Clinical trial NCT04906031: 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
Overall status: UNKNOWN
Phase: PHASE2
Conditions: 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
Lead sponsor: First Affiliated Hospital of Jinan University
Sponsor class: OTHER
Collaborators: name: Ruijin Hospital
First posted: 2021-05-28
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Overall response rate
timeFrame: At the end of Cycle 4 (each cycle is 28 days)
Secondary outcomes:
measure: Adverse Event (AE)
timeFrame: At the end of Cycle 4 (each cycle is 28 days)
Other outcomes:
Locations:
city: Guangzhou
country: China
facility: First Affiliated Hospital of Jinan University
state: Guangdong
Study officials:
affiliation: Ruijin Hospital
name: Min Lu, PHD
role: PRINCIPAL_INVESTIGATOR
References:
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.