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

Phase 2

• Conditions: Myelodysplastic Syndromes; Myeloid Malignancy; Sodium Stibogluconate; Temperature-Sensitive p53 Mutation; P53 Mutation; Acute Myeloid Leukemia
• Interventions: Drug: Sodium stibogluconate

• Registration Number: NCT04906031
• Lead Sponsor: First Affiliated Hospital of Jinan University

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.

Study Timeline

• Study Start: 2020-06-01
• Study First Submitted: 2021-05-18
• Study First Submitted QC: 2021-05-26
• Study First Posted: 2021-05-28
• Status Verified: 2021-06
• Last Update Submitted: 2021-06-05
• Last Update Posted: 2021-06-09
• Primary Completion: 2023-02-01
• Study Completion: 2024-02-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 5

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Overall response rate	At the end of Cycle 4 (each cycle is 28 days)	Partial response (PR) + complete response (CR) rate

Secondary Outcome Measures

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

Trial Locations

Locations (1)

First Affiliated Hospital of Jinan University; 🇨🇳 Guangzhou, Guangdong, China