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Trial registered on ANZCTR


Registration number
ACTRN12614000810617
Ethics application status
Approved
Date submitted
1/04/2014
Date registered
30/07/2014
Date last updated
20/09/2021
Date data sharing statement initially provided
4/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase Ib/II clinical evaluation of Ponatinib in combination with 5- Azacitidine in patients failing prior therapy for FLT3-ITD positive acute myeloid leukaemia (AMLM21)
Scientific title
A phase Ib/II clinical evaluation of Ponatinib in combination with 5- Azacitidine in patients failing prior therapy for FLT3-ITD positive acute myeloid leukaemia (AMLM21)
Secondary ID [1] 284378 0
ALLG AMLM21
Australiasian Leukaemia and Lymphoma Group
Universal Trial Number (UTN)
Trial acronym
PonAZA study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Myeloid Leukaemia (FLT3-ITD positive) 291545 0
Condition category
Condition code
Cancer 291924 291924 0 0
Leukaemia - Acute leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Phase I
1. Dose level 1
Azacitidine 60 mg/m2 (SC) D1-5 and 8-9 and Ponatinib (Oral) 30mg daily on days 5-25 (6 patients)
Each cycle will be 28 days in length. Continue until DLT, treatment failure or death.
-If there is no Ponatinib dose interruption or reduction for toxicity during cycle 1, the Ponatinib dose should be increased to 45mg in subsequent cycles if Complete Remission (CR) has not been achieved.

If dose level 1 tolerable (as assessed by the trial management committee) the next cohort opened will be Dose level 2. If dose level 1 is not tolerable, the next cohort to be opened will be Dose level -1.

2. Dose level 2
Azacitidine 75 mg/m2 D1-5 and 8-9 and ponatinib 30mg daily on days 5-25 (6 patients)
Each cycle will be 28 days in length. Continue until DLT, treatment failure or death.
-If there is no Ponatinib dose interruption or reduction for toxicity during cycle 1, the Ponatinib dose should be increased to 45mg in subsequent cycles if Complete Remission (CR) has not been achieved.

3. Dose level -1
Azacitidine 50mg/m2 days 1-5 and Ponatinib 30mg daily on days 5-25 (6 patients)
Each cycle will be 28 days in length. Continue until DLT, treatment failure or death.
-If there is no Ponatinib dose interruption or reduction for toxicity during cycle 1, the Ponatinib dose should be increased to 45mg in subsequent cycles if Complete Remission (CR) has not been achieved.
Intervention code [1] 289107 0
Treatment: Drugs
Comparator / control treatment
There are 2 intervention arms in Phase II being compared to each other
Control group
Active

Outcomes
Primary outcome [1] 291830 0
Phase Ib- To assess the tolerability (after 2 cycles of treatment) and recommend a Phase II dose of Azacitidine in combination with Ponatinib in patients with FLT3-ITD AML who have failed prior therapy
Timepoint [1] 291830 0
Phase Ib- The occurrence of a dose-limiting toxicity (DLT) in the first two cycles. A DLT is the occurrence of (i) any CTCAE grade 3 or 4 non-haematologic toxicity, which does not resolve to grade 1 within 21 days post drug cessation, or (ii) grade 4 neutropenia or thrombocytopenia unrelated to MDS/AML that does not resolve to at least grade 2 after 28 days post-drug cessation.
Secondary outcome [1] 307638 0
Phase Ib: To assess the preliminary efficacy of Ponatinib alone or in combination with Azacitidine in patients with FLT3-ITD AML
Timepoint [1] 307638 0
Phase Ib: Best response (CR/CRi/PR) within the first 4 cycles of treatment, haematologic and cytogenetic response, 1 year progression-free and overall survival, proportion bridged to allo-SCT, time to best response and duration of response.
Secondary outcome [2] 309446 0
Phase Ib: To investigate the quality of life of patients receiving Azacitidine in combination with Ponatinib.
Timepoint [2] 309446 0
Phase Ib: After 1, 2 and 4 cycles of therapy (EORTC-QLQ30 and AQoL-5D)

Eligibility
Key inclusion criteria
1. Provision of written informed consent
2. Enrolment to the ALLG National Blood Cancer Registry (Another Australiasian Leukaemia and Lymphoma group study)
3. FLT3-ITD AML (except Acute Promyelocytic Leukaemia) failing prior chemotherapy (excluding hydroxyurea and thioguanine which is not considered chemotherapy) or who are considered unfit for frontline intensive chemotherapy.
4. Age 18+
5. Eastern Cooperative Oncology Group performance status 0-2
6. Adequate haemostatic function (activated partial thromboplastin time (APTT) within 5 sec of ULN and INR less than 1.4x ULN)
7. Adequate hepatic function as defined by bilirubin less than or equal to 1.5 x the upper limit of normal (ULN) unless due to Gilbert’s syndrome and aspartate transaminase (AST) or alanine aminotransferase (ALT) less than or equal to 3 x ULN
8. Adequate pancreatic function as defined by the following criterion: serum lipase or amylase less than or equal to 1.5 × ULN
9. Adequate renal function as defined by serum creatinine less than 1.5 ULN
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Any serious medical condition which the investigator feels may interfere with the procedures or evaluations of the study
2. More than 2 prior lines of intensive chemotherapy
3. Prior exposure to ponatinib
4. If prior exposure to other FLT3 inhibitors, the presence of FLT3-TKD mutation must not be present at screening
5. Moderate/strong CYP3A4 inhibitors within 48 hours of cycle 1, day 1
6. Active graft versus host disease post-allograft or requiring steroid doses equivalent to prednisolone 15mg per day or greater
7. Prior exposure to a hypomethylating agent
8. Major surgery within 28 days prior to initiating therapy
9. History of acute pancreatitis within 1 year of study or a history of chronic pancreatitis
10. Uncontrolled diabetes
11. History of cardiovascular or thromboembolic disease including:
a. Myocardial infarction
b. Unstable angina within 6 months prior to randomization
c. Congestive heart failure within 6 months prior to randomization
d. History of clinically significant (as determined by the treating physician) atrial arrhythmia
e. Any history of ventricular arrhythmia
f. Cerebrovascular accident or transient ischemic attack
g. Any history of peripheral arterial occlusive disease requiring revascularization
h. Any history of venous thromboembolism including deep venous thrombosis (excluding catheter associated thrombosis) or pulmonary embolism
12. History of other malignancy requiring active systemic treatment or which is likely to result in an expected survival time of less than 2 years
13. Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication
14. Active infection or bleeding
15. Pregnant or breastfeeding females; women of childbearing potential may participate providing they agree to use at least 2 effective contraceptive methods throughout the study and for 30 days following completion. For females of childbearing potential, a negative pregnancy test must be documented within 7 days prior to starting treatment with ponatinib
16. Males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and for 30 days following the date of last dose

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
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
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,QLD,VIC
Recruitment hospital [1] 10535 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [2] 10536 0
The Alfred - Prahran
Recruitment hospital [3] 10537 0
Westmead Hospital - Westmead
Recruitment hospital [4] 10538 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [5] 10539 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [6] 10540 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [7] 10541 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [8] 13552 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 22256 0
2145 - Westmead
Recruitment postcode(s) [2] 26175 0
2170 - Liverpool
Recruitment postcode(s) [3] 22259 0
2298 - Waratah
Recruitment postcode(s) [4] 22255 0
3004 - Prahran
Recruitment postcode(s) [5] 22254 0
3052 - Parkville
Recruitment postcode(s) [6] 22258 0
3220 - Geelong
Recruitment postcode(s) [7] 22257 0
4029 - Herston
Recruitment postcode(s) [8] 22260 0
4102 - Woolloongabba

Funding & Sponsors
Funding source category [1] 289018 0
Commercial sector/Industry
Name [1] 289018 0
Millennium Pharmaceuticals, Inc.
Address [1] 289018 0
Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge Massachusetts 02139-4234
Country [1] 289018 0
United States of America
Primary sponsor type
Charities/Societies/Foundations
Name
Australasian Leukaemia and Lymphoma Group
Address
Australasian Leukaemia & Lymphoma Group
Address: Ground Floor, 35 Elizabeth Street,
Richmond, Victoria 3121
AUSTRALIA
Country
Australia
Secondary sponsor category [1] 287694 0
None
Name [1] 287694 0
Address [1] 287694 0
Country [1] 287694 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290824 0
Alfred Hospital Melbourne
Ethics committee address [1] 290824 0
Alfred Hospital
Commercial Road
Melbourne, Victoria 3004
Australia
Ethics committee country [1] 290824 0
Australia
Date submitted for ethics approval [1] 290824 0
16/11/2015
Approval date [1] 290824 0
18/04/2016
Ethics approval number [1] 290824 0
HREC/15/Alfred/94

Summary
Brief summary
This study is evaluating Ponatinib in combination with 5-Azacitidine in patients with FLT3- ITD positive acute myeloid leukaemia.

Who is it for? You may be eligible to join this study if you are aged over 18 years, have enrolled in the ALLG National Blood Cancer Registry, have FLT3-ITD AML (except Acute Promyelocytic Leukaemia) failing prior chemotherapy or are considered unfit for frontline intensive chemotherapy. You must have adequate liver function (unless due to Gilbert’s syndrome), adequate pancreatic function, and adequate kidney function. The full details of this study's inclusion and exclusion criteria can be found in the relevant sections within this record.

Trial details: This study has two parts:
Phase Ib involves finding the best dose of Azacitidine to combine with Ponatinib in terms of patient tolerability and safety. The first group of patients enrolled will be treated with 60 mg/m2 of Azacitidine on days 1 -5 & 8 – 9 and 30 mg of Ponatinib on days 5 – 25 of a 28 day cycle. If complete remission of AML is not achieved in the first cycle and no dose reductions for Ponatinib toxicity has occurred Ponatinib should be increased to 45 mg in subsequent cycles. The response to the treatment and adverse events will be assessed by the Trial Management Committee after 6 patients have been evaluated, subsequent patients will be recruited to receive either a higher (75 mg/m2 on days 1 – 5 & 8 – 9 on a 28 day cycle) or lower dose Azacitidine (50 mg/m2 on days 1 – 5 on a 28 day cycle) depending on the response. Both groups would also receive 30 mg of Ponatinib on days 5 – 25 of a 28 day cycle. If complete remission of AML is not achieved in the first cycle and no dose reductions for Ponatinib toxicity has occurred Ponatinib should be increased to 45 mg in subsequent cycles. The response to the treatment and adverse events of both groups will be assessed by the Trial Management Committee to determine a recommended phase II dose. All patients will then receive repeating 28 day cycles of daily oral Ponatinib and Azacitadine injections as long as the therapy continues to fight their leukaemia. Response to the treatment will be assessed at routine clinical visits with the usual clinical investigations that would monitor the status of your disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 47442 0
A/Prof Andrew Wei
Address 47442 0
Alfred Hospital
Commercial Road
Melbourne, Victoria 3004
Australia
Country 47442 0
Australia
Phone 47442 0
+61 (0)3 9076 3451
Fax 47442 0
+61 (0)3 9076 2298
Email 47442 0
andrew.wei@monash.edu
Contact person for public queries
Name 47443 0
Ms Delaine Smith
Address 47443 0
Australasian Leukaemia & Lymphoma Group
Ground Floor, 35 Elizabeth Street Richmond, VIC 3121
Country 47443 0
Australia
Phone 47443 0
+61 (0)3 8373 9701
Fax 47443 0
+61 (0)3 9429 8277
Email 47443 0
delaine.smith@allg.org.au
Contact person for scientific queries
Name 47444 0
Ms Delaine Smith
Address 47444 0
Australasian Leukaemia & Lymphoma Group
Ground Floor, 35 Elizabeth Street Richmond, VIC 3121
Country 47444 0
Australia
Phone 47444 0
+61 (0)3 8373 9701
Fax 47444 0
+61 (0)3 9429 8277
Email 47444 0
delaine.smith@allg.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be publicly available as it is the aggregate data that is under investigation.
What supporting documents are/will be available?
No other documents available
Summary results
No Results