Trial | NCT03381781  Report issue

Title

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

  • Phase

    Phase 2

  • Study Type

    Interventional

  • Status

    Unknown status

  • Study Participants

    100
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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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'.
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 Started
Mar 31
2018
Anticipated
Primary Completion
Nov 30
2019
Anticipated
Study Completion
Nov 30
2020
Anticipated
Last Update
Jan 04
2018

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: DNA damaging agent, Ara-C

Experimental group Experimental

Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.

Criteria 

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
No Results Posted