E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Myelofibrosis (PMF),
Post-Polycythemia Vera-Myelofibrosis (PPV-MF)
or
Post-Essential Thrombocythemia-Myelofibrosis (PET-MF) |
|
E.1.1.1 | Medical condition in easily understood language |
Primary Myelofibrosis (PMF),
Post-Polycythemia Vera-Myelofibrosis (PPV-MF)
or
Post-Essential Thrombocythemia-Myelofibrosis (PET-MF) |
|
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028537 |
E.1.2 | Term | Myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To compare the efficacy, safety and tolerability of INC424 given twice daily compared to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) and post essential thrombocythemia myelofibrosis (PET-MF).
|
|
E.2.2 | Secondary objectives of the trial |
To evaluate the population pharmacokinetics of INC424. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All subjects must meet the following inclusion criteria:
1.Subjects 18 years of age or older.
2.Subjects must be diagnosed with PMF, PPV-MF or PET-MF, according to the 2008 World Health Organization criteria, irrespective of JAK2 mutation status.
3.Subjects with myelofibrosis requiring therapy must be classified as high risk (3 or more prognostic factors) OR intermediate risk level 2 (2 or more prognostic factors). The prognostic factors, defined by the International Working Group (Cervantes et al, 2009) are:
•Age > 65 yrs
•Presence of constitutional symptoms (weight loss, fever, night sweats)
•Marked anemia (Hgb < 10g/dL)*
•Leukocytosis (history of WBC > 25 x10 E9/L)
•Circulating blasts ≥1%
* A hemoglobin value < 10 g/dL must be demonstrated during the Screening
Visit for subjects who are not transfusion dependent. Subjects receiving regular
transfusions of packed red blood cells will be considered to have hemoglobin
< 10 g/dL for the purpose of evaluation of risk factors.
4.Subjects with peripheral blood blast count of <10%.
5.Subjects with an ECOG performance status of 0, 1, 2 or 3
6.Subjects must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.
7.Subjects must have been on a stable therapeutic regimen for at least 2 weeks before Screening and no less than 4 weeks prior to Baseline.
8.Subjects who have not previously received treatment with a JAK inhibitor
|
|
E.4 | Principal exclusion criteria |
Any of the following are cause for exclusion from the study:
1.Subjects with a life expectancy of less than 6 months.
2.Females who are pregnant or are currently breastfeeding.
3.Subjects of childbearing potential who are unwilling to take appropriate precautions (from Screening through Follow-up) to avoid fathering a child or becoming pregnant.
•Females of non-childbearing potential are defined as postmenopausal if they have a history of amenorrhea for 1 year if over age 55, OR have been surgically sterile for at least 3 months
•For subjects of childbearing potential, appropriate precautions are those that are at least 99% effective in preventing the occurrence of pregnancy. These methods should be communicated to the subjects and their understanding confirmed.
4.Subjects with inadequate bone marrow reserve as demonstrated by:
a.Absolute neutrophil count (ANC) that is ≤ 1000/µL.
b.Platelet count that is < 100,000/µL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
5.Subjects with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason.
6.Subjects with inadequate liver or renal function as demonstrated by:
a.Direct bilirubin > 2.0x ULN.
b.Alanine aminotransferase (ALT) > 2.5x institutional upper limit of normal (ULN).
c.Creatinine >2.0 mg/dL.
7.Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy:
a.Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed
b.Patients with known active hepatitis A, B, C or who are HIV-positive.
8.Subjects must not currently have the option of stem cell transplantation, either because they are not a candidate, or because a suitable donor is not available.
9.Subjects with history of malignancy in past 5 years except for treated, early-stage squamous or basal cell carcinoma of the skin.
10.Subjects with cardiac disease which in the Investigator’s opinion may jeopardize the safety of the subject or the compliance with the protocol.
11.Subjects with currently uncontrolled or unstable angina.
12. Subjects under ongoing treatment with another investigational medication or having been treated with an investigational medication within 14 days or 6 half-lives (whichever is longer) prior to enrollment.
13.Subjects for whom the dose or dose-regimen of any therapies used to treat MF has been modified at any time from 2 weeks prior to the start of Screening through the beginning of Baseline evaluations.
14.Subjects who have had splenic irradiation within 12 months prior to Screening.
15.Subjects with currently rapid or paroxysmal atrial fibrillation.
16.Subjects undergoing treatment with hematopoietic growth factor receptor agonists (ie, erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag) at any time within 2 weeks prior to Screening or 4 weeks prior to Baseline.
17.Subjects with recent (approximately 6 months) myocardial infarction or acute coronary syndrome.
18.Resting heart rate > 110 beats per minute.
19.Resting systolic blood pressure > 160 mm Hg.
20.Resting diastolic blood pressure > 100 mm Hg.
21.Subjects who are unable to comprehend or are unwilling to sign an informed consent form (ICF).
22.Subjects with active alcohol or drug addiction which would interfere with their ability to comply with the study requirements.
23.Subjects with any concurrent condition that, in the Investigator’s opinion, would jeopardize the safety of the subject or compliance with the protocol.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of subjects achieving 35% reduction in spleen volume from
Baseline to Week 48 as measured by MRI (or by CT for subjects unable
to undergo MRI). |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
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 | Yes |
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 | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Best available therapy as selected by Investigator |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Best available therapy as selected by Investigator |
|
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Yes |
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 Study or Early Termination Visit constitutes the final study visit where study drug has been taken. An End of Study Visit may occur with a planned discontinuation for any reason (eg, at Week 20, it is determined that subject will participate in the study only 1 more month; therefore, the Week 24 Visit will become the End of Study Visit). |
|
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 | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |