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)
Australasian Leukaemia and Lymphoma Group
42 participants
Jun 16, 2016
Interventional
Conditions
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.
Eligibility
Inclusion Criteria9
- Provision of written informed consent
- Enrolment to the ALLG National Blood Cancer Registry (Another Australiasian Leukaemia and Lymphoma group study)
- 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.
- Age 18+
- Eastern Cooperative Oncology Group performance status 0-2
- Adequate haemostatic function (activated partial thromboplastin time (APTT) within 5 sec of ULN and INR less than 1.4x ULN)
- 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
- Adequate pancreatic function as defined by the following criterion: serum lipase or amylase less than or equal to 1.5 × ULN
- Adequate renal function as defined by serum creatinine less than 1.5 ULN
Exclusion Criteria24
- Any serious medical condition which the investigator feels may interfere with the procedures or evaluations of the study
- More than 2 prior lines of intensive chemotherapy
- Prior exposure to ponatinib
- If prior exposure to other FLT3 inhibitors, the presence of FLT3-TKD mutation must not be present at screening
- Moderate/strong CYP3A4 inhibitors within 48 hours of cycle 1, day 1
- Active graft versus host disease post-allograft or requiring steroid doses equivalent to prednisolone 15mg per day or greater
- Prior exposure to a hypomethylating agent
- Major surgery within 28 days prior to initiating therapy
- History of acute pancreatitis within 1 year of study or a history of chronic pancreatitis
- Uncontrolled diabetes
- 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
- History of other malignancy requiring active systemic treatment or which is likely to result in an expected survival time of less than 2 years
- Viral infection with known HIV or viral hepatitis type B or C not adequately controlled by antiviral medication
- Active infection or bleeding
- 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
- 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
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Interventions
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.
Locations(8)
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ACTRN12614000810617