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) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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) |
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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 collect additional safety of INC424 in patients with PMF, PPV MF, or PET MF, who have either received prior treatment with commercially available agents, investigational drug or never received treatment |
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E.2.2 | Secondary objectives of the trial |
To access the best overall response rate of INC424 in patients with PMF, PPV MF, or PET-MF as evaluated by the Investigator.
To collect (QoL) information in patients with PMF, PPV MF, or PET-MF treated with INC424.
To document MRU in patients with PMF, PPV MF, or PET-MF treated with INC424
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must give written informed consent according to local guidelines prior to any screening procedures.
2. Patients must not be eligible for another ongoing INC424 clinical trial.
3. Male or female patients aged ≥ 18 years of age.
4. Patients must be diagnosed with PMF, PPV-MF or PET-MF, according to the 2008 revised International Standard Criteria , irrespective of JAK2 mutation status.
5. Patients with PMF requiring therapy must be classified as high risk (3 prognostic factors) OR intermediate risk level 2 (2 prognostic factors, no more), OR intermediate risk level 1 with an enlarged spleen at the screening visit (assessment to occur at the Screening Visit). The prognostic factors, defined by the International Working Group (Cervantes 2009) are described in Section 1.1 and Section 5.2 and should be evaluated at the Screening Visit.
6. Patients with Intermediate-1 and splenomegaly, must have a palpable spleen measuring 5 cm or greater from the costal margin to the point of greatest splenic protrusion.
7. Patients with a peripheral blood blast percentage count of < 10%.
8. Patients with adequate liver function defined as total bilirubin or direct bilirubin ≤ 2.0 x ULN, and ALT ≤ 2.5 x ULN.
9. Patients with adequate renal function defined as serum creatinine ≤ 2 x ULN.
10. Patients with an ECOG performance status of 0, 1, or 2
11. Women of childbearing potential must have had a negative serum pregnancy test within 14 days prior to the administration of study drug.
12. Patients must have recovered or stabilized sufficiently from any adverse drug reactions associated with prior treatments before beginning treatment with INC424.
13. Fedratinib pretreated patients with documented complete physical examination including full neurologic examination and cardiology assessment, thiamine level testing, and MRI of the brain if indicated based on signs or symptoms. Patients pretreated with fedratinib should have completed or be receiving thiamine supplementation according to the investigator´s instructions. |
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E.4 | Principal exclusion criteria |
1. Patients eligible for hematopoietic stem cell transplantation (suitable candidate and a suitable donor is available).
2. Patients with a history of malignancy in the past 3 years, except for treated early stage squamous or basal cell carcinoma in situ.
3. Patients receiving any medications listed in the "Prohibited Medications" listing
4. Impairment of GI function or GI disease that may significantly alter the absorption of INC424
5. Patients with cardiac disease which in the Investigator's opinion may jeopardize the safety of the patient or the compliance with the protocol.
6. Patients with currently uncontrolled or unstable angina, rapid or paroxysmal fibrillation or recent (approximately 6 months) myocardial infarction or acute coronary syndrome.
7. Patients with clinically significant bacterial, fungal, parasitic or viral infection that requires therapy. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the
course of antibiotic therapy has been completed.
8. Patients with known active hepatitis A, B, C or who are HIV-positive.
9. Patients with inadequate bone marrow reserve at baseline visit as demonstrated by:
(a) ANC that is ≤ 1000/μL.
(b) Platelet count that is <75,000/μL without the assistance of growth factors, thrombopoietic factors or platelet transfusions.
10. Patients with any history of platelet counts < 50,000/μL or ANC <500/μL except during treatment for a MPD or treatment with cytotoxic therapy for any other reason.
11. Patients with coagulation parameters (PT, PTT, INR) >1.5 x ULN.
12. Patients with known hypersensitivity to INC424 or other JAK1/JAK2 inhibitors, or to its excipients.
13. Patients receiving ongoing treatment with another investigational medication or having been treated with an investigational medication within 30 days of screening or with fedratinib within 14 days of screening.
14. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until termination of gestation, confirmed by a positive βHCG laboratory test (> 5 mIU/mL).
15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male
partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using highly effective contraception methods (see Appendix II) defined as:
- Total abstinence and
- Female sterilization
- Combination of any two of the following (a+b or a+c or b+c):
(a) Use of oral, injected or implanted hormonal methods of contraception
(b) Placement of an intrauterine device (IUD) or intrauterine system (IUS)
(c) Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository
16. Patients who are unable to comprehend or are unwilling to sign an ICF.
17. Patients with active alcohol or drug addiction that would interfere with their ability to comply with the study requirements.
18. Patients with any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.
19. In the case of ruxolitinib pretreated patients, ruxolitinib primary resistant patient defined as:
● No spleen reduction within the first 12 weeks after front line therapy with ruxolitinib.
● No reduction in symptoms within the first 12 weeks after first-line treatment with ruxolitinib.
20. In the case of ruxolitinib pretreated patients, patients discontinuing ruxolitinib due to a Grade 4 AE related or suspected to be related to ruxolitinib. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety:
- Safety and tolerability will be collected by monitoring the frequency, duration and severity of all grade AEs by the National Cancer Institute CTCAE v. 3 0, performing physical exams (PE), and evaluating changes in vital signs (VS), ECOG performance status (PS), electrocardiograms (ECGs) and serum chemistry and hematology results.
- Grade 3 and 4 AEs, Serious Adverse Events (SAEs).
- Change in laboratory values from Baseline to End of Treatment (serum chemistry and hematology).
- Changes in weight from Baseline to each assessment point and at end of treatment.
- Cardiac function as assessed by electrocardiograms (ECGs).
Changes in vital signs.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Monthly for the first 3 months, then every 3 months and at study discontinuation |
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E.5.2 | Secondary end point(s) |
Quality of Life
- Change in ECOG PS from Baseline to each visit where measured.
- Change in Functional Assessment of Cancer Therapy for patients with Lymphoma (FACT-Lym) version 4 from Baseline to each visit where measured
- Change in Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue from baseline to each visit where measured
Medical resource utilization (MRU)
Medical resource utilization (MRU) will be assessed as follows:
- Frequency and duration of hospitalization from Baseline up to week 48 of therapy
- Frequency of emergency room visits from Baseline up to week 48 of therapy.
- Frequency of general practitioner, specialist, and urgent care visits from Baseline up to week 48 of therapy.
- Number of transfusions and transfusion dependency status end of study.
- Splenectomy and use of splenic irradiation.
- Changes in use of concomitant medications for MPN symptom management
Efficacy
- Best overall response to treatment as assessed by spleen palpation (calculated as the percentage change in spleen length compared with Baseline)
- Change in spleen length from Baseline to end of each visit.
- Change in WBC and platelet count from Baseline will be summarized to end of treatment.
- WBC and platelet count changes from Baseline will be summarized at end of each visit/month of therapy and at end of treatment.
- Shift in fibrosis in the bone marrow from Baseline to worst/best value on study (where bone marrow biopsies are performed – not mandatory).
- Progression free survival (PFS), acute myeloid leukemia free survival (LFS) and overall survival (OS).
- In patients without splenomegaly, patient reported outcome measure symptoms of the disease.
- In patients without splenomegaly, efficacy assessments will only be provided by the patient reported outcomes that measure symptoms of the disease. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Monthly for the first 3 months, then every 3 months and at study discontinuation |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of Life
Medical resource utilization (MRU) |
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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 | 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 | No |
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 | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 252 |
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 | No |
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 |
Algeria |
Argentina |
Brazil |
Canada |
Colombia |
Egypt |
Israel |
Kuwait |
Mexico |
Morocco |
Russian Federation |
Saudi Arabia |
South Africa |
Thailand |
Tunisia |
United Arab Emirates |
Venezuela, Bolivarian Republic of |
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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
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LPLV
End of study / treatment: Day of last dose of open-label INC424.
Follow-up period: 28 days following the last dose of open-label INC424. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 15 |