Genomic Predictors of Decitabine Response in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

Genomic Predictors of Decitabine Response in AML/MDS

This clinical trial studies potential genetic markers which might be used to predict which patients with acute myeloid leukemia or myelodysplastic syndromes respond to decitabine. This study will contribute to the efforts to find effective and less toxic therapies to provide durable remissions in a significant proportion of elderly AML patients.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia, Myeloid, Acute
• Intervention / Treatment: Drug: decitabine

• Study Type: Interventional
• Enrollment (Actual): 114
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

All of the following:

• Patient must have non-M3 AML or MDS

• An adverse risk karyotype defined by:

  • Complex karyotype by cytogenetics, or
  • Deletion of all or part of chromosome 5, 7, 12, or 17 defined by FISH or cytogenetics, or
  • Somatic TP53 mutation

All of the following:

1. Patient must have an ECOG performance status ≤ 2.
2. Patient must have >10% disease burden measured by cytomorphology, flow cytometry, or cytogenetics.
3. Patient must have peripheral white blood cell count < 50,000/mcl.

4. Patient must have adequate organ function, defined as:

   1. Total bilirubin < 1.5 x ULN
   2. AST/ALT < 2.5 x ULN
   3. Serum creatinine < 2.0 x ULN
5. Patient must have undergone ≤ 2 cycles of prior hypomethylating agent (decitabine or azacitidine).
6. Patient must be enrolled in HRPO# 201011766 ("Tissue Acquisition for Analysis of Genetic Progression Factors in Hematologic Diseases").
7. Patient must be > 18 years of age.
8. Patient must be able to understand and willing to sign an IRB-approved written informed consent document.

Exclusion Criteria:

• Patient must not be pregnant or nursing
• Patient must not have acute promyelocytic leukemia or t(15;17) observed by FISH.
• Patient must not have known central nervous system (CNS) leukemia
• Patient must not have a history of positive human immunodeficiency virus (HIV) serology
• Patient must not have a history of positive hepatitis C serology
• Patient must not have undergone prior allogeneic stem cell transplant
• Patient must not have any uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, ongoing or active graft-versus-host disease (GVHD), congestive heart failure of New York Heart Association (NYHA) class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements
• Patient must not have had radiation therapy within 14 days of enrollment
• Patient must not have received any chemotherapy within 21 days of enrollment and any acute treatment-related toxicities must have returned to baseline. Patients may be receiving hydrea at time of enrollment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Decitabine; Patients receive decitabine IV over 1 hour on days 1-10 of a 28-day cycle. Treatment continues for 2 cycles. Patients then receive decitabine IV over 1 hour on days 1-10, 1-5, or 1-3 (depending on response). Treatment continues in the absence of disease progression or unacceptable toxicity.	Drug: decitabine; Other Names: 5-aza-dCyd, 5AZA, DAC, Dacogen, deoxyazacytidine, dezocitidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation of Patient Specific Mutations With Overall Response Rate	-Best response after 4 treatment cycles as assessed according to International Working Group (IWG) criteria; bone marrow for gene sequencing will be collected at baseline; mutations will be correlated with overall response rate --Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Marrow complete remission (mCR), Partial remission (PR), Stable disease (SD), Progressive disease (PD)	4 months (4 treatment cycles)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls)	The overall response rate (CR/CRi/mCR/PR) and complete response rate (CR/CRi/mCR) will be compared with historical controls. Response assessed according to IWG criteria.	4 months (4 treatment cycles)
Rate of Mutation Clearance During Treatment	Samples collected at baseline and after 10, 28 and 56 days of therapy; the rate of mutation clearance was measured as mean VAF change per day of treatment and was estimated using linear mixed model for repeated measurement data .	Up to Day 56
Peripheral Blood Decitabine Plasma Levels	To determine whether steady state serum concentrations of decitabine correlated with responses; Complete remission (CR), Complete remission with incomplete hematologic recovery (CRi), Partial remission (PR), Stable disease (SD), Progressive disease (PD), Not applicable (NA) - assessed according to International Working Group (IWG) criteria	Day 4
Change in Bone Marrow Methylcytosine	-Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline to Day 10	Baseline and Day 10

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Welch John, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

General Publications

• Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon B, Lee YS, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA, Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ. TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med. 2016 Nov 24;375(21):2023-2036. doi: 10.1056/NEJMoa1605949.

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2013
• Primary Completion (Actual): June 23, 2017
• Study Completion (Actual): November 13, 2017

Study Registration Dates

• First Submitted: September 13, 2012
• First Submitted That Met QC Criteria: September 13, 2012
• First Posted (Estimate): September 18, 2012

Study Record Updates

• Last Update Posted (Actual): October 2, 2018
• Last Update Submitted That Met QC Criteria: September 5, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Decitabine
• Other Study ID Numbers: 201210102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No