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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
Sponsor:
Information provided by (Responsible Party):
Min Lu, Ruijin Hospital

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The investigators also found p53 dysfunctional cells quickly develop a DAC resistance mechanism in cultured tissue (unpublished data).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

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : January 10, 2018
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Arsenic

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 Name: DAC

Drug: Arsenic Trioxide
0.16mg/kg/d, intravenously, d1-d5, q4w(maximum dose: 10mg/d)
Other Name: ATO




Primary Outcome Measures :
  1. side effect [ Time Frame: during the whole treatment ]
    evaluate the side effects of current regimen


Secondary Outcome Measures :
  1. Overall response rate [ Time Frame: at the end of cycle 4 (each cycle is 28 days) ]
    Partial response (PR) + complete response (CR) rate



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

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


Contacts
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Contact: Min Lu, PhD 0086-21-64370045 ext 610805 min.lu@shsmu.edu.cn
Contact: Sujiang Zhang, MD, PhD zbruce.zhang@hotmail.com

Locations
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China, Shanghai
Hematological department, Shanghai Institute of Hematology, Ruijin Hospital Recruiting
Shanghai, Shanghai, China, 200025
Contact: Min Lu, PhD    0086-21-64370045 ext 610805    min.lu@shsmu.edu.cn   
Contact: Sujiang Zhang, PhD       zbruce.zhang@hotmail.com   
Sponsors and Collaborators
Ruijin Hospital
Investigators
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Principal Investigator: Sujiang Zhang, MD, PhD Shanghai Institute of Hematology, Ruijin Hospital
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Responsible Party: Min Lu, Professor, Ph.D., Ruijin Hospital
ClinicalTrials.gov Identifier: NCT03855371    
Other Study ID Numbers: Mutant p53-based trial
First Posted: February 26, 2019    Key Record Dates
Last Update Posted: November 4, 2022
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Min Lu, Ruijin Hospital:
p53 mutation
personalized treatment
Decitabine
Arsenic Trioxide
AML
MDS
Additional relevant MeSH terms:
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Neoplasms
Decitabine
Arsenic Trioxide
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors