Decitabine,Cytarabine and Arsenic Trioxide for Acute Myeloid Leukemia With p53 Mutations

January 2, 2018 updated by: Li Junmin

Decitabine,Cytarabine(Ara-C) and Arsenic Trioxide(ATO) in the Treatment of Acute Myeloid Leukemia With p53 Mutations

This is a prospective,uncontrolled and multi-institution trial.The aim is to identify if using decitabine,cytarabine and ATO as the therapy of acute myeloid leukemia(AML) with p53 mutations has better relapse free survival and complete response than using decitabine and cytarabine.

TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients.

Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH, 2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed quickly.

Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment. ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC, 1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014);

Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53 subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled. We designate trials aiming for a better treatment regimen for mp53 patients as 'PANDA-Trials'.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

This study is designed as a model of precision medicine. About 1500 AML patients will be applied for TP53 sequencing. The bone marrow samples will be collected and its p53 status will be Sanger sequenced in 3-5 days before drug administration. The 100 mp53-positive patients will be trialed, while the others (mp53-negative patients) will be subjected to standard treatment or other clinical trials.

In this study,100 patients with p53 mutations will be enrolled,including newly diagnosed AML aged 60-75,AML transferred from Myelodysplastic Syndrome(MDS) and therapy related AML.

Study Type

Interventional

Enrollment (Anticipated)

100

Phase

  • 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 Contact

Study Locations

  • China
      • Shanghai, China
        • Ruijin Hospital
        • Contact:
        • Principal Investigator:
          • Junming Li
      • Shanghai, China
        • Ruijin Hospital North
        • Contact:
        • Principal Investigator:
          • Sujiang Zhang, MD
      • Shanghai, China
        • Shanghai Institute of Hematology
        • Contact:
        • Principal Investigator:
          • Min Lu, Ph.D.

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

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • de novo elderly AML,AML transferred from MDS,therapy related AML
  • exclude acute promyelocytic leukemia(APL)
  • p53 mutations determined by DNA sequencing from bone marrow
  • ECOG<3,CCI≤1,ADL≥100
  • bone marrow is active
  • normal hepatic function and renal function
  • normal cardiac function
  • obtain informed consent

Exclusion Criteria:

  • APL
  • without p53 mutations
  • previously treated elderly AML
  • central nervous system is involved
  • abnormal hepatic function or renal function
  • severe cardiac disease,including myocardial infarction,cardiac dysfunction
  • ECG:QTc>0.44 sec in men,QTc>0.46 sec in women
  • with other malignant tumor meanwhile
  • active tuberculosis or HIV-positive patients
  • woman who are pregnant or breastfeeding
  • allergic to any drug in protocol or with contraindications
  • hypomethylation agent(HMA) is contraindicated
  • ECOG≥3,CCI>1,ADL<100
  • cannot understand or obey the protocol
  • with a history of allergies or intolerability
  • with a history of decitabine therapy
  • participate in other clinical trials meanwhile
  • any situations that hinder trial existed

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
Intervention / Treatment
Experimental: Experimental group
Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.
Drug: Decitabine
20mg/m^2,d1-5,ivgtt,28days as a duration
Other Names:
  • DNA demethylation agent
  • DNA damaging agent
Drug: Arsenic Trioxide
0.16mg/kg,d1-5,ivgtt,28days as a duration
Other Names:
  • As2O3
  • Arsenic
Drug: Cytarabine
15mg/m^2,hypodermic injection,q12h,d1-7
Other Names:
  • Ara-C
  • DNA damaging agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
relapse free survival
Time Frame: From date of complete release until the date of first documented relapse, assessed up to 6-8months
since a patient first being determined as complete release until relapse
From date of complete release until the date of first documented relapse, assessed up to 6-8months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
complete release
Time Frame: 2-4 months since the first cycle of treatment
the percent of patients with complete release in all patients enrolled
2-4 months since the first cycle of treatment
overall survival
Time Frame: primary estimated for 1year
from first diagnosed to death whichever the cause is
primary estimated for 1year

Collaborators and Investigators

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

Sponsor

Li Junmin

Investigators

  • Principal Investigator: Zhang Sujiang, Shanghai Ruijin Hospital North
  • Principal Investigator: Lu Min, Shanghai Institute of Hematology

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.

General Publications

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 (Anticipated)

March 1, 2018

Primary Completion (Anticipated)

November 1, 2019

Study Completion (Anticipated)

November 1, 2020

Study Registration Dates

First Submitted

November 21, 2017

First Submitted That Met QC Criteria

December 18, 2017

First Posted (Actual)

December 22, 2017

Study Record Updates

Last Update Posted (Actual)

January 4, 2018

Last Update Submitted That Met QC Criteria

January 2, 2018

Last Verified

January 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RuijinH mutant p53 AML

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

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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