Phase 3 Multicenter Open-Label Randomized Study of Fedratinib Versus Best Available Therapy in Intermediate/High-Risk Myelofibrosis Post-Ruxolitinib Treatment
- Trial ID
- 2024-511972-33-00
- Protocol
- FEDR-MF-002
- Sponsor
- Celgene Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the percentage of subjects with at least 35% **spleen volume reduction** in the fedratinib and the best available therapy (BAT) arms. This is clinically relevant as spleen volume reduction is a critical marker of therapeutic efficacy in managing myelofibrosis, a condition characterized by an enlarged spleen due to excessive blood cell production.
Secondary objectives include: - Evaluating myelofibrosis-associated symptoms using the Myelofibrosis Symptom Assessment Form (MFSAF). - Assessing the percentage of subjects with at least 25% spleen volume reduction. - Evaluating the safety of fedratinib. - Assessing spleen size reduction by palpation. - Evaluating the durability of spleen response by MRI/CT and palpation. - Assessing the durability of symptoms response. - Evaluating spleen and disease progression-free survival. - Assessing the effectiveness of the risk mitigation strategy for gastrointestinal events and encephalopathy, including Wernicke's. - Evaluating Health-Related Quality of Life (HRQoL) using the EORTC QLQ-C30. - Evaluating Patient Reported Outcomes (PRO) using the EQ-5D-5L questionnaire. - Evaluating Overall Survival (OS).
Participants
The clinical trial involves a total of **53 participants** diagnosed with **primary myelofibrosis**, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis. The study population includes both male and female subjects, aged 18 years and older, who are capable of adhering to the study protocol. Participants were selected based on specific criteria, including a diagnosis confirmed by the most recent local pathology report and a measurable splenomegaly. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) Performance Score of 0, 1, or 2, and those who have been previously exposed to ruxolitinib. The study population is characterized by a **DIPSS Risk score** of Intermediate-2 or High, and participants must have a measurable total symptoms score as assessed by the Myelofibrosis Symptom Assessment Form. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have resolved treatment-related toxicities to Grade 1 or pretreatment baseline before the start of the last therapy prior to randomization. The trial includes a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is a **Phase 3**, multicenter, open-label, randomized study designed to evaluate the efficacy and safety of **fedratinib** compared to the best available therapy in subjects with **primary myelofibrosis**, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis who have been previously treated with **ruxolitinib**. The primary objective is to assess the percentage of subjects achieving at least a 35% reduction in spleen volume. The trial is expected to run from August 23, 2019, to June 23, 2025.
Participants will be randomly assigned to receive either fedratinib or the best available therapy. The study is open-label, meaning both the researchers and participants know which treatment is being administered. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The expected duration of participant involvement is up to 60 days, with conditions for early termination including significant adverse events or withdrawal of consent.
Inclusion criteria require participants to be at least 18 years old, have a confirmed diagnosis of myelofibrosis, and have been previously treated with ruxolitinib. Participants must also have a measurable spleen volume and symptom score. Exclusion criteria are not specified in the provided data. The primary endpoint is the spleen volume response rate, with secondary endpoints including symptom response rate and a 25% spleen volume response rate. The study aims to provide valuable insights into the comparative effectiveness of fedratinib in this patient population.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Fedratinib** is the primary experimental medication, administered orally in the form of hard capsules. The maximum daily dose is 400 mg, with a total maximum dose of 438,000 mg over a treatment period of up to 60 days. Fedratinib is classified as a chemical entity and is designated as an orphan drug for this study.
**Danazol** is used as a comparator treatment, administered orally. It is a chemical substance with the pharmaceutical form code PHF00005MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Busulfan** is another comparator, administered as a concentrate for solution for infusion. It is a chemical substance with the pharmaceutical form code PHF00230MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Dimethyl fumarate**, also known as Pomalidomide, is administered orally as a comparator. It is a chemical substance with the pharmaceutical form code PHF00091MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Ruxolitinib** is administered orally as a comparator. It is a chemical substance with the pharmaceutical form code PHF00245MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Glatiramer acetate**, known as Pegfilgrastim, is administered as a solution for injection. It is a polymer substance with the pharmaceutical form code PHF00231MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Hydroxycarbamide** is administered orally as a comparator. It is a chemical substance with the pharmaceutical form code PHF00082MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Peginterferon alfa-2a** is administered as a solution for injection. It is a protein-based substance with the pharmaceutical form code PHF00231MIG. The dosing schedule and maximum dose are not specified, and it is not a pediatric formulation.
**Other non-experimental treatments** include glucocorticoids and other antianemic preparations, administered orally or as solutions for injection. These treatments are used as comparators in the study, with unspecified dosing schedules and maximum doses. Participant compliance with the dosing regimen is monitored throughout the trial to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the percentage of subjects achieving at least a 35% reduction in spleen volume. This primary endpoint will be measured in both the fedratinib and best available therapy (BAT) arms. The primary efficacy parameter, **spleen volume response rate (RR)**, will be determined using imaging techniques such as MRI or CT scans to ensure accurate and reliable measurements. Secondary endpoints include the **symptom response rate (SRR)** and a 25% spleen volume response rate (RR25). These endpoints will provide additional insights into the treatment's impact on symptom relief and spleen size reduction.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject is at least 18 years of age at the time of signing the informed consent form (ICF)
- Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2
- 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, confirmed by the most recent local pathology report
- Subject has a DIPSS Risk score of Intermediate-2 or High
- 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
- Subject has a measurable total symptoms score (≥ 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)
- Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b) 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
- Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization
- Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted
- Subject is willing and able to adhere to the study visit schedule and other protocol requirements
- 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.
- 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.
Exclusion Criteria
- 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
- Subject is pregnant or lactating female
- Subject with previous splenectomy
- Subject with previous or planned hematopoietic cell transplant
- Subject with prior history of encephalopathy including Wernicke's (WE)
- Subject with signs or symptoms of encephalopathy , including WE (eg, severe ataxia, ocular paralysis or cerebellar signs)
- 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
- 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
- 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
- Subject has received ruxolitinib within 14 days prior to randomization
- Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment
- Subject on treatment with aspirin with doses > 150 mg daily
- Subject with major surgery within 28 days prior to randomization
- Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)
- 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
- Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)
- Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)
- Subject with serious active infection
- Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication
- Subject is unable to swallow capsule
- Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
- 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
- Subject has any condition that confounds the ability to interpret data from the study
- Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization
- Subject with a life expectancy of less than 6 months
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 23 Aug 2019 | 12 |
 Belgium | Not Recruiting | 23 Aug 2019 | 12 |
 Czechia | Not Recruiting | 23 Aug 2019 | 6 |
 France | Not Recruiting | 23 Aug 2019 | 20 |
 Germany | Not Recruiting | 23 Aug 2019 | 20 |
 Hungary | Not Recruiting | 23 Aug 2019 | 10 |
 Ireland | Not Recruiting | 23 Aug 2019 | 6 |
 Italy | Not Recruiting | 23 Aug 2019 | 26 |
 Poland | Not Recruiting | 23 Aug 2019 | 12 |
 Spain | Not Recruiting | 23 Aug 2019 | 20 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DANAZOL | Comparator | PHF00005MIG | ORAL | 0 | 99999 | SCP128731 |
BUSULFAN | Comparator | PHF00230MIG | CONCENTRATE FOR SOLUTION FOR INFUSION | 0 | 99999 | SCP187251 |
- | Comparator | PHF00231MIG | ORAL | 0 | 99999 | H02AB |
POMALIDOMIDE | Comparator | PHF00091MIG | ORAL | 0 | 99999 | SCP271717 |
FEDRATINIB | Test | — | ORAL | 400 | 60 | SUB126288 |
RUXOLITINIB | Comparator | PHF00245MIG | ORAL | 0 | 99999 | SCP137353 |
PEGFILGRASTIM | Comparator | PHF00231MIG | SOLUTION FOR INJECTION | 0 | 99999 | SCP180112 |
HYDROXYCARBAMIDE | Comparator | PHF00082MIG | ORAL | 0 | 99999 | SCP137277 |
PEGINTERFERON ALFA-2A | Comparator | PHF00231MIG | SOLUTION FOR INJECTION | 0 | 99999 | SCP187427 |
- | Comparator | PHF00231MIG | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | 0 | 99999 | B03XA |