Summary

Eligibility
for people ages up to 22 years (full criteria)
Location
at UC Davis UCLA
Dates
study started
estimated completion
Principal Investigator
by William A. May (ucla)Marcio H. Malogolowkin (ucdavis)

Description

Summary

This phase III trial compares standard chemotherapy to therapy with 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.

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

Details

PRIMARY OBJECTIVE:

  1. 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 liposome-encapsulated daunorubicin-cytarabine (CPX-351) and GO.

SECONDARY OBJECTIVES:

  1. 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 mutations (Arm AC/Arm BC/Arm AD/Arm BD).

  1. 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.

  1. 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:

  1. 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 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.

  1. Develop a multi-marker risk prediction model incorporating significant host factors, treatment exposures, and echocardiographic predictors for the development of LVSD within 1 year of completing therapy.

VI. To describe the rates of CNS disease utilizing an updated strategy for diagnosing and defining CNS disease in pediatric AML.

VII. 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.

VIII. To describe disease-free survival (DFS) and overall survival (OS) in high risk patients based on multi-dimensional flow cytometry detection of measurable residual disease prior to hematopoietic stem cell transplant (HSCT).

IX. To describe plasma metabolomics that may impact efficacy, toxicity, and/or pharmacokinetics of allogeneic HSCT.

  1. To estimate the prevalence of non-risk stratifying cytogenetic/molecular variants and assess their impact on outcome in childhood AML.

OUTLINE: Patients are randomized to either Arm A or B and assigned to Arm C or D based on FLT3 testing results.

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 and 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 and 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 and 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 and 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) 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 QD on days 11-38.

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 6-33.

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 QD on days 7-34.

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 QD on days 10-37.

POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO 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 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 11-38.

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 6-33.

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 QD on days 7-34.

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 QD on days 10-37.

POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO 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 orally (PO) 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 QD on days 11-38.

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 6-33.

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 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 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 11-38.

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 6-33.

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 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 orally (PO) 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 QD on days 11-38.

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 6-33.

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 QD on days 7-34.

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 QD on days 10-37.

POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO 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 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 11-38.

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 6-33.

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 QD on days 7-34.

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 QD on days 10-37.

POST-CHEMOTHERAPY GILTERITINIB MAINTENANCE: Patients receive gilteritinib PO 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 orally (PO) 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 QD on days 11-38.

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 6-33.

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 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 11-38.

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 6-33.

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 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 and 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 10-37 (Induction 2) or days 10-37 (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.

After completion of study treatment, patients are followed up monthly for 6 months and then every other month for 6 months (year 1), every 4 months during year 2, every 6 months during year 3, then yearly for years 4-10. Patients who undergo HSCT are also followed up at 30, 100, and 180 days, 9 months, and 1 year post-HSCT.

Keywords

Acute Myeloid Leukemia Cytarabine Hydrocortisone Hydrocortisone 17-butyrate 21-propionate Hydrocortisone acetate Hydrocortisone hemisuccinate Methotrexate Etoposide Etoposide phosphate Daunorubicin Asparaginase Mitoxantrone Podophyllotoxin Gemtuzumab Dexrazoxane Razoxane Allogeneic Hematopoietic Stem Cell Transplantation Asparaginase Erwinia chrysanthemi Cogstate Assessment Battery Daunorubicin Hydrochloride Dexrazoxane Hydrochloride Gemtuzumab Ozogamicin Gilteritinib Fumarate Liposome-encapsulated Daunorubicin-Cytarabine Mitoxantrone Hydrochloride Therapeutic Hydrocortisone

Eligibility

You can join if…

Open to people ages up to 22 years

  • All patients must be enrolled on APEC14B1 and consented to Eligibility Screening (Part A) prior to enrollment and treatment on AAML1831. Submission of diagnostic specimens must be done according to the Manual of Procedures). Risk stratification will not be possible without the submission of viable samples. Given there are multiple required samples, bone marrow acquisition techniques such as frequent repositioning or performing bilateral bone marrow testing should be considered to avoid insufficient material for required studies. Consider a repeat marrow prior to starting treatment if there is insufficient diagnostic material for the required studies
  • Patients must be less than 22 years of age at the time of study enrollment
  • Patient must be newly diagnosed with de novo AML according to the 2016 World Health Organization (WHO) classification with or without extramedullary disease
  • Patient must have 1 of the following:
  • >= 20% bone marrow blasts (obtained within 14 days prior to enrollment)
  • In cases where extensive fibrosis may result in a dry tap, blast count can be obtained from touch imprints or estimated from an adequate bone marrow core biopsy
  • < 20% bone marrow blasts with one or more of the genetic abnormalities (sample obtained within 14 days prior to enrollment)
  • A complete blood count (CBC) documenting the presence of at least 1,000/uL (i.e., a white blood cell [WBC] count >= 10,000/uL with >= 10% blasts or a WBC count of >= 5,000/uL with >= 20% blasts) circulating leukemic cells (blasts) if a bone marrow aspirate or biopsy cannot be performed (performed within 7 days prior to enrollment)
  • ARM C: Patient must be >= 2 years of age at the time of Late Callback
  • ARM C: Patient must have FLT3/ITD allelic ratio > 0.1 as reported by Molecular Oncology
  • ARM C: Patient does not have any congenital long QT syndrome or congenital heart block
  • ARM C: Females of reproductive potential must agree to use effective contraception during treatment and for at least 6 months after the last dose of gilteritinib
  • ARM C: Lactating women must agree not to breastfeed during treatment with gilteritinib and for 2 months after the last dose of gilteritinib
  • ARM C: Males of reproductive potential must agree to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib
  • ARM D: Patient must be >= 2 years of age at the time of Late Callback
  • ARM D: Patient must have one of the clinically relevant non-ITD FLT3 activating mutations as reported by Foundation Medicine
  • ARM D: Females of reproductive potential must agree to use effective contraception during treatment and for at least 6 months after the last dose of gilteritinib
  • ARM D: Lactating women must agree not to breastfeed during treatment with gilteritinib and for 2 months after the last dose of gilteritinib
  • ARM D: Males of reproductive potential must agree to use effective contraception during treatment and for at least 4 months after the last dose of gilteritinib
  • NEUROPSYCHOLOGICAL TESTING: Patient must be enrolled on Arm A or Arm B. Patients who transfer to Arm C or Arm D are not eligible
  • NEUROPSYCHOLOGICAL TESTING: Patient must be 5 years or older at the time of enrollment
  • NEUROPSYCHOLOGICAL TESTING: English-, French- or Spanish-speaking
  • NEUROPSYCHOLOGICAL TESTING: No known history of neurodevelopmental disorder prior to diagnosis of AML (e.g., Down syndrome, fragile X, William syndrome, mental retardation)
  • NEUROPSYCHOLOGICAL TESTING: No significant visual or motor impairment that would prevent computer use or recognition of visual test stimuli
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met.

You CAN'T join if...

  • Patients with myeloid neoplasms with germline predisposition are not eligible
  • Fanconi anemia
  • Shwachman Diamond syndrome
  • Patients with constitutional trisomy 21 or with constitutional mosaicism of trisomy 21
  • Any other known bone marrow failure syndrome
  • Any concurrent malignancy
  • Juvenile myelomonocytic leukemia (JMML)
  • Philadelphia chromosome positive AML
  • Mixed phenotype acute leukemia
  • Acute promyelocytic leukemia
  • Acute myeloid leukemia arising from myelodysplasia
  • Therapy-related myeloid neoplasms
  • Administration of prior anti-cancer therapy except as outlined below:
  • Hydroxyurea
  • All-trans retinoic acid (ATRA)
  • Corticosteroids (any route)
  • Intrathecal therapy given at diagnosis
  • In particular, strong inducers of CYP3A4 and/or P-glycoprotein (P-gp) should be avoided from the time of enrollment until it is determined whether the patient will receive gilteritinib. Patients receiving gilteritinib will be required to avoid strong CYP3A4 inducers and/or strong P-gp inducers for the duration of the study treatment
  • Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential
  • Lactating females who plan to breastfeed their infants
  • Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
  • ARM D: Patients with congenital long QT syndrome or congenital heart block are not eligible for this treatment arm

Locations

  • Mattel Children's Hospital UCLA accepting new patients
    Los Angeles California 90095 United States
  • University of California Davis Comprehensive Cancer Center accepting new patients
    Sacramento California 95817 United States
  • Cedars Sinai Medical Center accepting new patients
    Los Angeles California 90048 United States
  • Children's Hospital Los Angeles accepting new patients
    Los Angeles California 90027 United States
  • Children's Hospital of Orange County accepting new patients
    Orange California 92868 United States

Lead Scientists at UC Health

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
Children's Oncology Group
ID
NCT04293562
Phase
Phase 3
Study Type
Interventional
Last Updated