Chronic Myeloid Leukaemia (CML) in Blast Phase MedDRA version: 20.1 Level: PT Classification code 10009013 Term: Chronic myeloid leukaemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Trade Name: Iclusig
Product Name: Iclusig
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ponatinib
CAS Number: 1114544-31-8
Other descriptive name: Iclusig
Concentration unit: mg millig
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: All of the following: • Ph-positive or BCR-ABL positive CML in blastic transformation. Defined as one or more of the following being present: o Blasts =30% in peripheral blood or bone marrow o Extramedullary blast proliferation or large foci or clusters of blasts in the bone marrow biopsy • Age: =16 • Suitable for intensive chemotherapy (FLAG-IDA) • Adequate renal function defined as serum creatinine =1.5 X upper limit of normal (ULN) • Adequate liver function defined as: o Total bilirubin 5 X ULN due to leukaemia may enter with a dose reduction of FLAG-IDA as per local guidelines and will be considered on a per patient basis following discussion with the Chief Investigator and Trial Office.) • Normal pancreatic status defined as: o Serum Amylase = 1.5 X ULN • Normal QTcF interval on screening ECG evaluation, defined as QTcF of = 450 ms in males or =470 ms in females. • Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout participation in this study until 4 months after the last dose of ponatinib. • Ability to comply with study procedures, in the Investigator’s opinion. • Valid Informed Consent Are the trial subjects under 18? yes Number of subjects for this age range: 0 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 10 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 3
Exclusion criteria
Exclusion criteria: • Any of the following will exclude: • Received chemotherapy other than hydroxycarbamide, anagrelide, low dose arabinosylcytarabine (LDAC), steroids, or interferon within 4 weeks of registration • Changed TKI therapy more than once since confirmation of blast phase CML or had prior treatment with ponatinib at any time. • Previous treatment with intensive acute leukaemia-style chemotherapy (FLAG-IDA). (Unless treatment was during an initial blast phase which returned to chronic phase for a prolonged period of time and the patient is now in a second blast phase.) • Prior allogeneic or autologous Stem Cell Transplant • Significant or active cardiovascular disease, specifically including but not restricted to: o Myocardial infarction, stroke or revascularization within 12 months prior to registration o History of clinically significant atrial arrhythmia o Any history of or ventricular arryhthmia o Unstable angina or transient ischemic attack within 6 months prior to registration o Congestive heart failure within 6 months prior to registration o Left ventricular ejection fraction (LVEF) less than lower limit of normal within 6 months prior to registration o Any history of unprovoked venous thromboembolism including deep venous thrombosis or pulmonary embolism o Uncontrolled hypertension (sustained diastolic blood pressure >90 mm Hg; systolic >140 mm Hg). • History of acute pancreatitis within 1 year prior to registration • History of chronic pancreatitis. • Uncontrolled hypertriglyceridaemia (>450 mg/dL) • Are pregnant or lactating • Are known galactose intolerant • Underwent major surgery (with the exception of minor surgical procedures, such as catheter placement or Bone Marrow biopsy) within 14 days prior to registration • Suffer from any condition or illness that, in the opinion of the investigator, would compromise patient safety or interfere with the evaluation of the safety of the study treatment
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The aim of this trial is to find a safe and effective dose of a drug called Ponatinib when used in combination with chemotherapy in patients with Chronic Myeloid Leukaemia (CML) whose disease has moved in to blast phase.;Secondary Objective: To find out how safe it is to treat patients in Blast Phase Chronic Myeloid Leukaemia with ponatinib and chemotherapy. To find out how effective this combination (ponatinib and chemotherapy) is by the end of the trial, to find out how good ponatinib is at maintaining a response to treatment once the combination (ponatinib and chemotherapy) treatment has ended (and after Stem Cell Transplant - if applicable to the patient), and how long that response can be maintained (i.e. until the patients leukaemia relapses or progresses). ;Primary end point(s): Tolerability; Identification of the dose of ponatinib that can be safely delivered in combination with chemotherapy (FLAG-IDA) is defined in terms of dose limiting toxicities. Dose Limiting Toxicity will be defined as: • Before the start of the second cycle of combination therapy or up to 8 weeks from the start of the first cycle of combination therapy, whichever is sooner: o Grade 3 or 4 clinically significant non-haematological toxicity that cannot be managed with optimal medical care and that in the opinion of the investigator is related to the ponatinib and is likely to endanger the life of the patient or result in long term effects o Pancreatitis grade 2 or above o Increased serum amylase grade 3 or 4* o Prolongation of the QT interval grade 3 or 4 o Myocardial infarction o Stroke o Development or progression of a thromboembotic event requiring revascularisation o Unprovoked venous thromboembolism • Toxicities will be measured and graded according to Version 4 CTCAE criteria. *In cases where the patient displays an increased serum amylase level but no clinical signs of pancreatitis, please test the pancreatic isoenzyme level to differentiate between pancreati | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Toxicity profile of ponatinib + chemotherapy (FLAG-IDA) within 6 months or up to transplant (whichever time point arrives first). Toxicities will be measured and graded according to the CTCAE criteria version 4. • Complete Cytogenetic Response (CCyR) within 2 cycles of treatment • Major Molecular Response (MMR) within 2 cycles of treatment • Haematological response within 2 cycles of treatment • 3 year disease free survival (DFS) • 3 year overall survival (OS) • 1 and 3 year relapse rate post allogeneic transplant or maintenance therapy • 1 and 3 year treatment related mortality • Incidence of Cytomegalovirus (CMV) reactivation rate and Graft Versus Host Disease (GVHD) post-transplant ;Timepoint(s) of evaluation of this end point: 6 months for toxicity profile of ponatinib and chemotherapy 8-16 weeks for complete cytogenetic response 8-16 weeks for haematological response 8-16 weeks for major molecular response 3 years for disease free survival and overall survival 1 year and 3 years for the relapse rates and mortality Any GVHD that happens within the first 100 days after SCT is considered acute GVHD (aGVHD). GVHD occurring after 100 days post-SCT is termed chronic GVHD (cGVHD). | — |
Countries
United Kingdom
Contacts
Public ContactMirjana Sirovica
University of Birmingham
Outcome results
None listed