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

Acute Myeloid Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03381781
• Other study ID #: RuijinH mutant p53 AML
• Status: Not yet recruiting
• Phase: Phase 2
• First received: November 21, 2017
• Last updated: January 2, 2018
• Start date: March 2018
• Est. completion date: November 2020

Study information

• Verified date: January 2018
• Source: Ruijin Hospital
• Contact: Li Junmin, MD
• Phone: 0086-21-64370045
• Email: drlijunmin[@]126.com
• Is FDA regulated: No
• Study type: Interventional

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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 100
• Est. completion date: November 2020
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• P53 Mutation

Intervention

Drug:
• 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

Locations

Country	Name	City	State
China	Ruijin Hospital	Shanghai
China	Ruijin Hospital North	Shanghai
China	Shanghai Institute of Hematology	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Li Junmin

Country where clinical trial is conducted

China, 

References & 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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	complete release	the percent of patients with complete release in all patients enrolled	2-4 months since the first cycle of treatment
Secondary	overall survival	from first diagnosed to death whichever the cause is	primary estimated for 1year