Epigenetic Reprogramming in Relapse AML

Summary

Successful treatment for children and young adults with relapsed acute myeloid leukemia (AML) continues to be a significant challenge. Despite relative improvements in survival for patients with newly diagnosed AML, an estimated 40-60% will relapse with the majority eventually dying of their relapsed disease. Attaining a subsequent remission in patients who relapse is the initial critical step toward achieving a potential cure. As chemotherapy resistance is one of the primary drivers of poor treatment response and subsequent relapse in AML, identifying methods to reverse this resistance are desperately needed. This clinical trial is aimed at improving the remission re-Induction rates for children and adults with relapsed or refractory AML through epigenetic modifying agents that have the ability to reverse chemotherapy resistance. Decitabine, a DNA methyltransferase inhibitor (DNMTi) and Vorinostat, a histone deacetylase inhibitor (HDACi), are two epigenetic modifying drugs that act on the methylation of proximal promoter regions of genes and on proteins involved in the wrapping of DNA around histones, respectively. Both processes play a critical role in regulating gene expression, and frequently these genes are involved in chemotherapy resistance. These agents are FDA-approved for treatment in adult hematologic malignancies, making this an opportune time to begin testing these novel therapies in pediatric leukemia trials. This study will investigate chemotherapy priming of relapsed/refractory AML using Decitabine and Vorinostat given for 5 days prior to standard re-Induction with Fludarabine, Cytarabine and G-CSF for children and adults.

Conditions

• Leukemia, Acute Myeloid

Interventions

DRUG

Decitabine

Dosing per protocol starting at hour 0 IV infusion over 1 hour on Days 1-5

DRUG

Vorinostat

180 mg per meter squared per day for those under age 18, 300mg BID for those age 18 and older. Given after the decitabine infusion by mouth on Days 1-5

DRUG

Fludarabine

30 mg per meter squared per day starting at hour 0 given immediately after G-CSF by IV infusion over 30 minutes on days 6-10

DRUG

Cytarabine

2000 mg per meter squared per day starting at hour 4 by IV over 3 hours on days 6-10

DRUG

Filgrastim

5 μ/kg/dose starting at hour 0 immediately before fludarabine by IV or SQ on days 5-12

DRUG

Cytarabine

Patient Age (years) IT Cytarabine Dose \> 1 30 mg * 2 and \< 3 50 mg * 3 and ≤ 18 70 mg \> 18 100 mg given IT on day 0 or -1

DRUG

Sorafenib

150 mg/m2/dose twice daily by mouth on days 11-28

Sponsors & Collaborators

• Children's Hospitals and Clinics of Minnesota

  collaborator OTHER

• Michael Burke

  lead OTHER

Principal Investigators

• Michael J Burke, MD · Medical College of Wisconsin/Children's Hospital of Wisconsin

Study Design

Allocation

NA

Purpose

TREATMENT

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

1 Year

Max Age

25 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2015-02-21

Primary Completion

2017-06-21

Completion

2017-06-21

Countries

• United States

Study Locations