Frontline Oral Arsenic Trioxide for APL

Study Overview
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Brief Summary
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The investigators have formulated an oral preparation of arsenic trioxide (oral-ATO), and shown that it is efficacious for APL in R1, inducing CR2 in more than 90% of patients [8,9]. Furthermore, in an effort to prevent relapse, the investigators have moved oral-ATO forward to the maintenance of CR1. This strategy results in favorable overall-survival (OS) and leukemia-free-survival (LFS) [10], implying that prolonged treatment with oral-ATO may prevent relapses. Current protocols have incorporated i.v.-ATO in the treatment of newly-diagnosed APL [11-15]. For regimens comprising oral-ATO, ATRA and chemotherapy, 5-year OS in excess of 90% is achieved [11-15]. The investigators have also published long-term data showing the use of oral-ATO is highly effective and safe in the relapsed and frontline settings [16,17]. In this study, the investigators evaluate the use of oral-ATO and ATRA based induction regimens in newly diagnosed patients with APL with no of minimal chemotherapy in a prospective multicentre phase 2 study.

Detailed Description
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After initial eligibility screening, patients will be recruited to oral arsenic trioxide, all-trans-retinoic acid, ascorbic acid (AAA) based-induction for 42 days. Daunorubicin or idarubicin will only be used during induction in patients <65 with presenting white blood cell count (WBC) ≥ 10 x 10^9/L. In patients not receiving daunorubicin, hydroxyurea if WBC ≥ 5 x 10^9/L within the first 14 days of induction. Molecular monitoring monitoring with RQ-PCR or ddPCR for PML-RARA will be performed weekly during induction. A reassessment bone marrow aspirate will be performed on day 28 of induction for assessment of morphologic remission. Four weeks after the completion of induction phase, all patients, regardless of initial WBC, will receive two cycles of chemotherapy-free AAA consolidation (14 days every 28 days). Four weeks after completion of consolidation, all patients will receive 12 cycles of chemotherapy-free AAA maintenance (14 days every 8 week). Molecular monitoring monitoring with RQ-PCR or ddPCR for PML-RARA will be performed during every 4 weeks during consolidation, every 8 weeks during maintenance, and every 3 months for 24 months after completion of maintenance.

Official Title
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Frontline Oral Arsenic Trioxide-based Induction in Newly Diagnosed Acute Promyelocytic Leukaemia

Conditions
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Acute Promyelocytic Leukemia

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: Newly diagnosed APL with t(15;17)(q24;q21) or acute myeloid leukaemia (AML) with variant RARA translocation according to the World Health Organization (WHO) Classification 2022 Ability and willingness to comply with the study procedures and restrictions Voluntary written informed consent Exclusion Criteria: ECOG performance score >2 Decompensated heart failure with left-ventricular ejection fraction of less than 40% and global hypokinesia on echocardiogram. Prolonged corrected QT interval (QTc) ≥ 500ms, in the absence of electrolyte disturbances and medications known to prolong QTc Significant liver function derangement (Bilirubin > 3 times upper limit normal and/or ALT > 5 times upper limit of normal) Glomerular filtration rate (GRF) by Cockcroft-Gault formula or eGFR (MDRD) of less than 30mL/min in adults (aged ≥ 18) or Creatinine clearance < 50ml/min/1.73m2 in paediatric and adolescent patients (Age ≤ 17) Female subject who is lactating or has positive pregnancy test result prior to the first dose of study drug
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, all-trans-retinoic acid, ascorbic acid (AAA)<br>Induction: Oral arsenic trioxide 10mg daily (0.16mg/kg/day in patients < 18 years-old, all-trans retinoic acid (ATRA) [45mg/m^2 (25mg/m^2 per day in patients < 18 years-old) in 2 divided doses) and ascorbic acid 1g daily (15mg/kg/day in patients < 18 years-old) for 42 days Consolidation: Oral arsenic trioxide daily, ATRA, and ascorbic acid daily for 14 days every 28 days for 2 cycles. Maintenance: Oral arsenic trioxide, ATRA and ascorbic acid daily for 2 weeks every 8 weeks for a total of 2 years (i.e. for 12 cycles in total). | Drug: Oral Arsenic Trioxide Formulation<br>* Patients will be recruited to oral arsenic trioxide, all-trans-retinoic acid, ascorbic acid (AAA) based-induction for 42 days. Daunorubicin or idarubicin will only be used during induction in patients <65 with presenting white blood cell count (WBC) ≥ 10 x 10^9/L. In patients not receiving daunorubicin, hydroxyurea if WBC ≥ 5 x 10^9/L within the first 14 days of induction. A reassessment bone marrow aspirate will be performed on day 28 of induction for assessment of morphologic remission. Four weeks after the completion of induction phase, all patients, regardless of initial WBC, will receive two cycles of chemotherapy-free AAA consolidation (14 days every 28 days). Four weeks after completion of consolidation, all patients will receive 12 cycles of chemotherapy-free AAA maintenance (14 days every 8 week).<br>* Other names: ARSENOL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-free survival (RFS) | Defined as the time (in months) from first complete morphologic remission (CR1) to morphologic or molecular relapse (event), or latest follow-up (censored). | 60 months | 
| Event-free survival (EFS) | Defined as the time (in months) from recruitment to treatment failure (event), morphologic or molecular relapse (event), or latest follow-up (censored). | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Defined as time (in months) from diagnosis to death (event) or latest follow-up (censored). | 60 months | 
| Treatment toxicities | Treatment toxicities by Common Toxicity Criteria for Adverse Everts (CTCAE) version 5.0. | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Promyelocytic Leukemia, Oral Arsenic Trioxide, Chemotherapy-free