Epigenetic Reprogramming in Relapse AML

NCT02412475 | Terminated Phase 1 DMC

• 1 other identifier: Epigenetic
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 2

Brief 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

Outcome Measures

Primary Outcomes (1)

• Achievement of Complete Remission by Bone Marrow Criteria

  Complete Remission (CR): Attainment of M1 bone marrow with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC \> 750/µL and PLT count \> 75,000/µL). Qualifying marrow and peripheral counts should be performed within 1 week of each other. M1 Marrow: Less than 5% blasts in a bone marrow aspirate and at least 200 cells counted

  60 days

Study Arms (1)

Treatment Plan - 2 treatment courses

EXPERIMENTAL

Drug Method Used to Give Drug Days Cytarabine IT 0 or -1 Decitabine IV over 1 hour 1-5 Vorinostat PO 1-5 Fludarabine IV over 30 minutes 6-10 Cytarabine IV over 3 hours 6-10 Filgrastim (G-CSF) IV or SQ 5-12 Sorafenib PO 11-28

Drug: Decitabine; Drug: Vorinostat; Drug: Fludarabine; Drug: Cytarabine; Drug: Filgrastim; Drug: Sorafenib

Interventions

Decitabine DRUG

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

Also known as: 5-AZA-2'-Deoxycytidine, Dacogen

Treatment Plan - 2 treatment courses

Vorinostat DRUG

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

Also known as: Suberoylanilide Hydroxamic Acid, Zolinza

Treatment Plan - 2 treatment courses

Fludarabine DRUG

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

Also known as: Oforta, Fludara

Treatment Plan - 2 treatment courses

Cytarabine DRUG

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

Also known as: Depocyt

Treatment Plan - 2 treatment courses

Filgrastim DRUG

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

Also known as: Neupogen

Treatment Plan - 2 treatment courses

Sorafenib DRUG

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

Also known as: Nexavar

Treatment Plan - 2 treatment courses

Eligibility Criteria

• Age: 1 Year - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• The eligibility criteria listed below are interpreted literally and cannot be waived.
• Age: Patients must be ≥ 1 and ≤ 25 years of age when originally diagnosed with AML.
• Diagnosis:
• o Patients must have a diagnosis of AML with \> 5% blast in the bone marrow and fall into one of the categories listed below:
• Any patient in 1st or greater relapse OR Patients failed to go into remission after first or greater relapse OR Patients failed to go into remission from original diagnosis after two or more induction attempts.
• o Patients with CNS 1 or CNS 2 leukemia are eligible
• Performance Level: (See Appendix 2 for Performance Scales)
• o Karnofsky Performance Status ≥ 50% for patients 16 years and older
• o Lansky Play Score ≥ 50 for patients under 16 years of age
• Life Expectancy:
• o Patients must have a life expectancy ≥ 8 weeks as determined by the enrolling investigator.
• Prior Therapy:
• o Cytotoxic Therapy: At least 7 days must have elapsed from prior chemotherapy with the exception of hydroxyurea which can be used up to 24 hours of starting this protocol therapy.
• o Hematopoietic Stem Cell Transplant (HSCT): Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of active Graft-versus-Host Disease (GVHD).
• o Prior Demethylating and/or HDAC Inhibitor Therapy: Patients who have received prior DNMTi (e.g. decitabine) and/or HDACi (e.g. vorinostat) are eligible to participate in this Phase 1 study.

You may not qualify if:

• Patients will be excluded if they meet any of the following criteria
• They are unable to swallow Vorinostat capsules or take oral solution.
• They are currently receiving other investigational drugs.
• There is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
• They have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance, interfere with consent, study participation, follow up, or interpretation of study results.
• They have a known allergy to any of the drugs used in the study.
• Patients with Down syndrome are excluded.
• They are receiving Valproic Acid (VPA) therapy.
• Patients with Acute Promyelocytic Leukemia (APL, APML) are excluded
• Patients with documented active and uncontrolled infection at the time of study entry are not eligible.

Sponsors & Collaborators

• Michael Burke: lead
• Children's Hospitals and Clinics of Minnesota: collaborator

Study Sites (2)

Children's Hospitals and Clinics of Minnesota

Minneapolis, Minnesota, 55404, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Pommert L, Schafer ES, Malvar J, Gossai N, Florendo E, Pulakanti K, Heimbruch K, Stelloh C, Chi YY, Sposto R, Rao S, Huynh VT, Brown P, Chang BH, Colace SI, Hermiston ML, Heym K, Hutchinson RJ, Kaplan JA, Mody R, O'Brien TA, Place AE, Shaw PH, Ziegler DS, Wayne A, Bhojwani D, Burke MJ. Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. Am J Hematol. 2022 May;97(5):613-622. doi: 10.1002/ajh.26510. Epub 2022 Mar 8.

  PMID: 35180323 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Decitabine; Vorinostat; fludarabine; fludarabine phosphate; Cytarabine; Filgrastim; Sorafenib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Anilides; Amides; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Arabinonucleosides; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Phenylurea Compounds; Urea; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Pyridines

Study Officials

• Michael J Burke, MD

  Medical College of Wisconsin/Children's Hospital of Wisconsin

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: April 6, 2015
• First Posted: April 9, 2015
• Study Start: February 21, 2015
• Primary Completion: June 21, 2017
• Study Completion: June 21, 2017
• Last Updated: January 24, 2019

Record last verified: 2019-01

Locations

US (2)