A Randomized Study of the JAK Inhibitor INC424 Tablets Compared to Best Available Therapy in Subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF)

• Register: EUCTR
• Last refreshed on: 4 August 2015
• Main ID: EUCTR2009-009858-24-GB
• Date of registration: 27/04/2009
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Sevices AG
• Public title: A Randomized Study of the JAK Inhibitor INC424 Tablets Compared to Best Available Therapy in Subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF)
• Scientific title: COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Treatment-II: (The COMFORT-II Trial) - The COMFORT-II Trial
• Date of first enrolment: 21/07/2009
• Target sample size: 150
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-009858-24
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: yes Single blind: no Double blind: no Parallel group: no Cross over: yes Other: yes Other trial design description: Best available therapy as selected by Investigator If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: yes Other specify the comparator: Best available therapy as selected by Investigator Number of treatment arms in the trial: 2

Countries of recruitment

Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom

Contacts

• Name: Medical Information Services
• Affiliation: Novartis Pharmaceuticals UK Limited

• Name: Medical Information Services
• Affiliation: Novartis Pharmaceuticals UK Limited

Key inclusion & exclusion criteria

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
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 x109/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 (Appendix IV).
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 inhibito

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:
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 a

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Primary Myelofibrosis (PMF), Post-Polycythemia Vera-Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia-Myelofibrosis (PET-MF)
MedDRA version: 14.1 Level: PT Classification code 10028537 Term: Myelofibrosis System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Ruxolitinib
Product Code: INC424
Pharmaceutical Form: Tablet
INN or Proposed INN: Ruxolitinib
CAS Number: 1092939-17-7
Current Sponsor code: INC424
Other descriptive name: INCB018424
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 5-

Primary Outcome(s)

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).

Timepoint(s) of evaluation of this end point: Week 48

Main Objective: 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) or post essential thrombocythemia myelofibrosis (PET-MF).

Secondary Objective: To evaluate the population pharmacokinetics of INC424.

Secondary Outcome(s)

Secondary end point(s): The key secondary efficacy endpoint is defined as:
• Proportion of subjects achieving a = 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24.
Other secondary efficacy endpoints are:
• Duration of maintenance of a = 35% reduction from Baseline in spleen volume.
• Time to achieve a first = 35% reduction in spleen volume from baseline.
• Progression free survival.
•Leukemia free survival.
• Overall survival.
• Change in bone marrow histomorphology.

The duration of = 35% reduction from baseline in spleen volume is defined as the longest duration of consecutive measurements of = 35% reduction observed prior to the time of database freeze for subjects who have at least one measured 35% reduction. Specifically:
1. If the first MRI showing = 35% reduction from baseline in spleen volume is the last MRI performed on a patient prior to database freeze for the primary analysis then the duration of maintenance will be considered censored with duration of at least one day.
2. If the last observed spleen volume value still represents = 35% reduction from Baseline at the time of database freeze and this measure belongs to the longest duration, the duration will be considered as censored with a duration of at least the observed duration plus one day.

Timepoint(s) of evaluation of this end point: Week 24 (Proportion of subjects achieving a = 35% reduction of spleen size as measured by MRI (or CT scan where applicable) from Baseline to Week 24)

Secondary ID(s)

2009-009858-24-BE

CINC424A2352

Source(s) of Monetary Support

Novartis Pharma Services AG