Mutant p53-based Personalized Trial Using Decitabine and Arsenic Trioxide on AML/MDS

Phase 1

Recruiting

• Conditions: P53 Mutation; Myeloid Malignancy; MDS; Aml
• Interventions: Drug: Decitabine; Drug: Arsenic Trioxide

• Registration Number: NCT03855371
• Lead Sponsor: Ruijin Hospital

Brief Summary

TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. Here the investigators try to evaluate the side effect and treatment potential of DAC+ATO in p53 mutated high-risk AML/MDS patients.

About 200 AML/MDS patients will be sequenced for TP53 sequence before recruitment. The investigators estimated about 5 patients, based on the reported p53 mutation frequency in AML/MDS, will be p53-mutated. In the trial, the investigators will selectively recruit the mp53 AML/MDS patients that are predicted to respond to DAC+ATO regimen with highest chance (based on the relevant basic studies).

The investigators designate mutant p53-based clinical trials as 'PANDA (P53 AND Arsenic)-Trials'.

Detailed Description

TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53 (mp53)-targeting regimen was clinically established. In two independent clinical trials reported recently, DNA demethylating drug Decitabine (DAC) treatment yielded a surprisingly high rate of complete remission (CR) in mp53-expressing myelodysplastic syndromes (MDS) patients and acute myeloid leukemia (AML) patients. Notably, all of the mp53-expressing patients in the two clinical studies, despite of CR, relapsed quickly. This was attributed to a failure in thoroughly clearing all leukemia-specific mutations and the preexisting mp53 subclone outgrew in all of the relapse patients. Indeed, The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data). Meanwhile, the investigators found arsenic trioxide (ATO) selectively inhibit p53-mutated cells involving mutant p53 reactivation and mutant p53 degradation (presumably mediated by upregulated mdm2 and RCHY1/Pirh2 through reactivated mutant p53). In addition, DAC and ATO show synergy in inhibiting p53-mutated cells.

In current phase I trial, the investigators try to evaluate the side effect and treatment potential of DAC+ATO in p53 mutated high-risk MDS patients. About 200 AML/MDS patients will be recruited for TP53 sequencing before being trialed. The investigators estimated about 50 patients, based on p53 mutation frequency in AML/MDS, will be sequenced to be mp53-positive. The mp53-positive AML/MDS patients are known to have an extremely poor prognosis. The investigators will select high-risk mp53 MDS patients that are predicted to respond to DAC+ATO with highest chance based on our relevant basic studies.

The other participants (free of p53 mutation) will be excluded from the trial.

Study Timeline

• Study First Submitted: 2017-12-27
• Study Start: 2018-01-10
• Study First Submitted QC: 2019-02-25
• Study First Posted: 2019-02-26
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-03
• Last Update Posted: 2022-11-04
• Primary Completion: 2023-07
• Study Completion: 2024-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 5

Inclusion Criteria

• Occurrence of p53 mutants that are predicted to respond to ATO+DAC with highest chance
• Patients newly diagnosed with myelodysplastic syndromes.
• ECOG Performance status ≤ 3.
• Aged from 18 to 75.
• Active bone marrow hyperplasia indicated by morphology
• Normal liver and renal function, bilirubin ≤35μmol/L, ASL/ALT lower than 2xULN, creatinine level ≤150μmol/L
• Normal cardiac function
• Written Informed consent.

Exclusion Criteria

• Patients previously treated.
• Confirmed CNS involvement.
• Abnormal liver function which does not meet the inclusion criteria.
• Severe cardiac diseases including myocardial infarction or heart insufficiency.
• QT interval ≥450ms on ECG.
• With other visceral malignancy.
• Active tuberculosis or HIV(+).
• Patients with pregnancy or lactation.
• Allergic or significantly contraindicated to any drugs involved in intervention.
• Significantly contraindicated to HMA chemotherapy.
• ECOG performance status ≥3, CCI >1, ADL <100.
• Unable to understand or follow the study protocol.
• Previous intolerance or allergy history to similar drugs.
• Aged <18 yrs or >75yrs
• MDS patients previously treated with decitabine.
• Participation at same time in another study in which investigational drugs are used.
• Any other conditions interfering the study.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Decitabine plus arsenic trioxide	Decitabine	decitabine: 20mg/m2/d, intravenously, d1-d5, q4w arsenic trioxide: 0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)
Decitabine plus arsenic trioxide	Arsenic Trioxide	decitabine: 20mg/m2/d, intravenously, d1-d5, q4w arsenic trioxide: 0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)

Primary Outcome Measures

Name	Time	Method
side effect	during the whole treatment	evaluate the side effects of current regimen

Secondary Outcome Measures

Name	Time	Method
Overall response rate	at the end of cycle 4 (each cycle is 28 days)	Partial response (PR) + complete response (CR) rate

Trial Locations

Locations (1)

Hematological department, Shanghai Institute of Hematology, Ruijin Hospital; 🇨🇳 Shanghai, Shanghai, China