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Trial registered on ANZCTR

Registration number

ACTRN12605000070639

Ethics application status

Approved

Date submitted

4/08/2005

Date registered

4/08/2005

Date last updated

4/08/2023

Date data sharing statement initially provided

4/08/2023

Type of registration

Retrospectively registered

Titles & IDs

Public title

Acute Promyelocytic Leukaemia APML4 Protocol

Scientific title

APML4 Protocol: A phase II trial in patients with previously untreated acute promyelocytic leukaemia to evaluate the effect on time to molecular relapse and early death rate as a result of: (i) adding arsenic trioxide to all-trans retinoic acid and idarubicin for remission induction, (ii) adding arsenic trioxide to all-trans retinoic acid as consolidation, (iii) the obligatory use of prednisone (or prednisolone) and aggressive haemostatic support during induction.

Secondary ID [1]

Australasian Leukaemia and Lymphoma Group (ALLG): ALLG APML4

Secondary ID [2]

National Clinical Trials Registry: NCTR569

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Acute promyelocytic leukaemia (APL)

Condition category

Condition code

Cancer

Leukaemia - Acute leukaemia

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

A single arm phase II study of all-trans retinoic acid (ATRA), idarubicin and arsenic trioxide (As2O3) over 36 days as induction therapy for acute promyelocytic leukaemia, followed by two cycles of consolidation with ATRA and As2O3 (over 28 days and 35 days respectively). Prednisone is administered during induction for all patients. Consolidation is followed by 2 years of maintenance therapy with daily 6-mercaptopurine, once weekly methotrexate, and 2 weeks of ATRA every 3 months. Bone marrow sampling for molecular monitoring is performed after each cycle of induction and consolidation, and then every 3 months for 2 years.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group

Uncontrolled

Outcomes

Primary outcome [1]

1. To evaluate in a group of patients with de novo APL the effect of a chemotherapy protocol consisting of arsenic trioxide added to standard induction (ATRA plus intensive idarubicin) and two cycles of consolidation (ATRA plus As2O3) on time to molecular relapse.

Timepoint [1]

Primary outcome [2]

2. To assess the effect of obligatory use of prednisone (or prednisolone) and aggressive haemostatic support, during induction, on early death rate (defined as death within the first 30 days).

Timepoint [2]

Secondary outcome [1]

1. To evaluate the use of peripheral blood as an alternative to bone marrow for molecular monitoring of minimal residual leukaemia by quantitative RT-PCR.

Timepoint [1]

Over a period of 2 years.

Secondary outcome [2]

2. To assess the relation of whole blood arsenic levels to
(a) efficacy of As2O3 as measured by time to molecular relapse, and (b) development of adverse reactions to the treatment regimen (during induction and consolidation).

Timepoint [2]

During induction and consolidation.

Secondary outcome [3]

3. To assess the impact of the GST-1 polymorphic status of individual patients on whole blood arsenic levels, as well as on efficacy and safety of As2O3.

Timepoint [3]

During induction and consolidation.

Secondary outcome [4]

4. To evaluate the effect of the chemotherapy protocol on complete remission rate (after induction and consolidation), time to relapse, and overall survival.

Timepoint [4]

At 2-5 years).

Secondary outcome [5]

5. To evaluate fertility before and at various times after the chemotherapy protocol.

Timepoint [5]

Every 12 months after maintenance is commenced until fertility status is clarified.

Eligibility

Key inclusion criteria

1. Morphological diagnosis of APL, either classical FAB-M3 or variant FAB-M3v. The leukaemia must have occurred de novo, with no previous history of preleukaemia, myelodysplasia, or myeloproliferative disorder. 2. Demonstration of PML-RARA fusion transcripts by reverse transcriptase-polymerase chain reaction (RT-PCR). 3. ECOG performance status 0-3. 4. Absence of previous history of serious cardiac, pulmonary, hepatic or renal disease, and absence of history of grand mal seizures. A serum creatinine >200umol/L or serum bilirubin >50umol/L precludes entry into the study, unless medically correctable. 5. A left ventricular ejection fraction of at least 50% as demonstrated by gated heart pool scan (preferably) or cardiac ultrasound. 6. ECG showing sinus rhythm and Q-Tc interval <500msec. Prolongation of Q-Tc due to medication or electrolyte disturbance must be corrected before registration. 7. No previous treatment for APL, or history of cancer (other than basal cell skin cancer, or carcinoma of cervix in situ). 8. No contra-indication to use of any of the study drugs. 9. A negative pregnancy test in females of child-bearing age. 10. Written informed consent

Minimum age

1 Years

Maximum age

Not stated

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

No exclusion criteria

Study design

Purpose of the study

Treatment

Allocation to intervention

Non-randomised trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Single group

Other design features

Phase

Phase 2

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

25/05/2004

Actual

10/11/2004

Date of last participant enrolment

Anticipated

Actual

23/09/2009

Date of last data collection

Anticipated

Actual

31/12/2013

Sample size

Target

125

Accrual to date

Final

129

Recruitment in Australia

Recruitment state(s)

NSW,NT,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

The Alfred - Prahran

Recruitment hospital [2]

The Canberra Hospital - Garran

Recruitment hospital [3]

The Children's Hospital at Westmead - Westmead

Recruitment hospital [4]

Concord Repatriation Hospital - Concord

Recruitment hospital [5]

Royal Darwin Hospital - Tiwi

Recruitment hospital [6]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [7]

Gosford Hospital - Gosford

Recruitment hospital [8]

Icon Cancer Care South Brisbane - South Brisbane

Recruitment hospital [9]

Icon Cancer Care Wesley - Auchenflower

Recruitment hospital [10]

Liverpool Hospital - Liverpool

Recruitment hospital [11]

Calvary Mater Newcastle - Waratah

Recruitment hospital [12]

Nepean Hospital - Kingswood

Recruitment hospital [13]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [14]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [15]

The Queen Elizabeth Hospital - Woodville

Recruitment hospital [16]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [17]

The Royal Childrens Hospital - Parkville

Recruitment hospital [18]

Royal Hobart Hospital - Hobart

Recruitment hospital [19]

Royal Melbourne Hospital - City campus - Parkville

Recruitment hospital [20]

Royal North Shore Hospital - St Leonards

Recruitment hospital [21]

Royal Perth Hospital - Perth

Recruitment hospital [22]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [23]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [24]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [25]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [26]

The Townsville Hospital - Douglas

Recruitment hospital [27]

Westmead Hospital - Westmead

Recruitment hospital [28]

Wollongong Hospital - Wollongong

Recruitment postcode(s) [1]

0810 - Tiwi

Recruitment postcode(s) [2]

2010 - Darlinghurst

Recruitment postcode(s) [3]

2050 - Camperdown

Recruitment postcode(s) [4]

2065 - St Leonards

Recruitment postcode(s) [5]

2139 - Concord

Recruitment postcode(s) [6]

2145 - Westmead

Recruitment postcode(s) [7]

2170 - Liverpool

Recruitment postcode(s) [8]

2250 - Gosford

Recruitment postcode(s) [9]

2298 - Waratah

Recruitment postcode(s) [10]

2500 - Wollongong

Recruitment postcode(s) [11]

2605 - Garran

Recruitment postcode(s) [12]

2747 - Kingswood

Recruitment postcode(s) [13]

3000 - Melbourne

Recruitment postcode(s) [14]

3004 - Prahran

Recruitment postcode(s) [15]

3050 - Parkville

Recruitment postcode(s) [16]

3052 - Parkville

Recruitment postcode(s) [17]

3065 - Fitzroy

Recruitment postcode(s) [18]

3220 - Geelong

Recruitment postcode(s) [19]

4066 - Auchenflower

Recruitment postcode(s) [20]

4101 - South Brisbane

Recruitment postcode(s) [21]

4102 - Woolloongabba

Recruitment postcode(s) [22]

4814 - Douglas

Recruitment postcode(s) [23]

5000 - Adelaide

Recruitment postcode(s) [24]

5011 - Woodville

Recruitment postcode(s) [25]

6000 - Perth

Recruitment postcode(s) [26]

6009 - Nedlands

Recruitment postcode(s) [27]

7000 - Hobart

Funding & Sponsors

Funding source category [1]

Charities/Societies/Foundations

Name [1]

Leukaemia Foundation of Australia

Address [1]

Country [1]

Australia

Primary sponsor type

Other Collaborative groups

Name

Australasian Leukaemia and Lymphoma Group

Address

Country

Australia

Secondary sponsor category [1]

None

Name [1]

nil

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

Approval date [1]

13/09/2004

Ethics approval number [1]

Ethics committee name [2]

Canberra

Ethics committee address [2]

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

Approval date [2]

Ethics approval number [2]

Ethics committee name [3]

Concord

Ethics committee address [3]

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

Approval date [3]

Ethics approval number [3]

Ethics committee name [4]

Mater Brisbane

Ethics committee address [4]

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

Approval date [4]

Ethics approval number [4]

Ethics committee name [5]

Mater Newcastle

Ethics committee address [5]

Ethics committee country [5]

Australia

Date submitted for ethics approval [5]

Approval date [5]

Ethics approval number [5]

Ethics committee name [6]

Queen Elizabeth

Ethics committee address [6]

Ethics committee country [6]

Australia

Date submitted for ethics approval [6]

Approval date [6]

Ethics approval number [6]

Ethics committee name [7]

Royal Melbourne

Ethics committee address [7]

Ethics committee country [7]

Australia

Date submitted for ethics approval [7]

Approval date [7]

Ethics approval number [7]

Ethics committee name [8]

Royal Perth

Ethics committee address [8]

Ethics committee country [8]

Australia

Date submitted for ethics approval [8]

Approval date [8]

Ethics approval number [8]

Ethics committee name [9]

Royal Prince Alfred

Ethics committee address [9]

Ethics committee country [9]

Australia

Date submitted for ethics approval [9]

Approval date [9]

Ethics approval number [9]

Ethics committee name [10]

St Vincent's Melbourne

Ethics committee address [10]

Ethics committee country [10]

Australia

Date submitted for ethics approval [10]

Approval date [10]

Ethics approval number [10]

Ethics committee name [11]

St Vincent's Sydney

Ethics committee address [11]

Ethics committee country [11]

Australia

Date submitted for ethics approval [11]

Approval date [11]

Ethics approval number [11]

Ethics committee name [12]

Westmead

Ethics committee address [12]

Ethics committee country [12]

Australia

Date submitted for ethics approval [12]

Approval date [12]

Ethics approval number [12]

Summary

Brief summary

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia that is characterized by distinct clinical and laboratory abnormalities. It is associated with a striking risk of early death due to bleeding. Fortunately, the outcome for patients with APL has improved dramatically following the introduction of all-trans retinoic acid (ATRA) and its combination with chemotherapeutic drugs such as idarubicin. Patients with a white cell count > 10 x 109/L at diagnosis are at particularly increased risk of early death and of relapse (disease recurrence). Arsenic trioxide (ATO) has proved to be even more effective than ATRA as a single agent, and
is now routinely used for the treatment of the 20%–30% of patients who relapse after initial treatment with ATRA and chemotherapy. ATO has a side-effect profile that is substantially different from both ATRA and chemotherapy.

In the APML4 trial, members of the Australasian Leukaemia and Lymphoma Group (ALLG) combined the 3 most active drugs used for APL (ATRA, idarubicin, and ATO) in induction, and then consolidated the responses with 2 cycles of ATRA and ATO without chemotherapy. This strategy helped reduce the total amount of chemotherapy compared with many other protocols available, in the hope of reducing long-term side effects such as bone marrow damage and heart damage. Two years of maintenance was used as per the ALLG standard practice for APL.

The results were very impressive. One hundred and twenty-four evaluable patients were enrolled between Nov 2004 and Sep 2009, and the outcomes were reported in 2 publications (Blood 2012, Lancet Haematology 2015). The early death rate was 3%, and 95% of patients achieved complete remission after induction with ATRA, ATO and idarubicin. All 112 patients who started consolidation achieved molecular remission (no detectable leukaemia by a very sensitive molecular assay).

The long term results that were reported in Lancet Haematology showed that the relapse rate at 5 years was only 5%. Patients traditionally regarded as at very high risk of relapse had the same low relapse rate as patients who were in the standard risk category, and this was a major achievement of the APML4 treatment plan. Overall, 94% of patients were still alive at 5 years. When the results were compared with the ALLG’s previous APML3 trial (which did not include ATO), the results were substantially better with less relapses and better overall survival. Although side effects occurred, as in every clinical trial for leukaemia, the overall side effect profile was widely acknowledged as acceptable (ie. not excessive).

Trial website

Trial related presentations / publications

Presentations
Harry Iland, Alberto Catalano, Shane Supple, Frank Firkin, Juliana Di Iulio and John Reynolds for the Australasian Leukaemia and Lymphoma Group (ALLG). Preliminary experience with the ALLG APML4 protocol: ATRA, idarubicin, and arsenic trioxide triple induction therapy for previously untreated acute promyelocytic leukemia. 4th International APL Symposium (Rome, September 2005)

Iland H, Firkin F, Supple S, Catalano A, Filshie R, Grigg A, Hertzberg M, Rowlings P, Taylor K, Tiley C, Seymour J, Di Iulio J and Reynolds J for the ALLG. All-trans retinoic acid (ATRA), Idarubicin (IDA), and Arsenic Trioxide (ATO) as Initial Therapy in Acute Promyelocytic Leukaemia (APL): An Australasian Leukaemia and Lymphoma Group (ALLG) study. Oral presentation, 5th International APL Symposium, Rome, 2009.

Iland H, Firkin F, Supple S, Catalano A, Bashfrod J, Filshie R, Grigg A, Hertzberg M, Moore J, Rowlings P, Taylor K, Tiley C, & Seymour JF for the ALLG	Interim analysis of the APML4 trial incorporating all-trans retinoic acid (ATRA), idarubicin, and intravenous arsenic trioxide (ATO) as initial therapy in acute promyelocytic leukaemia (APL): An Australasian Leukaemia and Lymphoma Group study. Proc Hong Kong Soc Haematol, Hong Kong Mar 26 – 28, 2010

Iland H, Firkin F, Supple S, Catalano A, Bashford J, Filshie R, Grigg A, Hertzberg M, Moore J, Rowlings P, Taylor K, Tiley C, Taper J, Szer J, Seymour J, Patton N, Fisher R, Di Iulio J and Beresford J for the ALLG. Interim analysis of the APML4 trial incorporating all-trans retinoic acid, idarubicin, and intravenous arsenic trioxide as initial therapy in acute promyelocytic leukaemia - An Australasian Leukaemia & Lymphoma Group study. Selected for oral presentation at the Clinical Trial Symposium (sponsored by Lancet Oncology and the Clinical Oncology Society of Australia), Asian Oncology Summit, Bali, April 2010.

Iland HJ, Collins M, Seymour J for the ALLG. The Australasian Leukaemia and Lymphoma Group APML4 trial – update on APL treatment down under. 6th International APL Symposium, Rome, September 2013.

Iland HJ, Collins M, Hertzberg MS, Seldon M, Grigg AP, Firkin F, Supple SG, Campbell LJ, Bradstock KF, Seymour JF. Final Analysis of the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 Trial: All-Trans Retinoic Acid (ATRA), Intravenous Arsenic Trioxide (ATO) and Idarubicin (IDA) As Initial Therapy for Acute Promyelocytic Leukemia (APL). Blood 2014 124:375; published ahead of print December 5, 2014 (oral presentation, American Society of Hematology Scientific Meeting, San Francisco, December 2014).

Publications
Iland, H. J., Bradstock, K., Supple, S. G., 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. and Seymour, J. F. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4) Blood 120(8): 1570-1580 (2012)

Iland HJ, Collins M, Bradstock K, Supple SG, Catalano A, Hertzberg M, Browett P, Grigg A, Firkin F, Campbell LJ, 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 for the Australasian Leukaemia and Lymphoma Group. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: a non-randomised phase 2 trial. Lancet Haematol 2015; 2(9):e357-366.

Mantha S, Goldman DA, Devlin SM, Lee J-W, Zannino D, Collins M, Douer D, Iland HJ, Litzow MR, Stein EM, Appelbaum FR, Larson RA, Stone RM, Powell BL, Geyer S, Laumann K, Rowe JM, Erba HP, Coutre S, Othus M, Park JH, Wiernik PH, Tallman MS. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood 2017; 129(13):1763-1767.

Iland H. First-line therapy: ATRA-ATO/reduced chemotherapy approach. In: Acute Promyelocytic Leukemia, O Abla, F Lo-Coco, MA Sanz (eds), Springer Publishing Company, 2017 (in press).

Public notes

Contacts

Principal investigator

Name

Prof Harry Iland

Address

Institute of Haematology Royal Prince Alfred Hospital Missenden Road Camperdown NSW 2050

Country

Australia

Phone

+61 2 95156111

Fax

[email protected]

Contact person for public queries

Name

A/Prof Harry Iland

Address

Institute of Haematology
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050

Country

Australia

Phone

+61 2 95156111

Fax

+61 2 95156255

[email protected]

Contact person for scientific queries

Name

A/Prof Harry Iland

Address

Institute of Haematology
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050

Country

Australia

Phone

+61 2 95156111

Fax

+61 2 95156255

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

De-identified IPD data, for all data collected during the trial

When will data be available (start and end dates)?

Data available 3 months following publication, for an indefinite period

Available to whom?

Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted.

Available for what types of analyses?

Any type of analysis
Assessed on a case-by-case basis

How or where can data be obtained?

Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
19911	Study protocol			[email protected]	Access can be requested via the Health Data Austra... [More Details]

Results publications and other study-related documents

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Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: A non-randomised phase 2 trial.	2015	https://dx.doi.org/10.1016/S2352-3026%2815%2900115-5
Embase	Evolving Chemotherapy Free Regimens for Acute Promyelocytic Leukemia.	2021	https://dx.doi.org/10.3389/fonc.2021.621566

N.B. These documents automatically identified may not have been verified by the study sponsor.

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