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

NCT ID: NCT03855371

Last Updated: 2022-11-04

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-10
• Study Completion Date: 2024-07-31

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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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.

Conditions

P53 Mutation; Myeloid Malignancy; MDS; Aml

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Decitabine plus arsenic trioxide

decitabine: 20mg/m2/d, intravenously, d1-d5, q4w arsenic trioxide: 0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)

Group Type: EXPERIMENTAL

Decitabine

Intervention Type: DRUG

20mg/m2/d, intravenously, d1-d5, q4w

Arsenic Trioxide

Intervention Type: DRUG

0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)

Interventions

Decitabine

20mg/m2/d, intravenously, d1-d5, q4w

Intervention Type: DRUG

Arsenic Trioxide

0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)

Intervention Type: DRUG

Other Intervention Names

DAC; ATO

Eligibility Criteria

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.

• 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.

Exclusion Criteria

• Patients previously treated.
• Confirmed CNS involvement.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ruijin Hospital

OTHER

Sponsor Role: lead

Responsible Party

Min Lu

Professor, Ph.D.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Sujiang Zhang, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Shanghai Institute of Hematology, Ruijin Hospital

Locations

Hematological department, Shanghai Institute of Hematology, Ruijin Hospital

Shanghai, Shanghai Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Min Lu, PhD

Role: CONTACT

min.lu@shsmu.edu.cn

0086-21-64370045 ext. 610805

Sujiang Zhang, MD, PhD

Role: CONTACT

zbruce.zhang@hotmail.com

Facility Contacts

Min Lu, PhD

Role: primary

min.lu@shsmu.edu.cn

0086-21-64370045 ext. 610805

Sujiang Zhang, PhD

Role: backup

zbruce.zhang@hotmail.com

Other Identifiers

Mutant p53-based trial

Identifier Type: -

Identifier Source: org_study_id