Oral-ATO for TP53-mutated Myeloid Malignancies

Phase 2

Not yet recruiting

• Conditions: Acute Myeloid Leukemia; Myelodysplastic Neoplasm; Chronic Myelomonocytic Leukemia; TP53 Gene Mutation; Arsenic Trioxide
• Interventions: Drug: Oral arsenic trioxide

• Registration Number: NCT06778187
• Lead Sponsor: The University of Hong Kong

Brief Summary

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).

Detailed Description

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.

Study Timeline

• Status Verified: 2025-01
• Study First Submitted: 2025-01-10
• Study First Submitted QC: 2025-01-10
• Last Update Submitted: 2025-01-10
• Study First Posted: 2025-01-16
• Last Update Posted: 2025-01-16
• Study Start: 2025-02
• Primary Completion: 2027-02
• Study Completion: 2028-02

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. Willing and able to provide informed consent
2. Age ≥18 years
3. Diagnosis of acute myeloid leukemia (AML), myelodysplastic neoplasm (MDS) or chronic myelonocytic leukaemia (CMML) by World Health Organization (WHO) 2022 criteria (1, 3)
4. Presence of TP53 mutation
5. Previously untreated patients for Cohort A (Treatment-naïve), or Patients failing 1 or more lines of prior treatment for Cohort B (Relapsed and Refractory)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
7. 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.

Exclusion Criteria

Inclusion Criteria

1. Willing and able to provide informed consent
2. Age ≥18 years
3. Diagnosis of acute myeloid leukemia (AML), myelodysplastic neoplasm (MDS) or chronic myelonocytic leukaemia (CMML) by World Health Organization (WHO) 2022 criteria (1, 3)
4. Presence of TP53 mutation
5. Previously untreated patients for Cohort A (Treatment-naïve), or Patients failing 1 or more lines of prior treatment for Cohort B (Relapsed and Refractory)
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
7. 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.

Exclusion Criteria

1. 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

2. Known hypersensitivity to arsenic trioxide, ascorbic acid, venetoclax or azacitidine/decitabine/oral-decitabine-cedazuridine or their excipients.

3. Uncontrolled, active infection

4. Major surgery within 4 weeks of starting the study drug, or not recovered from side effects of surgery

5. Any other serious medical conditions that could compromise study participation, in the opinion of the investigator

6. Known HIV infection or known, active hepatitis B or hepatitis C infection

7. Concurrent second active and non-stable malignancy (patients with a concurrent second active but stable malignancy, i.e., non-melanoma skin cancers, are eligible)

8. Known history of long QT syndrome (LQTS) or corrected QT interval by Fridericia formula (QTcF) ≥ 480 ms

9. 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:

   1. Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation or eGFR; using CKD-EPI) < 40 mL/min
   2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3 x the local upper limit of normal

10. Pregnant or lactating females, or females planning to become pregnant at any time during the study

11. Unwilling or unable to comply with the study protocol

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Oral arsenic trixoide	Oral arsenic trioxide	Patients will be treated in 28-day cycles. Each cycles will comprise: Oral ATO (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 (25mg/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)

Primary Outcome Measures

Name	Time	Method
Adverse events	24 months	Enumeration and description of adverse events (AEs), serious adverse events (SAEs), and other AEs

Secondary Outcome Measures

Name	Time	Method
Response rates	24 months	Proportion of patients who achieve a response by European LeukemiaNet (ELN) criteria (for AML) and International Working Group (IWG) criteria (for MDS and CMML)
Rates of molecular responses	24 months	Changes in mutant allele frequencies of TP53 mutations and other co-mutations during treatment

Trial Locations

Locations (1)

Queen Mary Hospital, Hong Kong; 🇭🇰 Hong Kong, Hong Kong