PANDA-T0: Mutant p53-based Personalized Trial Using Decitabine and Arsenic Trioxide on AML/MDS

Sponsor

Ruijin Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT03855371

Collaborator

(none)

Enrollment

Location

Arm

41.7

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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'.

Condition or Disease	Intervention/Treatment	Phase
P53 Mutation Myeloid Malignancy MDS Aml	Drug: Decitabine Drug: Arsenic Trioxide	Phase 1

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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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

Study Type:

Interventional

Anticipated Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Combination of Decitabine and ATO to Treat AML/MDS Expressing a Classified Type of Mutant p53

Actual Study Start Date :

Jan 10, 2018

Anticipated Primary Completion Date :

Jul 1, 2021

Anticipated Study Completion Date :

Jul 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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)	Drug: Decitabine 20mg/m2/d, intravenously, d1-d5, q4w Other Names: DAC Drug: Arsenic Trioxide 0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d) Other Names: ATO

Arm

Intervention/Treatment

Experimental: 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)

Drug: Decitabine

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

Other Names:

DAC

Drug: Arsenic Trioxide

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

Other Names:

ATO

Outcome Measures

Primary Outcome Measures

side effect [during the whole treatment]
evaluate the side effects of current regimen

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.