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

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ClinicalTrials.gov Identifier: NCT03381781

Recruitment Status : Unknown

Verified January 2018 by Li Junmin, Ruijin Hospital.
Recruitment status was: Not yet recruiting

First Posted : December 22, 2017

Last Update Posted : January 4, 2018

View this study on Beta.ClinicalTrials.gov

Sponsor:

Information provided by (Responsible Party):

Li Junmin, Ruijin Hospital

Study Description

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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia P53 Mutation	Drug: Decitabine Drug: Arsenic Trioxide Drug: Cytarabine	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	100 participants
Allocation:	N/A
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Decitabine,Cytarabine(Ara-C) and Arsenic Trioxide(ATO) in the Treatment of Acute Myeloid Leukemia With p53 Mutations
Estimated Study Start Date :	March 2018
Estimated Primary Completion Date :	November 2019
Estimated Study Completion Date :	November 2020

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Familial acute myeloid leukemia with mutated CEBPA Cytogenetically normal acute myeloid leukemia Core binding factor acute myeloid leukemia

MedlinePlus related topics: Acute Myeloid Leukemia Arsenic Leukemia

Drug Information available for: Cytarabine Arsenic trioxide Decitabine Arsenic

Genetic and Rare Diseases Information Center resources: Myeloid Leukemia Acute Myeloid Leukemia Acute Non Lymphoblastic Leukemia Acute Graft Versus Host Disease

U.S. FDA Resources

Arms and Interventions

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: DNA damaging agent Ara-C

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 75 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03381781

Contacts

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Contact: Li Junmin, MD	0086-21-64370045 ext 665251	drlijunmin@126.com

Locations

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China
Ruijin Hospital North
Shanghai, China
Contact: Sujiang Zhang, MD 0086-21-67888761 zbruce.zhang@hotmail.com
Principal Investigator: Sujiang Zhang, MD
Ruijin Hospital
Shanghai, China
Contact: Junmin Li 021-86-64370045 ext 665251 drlijunming@126.com
Principal Investigator: Junming Li
Shanghai Institute of Hematology
Shanghai, China
Contact: Min Lu, Ph.D. 86-21-64370045 ext 610805 min.lu@shsmu.edu.cn
Principal Investigator: Min Lu, Ph.D.

Sponsors and Collaborators

Li Junmin

Investigators

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Principal Investigator:	Zhang Sujiang	Shanghai Ruijin Hospital North
Principal Investigator:	Lu Min	Shanghai institute of Hematology

More Information

Publications:

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.

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.

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. Erratum In: Cancer Cell. 2016 Nov 14;30(5):822-823.

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.

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.

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.

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Responsible Party:	Li Junmin, director of the hematology department, Ruijin Hospital
ClinicalTrials.gov Identifier:	NCT03381781
Other Study ID Numbers:	RuijinH mutant p53 AML
First Posted:	December 22, 2017 Key Record Dates
Last Update Posted:	January 4, 2018
Last Verified:	January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

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

Keywords provided by Li Junmin, Ruijin Hospital:


p53 mutation acute myeloid leukemia decitabine Arsenic trioxide cytarabine

Additional relevant MeSH terms:

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Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Neoplasms by Histologic Type Neoplasms Cytarabine Decitabine Arsenic Trioxide Antimetabolites, Antineoplastic	Antimetabolites Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antiviral Agents Anti-Infective Agents Immunosuppressive Agents Immunologic Factors Physiological Effects of Drugs Enzyme Inhibitors

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