Oral-ATO for TP53-mutated Myeloid Malignancies

The University of Hong Kong (HKU)

Status and phase: Enrolling; Phase 2

Conditions: Arsenic Trioxide; Myelodysplastic Neoplasm; TP53 Gene Mutation; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia

Treatments: Drug: Oral arsenic trioxide

Study type: Interventional

Funder types: Other

Identifiers

NCT06778187

ATO-IIS001

Details and patient eligibility

About

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).

Full 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.

Enrollment: 30 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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30 participants in 1 patient group

Oral arsenic trixoide

Experimental group

Description:

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 (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)

Treatment:

Drug: Oral arsenic trioxide