Decitabine,Cytarabine and Arsenic Trioxide for Acute Myeloid Leukemia With p53 Mutations
NCT ID: NCT03381781
Last Updated: 2018-01-04
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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UNKNOWN
PHASE2
100 participants
INTERVENTIONAL
2018-03-31
2020-11-30
Brief Summary
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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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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'.
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Experimental group
Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.
Decitabine
20mg/m\^2,d1-5,ivgtt,28days as a duration
Arsenic Trioxide
0.16mg/kg,d1-5,ivgtt,28days as a duration
Cytarabine
15mg/m\^2,hypodermic injection,q12h,d1-7
Interventions
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Decitabine
20mg/m\^2,d1-5,ivgtt,28days as a duration
Arsenic Trioxide
0.16mg/kg,d1-5,ivgtt,28days as a duration
Cytarabine
15mg/m\^2,hypodermic injection,q12h,d1-7
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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
18 Years
75 Years
ALL
No
Sponsors
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Li Junmin
OTHER
Responsible Party
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Li Junmin
director of the hematology department
Principal Investigators
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Zhang Sujiang
Role: PRINCIPAL_INVESTIGATOR
Shanghai Ruijin Hospital North
Lu Min
Role: PRINCIPAL_INVESTIGATOR
Shanghai institute of Hematology
Locations
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Ruijin Hospital North
Shanghai, , China
Ruijin Hospital
Shanghai, , China
Shanghai Institute of Hematology
Shanghai, , China
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
Other Identifiers
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RuijinH mutant p53 AML
Identifier Type: -
Identifier Source: org_study_id
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