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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: Sodium stibogluconate


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelodysplastic Syndromes, Acute Myeloid Leukemia, Myeloid Malignancy, Temperature-sensitive p53 Mutations, Sodium Stibogluconate, p53, precision medicine, antimonial