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

• ClinicalTrials.gov Identifier: NCT01687400
• Recruitment Status: Completed
• First Posted: September 18, 2012
• Results First Posted: October 2, 2018
• Last Update Posted: October 2, 2018
• Sponsor: Washington University School of Medicine
• Information provided by (Responsible Party): Washington University School of Medicine

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myeloid, Acute; Myelodysplastic Syndromes	Drug: decitabine	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 114 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Genomic Predictors of Decitabine Response in AML/MDS
• Actual Study Start Date: February 12, 2013
• Actual Primary Completion Date: June 23, 2017
• Actual Study Completion Date: November 13, 2017

Arms and Interventions

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 Name: 5-aza-dCyd, 5AZA, DAC, Dacogen, deoxyazacytidine, dezocitidine

Outcome Measures

Primary Outcome Measures :

1. Correlation of Patient Specific Mutations With Overall Response Rate [ Time Frame: 4 months (4 treatment cycles) ]

   -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)

Secondary Outcome Measures :

1. Compare Outcomes of a 10-day Decitabine Per Cycle Regimen to a 5-day Regimen (Historical Controls) [ Time Frame: 4 months (4 treatment cycles) ]
   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.
2. Rate of Mutation Clearance During Treatment [ Time Frame: Up to Day 56 ]
   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 .
3. Peripheral Blood Decitabine Plasma Levels [ Time Frame: Day 4 ]
   • 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
4. Change in Bone Marrow Methylcytosine [ Time Frame: Baseline and Day 10 ]
   -Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline to Day 10

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, Missouri

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

Sponsors and Collaborators

Washington University School of Medicine

Investigators

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

  Study Documents (Full-Text)

Documents provided by Washington University School of Medicine:

Study Protocol and Statistical Analysis Plan  [PDF] November 15, 2016

More Information

Additional Information:

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

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Washington University School of Medicine
• ClinicalTrials.gov Identifier: NCT01687400
• Other Study ID Numbers: 201210102
• First Posted: September 18, 2012
• Results First Posted: October 2, 2018
• Last Update Posted: October 2, 2018
• Last Verified: September 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Disease; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Bone Marrow Diseases; Precancerous Conditions; Decitabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors