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

Tracking Information

• First Submitted Date: September 13, 2012
• First Posted Date: September 18, 2012
• Results First Submitted Date: June 13, 2018
• Results First Posted Date: October 2, 2018
• Last Update Posted Date: October 2, 2018
• Actual Study Start Date: February 12, 2013
• Actual Primary Completion Date: June 23, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 5, 2018)

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)

Original Primary Outcome Measures (submitted: September 13, 2012)

Correlation of patient specific mutations with overall response rate [ Time Frame: 4 months ]

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 and their respective 95% confidence intervals will be provided.

Current Secondary Outcome Measures (submitted: September 5, 2018)

• 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.
• 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 .
• 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
• 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

Original Secondary Outcome Measures (submitted: September 13, 2012)

• Compare efficacy of a10-day decitabine per cycle regimen to a 5-day regimen (historical controls) [ Time Frame: 4 months (4 treatment cycles) ]
  Efficacy defined as complete response (complete response [CR]/CR with incomplete blood count recovery [CRi]) and overall response (CR+CRi + partial response [PR]); response assessed according to IWG criteria;
• Bone marrow mutation expression profile and change in profile during decitabine treatment [ Time Frame: 60 days ]
  Samples collected at baseline and after 10, 28 and 56 days of therapy; compare the rate of mutation clearance and lowest mutation frequencies between the patients who achieve a CR/CRi after 4 cycles and those who do not
• Steady-state serum decitabine concentration [ Time Frame: Day 4 ]
  The steady-state serum decitabine concentration on day 4 +/- 1 will be measured and correlated with clinical overall response.
• Decrease in bone marrow methylcytosine [ Time Frame: Baseline and Day 10 ]
  Change of total bone marrow deoxyribonucleic acid (DNA) methylcytosine from baseline and its association with both steady-state serum drug levels and response will be assessed using 2-way ANOVA for repeated measurement data

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Genomic Predictors of Decitabine Response in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes
• Official Title: Genomic Predictors of Decitabine Response in AML/MDS
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes

Intervention

Drug: decitabine

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

Study Arms

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.

Intervention: Drug: decitabine

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 18, 2017): 114
• Original Estimated Enrollment (submitted: September 13, 2012): 125
• Actual Study Completion Date: November 13, 2017
• Actual Primary Completion Date: June 23, 2017 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01687400
• Other Study ID Numbers: 201210102
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Washington University School of Medicine
• Original Responsible Party: Same as current
• Current Study Sponsor: Washington University School of Medicine
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Washington University School of Medicine
• Verification Date: September 2018