NCT03381781

Brief Summary

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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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'.

Trial Health

43
At Risk

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Trial has exceeded expected completion date
Enrollment
100

participants targeted

Target at P50-P75 for phase_2

Timeline
Completed

Started Mar 2018

Geographic Reach
1 country

3 active sites

Status
unknown

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

November 21, 2017

Completed
1 month until next milestone

First Posted

Study publicly available on registry

December 22, 2017

Completed
2 months until next milestone

Study Start

First participant enrolled

March 1, 2018

Completed
1.7 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 1, 2019

Completed
1 year until next milestone

Study Completion

Last participant's last visit for all outcomes

November 1, 2020

Completed
Last Updated

January 4, 2018

Status Verified

January 1, 2018

Enrollment Period

1.7 years

First QC Date

November 21, 2017

Last Update Submit

January 2, 2018

Conditions

Acute Myeloid LeukemiaP53 Mutation

Keywords

p53 mutationacute myeloid leukemiadecitabineArsenic trioxidecytarabine

Outcome Measures

Primary Outcomes (1)

  • relapse free survival

    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 Outcomes (2)

  • complete release

    2-4 months since the first cycle of treatment

  • overall survival

    primary estimated for 1year

Study Arms (1)

Experimental group

EXPERIMENTAL

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

Drug: DecitabineDrug: Arsenic TrioxideDrug: Cytarabine

Interventions

DecitabineDRUG

20mg/m\^2,d1-5,ivgtt,28days as a duration

Also known as: DNA demethylation agent, DNA damaging agent
Experimental group
Arsenic TrioxideDRUG

0.16mg/kg,d1-5,ivgtt,28days as a duration

Also known as: As2O3, Arsenic
Experimental group
CytarabineDRUG

15mg/m\^2,hypodermic injection,q12h,d1-7

Also known as: DNA damaging agent, Ara-C
Experimental group

Eligibility Criteria

Age18 Years - 75 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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
  • +3 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (3)

Ruijin Hospital North

Shanghai, China

Location

Ruijin Hospital

Shanghai, China

Location

Shanghai Institute of Hematology

Shanghai, China

Location

Related Publications (6)

  • Chang CK, Zhao YS, Xu F, Guo J, Zhang Z, He Q, Wu D, Wu LY, Su JY, Song LX, Xiao C, Li X. TP53 mutations predict decitabine-induced complete responses in patients with myelodysplastic syndromes. Br J Haematol. 2017 Feb;176(4):600-608. doi: 10.1111/bjh.14455. Epub 2016 Dec 16.

    PMID: 27984642BACKGROUND

  • 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.

    PMID: 27959731BACKGROUND

  • Lu M, Breyssens H, Salter V, Zhong S, Hu Y, Baer C, Ratnayaka I, Sullivan A, Brown NR, Endicott J, Knapp S, Kessler BM, Middleton MR, Siebold C, Jones EY, Sviderskaya EV, Cebon J, John T, Caballero OL, Goding CR, Lu X. Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP. Cancer Cell. 2013 May 13;23(5):618-33. doi: 10.1016/j.ccr.2013.03.013. Epub 2013 Apr 25.

    PMID: 23623661BACKGROUND

  • Lu M, Muers MR, Lu X. Introducing STRaNDs: shuttling transcriptional regulators that are non-DNA binding. Nat Rev Mol Cell Biol. 2016 Aug;17(8):523-32. doi: 10.1038/nrm.2016.41. Epub 2016 May 25.

    PMID: 27220640BACKGROUND

  • Lu M, Zak J, Chen S, Sanchez-Pulido L, Severson DT, Endicott J, Ponting CP, Schofield CJ, Lu X. A code for RanGDP binding in ankyrin repeats defines a nuclear import pathway. Cell. 2014 May 22;157(5):1130-45. doi: 10.1016/j.cell.2014.05.006.

    PMID: 24855949BACKGROUND

  • Yan W, Jung YS, Zhang Y, Chen X. Arsenic trioxide reactivates proteasome-dependent degradation of mutant p53 protein in cancer cells in part via enhanced expression of Pirh2 E3 ligase. PLoS One. 2014 Aug 12;9(8):e103497. doi: 10.1371/journal.pone.0103497. eCollection 2014.

    PMID: 25116336BACKGROUND

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

DecitabineArsenic TrioxideArsenicCytarabine

Condition Hierarchy (Ancestors)

Leukemia, MyeloidLeukemiaNeoplasms by Histologic TypeNeoplasmsHematologic DiseasesHemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

AzacitidineAza CompoundsOrganic ChemicalsCytidinePyrimidine NucleosidesPyrimidinesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsNucleosidesNucleic Acids, Nucleotides, and NucleosidesRibonucleosidesArsenicalsInorganic ChemicalsOxidesOxygen CompoundsMetalloidsElementsArabinonucleosides

Study Officials

  • Zhang Sujiang

    Shanghai Ruijin Hospital North

    PRINCIPAL INVESTIGATOR

  • Lu Min

    Shanghai institute of Hematology

    PRINCIPAL INVESTIGATOR

Central Study Contacts

Li Junmin, MD

CONTACT

0086-21-64370045drlijunmin@126.com

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR INVESTIGATOR
PI Title
director of the hematology department

Study Record Dates

First Submitted

November 21, 2017

First Posted

December 22, 2017

Study Start

March 1, 2018

Primary Completion

November 1, 2019

Study Completion

November 1, 2020

Last Updated

January 4, 2018

Record last verified: 2018-01

Locations

CN(3)