Oral Arsenic Trioxide for NPM1-mutated AML

Study Overview
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Brief Summary
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A prospective open-label phase 2 study will be designed to assess the efficacy of oral arsenic trioxide plus azacitidine in preventing relapses in patients with NPM1-mutant AML. After screening and eligibility assessment, patients will receive treatment with oral arsenic trioxide plus azacitidine for 12 months. The recruitment period will last for 24 months and it will take approximately 36 months for study completion.

Detailed Description
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Eligible subjects with NPM1 MRD positivity will receive oral arsenic trioxide (oral-As2O3) (Arsenol ®) (5-10mg per day, from days 1-7 per cycle), ascorbic acid (1g per day, from days 1 - 7 per cycle) plus azacitidine (75mg/m2 per day subcutaneously, from days 1 to 3 per cycle). Each cycle of oral-As2O3 plus azacitidine will be given once every 28 days. The total duration of treatment is 12 months (12 cycles). Treatment will be day-care and outpatient based. Reduction in the dosage and duration of oral-As2O3 is required if the subject is experiencing adverse events (AEs). In case of grade 3 or above toxicity, the dosage of oral-As2O3 will be reduced to 5mg per day. Changes or interruption in dosages, their dates and time points will be recorded on the dosage administration record and the electronic case report form (eCRF).

Official Title
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Measurable-residual Disease (MRD) Monitoring of Nucleophosmin 1 (NPM1)-Mutated Acute Myeloid Leukaemia (AML) and Pre-emptive Therapy With Oral Arsenic Trioxide-based Regimen

Conditions
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NPMc+ AML

Intervention / Treatment
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* Drug: Oral Arsenic Trioxide Formulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults ≥ 18 years Diagnosis of AML with NPM1 mutation Positive MRD for NPM1 mutation after completion of consolidation in transplant-ineligible patients Positive MRD for NPM1 mutation after allogeneic HSCT bilirubin ≤ 1.5 x upper limit normal (ULN); alanine aminotransferase (ALT) ≤ 2 x ULN or aspartate aminotransferase (AST) ≤ 2 x ULN; and prothrombin time versus control <3 seconds at screening Glomerular filtration rate ≥ 50 mL/min (by MDRD equation or Cockcroft-Gault formula) Corrected QT interval (QTc) (by Framingham formula) <500ms. Able to give a written informed consent and fully comply to the requirements of the study. Exclusion Criteria: Patients on other investigational therapies Prior exposure to azacitidine, decitabine or arsenic trioxide Uncontrolled graft-versus-host disease (GVHD) Eastern Cooperative Oncology Group (ECOG) performance status > 2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral arsenic trioxide-Azacitidine<br>12 monthly cycles of oral arsenic trioxide (oral-As2O3) (Arsenol ®) (5-10mg per day, from days 1-7 per cycle), ascorbic acid (1g per day, from days 1 - 7 per cycle) plus azacitidine (75mg/m2 per day subcutaneously, from days 1 to 3 per cycle). | Drug: Oral Arsenic Trioxide Formulation<br>* Eligible subjects with NPM1 MRD positivity will receive oral arsenic trioxide (oral-As2O3) (Arsenol ®) (5-10mg per day, from days 1-7 per cycle), ascorbic acid (1g per day, from days 1 - 7 per cycle) plus azacitidine (75mg/m2 per day subcutaneously, from days 1 to 3 per cycle). Each cycle of oral-As2O3 plus azacitidine will be given once every 28 days. The total duration of treatment is 12 months (12 cycles). Treatment will be day-care and outpatient based. Reduction in the dosage and duration of oral-As2O3 is required if the subject is experiencing adverse events (AEs). In case of grade 3 or above toxicity, the dosage of oral-As2O3 will be reduced to 5mg per day.<br>* Other names: Arsenol;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of NPM1 MRD negativity. | This is defined as undetectable NPM1 mutant transcript with RQ-PCR on both the PB and BM following treatment, at a limit of detection of 10^-5. | 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response | defined as the time from achievement of undetectable NPM1 MRD to Documented molecular recurrence (defined as detectable MRD on PB or BM at a limit of detection of 10^5. | 36 months | 
| Leukaemia-free survival (LFS) | This is defined as the time, in months, from the start of oral-As2O3 plus azacitidine to morphologic relapse of AML. | 36 months | 
| Safety of oral-As2O3 plus azacitidine, assessed using the common toxicity criteria for adverse events (CTCAE) version 5.0. | The incidence of treatment emergent adverse events will be determined as a measure of safety | 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NPM1 mutation, Acute myeloid leukemia, Oral arsenic trioxide