Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

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

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.
  50 AML/MDS patients will be sequenced for TP53 sequence before recruitment. The investigators estimated 2-5 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-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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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 degradation. 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. 50 AML/MDS patients will be recruited for TP53 sequencing before being trialed. The investigators estimated 2-5 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 (estimated 45-48) will be excluded from the trial.

Eligibility: 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.

Relevance to patient case: not relevant