An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis Post-polycythemia Vera Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib

  • STATUS
    Recruiting
  • End date
    Dec 23, 2024
  • participants needed
    192
  • sponsor
    Celgene
Updated on 29 September 2021
cancer
anemia
ruxolitinib
thrombocytopenia
essential thrombocythemia
thrombocytosis
fedratinib
polycythemia

Summary

A Phase 3, multicenter, open-label, randomized study to evaluate the efficacy and safety of fedratinib compared to best available therapy (BAT) in subjects with DIPSS (Dynamic International Prognostic Scoring System)-intermediate or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF) and previously treated with ruxolitinib. The primary objective of the study is to evaluate the percentage of subjects with at least 35% spleen volume reduction in the fedratinib and the BAT arms.

Description

This Phase 3, multicenter, randomized, two-arm, open-label study will include subjects with intermediate or high-risk (as per the DIPSS score) primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCPs).

Study design includes:

  • A 28-day Screening Period
  • 2:1 Randomization to fedratinib or best available therapy (BAT)
  • Stratification at Randomization according to:
  • Spleen size by palpation: < 15 cm below left costal margin (LCM) versus 15 cm below LCM
  • Platelets 50 to < 100 x 109/L versus platelets 100 x 109/L
  • Refractory or relapsed to ruxolitinib treatment versus intolerant to ruxolitinib treatment
  • Study Treatment Period (time on study drug plus 30 days after last dose)
  • Subjects are allowed to crossover from BAT to the fedratinib arm after the Cycle 6 response assessment or before the Cycle 6 response assessment in the event of a confirmed progression of splenomegaly by MRI/CT scan
  • A Survival Follow-up Period for progression and survival

Details
Condition Myelosclerosis with myeloid metaplasia, Myelofibrosis, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera, Post-Polycythemia Vera
Treatment Best Available Therapy (BAT), FEDRATINIB
Clinical Study IdentifierNCT03952039
SponsorCelgene
Last Modified on29 September 2021

Eligibility

Yes No Not Sure

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 (relapsed) to these parameters following an initial response
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
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
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
Note: A female of childbearing potential (FCBP) is a female who: 1) has
achieved menarche at some point, 2) has not undergone a hysterectomy or
bilateral oophorectomy, or 3) has not been naturally postmenopausal
(amenorrhea following cancer therapy does not rule out childbearing potential)
for at least 24 consecutive months (ie, has had menses at any time in the
preceding 24 consecutive months)
\. 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
Platelets < 50 x 109/L
Absolute neutrophil count (ANC) < 1.0 x 109/L
White blood count (WBC) > 100 x 109/L
Myeloblasts 5 % in peripheral blood
Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease [MDRD] formula)
Serum amylase or lipase > 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN)
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
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