Description:
This is a prospective,uncontrolled and multi-institution trial.The aim is to identify if
using decitabine,cytarabine and ATO as the therapy of acute myeloid leukemia(AML) with p53
mutations has better relapse free survival and complete response than using decitabine and
cytarabine.
TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53
(mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated
with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia
(AML) patients.
Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials
reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of
complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH,
2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed
quickly.
Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed
efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment.
ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and
unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via
exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat
Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of
ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely
reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC,
1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation
by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014);
Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring
AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53
subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC
and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled.
We designate trials aiming for a better treatment regimen for mp53 patients as
'PANDA-Trials'.
Title
- Brief Title: Decitabine,Cytarabine and Arsenic Trioxide for Acute Myeloid Leukemia With p53 Mutations
- Official Title: Decitabine,Cytarabine(Ara-C) and Arsenic Trioxide(ATO) in the Treatment of Acute Myeloid Leukemia With p53 Mutations
Clinical Trial IDs
- ORG STUDY ID:
RuijinH mutant p53 AML
- NCT ID:
NCT03381781
Conditions
- Acute Myeloid Leukemia
- P53 Mutation
Interventions
| Drug | Synonyms | Arms |
|---|
| Decitabine | DNA demethylation agent, DNA damaging agent | Experimental group |
| Arsenic Trioxide | As2O3, Arsenic | Experimental group |
| Cytarabine | DNA damaging agent, Ara-C | Experimental group |
Purpose
This is a prospective,uncontrolled and multi-institution trial.The aim is to identify if
using decitabine,cytarabine and ATO as the therapy of acute myeloid leukemia(AML) with p53
mutations has better relapse free survival and complete response than using decitabine and
cytarabine.
TP53 mutation is commonly associated with poor cancer patient prognosis yet no mutant p53
(mp53)-targeting regimen was clinically established. Particularly, p53 mutation is associated
with extremely poor prognosis in myelodysplastic syndromes (MDS) and acute myeloid leukemia
(AML) patients.
Decitabine (DAC) is a FDA approved drug for MDS treatment. In two independent clinical trials
reported recently, DNA demethylating drug DAC treatment yielded a surprisingly high rate of
complete remission (CR) in mp53-harboring AML/MDS patients (Welch, NEJM, 2016; Chang, BJH,
2017). Notably, all of the mp53-expressing patients in the two clinical studies relapsed
quickly.
Arsenic trioxide (ATO) is a FDA approved drug for M3-AML treatment. Despite of the observed
efficacy in treating non-APL patients, ATO is not yet approved for non-APL cancer treatment.
ATO plays key role in regulating both wild-type p53 (wtp53) and mp53. Our published and
unpublished data suggest ATO potentially hijacks nuclear iASPP-mediated STRaND pathway via
exposing iASPP's RaDAR nuclear import code (Lu, Cancer Cell, 2013; Lu, Cell, 2014; Lu, Nat
Rev Mol Cell Biol, 2016; Lu, unpublished). Our unpublished data also suggests a key role of
ATO in regulating mp53 (Lu, The 17th International p53 Workshop, 2017). ATO is widely
reported to be able to degrade and thus inhibit mp53's oncogenic function (Hamadeh, BBRC,
1999)(Liu, Blood, 2003). ATO suppressed cancer cell growth by targeting mp53 for degradation
by Pirh2 degradation pathway (Yang, JBC, 2011; Yan, PLOS one, 2014);
Here we explore the potential of combination of DAC and ATO in improving the mp53-harboring
AML/MDS patients' relapse free survival (RFS) and the ability to thoroughly eliminate mp53
subclone. Basic researches aiming to explore the mechanisms how mp53 cells responds to DAC
and/or ATO treatment and how mp53 cells develop resistance to DAC and/or ATO will be coupled.
We designate trials aiming for a better treatment regimen for mp53 patients as
'PANDA-Trials'.
Detailed Description
This study is designed as a model of precision medicine. About 1500 AML patients will be
applied for TP53 sequencing. The bone marrow samples will be collected and its p53 status
will be Sanger sequenced in 3-5 days before drug administration. The 100 mp53-positive
patients will be trialed, while the others (mp53-negative patients) will be subjected to
standard treatment or other clinical trials.
In this study,100 patients with p53 mutations will be enrolled,including newly diagnosed AML
aged 60-75,AML transferred from Myelodysplastic Syndrome(MDS) and therapy related AML.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| Experimental group | Experimental | Patients with p53 mutations will be treated with Decitabine,Arsenic Trioxide and Cytarabine. | - Decitabine
- Arsenic Trioxide
- Cytarabine
|
Eligibility Criteria
Inclusion Criteria:
- de novo elderly AML,AML transferred from MDS,therapy related AML
- exclude acute promyelocytic leukemia(APL)
- p53 mutations determined by DNA sequencing from bone marrow
- ECOG<3,CCI≤1,ADL≥100
- bone marrow is active
- normal hepatic function and renal function
- normal cardiac function
- obtain informed consent
Exclusion Criteria:
- APL
- without p53 mutations
- previously treated elderly AML
- central nervous system is involved
- abnormal hepatic function or renal function
- severe cardiac disease,including myocardial infarction,cardiac dysfunction
- ECG:QTc>0.44 sec in men,QTc>0.46 sec in women
- with other malignant tumor meanwhile
- active tuberculosis or HIV-positive patients
- woman who are pregnant or breastfeeding
- allergic to any drug in protocol or with contraindications
- hypomethylation agent(HMA) is contraindicated
- ECOG≥3,CCI>1,ADL<100
- cannot understand or obey the protocol
- with a history of allergies or intolerability
- with a history of decitabine therapy
- participate in other clinical trials meanwhile
- any situations that hinder trial existed
| Maximum Eligible Age: | 75 Years |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | relapse free survival |
| Time Frame: | From date of complete release until the date of first documented relapse, assessed up to 6-8months |
| Safety Issue: | |
| Description: | since a patient first being determined as complete release until relapse |
Secondary Outcome Measures
| Measure: | complete release |
| Time Frame: | 2-4 months since the first cycle of treatment |
| Safety Issue: | |
| Description: | the percent of patients with complete release in all patients enrolled |
| Measure: | overall survival |
| Time Frame: | primary estimated for 1year |
| Safety Issue: | |
| Description: | from first diagnosed to death whichever the cause is |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Unknown status |
| Lead Sponsor: | Li Junmin |
Trial Keywords
- p53 mutation
- acute myeloid leukemia
- decitabine
- Arsenic trioxide
- cytarabine
Last Updated
January 4, 2018
