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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; P53 Mutation; Myeloid Malignancy; Temperature-Sensitive p53 Mutation; Sodium Stibogluconate
• Intervention / Treatment: Drug: Sodium stibogluconate

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.

• Study Type: Interventional
• Enrollment (Anticipated): 5
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Hui Zeng, MD; Phone Number: +86 18002201919; Email: androps2011@hotmail.com
• Study Contact Backup: Name: Huien Zhan, MD; Phone Number: +86 15084958382; Email: zhanhuien@163.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510632
      • Recruiting
      • First Affiliated Hospital of Jinan University
      • Contact: Hui Zeng, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Pathologically confirmed myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
2. 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.
3. Life expectancy >12 weeks.
4. ECOG Performance status < 3.
5. Aged from 18 to 75.
6. Active bone marrow hyperplasia indicated by morphology.
7. Normal liver and renal function, bilirubin ≤35μmol/L, ASL/ALT lower than 2xULN, creatinine level ≤150μmol/L.
8. Normal cardiac function.
9. Lung function: dyspnea ≤ CTC AE grade 1 and SaO2≥ 92% in indoor air environment.
10. Written Informed consent.

Exclusion Criteria:

1. Confirmed CNS involvement.
2. Severe cardiac diseases including myocardial infarction or heart insufficiency.
3. QT interval ≥450ms on ECG.
4. With other visceral malignancy.
5. Active tuberculosis or HIV(+).
6. Patients with pregnancy or lactation.
7. Allergic or significantly contraindicated to any drugs involved in intervention.
8. Previous intolerance or allergy history to similar drugs.
9. Participation at same time in another study in which investigational drugs are used.
10. Any other conditions interfering the study.
11. Abnormal liver function which does not meet the inclusion criteria.
12. ECOG performance status ≥3, CCI >1, ADL <100.
13. Aged <18 years or >75years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sodium stibogluconate; Sodium stibogluconate 900 mg/m2/day will be given on d1-5 and d15-19. 28 days per cycle.	Drug: Sodium stibogluconate; Sodium stibogluconate 900 mg/m2/day will be given on d1-5 and d15-19. 28 days per cycle.; Other Names: SSG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate	Partial response (PR) + complete response (CR) rate	At the end of Cycle 4 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Event (AE)	Adverse events (AEs) will be reported and graded	At the end of Cycle 4 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Jinan University
• Collaborators: Ruijin Hospital
• Investigators: Principal Investigator: Min Lu, PHD, Ruijin Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2020
• Primary Completion (Anticipated): February 1, 2023
• Study Completion (Anticipated): February 1, 2024

Study Registration Dates

• First Submitted: May 18, 2021
• First Submitted That Met QC Criteria: May 26, 2021
• First Posted (Actual): May 28, 2021

Study Record Updates

• Last Update Posted (Actual): June 9, 2021
• Last Update Submitted That Met QC Criteria: June 5, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; p53; Myelodysplastic Syndromes; precision medicine; Myeloid Malignancy; Temperature-sensitive p53 Mutations; Sodium Stibogluconate; antimonial
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Neoplasms; Hypersensitivity; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Anthelmintics; Schistosomicides; Antiplatyhelmintic Agents; Antimony Sodium Gluconate
• Other Study ID Numbers: FirstJinanU_SSG

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No