Oral-ATO for TP53-mutated Myeloid Malignancies

Официальное название

A Phase 2 Study of Oral Arsenic Trioxide (Arsenol ®)-Based Low-intensity Treatment for Previously Untreated or Relapsed/Refractory TP53-mutated Myeloid Malignancies

Обзор

This is an open-label, phase 2 study of oral arsenic trioxide (Arsenol ®) in combination with ascorbic acid and investigator choice of low-intensity therapy in patients with previously untreated or relapse/refractory TP53-mutated acute myeloid leukemia (AML), myelodysplastic neoplasm (MDS), chronic myelomonocytic leukemia (CMML).

Подробное описание

Approximately 30 patients will be enrolled prospectively. Approximately 15 patients will be previously untreated and 15 patients will be relapsed or refractory to 1 or more lines of therapy.

Oral arsenic trioxide (oral-ATO) (Arsenol ®) will be used in combination with ascorbic acid, and investigator choice of low-intensity therapy that comprised hypomethylating agent (HMA) with or without venetoclax. The choice of hypomethylating agents include subcutaneous (s.c.) / intravenous (i.v.) azacitidine, i.v. decitabine or oral-decitabine-cedazuridine. Patients will be treated in 28-day days cycles.

Pending study team review of the tolerability, hematologic response, and molecular response to the combination, a future randomized Phase 2 efficacy study may be planned.

Вмешательства

• Препарат Oral arsenic trioxide
  Patients will be treated in 28-day cycles. Each cycles will comprise: Oral arsenic trixoide (10mg/day or 0.15mg/kg/day in patients \< 50kg) from Days 1-14 PLUS: * Oral ascorbic acid (1000mg/day) from Days 1-14 * Azacitidine (75mg/m2/day s.c. or i.v.) from days 1-7; OR Decitabine (20mg/m2/day i.v.) from days 1-5; OR Oral-decitabine-cedazuridine (1 tablet/day) from days 1-5. * Venetoclax (100mg-400mg/day) from Days 1-14 (if used)

Первичные конечные точки

• Adverse events [Срок оценки: 24 months]

Вторичные конечные точки (2)

• Response rates [Срок оценки: 24 months]
• Rates of molecular responses [Срок оценки: 24 months]

Критерии участия

Критерии включения

• Willing and able to provide informed consent
• Age ≥18 years
• Diagnosis of acute myeloid leukemia (AML), myelodysplastic neoplasm (MDS) or chronic myelonocytic leukaemia (CMML) by World Health Organization (WHO) 2022 criteria (1, 3)
• Presence of TP53 mutation
• Previously untreated patients for Cohort A (Treatment-naïve), or Patients failing 1 or more lines of prior treatment for Cohort B (Relapsed and Refractory)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Women of childbearing potential and fertile men must agree to use an approved method of contraception from Screening until 30 days after the last dose of oral arsenic trioxide, ascorbic acid, venetoclax and azacitidine/decitabine/oral-decitabine-cedazuridine.

Критерии исключения

Критерии включения

• Willing and able to provide informed consent
• Age ≥18 years
• Diagnosis of acute myeloid leukemia (AML), myelodysplastic neoplasm (MDS) or chronic myelonocytic leukaemia (CMML) by World Health Organization (WHO) 2022 criteria (1, 3)
• Presence of TP53 mutation
• Previously untreated patients for Cohort A (Treatment-naïve), or Patients failing 1 or more lines of prior treatment for Cohort B (Relapsed and Refractory)
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Women of childbearing potential and fertile men must agree to use an approved method of contraception from Screening until 30 days after the last dose of oral arsenic trioxide, ascorbic acid, venetoclax and azacitidine/decitabine/oral-decitabine-cedazuridine.

Критерии исключения

• Use of an investigational agent within 14 days of study treatment (or at least 7 half-lives of that agent, whichever is longer), prior to the first dose of oral arsenic trioxide
• Known hypersensitivity to arsenic trioxide, ascorbic acid, venetoclax or azacitidine/decitabine/oral-decitabine-cedazuridine or their excipients.
• Uncontrolled, active infection
• Major surgery within 4 weeks of starting the study drug, or not recovered from side effects of surgery
• Any other serious medical conditions that could compromise study participation, in the opinion of the investigator
• Known HIV infection or known, active hepatitis B or hepatitis C infection
• Concurrent second active and non-stable malignancy (patients with a concurrent second active but stable malignancy, i.e., non-melanoma skin cancers, are eligible)
• Known history of long QT syndrome (LQTS) or corrected QT interval by Fridericia formula (QTcF) ≥ 480 ms
• Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due to hemolysis) as defined by any of the following local laboratory parameters:

• Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation or eGFR; using CKD-EPI) < 40 mL/min
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 x the local upper limit of normal
• Pregnant or lactating females, or females planning to become pregnant at any time during the study
• Unwilling or unable to comply with the study protocol

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Гонконг · 1 центр

• Queen Mary Hospital, Hong Kong — Гонконг

Публикации

• Sallman DA, Stahl M. TP53-mutated acute myeloid leukemia: how can we improve outcomes? Blood. 2025 Jun 12;145(24):2828-2833. doi: 10.1182/blood.2024024245. PMID 39236289

Идентификаторы

NCT: NCT06778187 · ATO-IIS001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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