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

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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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

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

Conditions
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MDS, P53 Mutation, Myeloid Malignancy, Aml

Intervention / Treatment
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* Drug: Decitabine
* Drug: Arsenic Trioxide


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Decitabine plus arsenic trioxide<br>decitabine: 20mg/m2/d, intravenously, d1-d5, q4w arsenic trioxide: 0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d) | Drug: Decitabine<br>* 20mg/m2/d, intravenously, d1-d5, q4w<br>* Other names: DAC;Drug: Arsenic Trioxide<br>* 0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)<br>* Other names: ATO;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| side effect | evaluate the side effects of current regimen | during the whole treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate | Partial response (PR) + complete response (CR) rate | at the end of cycle 4 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, p53 mutation, personalized treatment, Decitabine, Arsenic Trioxide, MDS