NCT02412475

Epigenetic Reprogramming in Relapse AML

Epigenetic Reprogramming in Relapse AML: A Phase 1 Study of Decitabine and Vorinostat Followed by Fludarabine, Cytarabine and G-CSF (FLAG) in Children and Young Adults With Relapsed/Refractory AML

• Status: Terminated
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 3 (actual)
• Sponsor: Michael Burke · Academic / Other
• Sex: All
• Age: 1 Year – 25 Years
• Healthy volunteers: Not accepted

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.

Detailed description

Phase 1 Study Number of Patients: 12 to 24 evaluable subjects will be required to enroll subjects in all 4 dose levels. Study Objectives: Primary Objectives * To determine the maximum tolerated dose (MTD) of decitabine when used in this combination with vorinostat, fludarabine, high dose cytarabine and G-CSF (FLAG) for children and young adults with relapsed or refractory AML. * To evaluate the ability to safely deliver the combination of decitabine and vorinostat followed by fludarabine, high dose cytarabine and G-CSF (FLAG) in pediatric and young adult patients with relapsed or refractory AML. Secondary Objectives o To establish the extent of hypomethylation of peripheral blood (PB) and bone marrow (BM) pre- and post- decitabine and vorinostat treatment by: LINE-1 methylation assay as a surrogate marker of global DNA methylation. Direct Comprehensive DNA methylation analysis Gene expression profiling to assess genetic changes * To analyze the correlation between DNA methylation and gene expression pre- and post-treatment with decitabine and vorinostat. * To analyze the correlation between biological changes and clinical response Selection of Study Patients: • Study entry is open to patients regardless of gender or ethnic background. While there will be every effort to seek out and include females and minority patients, the patient population is expected to be no different than that of other acute leukemia studies at the Medical College of Wisconsin.

Conditions

• Leukemia, Acute Myeloid

Interventions

Type	Name	Description
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

Timeline

• Start date: 2015-02-21
• Primary completion: 2017-06-21
• Completion: 2017-06-21
• First posted: 2015-04-09
• Last updated: 2019-01-24

Locations

2 sites across 1 country: United States