGNITIVE STUDY:
Patients may complete the Cogstate assessment battery at the end of Induction 1, at the
end of therapy, and at 9 and 60 months post-enrollment.
