Single Agent Decitabine in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia

May 9, 2022 updated by: Washington University School of Medicine

An Open Label, Multicenter, Phase II Trial Testing Single Agent Decitabine in TP53 Mutated Relapsed/Refractory Acute Myeloid Leukemia

In this study, the investigators seek to determine whether decitabine therapy can improve outcomes, specifically overall survival this selected subset of acute myeloid leukemia (AML) patients with the poorest prognosis based on refractoriness to induction treatment and high risk genetic mutations.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
17

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • TP53 mutant AML. The presence of a TP53 mutation should be determined by Genoptix (or institutional preferred equivalent assay). Detection of a TP53 mutation at the time of initial diagnosis is sufficient for enrollment at the time of relapsed/refractory disease. Detection of a TP53 mutation in either the peripheral blood or bone marrow is adequate for enrollment. Alternatively, patients who have not had TP53 mutation analysis performed, but who have > 20% TP53 positive cells by immunohistochemistry detected on a bone marrow aspirate may also be enrolled,29 provided that mutation analysis is requested at the time of enrollment.

  • Relapsed/refractory AML following 7+3 (or similar cytarabine containing induction chemotherapy for AML) disease detected by one of the following methods:

    • bone marrow blasts > 5%, or
    • Hematologics flow cytometry assay (threshold > 0.5%) (alternative equivalent assay may be substituted), or
    • Persistent cytogenetic abnormality (e.g. del5, del17p, etc), by FISH or conventional karotyping, or
    • Persistent TP53 mutation (at least 5 variant reads with at least 50x coverage) determined by Genoptix (or institutional preferred equivalent assay).
  • Patients with > 10% blasts on a day +14 bone marrow biopsy following 7+3 may either be enrolled or may be treated with a course of standard re-induction (e.g. 5+2 or similar) and then re-evaluated for response. Eligible patients will meet any of the above criteria on a subsequent biopsy.

  • Bone marrow and organ function as defined below:

    • Peripheral white blood cell count < 50,000/mcl (patients may receive hydroxyurea as necessary for cytoreduction),
    • Total bilirubin < 1.5 x upper limit of normal,
    • AST and ALT < 2.5 x upper limit of normal,
    • Serum creatinine < 2.0 x upper limit of normal, and,
  • At least 18 years of age.
  • Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control, abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately
  • Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable
  • Performance status ≤ 3

Exclusion Criteria:

  • Prior treatment with either decitabine or azacitidine or an investigational agent
  • Acute promyelocytic leukemia with PML-RARA or t(15;17).
  • History of HIV, Hepatitis B, or Hepatitis C infection.
  • Concurrent illness including, but not limited to, ongoing uncontrolled infection, symptomatic NYHA class 3 or 4 congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
  • Radiation therapy within 14 days of enrollment.
  • Chemotherapy administration in the 7 days preceding enrollment with the exception of hydroxyurea, which can be continued until Cycle 2. A washout period for oral tyrosine kinase inhibitors (e.g. Jakafi, etc) is not required, although tyrosine kinase inhibitors therapy must be discontinued prior to enrollment.
  • Malignancies (other than AML) requiring active therapy or diagnosed within the last year, with the exception of non-melanoma skin cancer which can be treated or in situ malignancies (such as cervical, breast, prostate, etc.)
  • Currently receiving any other investigational agents.
  • Known central nervous system (CNS) leukemia or testicular involvement of leukemia
  • A history of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine or other agents used in the study.
  • Pregnant and/or breastfeeding. Women of childbearing potential must have a negative urine pregnancy test within 7 days of study entry.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Decitabine
  • Cycle 1: All patients will receive decitabine 20 mg/m^2 IV infusion per day over one hour on Days 1-10 of a 28-day cycle
  • Cycle 2: Patients with bone marrow blast counts < 5% may receive decitabine 20 mg/m^2 IV infusion per day over one hour on Days 1-5 of a 28-day cycle. All other patients will receive decitabine 20 mg/m^2 IV infusion per day over one hour on Days 1-10 of a 28-day cycle.
  • Cycle 3 and subsequent cycles: All patients will receive 20 mg/m^2 IV infusion per day over one hour on Days 1-5 of the 28-day cycle
Drug: Decitabine
  • After 2 cycles, patients with progressive disease or relapse (a clear progression with at least >20% bone marrow blasts and an increase of at least 50% from prior biopsy) should be removed from protocol and proceed to salvage treatment according to center preference
  • Transplant eligible patients who achieve CR, CRc, or CRi, after 3 cycles with a suitable donor will proceed to conditioning regimen and transplant
  • Transplant eligible patients with PR after 3 cycles may be removed from protocol and proceed to salvage treatment according to center preference
  • Transplant eligible patients with a suitable donor who achieve mLFS, CR, CRc, or CRi, may proceed to transplant after at 3 cycles
  • Transplant ineligible patients with (CR, CRc or CRi, PR) will continue on maintenance doses
  • Transplant ineligible patient with SD after cycle 4 may be removed from protocol and proceed to alternative treatment or continue on protocol according to treating physician's preference.
Other Names:
  • 5-aza-2'-deoxycytidine
Procedure: Bone marrow biopsy/aspirate
  • Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression or relapse
  • Biopsy/aspirate on Cycle 1 Day 10 is for participants enrolled at Washington University only
  • Biopsy/aspirate on Cycle 2 Day 28 is at the discretion of the treating physician
Procedure: Peripheral blood draw
-Baseline, Cycle 1 Day 10, Cycle 1 Day 28, Cycle 2 Day 28, Cycle 3 Day 28, and Progression/Relapse
Procedure: Skin biopsy
  • Optional but if refuse skin biopsy then participant can provided buccal swab
  • There is no required time frame for this sample - it may have been collected months or even years prior to the first dose of decitabine
  • If WBC at time of enrollment is >30,000/µl, skin biopsy should be collected at the time of C1D28 bone marrow biopsy or thereafter
Procedure: Buccal swab
-Baseline (if skin biopsy declined) and Cycle 2 Day 28

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Overall Survival of Participants With TP53 Mutation
Time Frame: 1 year
  • Overall survival (OS) is defined as the time from enrollment to death due to any cause. For a patient who is not known to be alive at the end of study follow up, observation of OS is censored on the date the patient was last known to be alive
  • To be evaluable for this outcome measure the participant would have to have received at least one dose of decitabine
1 year

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Percentage of Responding TP53 Mutated Patients (CR, CRi)
Time Frame: 12 weeks
  • Complete remission (CR) - Defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1,000/μL); platelet count >100 x 109/L (100,000/μL).
  • Complete remission with incomplete hematologic recovery (CRi): All CR criteria except for residual neutropenia - <1.0 x 109/L (1,000/μL) or thrombocytopenia -<100 x 109/L (100,000/μL)
12 weeks
Time to Stem Cell Transplant Among Participants Who Are Suitable Candidates for Transplant and Have an Identified Donor
Time Frame: 12 weeks
  • Document the number of days that it takes each participant to reach transplant
  • Transplant eligible participants are those who achieve complete remission (CR), cytogenetic complete remission (CRc), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia free state (mLFS) per 2017 ELN AML Recommendations.
12 weeks
Median Time to Leukemia Relapse (TTLR) in Non-transplant Patients
Time Frame: 2 years
-Recurrence/morphologic relapse - Defined as relapse following complete remission is defined as reappearance of blasts in the blood or the finding of ≥ 5% blasts in the bone marrow, not attributable to any other cause. New dysplastic changes is considered relapse. If there are no blasts in the peripheral blood and 5-20% blasts in the bone marrow, bone marrow biopsy should be repeated in > 1 week to confirm relapse.
2 years
Event-free Survival (EFS)
Time Frame: 2 year
-Event-free survival is defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, death due to any cause, or loss to follow up.
2 year
Average Number of Hospital Days
Time Frame: During cycles 1 and 2 (60 days)
-Document number of hospital days that each participant stays and obtain average for all evaluable participants
During cycles 1 and 2 (60 days)
Response Compared Between Patients With Morphologically Evident Disease Versus Patients With Molecularly Detected Disease at the Time of Enrollment
Time Frame: Through 12 weeks
  • Morphologically evident disease (>5% blasts by cytomorphology)
  • Molecularly detected disease (disease detected with flow cytometry, cytogenetic, or mutational analysis if ≤ 5% blasts by cytomorphology)
  • Response will be assessed according to the 2017 European LeukemiaNet (ELN) Acute Myeloid Leukemia (AML) recommendations
Through 12 weeks
Survival Compared Between Patients With Morphologically Evident Disease Versus Patients With Molecularly Detected Disease at the Time of Enrollment
Time Frame: 2 years
  • Morphologically evident disease (>5% blasts by cytomorphology)
  • Molecularly detected disease (disease detected with flow cytometry, cytogenetic, or mutational analysis with ≤ 5% blasts by cytomorphology)
2 years
Response Compared Between Patients With de Novo AML Versus Patients With Secondary AML Versus Patients With Treatment-related AML
Time Frame: Through 12 weeks
-Response will be assessed according to the 2017 European LeukemiaNet (ELN) Acute Myeloid Leukemia (AML) recommendations
Through 12 weeks
Survival Compared Between Patients With de Novo AML Versus Patients With Secondary AML Versus Patients With Treatment-related AML
Time Frame: 2 years
2 years
Response Compared Between Patients With Presence of Cytogenetic Abnormalities in Addition to TP53 Mutations Versus Patients With Absence of Cytogenetic Abnormalities in Addition to TP53 Mutations
Time Frame: 12 weeks
-Response will be assessed according to the 2017 European LeukemiaNet (ELN) Acute Myeloid Leukemia (AML) recommendations
12 weeks
Survival Compared Between Patients With Presence of Cytogenetic Abnormalities in Addition to TP53 Mutations Versus Patients With Absence of Cytogenetic Abnormalities in Addition to TP53 Mutations
Time Frame: 2 years
2 years
Median Number of Hospital Stays
Time Frame: During cycles 1 and 2 (60 days)
-Document number of hospital days that each participant stays and obtain median for all evaluable participants
During cycles 1 and 2 (60 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Cancer Institute (NCI)
National Institutes of Health (NIH)
Janssen Pharmaceuticals

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: John Welch, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 14, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
February 13, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 16, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 20, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 20, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 24, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
June 2, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 9, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 201911185-1001
  • 3P50CA171963-06S1 (U.S. NIH Grant/Contract)

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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