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Sodium Stibogluconate in the MDS/AML With One of the 65 Defined p53 Mutations

Primary Purpose

Myelodysplastic Syndromes, Acute Myeloid Leukemia, Myeloid Malignancy

Status

Recruiting

Phase

Phase 2

Locations

China

Study Type

Interventional

Intervention

Sodium stibogluconate

About this trial

This is an interventional treatment trial for Myelodysplastic Syndromes focused on measuring Myelodysplastic Syndromes, Acute Myeloid Leukemia, Myeloid Malignancy, Temperature-sensitive p53 Mutations, Sodium Stibogluconate, p53, precision medicine, antimonial

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Pathologically confirmed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
Patients with one of the 65 antimonial-treatable p53 mutations with > 5% VAF: Q136P, Y234H, V272M, F270V, P278A, R213L, Y126H, T253N, T253I, R158L, Q136E, P142F, A129D, L194R, R110P, V172G, C176F, I254N, K305R, E285D, T155P, H296D, E258G, G279V, T211A, R213P, C229Y, I232F, E294K, P152R, R196P, M160T, N131S, N131H, K139N, L330H, Y220N, E298Q, D148E, L264R, E224D, H168P, N263H, K320N, S227C, E286D, K292T, V203A, M237R, F212L, K132Q, Y236S, Y126S, Q136H, E221A, I232S, Y163H, P190T, C182Y, P142L, Y163S, V218E, I195S, V272A, and S106R.
Life expectancy >12 weeks.
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.
Lung function: dyspnea ≤ CTC AE grade 1 and SaO2≥ 92% in indoor air environment.
Written Informed consent.

Exclusion Criteria:

Confirmed CNS involvement.
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.
Previous intolerance or allergy history to similar drugs.
Participation at same time in another study in which investigational drugs are used.
Any other conditions interfering the study.
Abnormal liver function which does not meet the inclusion criteria.
ECOG performance status ≥3, CCI >1, ADL <100.
Aged <18 years or >75years

Sites / Locations

First Affiliated Hospital of Jinan UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Sodium stibogluconate

Arm Description

Sodium stibogluconate 900 mg/m2/day will be given on d1-5 and d15-19. 28 days per cycle.

Outcomes

Primary Outcome Measures

Overall response rate

Partial response (PR) + complete response (CR) rate

Secondary Outcome Measures

Adverse Event (AE)

Adverse events (AEs) will be reported and graded

Full Information

NCT ID

NCT04906031

First Posted

May 18, 2021

Last Updated

June 5, 2021

Sponsor

First Affiliated Hospital of Jinan University

Collaborators

Ruijin Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04906031

Brief Title

Sodium Stibogluconate in the MDS/AML With One of the 65 Defined p53 Mutations

Official Title

Sodium Stibogluconate in the Myelodysplastic Syndromes/Acute Myeloid Leukemia With One of the 65 Defined p53 Mutations That Can be Functionally Rescued by Sodium Stibogluconate

Study Type

Interventional

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Recruiting

Study Start Date

June 1, 2020 (Actual)

Primary Completion Date

February 1, 2023 (Anticipated)

Study Completion Date

February 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

First Affiliated Hospital of Jinan University

Collaborators

Ruijin Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

5. Study Description

Brief Summary

To evaluate the safety and effectiveness of Sodium Stibogluconate in the treatment of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) with p53 mutation from a defined list. The list includes 65 p53 mutations that were experimentally confirmed to be pharmacologically restored with tumor-suppressive function by antimonials.

Detailed Description

p53 is inactivated by over hundreds of diverse mutations in cancer. The investigator purposefully selected the phenotype-reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue, and pertinently used p53 thermostability as readout to screen for TS p53 mutation rescue compounds. By this, the investigator identified antiparasitic drug antimonials efficiently thermostabilized the TS mutants by noncovalent binding. The antimonials met the three go-to criteria as a targeted drug-availability of co-crystal structure, structure model-compatible Structure-Activity Relationship, and target (p53)-specificity in cells, and consequently extended survival of xenograft mouse with TS p53 mutant. Under the clinical antiparasitic dosage, the antimonials effectively rescued TS p53 mutant in patient-derived primary acute myeloid leukemia cells. Scan of the most frequent 815 p53 missense mutations identified 65 of them, predominantly TS mutations, as the antimonial-treatable mutations. Thus, the trial aims to evaluate the safety and effectiveness of the approved antimonial-Sodium Stibogluconate-in the treatment of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) with the 65 antimonial-treatable p53 mutants.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Myelodysplastic Syndromes, Acute Myeloid Leukemia, Myeloid Malignancy, Temperature-Sensitive p53 Mutation, Sodium Stibogluconate, P53 Mutation

Keywords

Myelodysplastic Syndromes, Acute Myeloid Leukemia, Myeloid Malignancy, Temperature-sensitive p53 Mutations, Sodium Stibogluconate, p53, precision medicine, antimonial

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Sodium stibogluconate

Arm Type

Experimental

Arm Description

Sodium stibogluconate 900 mg/m2/day will be given on d1-5 and d15-19. 28 days per cycle.

Intervention Type

Drug

Intervention Name(s)

Sodium stibogluconate

Other Intervention Name(s)

SSG

Intervention Description

Sodium stibogluconate 900 mg/m2/day will be given on d1-5 and d15-19. 28 days per cycle.

Primary Outcome Measure Information:

Title

Overall response rate

Description

Partial response (PR) + complete response (CR) rate

Time Frame

At the end of Cycle 4 (each cycle is 28 days)

Secondary Outcome Measure Information:

Title

Adverse Event (AE)

Description

Adverse events (AEs) will be reported and graded

Time Frame

At the end of Cycle 4 (each cycle is 28 days)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Pathologically confirmed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Patients with one of the 65 antimonial-treatable p53 mutations with > 5% VAF: Q136P, Y234H, V272M, F270V, P278A, R213L, Y126H, T253N, T253I, R158L, Q136E, P142F, A129D, L194R, R110P, V172G, C176F, I254N, K305R, E285D, T155P, H296D, E258G, G279V, T211A, R213P, C229Y, I232F, E294K, P152R, R196P, M160T, N131S, N131H, K139N, L330H, Y220N, E298Q, D148E, L264R, E224D, H168P, N263H, K320N, S227C, E286D, K292T, V203A, M237R, F212L, K132Q, Y236S, Y126S, Q136H, E221A, I232S, Y163H, P190T, C182Y, P142L, Y163S, V218E, I195S, V272A, and S106R. Life expectancy >12 weeks. 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. Lung function: dyspnea ≤ CTC AE grade 1 and SaO2≥ 92% in indoor air environment. Written Informed consent. Exclusion Criteria: Confirmed CNS involvement. 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. Previous intolerance or allergy history to similar drugs. Participation at same time in another study in which investigational drugs are used. Any other conditions interfering the study. Abnormal liver function which does not meet the inclusion criteria. ECOG performance status ≥3, CCI >1, ADL <100. Aged <18 years or >75years

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Hui Zeng, MD

Phone

+86 18002201919

androps2011@hotmail.com

First Name & Middle Initial & Last Name or Official Title & Degree

Huien Zhan, MD

Phone

+86 15084958382

zhanhuien@163.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Min Lu, PHD

Organizational Affiliation

Ruijin Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

First Affiliated Hospital of Jinan University

City

Guangzhou

State/Province

Guangdong

ZIP/Postal Code

510632

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hui Zeng, MD

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

35417717

Citation

Tang Y, Song H, Wang Z, Xiao S, Xiang X, Zhan H, Wu L, Wu J, Xing Y, Tan Y, Liang Y, Yan N, Li Y, Li J, Wu J, Zheng D, Jia Y, Chen Z, Li Y, Zhang Q, Zhang J, Zeng H, Tao W, Liu F, Wu Y, Lu M. Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations. Cell Rep. 2022 Apr 12;39(2):110622. doi: 10.1016/j.celrep.2022.110622.

Results Reference

derived

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Sodium Stibogluconate in the MDS/AML With One of the 65 Defined p53 Mutations

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