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Induction:

* Oral arsenic trioxide 10mg daily, all-trans retinoic acid (ATRA) (45mg/m2 per day in divided doses) and Ascorbic acid 1g daily for 42 days
* Daunorubicin at 50mg/m2 daily for 3 days (omitted if WBC at diagnosis \< 10 x 10\^9/L; or age ≥ 65 years; or cardiac function impairment)
* Hydroxyurea 2-4g per day if WBC \> 5 x 10\^9/L during the first 7 days of induction.

Consolidation (for all patients):

- Oral arsenic trioxide 10mg daily, all-trans retinoic acid (ATRA) (45mg/m2 per day in divided doses) and ascorbic acid 1g daily for 14 days every 28 days for 2 cycles

Maintenance (for all patients):

- Oral Arsenic trioxide 10mg daily, ATRA (45mg/m2 per day in divided doses) and ascorbic acid 1g daily for 2 weeks every 2 months for 24 months.

Oral arsenic trioxide-based frontline induction, consolidation and maintenance will be provided to patients with newly diagnosed acute promyelocytic leukemia.

Oral arsenic Trioxide, ATRA and ascorbic acid

Harinder Singh Harry Gill, MBBS

Harinder Singh Harry Gill

Acute promyelocytic leukemia (APL) is characterized by t(15;17)(q24;21) and the fusion gene PML-RARA. We have formulated an oral preparation of As2O3 (oral-As2O3), and shown that it is efficacious for APL in R1, inducing CR2 in more than 90% of patients. Furthermore, in an effort to prevent relapse, we have moved oral-As2O3 forward to the maintenance of CR1. This strategy results in favorable overall-survival (OS) and leukemia-free-survival (LFS), implying that prolonged treatment with oral-As2O3 may prevent relapses. Current protocols have incorporated i.v.-As2O3 in the treatment of newly-diagnosed APL. In regimens comprising i.v.-As2O3, ATRA and chemotherapy, 5-year overall survivals in excess of 90% is achieved. In this study, we evaluate the use of oral-As2O3 and ATRA based induction regimens in newly diagnosed patients with APL. In this study, we evaluate the efficacy and tolerability of frontline oral arsenic trioxide-based regimen in newly diagnosed patients with acute promyelocytic leukaemia

Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia

Risk-stratified Frontline Oral Arsenic Trioxide-based Induction in Newly Diagnosed Acute Promyelocytic Leukaemia

Time (in months) from diagnosis to death (event) or latest follow-up (censor)

Time (in months) from first remission to relapse (event), death (event) or latest follow-up (censor)

Treatment toxicities by Eastern Cooperative Oncology (ECOG)-Common Toxicity Criteria (CTC)

The University of Hong Kong

Keratolytic Agents

Induction: a) RIF: 60 mg/kg daily until CR, b) ATRA: 25 mg/m² daily until CR; Consolidation: a) RIF: 60 mg/kg daily, in a 4-week on 4-week off regimen for four cycles in a 4-week on 4-week off regimen for four cycles b) ATRA: 25 mg/m² daily, in a 2-week on 2-week off regimen for seven cycles

Induction: a) Arsenic trioxide: 0·15 mg/kg daily until CR, b) ATRA: 25 mg/m² daily until CR Consolidation: a) Arsenic trioxide: 0.15mg/kg daily, in a 4-week on 4-week off regimen for four cycles b) ATRA: 25 mg/m² daily, in a 2-week on 2-week off regimen for seven cycles Expected Efficacy: Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for achieving 2-year EFS.

Randomization is done centrally according to trial centers Eligible patients are randomly assigned (2:1) to the Treatment Group or the Control Group, with a 24-month follow-up.

Compound Realgar-Indigo Naturalis Formula Plus Retinoic Acid

Hao Jiang, MD

Sheng ye Lu, PhD & MD

Xiao-Jun Huang, MD

Acute Promyelocytic Leukaemia (APL) has been known as a type of cancer, which is of great significance to improve its eradication rate. Recent clinical trials show that ATRA plus ATO treatment regimen can result in complete response (CR) in 90-94% of patients and 5-year disease-free survival (DFS) in more than 90% of patients. However, the ATRA plus ATO treatment regimen can achieve considerate survival rate, patients still need to receive infusion therapy in hospital. If oral arsenic can replace intravenous ATO without reduction of the efficacy, patients would not need to be administered to receive treatment, which would highly increase their quality of lives. Phase I, II Clinical trials have verified the security and efficacy of the Compound Realgar-Indigo Naturalis Formula. Compound Realgar-Indigo Naturalis Formula was approved by the China Food and Drug Administration in 2009. Investergators have done a multi-centre, randomized, controlled, non-inferiority phase 3 clinical trial in China. And the result showed that oral arsenic plus retinoic acid has an anti-leukaemic efficacy similar to the intravenous arsenic treatment. So Investigators performed an international multi-center, Randomized controlled clinical trialsto compare the efficacy of oral RIF plus ATRA with intravenous arsenic trioxide plus ATRA in patients with non-high-risk APL in different racial types.

Acute Promyelocytic Leukaemia (APL) has been known as a type of cancer, seriously endangering human health especially for young adults. It is of great significance to improve its eradication rate. Recent clinical trials show that ATRA plus ATO treatment regimen can result in complete response (CR) in 90-94% of patients and 5-year disease-free survival (DFS) in more than 90% of patients.

However, the ATRA plus ATO treatment regimen can achieve considerate survival rate, patients still need to receive infusion therapy in hospital. If oral arsenic can replace intravenous ATO without reduction of the efficacy, patients would not need to be administered to receive treatment, which would highly increase their quality of lives. The research and development of oral arsenic has therefore become a hotpoint. Professor Huang, Shilin from he 210th Hospital of PLA, according to the Prescription Theory "Jun Chen Zuo Shi", developed and designed an oral arsenic, the Compound Realgar-Indigo Naturalis Formula. Phase I, II Clinical trials have verified the security and efficacy of the Compound Realgar-Indigo Naturalis Formula. Research Team led by Professor Huang, Saijun, Shanghai Institute of Haematology (China), studied Compound Realgar-Indigo Naturalis Formula's mechanism of action from vitro cell lines and mice.

In the following Phase II clinical trial, APL patients received Compound Realgar-Indigo Naturalis Formula solo treatment regime. It resulted in 96.7% of CR and high safety rate Compound Realgar-Indigo Naturalis Formula was approved by the China Food and Drug Administration in 2009. Investigators have done a multi-centre, randomized, controlled, non-inferiority phase 3 clinical trial in China. 242 newly diagnosed APL patients (with newly diagnosed WBC\<50×10\^9/L) were enrolled. And the result showed that oral arsenic plus retinoic acid has an anti-leukaemic efficacy similar to the intravenous arsenic treatment.

This study is a prospective, non-inferiority, randomized controlled clinical trial. The non-inferiority is concluded if the lower limit of the 95% CI for the difference in proportion of patients achieving EFS is greater than the -10% non-inferiority margin. The survival curves are estimated by using the Kaplan-Meier method and will be compared by using the log-rank test.

Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL

Implement Randomized, Controlled, International Multi-center Clinical Trial of Compound Realgar-Indigo Naturalis Formula Plus Retinoic Acid for Non-high-risk Acute Promyelocytic Leukaemia

treatment failure (no CR after 45-day induction therapy, or no molecular complete remission after 3-month consolidation therapy), relapse (molecular relapse, or haematological relapse); or death from any cause.

Ministry of Science and Technology of the People´s Republic of China

Peking University People's Hospital

Director of Hematology Department

Idarubicin

Arsenic trioxide

ATRA

Lionel ADES, MD

Lionel ADES, MD,PhD

To assess the role of Arsenic trioxide and/or ATRA during consolidation course in APL. It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen.

Definition: Extended description of the protocol, including information not already contained in other fields, such as comparison(s) studied.

APL is a specific type of acute myeloid leukemia (AML) characterized by its morphology (M3 or M3v in the FAB classification), t(15;17) translocation leading to PML-RARa fusion gene, and by a specific coagulopathy combining D.I.C., fibrinolysis and non specific proteolysis. ATRA can differentiate APL blasts in VITRO and in vivo. The combination of ATRA and anthracycline based chemotherapy yields CR rates greater than 90% in newly diagnosed APL. With early introduction of anthracycline AraC chemotherapy during induction treatment, and maintenance combining continuous 6MP and MTX to intermittent ATRA, the relapse risk in APL therefore now appears to be in the range of 10 to 15%.

Nevertheless, 5 to 10% of the patients do not achieve CR and 10% to 15% still relapse. Another subset of patients (5 to 7% in APL 93 trial including 17% of patients aged greater than 65 years) die in CR, from complications of the consolidation treatment phase, mainly from infection during chemotherapy induced aplasia. Failure to achieve CR with current treatment approaches is almost exclusively due to early death during induction treatment. Causes of death are predominantly bleeding, ATRA syndrome and less often infection. Early deaths predominate in elderly patients and patients with high WBC counts. Reducing the amount of chemotherapy administered to newly diagnosed APL patients diminishes this toxicity. The Spanish PETHEMA group reported results of two successive phase II trials in newly diagnosed APL with ATRA and chemotherapy with intercalating agents (idarubicin and mitoxantrone) without AraC followed by maintenance combining ATRA and low dose chemotherapy (LPA96 and LPA99 trials). Results appeared similar to those of the best arm of APL 93 trial, but with less toxicity and only 2 to 3 % death in CR were seen, including in elderly patients.

Arsenic trioxide (As2O3 or ATO) is an effective agent in relapsing or refractory APL, which induced 85% hematological and 79% molecular CR rates in a pivotal US study. The interest of ATO in the front-line therapy of newly-diagnosed APL has been strongly suggested in three studies which showed high complete remission rate, low incidence of relapse and limited toxicity.

In this study, patients will be stratified based on age (≤ 70 years and \> 70 years) and WBC count at diagnosis (WBC\<10.000/mm3 and \>10.000 /mm3).

-Patients aged 70 years or less with WBC\<10.000/mm3.

In this population (about 70 % of APL) the best treatment group of APL2000 trial (ATRA with early introduction of anthracycline-AraC chemotherapy but where Idarubicin will be substituted for Daunorubicin, followed by 2 anthracycline-AraC consolidation courses and maintenance combining continuous chemotherapy and intermittent ATRA) will be compared to the same regimen, but without AraC during consolidation courses which will be replaced by:

* either ATO
* or ATRA It is hoped that the investigational arms will further increase the event-free survival at 2 years, with reduced toxicity and without increasing the relapse rate by comparison with a classical anthracycline-AraC consolidation regimen.

  * Patients aged 70 years or less with WBC\>10.000/mm3 Patients ages 70 years or less with initial WBC counts \> 10000/mm3 (ie very high counts for APL), which represent about 20% of APL, remain at relatively high risk of relapse even with the current reference treatment. The main objective of the study will be to test the addition of ATO during consolidation courses to our current standard ATRA and chemotherapy regimen. Patients will receive the best treatment group of APL 2000 trial (but where Idarubicin will be substituted for Daunorubicin) with or without ATO during the 2 consolidation cycles.
  * Patients older than 70 years with WBC\<10.000 /mm3. Elderly patients with initial WBC ≤ 10000/m3 (about 8% of APL) and no contra indication to this treatment will receive a regimen with reduced cumulative dose of chemotherapy but addition of ATO during consolidation courses and during the first year of maintenance treatment. The main purpose of this non randomized part of the trial is to reduce the early death mortality and death in CR observed in elderly patients, without increasing the relapse rate.
  * Patients older than 70 years with WBC\>10.000 /mm3. Elderly patients with initial WBC \> 10000/m3 (about 2 to 3% of APL) and no contra indication to intensive regimen will receive the same regimen as those with low WBC but with moderate doses of Aracytine during the induction and during the first consolidation course. The main purpose of this non randomized part of the trial is to reduce the early death mortality and death in CR observed in elderly patients, without increasing the relapse rate.

Acute Promyelocytic Leukemia 2006 (APL)

A Randomized Trial Assessing the Role of Arsenic Trioxide and/or ATRA During Consolidation Course in Newly Diagnosed Acute Promyelocytic Leukemia (APL)

For Patients aged 70 years or less with WBC\<10.000/mm3, The primary end point

For patients older than 70 years with WBC\>10.000 /mm3, The primary end point will be EFS at 2 years from diagnosis

For Patients aged 70 years or less with WBC\<10.000/mm3 :

Kinetics of decrease of PML-RARA transcript level during and after consolidation course.

Side effects of the treatment, including treatment-related mortality and morbidity of consolidation treatment.

Days on antibiotics, transfusion requirement and nights spent in Hospital

For Patients aged 70 years or less with WBC\>10.000/mm3

event free survival at 2 years from CR achievement

For Patients older than 70 years with WBC\<10.000 /mm3

Kinetics of decrease of PML-RARA transcript level during and after

Side effects of the treatment, including mortality and morbidity of

For patients older than 70 years with WBC\>10.000 /mm3

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia	NCT03624270	Acute Promyeloc...	Oral arsenic Tr...	18 Years -	The University of Hong Kong
Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia	NCT03624270	Acute Promyeloc...	Oral arsenic Tr...	18 Years -	The University of Hong Kong
Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL	NCT04175587	Acute Promyeloc...	Compound Realga...	18 Years - 70 Years	Peking University People's Hospital
Randomized,International Multi-center Clinical Trial of RIF Plus RA for Non-high-risk APL	NCT04175587	Acute Promyeloc...	Compound Realga...	18 Years - 70 Years	Peking University People's Hospital
Acute Promyelocytic Leukemia 2006 (APL)	NCT00378365	Leukemia, Promy...	Arsenic trioxid... ATRA	18 Years -	Assistance Publique - Hôpitaux de Paris
Oral Arsenic Trioxide for Newly Diagnosed Acute Promyelocytic Leukaemia	NCT03624270	Acute Promyeloc...	Oral arsenic Tr...	18 Years -	The University of Hong Kong
Acute Promyelocytic Leukemia 2006 (APL)	NCT00378365	Leukemia, Promy...	Arsenic trioxid... ATRA	18 Years -	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for acute promyelocytic leukaemia