Frontline Oral Arsenic Trioxide for APL

Acute Promyelocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04687176
• Other study ID #: APL003
• Status: Recruiting
• Phase: Phase 2
• Start date: January 1, 2021
• Est. completion date: June 30, 2026

Study information

• Verified date: October 2022
• Source: The University of Hong Kong
• Contact: Harry Gill, MD
• Phone: +852 22554542
• Email: gillhsh[@]hku.hk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: June 30, 2026
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Inclusion Criteria:

1. 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

2. Ability and willingness to comply with the study procedures and restrictions

3. Voluntary written informed consent

Exclusion Criteria:

1. ECOG performance score >2

2. Decompensated heart failure with left-ventricular ejection fraction of less than 40% and global hypokinesia on echocardiogram.

3. Prolonged corrected QT interval (QTc) = 500ms, in the absence of electrolyte disturbances and medications known to prolong QTc

4. Significant liver function derangement (Bilirubin > 3 times upper limit normal and/or ALT > 5 times upper limit of normal)

5. 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)

6. Female subject who is lactating or has positive pregnancy test result prior to the first dose of study drug

Related Conditions & MeSH terms

• Acute Promyelocytic Leukemia
• Leukemia
• Leukemia, Promyelocytic, Acute

Intervention

Drug:
• Oral Arsenic Trioxide Formulation
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).

Locations

Country	Name	City	State
Hong Kong	The University of Hong Kong	Hong Kong

Sponsors (1)

Lead Sponsor	Collaborator
The University of Hong Kong

Country where clinical trial is conducted

Hong Kong, 

References & Publications (19)

Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, Faderl S, O'Brien S, Wierda W, Pierce S, Brandt M, McCue D, Luthra R, Patel K, Kornblau S, Kadia T, Daver N, DiNardo C, Jain N, Verstovsek S, Ferrajoli A, Andreeff M, Konopleva M, Estrov Z, Foudray M, McCue D, Cortes J, Ravandi F. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood. 2017 Mar 9;129(10):1275-1283. doi: 10.1182/blood-2016-09-736686. Epub 2016 Dec 21. — View Citation

Au WY, Kumana CR, Kou M, Mak R, Chan GC, Lam CW, Kwong YL. Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia. Blood. 2003 Jul 1;102(1):407-8. doi: 10.1182/blood-2003-01-0298. No abstract available. — View Citation

Au WY, Kumana CR, Lee HK, Lin SY, Liu H, Yeung DY, Lau JS, Kwong YL. Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study. Blood. 2011 Dec 15;118(25):6535-43. doi: 10.1182/blood-2011-05-354530. Epub 2011 Oct 12. — View Citation

Au WY, Li CK, Lee V, Yuen HL, Yau J, Chan GC, Ha SY, Kwong YL. Oral arsenic trioxide for relapsed acute promyelocytic leukemia in pediatric patients. Pediatr Blood Cancer. 2012 Apr;58(4):630-2. doi: 10.1002/pbc.23306. Epub 2011 Sep 2. — View Citation

Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin MF, Hunter A, Clark RE, Grimwade D; UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2015 Oct;16(13):1295-305. doi: 10.1016/S1470-2045(15)00193-X. Epub 2015 Sep 14. — View Citation

Gill H, Kumana CR, Yim R, Hwang YY, Chan TSY, Yip SF, Lee HKK, Mak V, Lau JSM, Chan CC, Kho B, Wong RSM, Li W, Lin SY, Lau CK, Ip HW, Leung RYY, Lam CCK, Kwong YL. Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5-year prospective study. Cancer. 2019 Sep 1;125(17):3001-3012. doi: 10.1002/cncr.32180. Epub 2019 May 15. — View Citation

Gill H, Yim R, Lee HKK, Mak V, Lin SY, Kho B, Yip SF, Lau JSM, Li W, Ip HW, Hwang YY, Chan TSY, Tse E, Au WY, Kumana CR, Kwong YL. Long-term outcome of relapsed acute promyelocytic leukemia treated with oral arsenic trioxide-based reinduction and maintenance regimens: A 15-year prospective study. Cancer. 2018 Jun 1;124(11):2316-2326. doi: 10.1002/cncr.31327. Epub 2018 Mar 26. — View Citation

Gill HS, Yim R, Kumana CR, Tse E, Kwong YL. Oral arsenic trioxide, all-trans retinoic acid, and ascorbic acid maintenance after first complete remission in acute promyelocytic leukemia: Long-term results and unique prognostic indicators. Cancer. 2020 Jul 15;126(14):3244-3254. doi: 10.1002/cncr.32937. Epub 2020 May 4. — View Citation

Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. doi: 10.1073/pnas.0813280106. Epub 2009 Feb 18. — View Citation

Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, Browett P, Grigg A, Firkin F, Hugman A, Reynolds J, Di Iulio J, Tiley C, Taylor K, Filshie R, Seldon M, Taper J, Szer J, Moore J, Bashford J, Seymour JF; Australasian Leukaemia and Lymphoma Group. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood. 2012 Aug 23;120(8):1570-80; quiz 1752. doi: 10.1182/blood-2012-02-410746. Epub 2012 Jun 19. — View Citation

Kelaidi C, Chevret S, De Botton S, Raffoux E, Guerci A, Thomas X, Pigneux A, Lamy T, Rigal-Huguet F, Meyer-Monard S, Chevallier P, Maloisel F, Deconinck E, Ferrant A, Fegueux N, Ifrah N, Sanz M, Dombret H, Fenaux P, Ades L. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol. 2009 Jun 1;27(16):2668-76. doi: 10.1200/JCO.2008.18.4119. Epub 2009 May 4. — View Citation

Kumana CR, Mak R, Kwong YL, Gill H. Resurrection of Oral Arsenic Trioxide for Treating Acute Promyelocytic Leukaemia: A Historical Account From Bedside to Bench to Bedside. Front Oncol. 2020 Aug 4;10:1294. doi: 10.3389/fonc.2020.01294. eCollection 2020. — View Citation

Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S, Ludwig WD, Staib P, Aul C, Gruneisen A, Kern W, Reichle A, Serve H, Berdel WE, Braess J, Spiekermann K, Wormann B, Sauerland MC, Heinecke A, Hiddemann W, Hehlmann R, Buchner T; German AML Cooperative Group. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009 Dec;23(12):2248-58. doi: 10.1038/leu.2009.183. Epub 2009 Sep 10. — View Citation

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Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, Di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lubbert M, Hanel M, Schmitz N, Link H, Kropp MG, Rambaldi A, La Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Dohner K, Sauer M, Ganser A, Amadori S, Mandelli F, Dohner H, Ehninger G, Schlenk RF, Platzbecker U; Gruppo Italiano Malattie Ematologiche dell'Adulto; German-Austrian Acute Myeloid Leukemia Study Group; Study Alliance Leukemia. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013 Jul 11;369(2):111-21. doi: 10.1056/NEJMoa1300874. — View Citation

Niu C, Yan H, Yu T, Sun HP, Liu JX, Li XS, Wu W, Zhang FQ, Chen Y, Zhou L, Li JM, Zeng XY, Yang RR, Yuan MM, Ren MY, Gu FY, Cao Q, Gu BW, Su XY, Chen GQ, Xiong SM, Zhang TD, Waxman S, Wang ZY, Chen Z, Hu J, Shen ZX, Chen SJ. Studies on treatment of acute promyelocytic leukemia with arsenic trioxide: remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999 Nov 15;94(10):3315-24. — View Citation

Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, Stone RM, Kalaycio M, Scheinberg DA, Steinherz P, Sievers EL, Coutre S, Dahlberg S, Ellison R, Warrell RP Jr. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001 Sep 15;19(18):3852-60. doi: 10.1200/JCO.2001.19.18.3852. — View Citation

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* Note: There are 19 references in all — Click here to view all references

Outcome

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