E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary myelofibrosis, post-polycythemia vera myelofibrosis , or post-essential thrombocythemia myelofibrosis |
|
E.1.1.1 | Medical condition in easily understood language |
Cancer of the bone marrow where normal blood cell growth is affected and collagen fibers begin to develop in the marrow |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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) |
|
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 evaluate the percentage of subjects with at least 35% spleen volume reduction in the fedratinib and the BAT arms. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate myelofibrosis (MF)-associated symptoms as measured by the Myelofibrosis Symptom Assessment Form (MFSAF) (Appendix B)
To evaluate the percentage of subjects with at least 25% spleen volume reduction (SVR)
To evaluate the safety of fedratinib
To evaluate the reduction of spleen size by palpation
To evaluate durability of spleen response by MRI/CT and by palpation
To evaluate the durability of symptoms response
To evaluate spleen and disease progression free survival
To assess the effectiveness of the risk mitigation strategy for gastrointestinal events and Encephalopathy including Wernicke
To evaluate Health-Related Quality of Life (HRQoL) as measured by the European Organization for Research and Treatment of Cancer Quality of Life C30 (EORTC QLQ-C30) (Appendix C)
To evaluate Patient Reported Outcomes (PRO) as measured by the EQ-5D-5L questionnaire (Appendix D)
To evaluate Overall Survival (OS) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF)
2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2
3. Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria,
onfirmed by the most recent local pathology report
4. Subject has a DIPSS Risk score of Intermediate-2 or High
5. Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of ≥ 450 cm3 by MRI or CT-scan and by palpable spleen measuring ≥ 5 cm below the left costal margin
6. Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b)
a. Treatment with ruxolitinib for ≥ 3 months with inadequate efficacy response (refractory) defined as < 10% spleen volume reduction by MRI or < 30% decrease from baseline in spleen size by palpation or regrowth (relapse) to these parameters following an initial response
b. Treatment with ruxolitinib for ≥ 28 days complicated by any of the following (intolerant):
Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months) or
Grade ≥ 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib
8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization
9. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements
11. A female of childbearing potential (FCBP) must:
a. Have 2 negative pregnancy tests as verified by the Investigator during screening prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.
b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with highly effective contraception without interruption, –14 days prior to starting investigational product, during the study treatment (including dose
interruptions), and for 30 days after discontinuation of study treatment.
12. A male subject must:
Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy. |
|
E.4 | Principal exclusion criteria |
1. Any of the following laboratory abnormalities:
a. Platelets < 50 x 10^9/L
b. Absolute neutrophil count (ANC) < 1.0 x 10^9/L
c. White blood count (WBC) > 100 x 10^9/L
d. Myeloblasts ≥ 5 % in peripheral blood
e. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
f. Serum amylase or lipase > 1.5 x upper limit of normal (ULN)
g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN)
h. Total bilirubin > 1.5 x ULN, subject’s total bilirubin between 1.5 – 3.0 x ULN are eligible if the direct bilirubin fraction is < 25% of the total bilirubin
2. Subject is pregnant or lactating female
3. Subject with previous splenectomy
4. Subject with previous or planned hematopoietic cell transplant
5. Subject with prior history of encephalopathy including Wernicke's
6. Subject with signs or symptoms of encephalopathy , including WE (eg, severe ataxia, ocular paralysis or cerebellar signs) without documented exclusion of WE by thiamine level and brain MRI
7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to the central laboratory and not demonstrated to be corrected prior to randomization
8.Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of
Cytochrome P450 3A4 (CYP3A4), or dual CYP2C19 and CYP3A4 inhibitors
9. Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids > 10 mg/day prednisone or equivalent. Subjects who have had prior exposure to hydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to randomization
10. Subject has received ruxolitinib within 14 days prior to randomization
11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment
12. Subject on treatment with aspirin with doses > 150 mg daily
13. Subject with major surgery within 28 days prior to randomization
14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)
15. Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to randomization. However, subject with the following history/concurrent conditions provided successfully treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system), or is free of disease and on hormonal treatment only
16. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
17. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
18. Subject with serious active infection
19. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
20. Subject is unable to swallow capsule
21. Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
23. Subject has any condition that confounds the ability to interpret data from the study
24. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization
25. Subject with a life expectancy of less than 6 months |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Spleen volume response rate (RR) |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
From Screening to the end of Cycle 6 |
|
E.5.2 | Secondary end point(s) |
1. Symptom response rate (SRR)
2. Spleen volume response rate (RR25) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. From C1D1 to the end of Cycle 6
2. From Screening to the end of Cycle 6 |
|
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 | 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 | 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 | Yes |
E.8.2.3.1 | Comparator description |
Best available therapy (BAT) |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 75 |
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 |
Australia |
China |
Korea, Republic of |
Russian Federation |
United Kingdom |
Austria |
Belgium |
Czechia |
France |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Poland |
Spain |
|
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
|
LVLS or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 22 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |