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)
- Conditions
- Acute Myeloid Leukaemia (FLT3-ITD positive)Cancer - Leukaemia - Acute leukaemia
- Registration Number
- ACTRN12614000810617
- Lead Sponsor
- Australasian Leukaemia and Lymphoma Group
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Active, not recruiting
- Sex
- All
- Target Recruitment
- 35
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
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
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 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[ 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 Measures
Name Time Method Phase Ib: To assess the preliminary efficacy of Ponatinib alone or in combination with Azacitidine in patients with FLT3-ITD AML[ 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.];Phase Ib: To investigate the quality of life of patients receiving Azacitidine in combination with Ponatinib.[ Phase Ib: After 1, 2 and 4 cycles of therapy (EORTC-QLQ30 and AQoL-5D)]