Myeloproliferative disorders including Primary Myelofibrosis (PMF) and Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF). MedDRA version: 9.1 Level: HLT Classification code 10028578 Term: Myeloproliferative disorders (excl leukaemias) MedDRA version: 9.1 Level: LLT Classification code 10036057 Term: Polycythaemia vera
Conditions
Interventions
Product Code: AZD1480
Pharmaceutical Form: Capsule*
CAS Number: 935666-88-9
Current Sponsor code: AZD1480
AZ12561101
Other descriptive name: 2,4-Pyrimidinediamine,5-chloro-N2-[(1S)1-(5-fluoro-2-pyrimidinyl]ethyl-N4-(5-methyl-1H-pyrazol-3-yl)
Concentration unit: mg milligram(s)
Concentration type: equal
Co
Sponsors
AstraZeneca AB
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provision of informed consent 2. Male or female aged 25 years and over 3. Patients with myelofibrosis requiring therapy, including those previously treated by myelofibrosis directed therapy who have subsequently relapsed or are refractory, or if newly diagnosed should be intermediate or high risk according to Lille (Dupriez et al 1996) Scoring System (adverse prognostic risk factors are: Hgb 4.0 or >30.0 X 109/L; risk group: 0 factor=low, 1 factor = intermediate, 2 factors = high); or with symptomatic splenomegaly (causing e.g. 5-10% weight loss, significant fever, or significant splenic pain affecting performance status) that is = 10 cm below left costal margin. 4. ECOG Performance Status of 0-2 5. Evidence of post-menopausal status, permanent or surgically sterile, or negative urine pregnancy test for female patients of child-bearing potential. Women will be considered postmenopausal if they are over 50 years old and have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments. Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal occlusion. Tubal occlusion is considered a highly effective method of birth control but does not absolutely exclude the possibility of pregnancy. (The term occlusion refers to both occluding and ligating techniques that do not physically remove the oviducts). Women who have undergone tubal occlusion should be managed as if they are of child-bearing potential (e.g., undergo pregnancy testing as required by the study). For inclusion in the optional genetic research, patients must fulfil the following criterion: 1. Provision of informed consent for genetic research (pharmacogenetics) If a patient declines to participate in the optional genetic research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, as long as they meet the inclusion criteria and give full informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.Prior therapy with any JAK tyrosine kinase inhibitors 2.Prior therapy with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), or busulfan, or bleomycin 3.Previous radiation therapy to chest wall with extensive pulmonary tissue exposure. 4.Platelet count 1.5 x ULN or creatinine clearance =50 mL/min (measured or calculated by Cockcroft-Gault method, or similar method) 6.Serum total bilirubin >1.5 x ULN 7.ALT or AST >2.5 x ULN, or if the liver is involved by the documented malignancy, =5X institutional upper limit of normal 8.Evidence of established interstitial lung disease on screening HRCT 9.Chronic Obstructive Pulmonary Disease (COPD) spirometric classification =Stage 2, which is Forced Vital Capacity (FVC)/ Forced Expiratory Volume in first second (FEV1) 500 ms from three ECGs using Fridericia’s correction formula, QTcF = QT/3vRR (QT and RR are in second) 16.Abnormality of cornea (other than scars, congenital abnormality or corneal tear film) 17.Currently receiving any of the following drugs with known corneal toxicology: chloroquine, hydroxychloroquine, amiodarone, tamoxifen, or chlorpromazine 18.History of ocular surface diseases (including Steven’s Johnson syndrome, alkali burns); or history of corneal surgery, including laser refractive surgery within the past 12 months; or history of current or recurrent ocular conditions anticipated to cause eye symptoms during the trial; or history of dry eye syndrome of any etiology, or history of wet and dry macular degeneration 29. Patients receiving potent inhibitors, inducers or substrates of CYP1A2 and CYP3A4 within the defined timeframe (detail provided in protocol section 3.3.3)
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety and tolerability of AZD1480 in patients with Primary Myelofibrosis (PMF) and Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF). To determine the pharmacokinetics (PK) of AZD1480 following both single and multiple oral dosing of AZD1480. To evaluate the extent of inhibition of phosphorylation of STAT3 following treatment with AZD1480. ;Secondary Objective: To explore the role of JAK2 V617F mutation load in patient response. To provide information on preliminary signs of efficacy. ;Primary end point(s): The primary variable is safety assessed by the incidence and severity of AEs (CTCAE Version 3.0), vital signs, ECG parameters, clinical chemistry, hematology, coagulation, urinalysis, PFTs, HRCTs and clinical examinations (including opthalmic assessments). PK and PD parameters are also primary variables for this study. | — |
Countries
France
Outcome results
None listed