Mutant p53-based Personalized Trial Using Decitabine and Arsenic Trioxide on AML/MDS (PANDA-T0)
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|ClinicalTrials.gov Identifier: NCT03855371|
Recruitment Status : Recruiting
First Posted : February 26, 2019
Last Update Posted : November 4, 2022
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|
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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||5 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Combination of Decitabine and ATO to Treat AML/MDS Expressing a Classified Type of Mutant p53|
|Actual Study Start Date :||January 10, 2018|
|Estimated Primary Completion Date :||July 2023|
|Estimated Study Completion Date :||July 2024|
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)
20mg/m2/d, intravenously, d1-d5, q4w
Other Name: DAC
Drug: Arsenic Trioxide
0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)
Other Name: ATO
- side effect [ Time Frame: during the whole treatment ]evaluate the side effects of current regimen
- Overall response rate [ Time Frame: at the end of cycle 4 (each cycle is 28 days) ]Partial response (PR) + complete response (CR) rate
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03855371
|Contact: Min Lu, PhD||0086-21-64370045 ext email@example.com|
|Contact: Sujiang Zhang, MD, PhDfirstname.lastname@example.org|
|Principal Investigator:||Sujiang Zhang, MD, PhD||Shanghai Institute of Hematology, Ruijin Hospital|