NCT03164057

A Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia

A Phase II Trial of Epigenetic Priming in Patients With Newly Diagnosed Acute Myeloid Leukemia

• Status: Active Not Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 206 (actual)
• Sponsor: St. Jude Children's Research Hospital · Academic / Other
• Sex: All
• Age: 29 Days – 21 Years
• Healthy volunteers: Not accepted

Summary

The overall aim of this study is to determine if epigenetic priming with a DNA methyltransferase inhibitor (DMTi) prior to chemotherapy blocks is tolerable and carries evidence of a clinical efficacy signal as determined by minimal residual disease (MRD), event-free survival (EFS), and overall survival (OS). Tolerability for each of the agents, as well as total reduction in DNA methylation and outcome assessments will be done to simultaneously obtain preliminary biological and clinical data for each DMTi in parallel. PRIMARY OBJECTIVES: * Evaluate the tolerability of five days of epigenetic priming with azacitidine and decitabine as a single agent DMTi prior to standard AML chemotherapy blocks. * Evaluate the change in genome-wide methylation burden induced by five days of epigenetic priming and the association of post-priming genome-wide methylation burden with event-free survival among pediatric AML patients. SECONDARY OBJECTIVES * Describe minimal residual disease levels following Induction I chemotherapy in patients that receive DMTi. * Estimate the event-free survival and overall survival of patients receiving a DMTi prior to chemotherapy courses.

Detailed description

To determine tolerability, priming with DMTi (azacitidine or decitabine) will be limited to Induction I and II during Part 1 of the study. If DMTi treatment is tolerated during Part 1, the investigators will go on to an Expansion Phase (Part 2) that includes DMTi priming prior to all chemotherapy blocks. Treatment will consist of 5 blocks of conventional chemotherapy: Induction I, Induction II, Intensification I, Intensification II, and Intensification III over approximately 5 months. RANDOMIZATION: Patients will be randomized to receive one of two DMTi (azacitidine or decitabine) for 5 days prior to Induction I. Intrathecal (ITHMA) treatments will be given right before treatment on this study or on Day 1 of Induction I treatment. Leucovorin will be given 24-30 hours following ITHMA. INDUCTION I CHEMOTHERAPY: Patients receive cytarabine, daunorubicin, and etoposide. INDUCTION II CHEMOTHERAPY; Patients receive their assigned DMTi for 5 days followed by fludarabine, cytarabine, G-CSF, and idarubicin. Patients are then evaluated and assigned to either the low-risk arm, intermediate-risk arm, or the high-risk arm for Intensification therapy. Patients with ≥ 5% blasts following Induction II will be considered refractory and will go off therapy. The rare high risk patient with an MRD \< 0.1% following Induction I may proceed directly to stem cell transplant (SCT) after Induction II - if a suitable donor is available and the transplant can be performed without delay. MDS patients may proceed to SCT once they have achieved MRD \<0.1% irrespective of the number of chemotherapy courses received. INTENSIFICATION I CHEMOTHERAPY - LOW-RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive cytarabine and etoposide. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to cytarabine and etoposide. INTENSIFICATION II CHEMOTHERAPY - LOW RISK AML, INTERMEDIATE-RISK AML, and HIGH-RISK AML with no donor: Patients receive mitoxantrone and cytarabine. After administration of 5 days of a DMTi prior to Inductions I and II satisfies a tolerability determination criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine. INTENSIFICATION I CHEMOTHERAPY - HIGH-RISK AML with a donor: Patients receive mitoxantrone and cytarabine followed by stem cell transplant (SCT). Treatment related AML patients and patients with treatment related MDS who have a donor but are not able to receive a SCT without delay will proceed to HR Intensification III and receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to mitoxantrone and cytarabine or erwinia asparaginase and cytarabine. Treatment related AML patients and treatment related MDS patients that are not able to receive a SCT should go off treatment following Intensification II. INTENSIFICATION III CHEMOTHERAPY - INTERMEDIATE-RISK AML and HIGH-RISK AML with no donor: Patients receive erwinia asparaginase and cytarabine. After administration of 5 days of a DMTi prior to earlier courses satisfies a tolerability criterion, patients will also receive their randomly assigned DMTi for five days prior to erwinia asparaginase and cytarabine.

Conditions

• Acute Myeloid Leukemia
• Myelodysplastic Syndromes

Interventions

Type	Name	Description
DRUG	Azacitidine	Azacitidine solution is administered intravenously (IV) over a period of 10-40 minutes.
DRUG	Decitabine	Administered intravenously (IV) over approximately one hour.
DRUG	Cytarabine	Given IV or intrathecally (IT).
DRUG	Daunorubicin	Given IV.
DRUG	Etoposide	Given IV.
COMBINATION_PRODUCT	ITMHA	Given IT.
DRUG	Idarubicin	Given IV.
DRUG	Fludarabine	Given IV over approximately 30 minutes.
DRUG	Mitoxantrone	Given IV.
DRUG	Erwinia asparaginase	Given IV or intramuscularly (IM).
DRUG	Sorafenib	Given PO.
DRUG	G-CSF	Given IV.
DRUG	Dexrazoxane	Given IV immediately before idarubicin administration.
BIOLOGICAL	Stem Cell Transplant	The transplant protocol will depend on the patient's donor and transplant physician's preference.
DRUG	Asparaginase Erwinia Chrysanthemi, Recombinant-Rywn	May be used in the event of an Erwinia asparaginase shortage. Given intramuscularly (IM).

Timeline

• Start date: 2017-06-15
• Primary completion: 2025-09-20
• Completion: 2027-06-01
• First posted: 2017-05-23
• Last updated: 2026-01-28

Locations

10 sites across 1 country: United States

Regulatory

• FDA-regulated drug study