Ignite Creation Date:
2024-05-06 @ 2:22 PM
Last Modification Date:
2024-10-26 @ 1:29 PM
Study NCT ID:
NCT04293562
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-04-22
First Post:
2020-02-18
Brief Title:
A Study to Compare Standard Chemotherapy to Therapy With CPX-351 andor Gilteritinib for Patients With Newly Diagnosed AML With or Without FLT3 Mutations
Sponsor:
Childrens Oncology Group
Organization:
Childrens Oncology Group
Study Overview
Official Title:
A Phase 3 Randomized Trial for Patients With De Novo AML Comparing Standard Therapy Including Gemtuzumab Ozogamicin GO to CPX-351 With GO and the Addition of the FLT3 Inhibitor Gilteritinib for Patients With FLT3 Mutations
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This phase III trial compares standard chemotherapy to therapy with liposome-encapsulated daunorubicin-cytarabine CPX-351 andor 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 andor 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 andor bad of adding gilteritinib to AML therapy for patients with high amounts of FLT3ITD or other FLT3 mutations and 3 to study changes in heart function during and after treatment for AML Giving CPX-351 andor gilteritinib with standard chemotherapy may work better in treating patients with acute myeloid leukemia compared to standard chemotherapy alone
Detailed 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 FLT3ITD as defined by allelic ratio 01 without favorable cytomolecular characteristics NPM1 andor 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 FLT3ITD and FLT3TKD mutations Arm ACArm BCArm ADArm BD
V To compare EOI1 MRD and EFS in patients with FLT3ITD AML allelic ratio AR 01 without favorable cytogeneticmolecular 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 ie post-Induction 1 decline in GLS and elevations in circulating cardiac biomarkers ie 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 FLT3ITD patients as historically defined by an AR 04 receiving gilteritinib in combination with DA-GO Arm AC with AR 04
II To estimate the EFS OS and rate of EOI1 MRD in FLT3ITD patients as defined by allelic ratio 01 with NPM1 andor 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 marrowCNS 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 andor pharmacokinetics of allogeneic HSCT
IX To estimate the prevalence of non-risk stratifying cytogeneticmolecular 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 FLT3ITD AML AR 01 without favorable cytogeneticmolecular 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 FLT3ITD MUTATIONS ITD AR 01
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 POnasogastric NGgastrostomy 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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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
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 FLT3ITD as defined by allelic ratio 01 without favorable cytomolecular characteristics NPM1 andor 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 FLT3ITD and FLT3TKD mutations Arm ACArm BCArm ADArm BD
V To compare EOI1 MRD and EFS in patients with FLT3ITD AML allelic ratio AR 01 without favorable cytogeneticmolecular 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 ie post-Induction 1 decline in GLS and elevations in circulating cardiac biomarkers ie 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 FLT3ITD patients as historically defined by an AR 04 receiving gilteritinib in combination with DA-GO Arm AC with AR 04
II To estimate the EFS OS and rate of EOI1 MRD in FLT3ITD patients as defined by allelic ratio 01 with NPM1 andor 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 marrowCNS 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 andor pharmacokinetics of allogeneic HSCT
IX To estimate the prevalence of non-risk stratifying cytogeneticmolecular 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 FLT3ITD AML AR 01 without favorable cytogeneticmolecular 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 FLT3ITD MUTATIONS ITD AR 01
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 POnasogastric NGgastrostomy 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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-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 PONGG-tube QD on days 10-30
POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE Patients receive gilteritinib PONGG-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 PONGG-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 PONGG-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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NCI-2020-00546 | REGISTRY | None | None |
| AAML1831 | OTHER | None | None |
| AAML1831 | OTHER | None | None |
| U10CA180886 | NIH | CTEP | httpsreporternihgovquickSearchU10CA180886 |