Trial registered on ANZCTR


Trial ID
ACTRN12605000070639
Ethics application status
Approved
Date submitted
4/08/2005
Date registered
4/08/2005
Date last updated
8/08/2017
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] 95 0
Australasian Leukaemia and Lymphoma Group (ALLG): ALLG APML4
Secondary ID [2] 96 0
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) 142 0
Condition category
Condition code
Cancer 162 162 0 0
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] 109 0
Treatment: drugs
Comparator / control treatment
-
Control group
Uncontrolled

Outcomes
Primary outcome [1] 202 0
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] 202 0
-
Primary outcome [2] 203 0
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] 203 0
-
Secondary outcome [1] 459 0
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] 459 0
Over a period of 2 years.
Secondary outcome [2] 460 0
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] 460 0
During induction and consolidation.
Secondary outcome [3] 461 0
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] 461 0
During induction and consolidation.
Secondary outcome [4] 462 0
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] 462 0
At 2-5 years).
Secondary outcome [5] 463 0
5. To evaluate fertility before and at various times after the chemotherapy protocol.
Timepoint [5] 463 0
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
Gender
Both males and females
Can healthy volunteers participate?
No
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
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment hospital [1] 8719 0
The Alfred - Prahran
Recruitment hospital [2] 8720 0
The Canberra Hospital - Garran
Recruitment hospital [3] 8721 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 8722 0
Concord Repatriation Hospital - Concord
Recruitment hospital [5] 8723 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [6] 8724 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [7] 8725 0
Gosford Hospital - Gosford
Recruitment hospital [8] 8726 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [9] 8727 0
Icon Cancer Care Wesley - Auchenflower
Recruitment hospital [10] 8728 0
Liverpool Hospital - Liverpool
Recruitment hospital [11] 8729 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [12] 8730 0
Nepean Hospital - Kingswood
Recruitment hospital [13] 8731 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [14] 8732 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [15] 8733 0
The Queen Elizabeth Hospital - Woodville
Recruitment hospital [16] 8734 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [17] 8735 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [18] 8736 0
Royal Hobart Hospital - Hobart
Recruitment hospital [19] 8737 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [20] 8738 0
Royal North Shore Hospital - St Leonards
Recruitment hospital [21] 8739 0
Royal Perth Hospital - Perth
Recruitment hospital [22] 8740 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [23] 8741 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment hospital [24] 8742 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [25] 8743 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [26] 8744 0
The Townsville Hospital - Douglas
Recruitment hospital [27] 8745 0
Westmead Hospital - Westmead
Recruitment hospital [28] 8746 0
Wollongong Hospital - Wollongong
Recruitment postcode(s) [1] 16840 0
3004 - Prahran
Recruitment postcode(s) [2] 16841 0
2605 - Garran
Recruitment postcode(s) [3] 16842 0
2145 - Westmead
Recruitment postcode(s) [4] 16843 0
2139 - Concord
Recruitment postcode(s) [5] 16844 0
0810 - Tiwi
Recruitment postcode(s) [6] 16845 0
3220 - Geelong
Recruitment postcode(s) [7] 16846 0
2250 - Gosford
Recruitment postcode(s) [8] 16847 0
4101 - South Brisbane
Recruitment postcode(s) [9] 16848 0
4066 - Auchenflower
Recruitment postcode(s) [10] 16849 0
2170 - Liverpool
Recruitment postcode(s) [11] 16850 0
2298 - Waratah
Recruitment postcode(s) [12] 16851 0
2747 - Kingswood
Recruitment postcode(s) [13] 16852 0
3000 - Melbourne
Recruitment postcode(s) [14] 16853 0
4102 - Woolloongabba
Recruitment postcode(s) [15] 16854 0
5011 - Woodville
Recruitment postcode(s) [16] 16855 0
5000 - Adelaide
Recruitment postcode(s) [17] 16856 0
3052 - Parkville
Recruitment postcode(s) [18] 16857 0
7000 - Hobart
Recruitment postcode(s) [19] 16858 0
3050 - Parkville
Recruitment postcode(s) [20] 16859 0
2065 - St Leonards
Recruitment postcode(s) [21] 16860 0
6000 - Perth
Recruitment postcode(s) [22] 16861 0
2050 - Camperdown
Recruitment postcode(s) [23] 16862 0
6009 - Nedlands
Recruitment postcode(s) [24] 16863 0
3065 - Fitzroy
Recruitment postcode(s) [25] 16864 0
2010 - Darlinghurst
Recruitment postcode(s) [26] 16865 0
4814 - Douglas
Recruitment postcode(s) [27] 16866 0
2500 - Wollongong

Funding & Sponsors
Funding source category [1] 215 0
Charities/Societies/Foundations
Name [1] 215 0
Leukaemia Foundation of Australia
Address [1] 215 0
-
Country [1] 215 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
-
Country
Australia
Secondary sponsor category [1] 162 0
None
Name [1] 162 0
nil
Address [1] 162 0
Country [1] 162 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 980 0
Alfred
Ethics committee address [1] 980 0
Ethics committee country [1] 980 0
Australia
Date submitted for ethics approval [1] 980 0
Approval date [1] 980 0
13/09/2004
Ethics approval number [1] 980 0
Ethics committee name [2] 981 0
Canberra
Ethics committee address [2] 981 0
Ethics committee country [2] 981 0
Australia
Date submitted for ethics approval [2] 981 0
Approval date [2] 981 0
Ethics approval number [2] 981 0
Ethics committee name [3] 982 0
Concord
Ethics committee address [3] 982 0
Ethics committee country [3] 982 0
Australia
Date submitted for ethics approval [3] 982 0
Approval date [3] 982 0
Ethics approval number [3] 982 0
Ethics committee name [4] 983 0
Mater Brisbane
Ethics committee address [4] 983 0
Ethics committee country [4] 983 0
Australia
Date submitted for ethics approval [4] 983 0
Approval date [4] 983 0
Ethics approval number [4] 983 0
Ethics committee name [5] 984 0
Mater Newcastle
Ethics committee address [5] 984 0
Ethics committee country [5] 984 0
Australia
Date submitted for ethics approval [5] 984 0
Approval date [5] 984 0
Ethics approval number [5] 984 0
Ethics committee name [6] 985 0
Queen Elizabeth
Ethics committee address [6] 985 0
Ethics committee country [6] 985 0
Australia
Date submitted for ethics approval [6] 985 0
Approval date [6] 985 0
Ethics approval number [6] 985 0
Ethics committee name [7] 986 0
Royal Melbourne
Ethics committee address [7] 986 0
Ethics committee country [7] 986 0
Australia
Date submitted for ethics approval [7] 986 0
Approval date [7] 986 0
Ethics approval number [7] 986 0
Ethics committee name [8] 987 0
Royal Perth
Ethics committee address [8] 987 0
Ethics committee country [8] 987 0
Australia
Date submitted for ethics approval [8] 987 0
Approval date [8] 987 0
Ethics approval number [8] 987 0
Ethics committee name [9] 988 0
Royal Prince Alfred
Ethics committee address [9] 988 0
Ethics committee country [9] 988 0
Australia
Date submitted for ethics approval [9] 988 0
Approval date [9] 988 0
Ethics approval number [9] 988 0
Ethics committee name [10] 989 0
St Vincent's Melbourne
Ethics committee address [10] 989 0
Ethics committee country [10] 989 0
Australia
Date submitted for ethics approval [10] 989 0
Approval date [10] 989 0
Ethics approval number [10] 989 0
Ethics committee name [11] 990 0
St Vincent's Sydney
Ethics committee address [11] 990 0
Ethics committee country [11] 990 0
Australia
Date submitted for ethics approval [11] 990 0
Approval date [11] 990 0
Ethics approval number [11] 990 0
Ethics committee name [12] 991 0
Westmead
Ethics committee address [12] 991 0
Ethics committee country [12] 991 0
Australia
Date submitted for ethics approval [12] 991 0
Approval date [12] 991 0
Ethics approval number [12] 991 0

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 35209 0
Prof Harry Iland
Address 35209 0
Institute of Haematology Royal Prince Alfred Hospital Missenden Road Camperdown NSW 2050
Country 35209 0
Australia
Phone 35209 0
+61 2 95156111
Fax 35209 0
Email 35209 0
harry@email.cs.nsw.gov.au
Contact person for public queries
Name 9298 0
Prof A/Prof Harry Iland
Address 9298 0
Institute of Haematology
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 9298 0
Australia
Phone 9298 0
+61 2 95156111
Fax 9298 0
+61 2 95156255
Email 9298 0
harry@email.cs.nsw.gov.au
Contact person for scientific queries
Name 226 0
Prof A/Prof Harry Iland
Address 226 0
Institute of Haematology
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 226 0
Australia
Phone 226 0
+61 2 95156111
Fax 226 0
+61 2 95156255
Email 226 0
harry@email.cs.nsw.gov.au