Treatment of Acute Myeloid Leukemia With Arsenic and All-trans Retinoid Acid

Acute Myeloid Leukemia Clinical Trial

Official title:

Treatment of Acute Myeloid Leukemia With Arsenic and All-trans Retinoid Acid (ATRA)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05297123
• Other study ID #: XJTU1AF2019LSK-077
• Status: Recruiting
• Phase: Phase 1
• Start date: February 3, 2019
• Est. completion date: December 31, 2023

Study information

• Verified date: August 2021
• Source: First Affiliated Hospital Xi'an Jiaotong University
• Contact: Huaiyu Wang, Dr.
• Phone: 008615809207527
• Email: whymed[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The clinical trial was designed to prove that Arsenic plus ATRA possibly had an effect on improving the symptoms, reducing the early mortality rate and prolonging the total survival time of patients with newly diagnosed or relapsed AML.

Description:

Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a highly variable prognosis and an overall high mortality rate. The 5-year overall survival of adult AML patients is less than 50%, and only 20% of elderly patients survive over 2 years. Acute promyelocytic leukemia (APL) accounts for 10% - 15% of acute myeloid leukemia. Arsenic and ATRA are very effective treatments for APL, a distinct AML subtype characterized by the expression of the PML/RARA fusion protein. PML/RARA expression disrupts PML NBs and blunts p53 signaling, which contributes to increased self-renewal of myeloid progenitors. The application of all-trans retinoic acid (ATRA) and arsenic modifies APL from highly fatal to highly curable. Both RA and arsenic induce degradation of PML/RARA through distinct pathways. Nucleophosmin-1(NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). According to El Hajj's research, RA or arsenic trioxide synergistically induces proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. Combined ATRA/arsenic treatment significantly reduced bone marrow blasts in 3 AML patients and restored the subnuclear localization of both NPM1 and PML. Overall, there is no consensus yet as to whether the addition of ATRA/arsenic improves the outcome of patients with NPM1 mutant AML. However, it still needs clinical research to confirm. The investigators design a clinical trial to prove that arsenic plus ATRA is possibly improving the symptoms of AML patients, reduce early mortality, and extending overall survival time.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 31, 2023
• Est. primary completion date: December 3, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Newly diagnosed or relapsed AML.Diagnosis based on Chinese guidelines for diagnosis and treatment of adult acute myeloid leukemia(not APL)(2018)
• Older than 18 years old
• Patients or their families signed written informed consent

Exclusion Criteria:

• Be allergic to the drug ingredient, the supplementary material or the allergic constitution person
• Cardiac insufficiency, renal insufficiency, significant arrhythmias, EKG abnormalities or other important organ dysfunction
• Combined with other malignant tumors
• Pregnant and lactating women
• Participants in other drug trials in the last 3 months
• Suffering from mental illness or other circumstances which unable to carry out the plan
• Other patients who were not suitable for the study

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• All-trans retinoic acid
All-trans retinoic acid (ATRA) 20mg 3 times a day for 8 weeks.
• Arsenic Trioxide
ATO 0.15mg/kg/d for 8 weeks (If the total daily amount is greater than 10mg, only 10mg/d can be given)
• Realgar-Indigo naturalis formula
60 mg/kg/d for 8 weeks

Locations

Country	Name	City	State
China	First Affiliated Hospital of Xi'an Jiaotong University	Xi'an	Shaanxi

Sponsors (1)

Lead Sponsor	Collaborator
First Affiliated Hospital Xi'an Jiaotong University

Country where clinical trial is conducted

China, 

References & Publications (5)

Bennett DA. How can I deal with missing data in my study? Aust N Z J Public Health. 2001 Oct;25(5):464-9. — View Citation

de Thé H, Chen Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer. 2010 Nov;10(11):775-83. doi: 10.1038/nrc2943. Epub 2010 Oct 22. Review. — View Citation

Dos Santos GA, Kats L, Pandolfi PP. Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. J Exp Med. 2013 Dec 16;210(13):2793-802. doi: 10.1084/jem.20131121. Review. — View Citation

El Hajj H, Dassouki Z, Berthier C, Raffoux E, Ades L, Legrand O, Hleihel R, Sahin U, Tawil N, Salameh A, Zibara K, Darwiche N, Mohty M, Dombret H, Fenaux P, de Thé H, Bazarbachi A. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. Blood. 2015 May 28;125(22):3447-54. doi: 10.1182/blood-2014-11-612416. Epub 2015 Mar 23. — View Citation

Zhao Z, Zuber J, Diaz-Flores E, Lintault L, Kogan SC, Shannon K, Lowe SW. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 2010 Jul 1;24(13):1389-402. doi: 10.1101/gad.1940710. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Early death rate (ED)	Death reported within the first month of diagnosis	30 days
Primary	Overall survival (OS)	the time from enrolled to death from any cause	From date of enrollment until the date of death from any cause, assessed up to 3 years
Secondary	Hematologic complete remission (HCR)	Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0×10^9 /L; platelet count >100× 10^9 /L.	30 days
Secondary	Cumulative relapse rate		From the date of enrollment to the date of relpase proved by bone marrow test, assessed up to 3 years