Clinical trial NCT06778187: Oral-ATO for TP53-mutated Myeloid Malignancies
Official title: A Phase 2 Study of Oral Arsenic Trioxide (Arsenol ®)-Based Low-intensity Treatment for Previously Untreated or Relapsed/Refractory TP53-mutated Myeloid Malignancies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Myelodysplastic Neoplasm
Chronic Myelomonocytic Leukemia
TP53 Gene Mutation
Arsenic Trioxide
Keywords: Acute myeloid leukemia
Myelodysplastic neoplasm
Chronic myelomonocytic leukemia
TP53 mutation
Oral arsenic trioxide
Lead sponsor: The University of Hong Kong
Sponsor class: OTHER
First posted: 2025-01-16
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility 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:

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

Primary outcomes:
measure: Adverse events
timeFrame: 24 months
Secondary outcomes:
measure: Response rates
timeFrame: 24 months
measure: Rates of molecular responses
timeFrame: 24 months
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital, Hong Kong
Study officials:
affiliation: The University of Hong Kong
name: Harinder Gill, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sallman DA, Stahl M. TP53-Mutated Acute Myeloid Leukemia: How Can We Improve Outcomes? Blood. 2024 Sep 5:blood.2024024245. doi: 10.1182/blood.2024024245. Online ahead of print.