Clinical trial NCT03855371: Mutant p53-based Personalized Trial Using Decitabine and Arsenic Trioxide on AML/MDS
Official title: Combination of Decitabine and ATO to Treat AML/MDS Expressing a Classified Type of Mutant p53
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: P53 Mutation
Myeloid Malignancy
MDS
Aml
Keywords: p53 mutation
personalized treatment
Decitabine
Arsenic Trioxide
AML
MDS
Lead sponsor: Ruijin Hospital
Sponsor class: OTHER
First posted: 2019-02-26
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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

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.

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.

Primary outcomes:
measure: side effect
timeFrame: during the whole treatment
Secondary outcomes:
measure: Overall response rate
timeFrame: at the end of cycle 4 (each cycle is 28 days)
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Hematological department, Shanghai Institute of Hematology, Ruijin Hospital
state: Shanghai
Study officials:
affiliation: Shanghai Institute of Hematology, Ruijin Hospital
name: Sujiang Zhang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: