Decitabine and Arsenic Trioxide for Myelodysplastic Syndrome(MDS)

NCT03377725 | Withdrawn Phase 3

• 1 other identifier: RuijinH mutant p53 MDS
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 3

Brief Summary

This is a prospective,controlled and multi-institution trial.The aim is to identify if using decitabine and Arsenic Trioxide(ATO) as the therapy of Myelodysplastic Syndrome(MDS) has better relapse free survival and complete response than using decitabine alone. 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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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'.

Conditions

Myelodysplastic Syndromes; P53 Mutation

Keywords

Myelodysplastic Syndromes; Decitabine; Arsenic Trioxide; P53 Mutations

Outcome Measures

Primary Outcomes (1)

• relapse free survival

  since a patient first being determined as complete release until relapse

  up to 6-8 months after complete release

Secondary Outcomes (2)

• complete release

  2-4 months since the first cycle of treatment

• overall survival

  primary estimated for 1year

Study Arms (2)

Experimental group

EXPERIMENTAL

MDS patients of the experimental group will be treated with decitabine and arsenic trioxide.

Drug: Decitabine; Drug: Arsenic Trioxide

Controlled group

ACTIVE COMPARATOR

MDS patients of the controlled group will be treated with decitabine alone.

Drug: Decitabine

Interventions

Decitabine DRUG

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

Also known as: DNA demethylation agent, DNA damaging agent

Controlled group; Experimental group

Arsenic Trioxide DRUG

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

Also known as: As2O3, Arsenic

Experimental group

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• de novo MDS
• The Revised International Prognostic Scoring System(IPSS-R) is intermediate,poor or very poor
• years old(including 18-year-old and 75-year-old patients)
• 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:

• previously treated MDS patients
• 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

Sponsors & Collaborators

• Li Junmin: lead

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: 27984642 BACKGROUND

• 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: 27959731 BACKGROUND

• 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: 23623661 BACKGROUND

• 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: 27220640 BACKGROUND

• 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: 24855949 BACKGROUND

• 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: 25116336 BACKGROUND

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Decitabine; Arsenic Trioxide; Arsenic

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Arsenicals; Inorganic Chemicals; Oxides; Oxygen Compounds; Metalloids; Elements

Study Officials

• Zhang Sujiang

  Shanghai Ruijin Hospital North

  PRINCIPAL INVESTIGATOR

• Lu Min

  Shanghai institute of Hematology

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: director of the hematology department

Study Record Dates

• First Submitted: December 13, 2017
• First Posted: December 19, 2017
• Study Start: March 20, 2018
• Primary Completion: March 31, 2018
• Study Completion: March 31, 2018
• Last Updated: August 16, 2023

Record last verified: 2018-01

Locations

CN (3)