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

Phase 2

• Conditions: Acute Myeloid Leukemia; P53 Mutation
• Interventions: Drug: Decitabine; Drug: Arsenic Trioxide; Drug: Cytarabine

• Registration Number: NCT03381781
• Lead Sponsor: Li Junmin

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 Our published and unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017).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

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 Timeline

• Study First Submitted: 2017-11-21
• Study First Submitted QC: 2017-12-18
• Study First Posted: 2017-12-22
• Status Verified: 2018-01
• Last Update Submitted: 2018-01-02
• Last Update Posted: 2018-01-04
• Study Start: 2018-03
• Primary Completion: 2019-11
• Study Completion: 2020-11

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Experimental group	Decitabine	Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.
Experimental group	Arsenic Trioxide	Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.
Experimental group	Cytarabine	Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine.

Primary Outcome Measures

Name	Time	Method
relapse free survival	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

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

Trial Locations

Locations (3)

Ruijin Hospital North; 🇨🇳 Shanghai, China

Ruijin Hospital; 🇨🇳 Shanghai, China

Shanghai Institute of Hematology; 🇨🇳 Shanghai, China