| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myeloproliferative disorders including Primary Myelofibrosis (PMF) and Post-Polycythaemia Vera/Essential Thrombocythaemia Myelofibrosis (Post-PV/ET MF). |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028578 |
| E.1.2 | Term | Myeloproliferative disorders (excl leukaemias) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036057 |
| E.1.2 | Term | Polycythaemia vera |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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.
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| E.2.2 | Secondary objectives of the trial |
To explore the role of JAK2 V617F mutation load in patient response.
To provide information on preliminary signs of efficacy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 < 10g/dL, WBC < 4 or > 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.
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| E.4 | Principal 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 <50 x 109/L 5.Serum creatinine >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) <0.70; 50% ≤ Measured FEV1 <80% predicted FEV1.
10.DLCO <60% predicted, pulse oximetry < 88% O2 saturation after walking down and up a set of 10 stairs (7 inch rise).
11.Persistent asthma (patients receiving no more than “rescue” short acting bronchodilators and/or inhaled low dose corticosteroids are permitted to enter the trial as long as the symptoms are intermittent, defined as occurring less than once per week with only brief exacerbations and with nocturnal symptoms occurring not more than twice per month.
12.History of pulmonary fibrosis either idiopathic or due to occupational/ environmental exposure, drugs/radiation, vasculitides, collagen vascular disorders, sarcoidosis, hypersensitivity pneumonitis or immunosuppression/transplantation
13.Chest infection requiring antibiotics within the 28 days prior to screening
14.Heart failure classified as New York Heart Association (NYHA) Grade ≥2 which are: Slight limitation of physical activity; Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnoea. 15. Mean QTc interval of >500 ms from three ECGs using Fridericia’s correction formula, QTcF = QT/3√RR (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) |
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| E.5 End points |
| E.5.1 | 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. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 1 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as 30 days after the last patient discontinues study treatment. However, primary analysis of the data will be performed after the last patient recruited into Part B has received at least one dose of AZD1480. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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