A Study of Fedratinib in Japanese 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)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2024
  • participants needed
    31
  • sponsor
    Celgene
Updated on 1 August 2021

Summary

The study will be conducted in compliance with the International Council for Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical Practice (GCP) and applicable regulatory requirements.

This is a Phase 1/2 multicenter, single arm, open-label study in Japanese subjects with DIPSS intermediate or high-risk PMF, post-PV or post-ET MF. The study consists of 2 parts: Phase 1 part to determine safety and tolerability and a RP2D. The Phase 1 portion of the study will explore one or more drug doses for fedratinib (300 mg and 400 mg) using a mTPI-2 design. Following completion of dose escalation and determination of MTD and/or a RP2D, the study will progress into the Phase 2 part to further evaluate the efficacy and safety.

The study will consist of 3 periods: a Screening Period, a Treatment Period including a 30-day follow-up after last dose visit and a survival follow-up period.

Details
Condition Myelosclerosis with myeloid metaplasia, Myelofibrosis
Treatment FEDRATINIB
Clinical Study IdentifierNCT04446650
SponsorCelgene
Last Modified on1 August 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study
Subject is 20 years of age at the time of signing the informed consent form (ICF)
Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status (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- Polycythemia vera (PV) Myelofibrosis (MF) according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report
Subject has a Dynamic International Prognostic Scoring System (DIPSS) Risk score of Intermediate-1 with symptom(s), Intermediate-2 or High
Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of 450 cm3 by magnetic resonance imaging (MRI) or computed tomography (CT) scan or by palpable spleen measuring 5 cm below the left costal margin
Subject must meet at least one of the following criteria of (a or b)
Note: reason to discontinue ruxolitinib treatment (lack of efficacy and/or
intolerability, etc) and physician decision as to the study participation as
being appropriate should be recorded in the case report form
Previously received ruxolitinib treatment for PMF or post-PV MF or post-ET MF for at least 14 days (exposure of < 14 days is allowed for subjects who discontinued ruxolitinib due to intolerability or allergy)
Never received ruxolitinib treatment and is expected to derive clinical benefit from this study participation based on the clinical judgement of the Investigator Only those subjects who previously received ruxolitinib treatment are eligible for the Phase 1 part of the study to avoid overestimating tolerability of fedratinib
Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to starting the fedratinib treatment
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 fedratinib treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of fedratinib 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 fedratinib treatment (including dose interruptions), and for 30 days after discontinuation of fedratinib treatment
If breastfeeding, agree to stop breastfeeding prior to the participation in the study and not to resume breastfeeding for at least 30 days after treatment discontinuation of the fedratinib 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 or amenorrhea due to other medical
reasons 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 fedratinib discontinuation
or longer if required by local regulations, even if he has undergone a
successful vasectomy
True abstinence is acceptable when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation
symptothermal, postovulation methods] and withdrawal are not acceptable
methods of contraception)
Agreement to use highly effective methods of contraception that alone or in
combination resulting in a failure rate of a Pearl index of less than 1% per
year when used consistently and correctly throughout the course of the study
Such methods include combined (estrogen and progestogen containing) hormonal
contraception (oral), progestogen-only hormonal contraception associated with
inhibition of ovulation (oral), placement of an intrauterine device, placement
of an intrauterine hormone-releasing system, bilateral tubal occlusion, and
vasectomized partner

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment
Any of the following laboratory abnormalities
Platelets < 50 x 109/L (without platelet transfusion)
Absolute neutrophil count (ANC) < 1.0 x 109/L
White blood count (WBC) > 100 x 109/L
Myeloblasts 5 % in peripheral blood
Estimated creatinine clearance < 30 mL/min (as estimated by Cockcroft-Gault formula)
Serum amylase or lipase > 1.5 x upper limit of normal
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 breastfeeding female
Subject with previous splenectomy
Subject with previous or planned hematopoietic Stem-cell transplantation (SCT)
Subject with prior history of Encephalopathy, including Wernicke encephalopathy (WE)
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
Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not demonstrated to be corrected prior to starting the fedratinib treatment
Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 (CYP) 3A4, and 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 starting the fedratinib treatment
Subject on treatment with myeloid growth factor (eg, granulocyte-colony stimulating factor [G-CSF]) within 14 days prior to starting the fedratinib treatment
Subject with previous exposure to JAK inhibitor(s) other than ruxolitinib treatment
Subject has received ruxolitinib within 14 days prior to starting the fedratinib treatment
Subject on treatment with aspirin with doses > 150 mg daily
Subject with major surgery within 28 days prior to starting the fedratinib treatment
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 the start of fedratinib treatment. 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)
Seropositive for and with evidence of active viral infection with hepatitis B virus (HBV)
Subject who are hepatitis B surface antigen (HBsAg) negative but HB core anti-body (HBcAb) positive or HBsAb positive are eligible in case HBV viral deoxyribonucleoside (DNA) negative
Subject who had HBsAg positive but show non-detectable viral DNA for at least 6 months prior to starting the fedratinib treatment where appropriate anti-viral treatment should have been given/considered to prevent HBV reactivation based on the standard practice are eligible
Subject who are seropositive because of hepatitis B virus vaccine are eligible
Seropositive for and with active viral infection with hepatitis C virus (HCV)
Subject who had hepatitis C but show no detectable HCV viral ribonucleotide
(RNA) for at least 6 months prior to starting the fedratinib treatment are
eligible
\. Evidence of human immunodeficiency virus (HIV) infection
\. Subject with serious active infection
\. Subject with presence of any significant gastric or other disorder that
Additionally, subject with history of active severe acute respiratory syndrome
would inhibit absorption of oral medication
coronavirus 2 (SARS-CoV-2) infection within 4 weeks prior to screening, unless
\. Subject is unable to swallow capsule
the subject has adequately recovered from coronavirus disease (COVID) symptoms
\. Subject with any significant medical condition, laboratory abnormality
and related complications as per investigator's discretion, and following a
or psychiatric illness that would prevent the subject from participating in
discussion with the Medical Monitor
the study
\. Subject has any condition including the presence of laboratory
abnormalities, which places the subject at unacceptable risk if the subject
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 starting the fedratinib
treatment
\. Subject with a life expectancy of less than 6 months from the planned
first dose of fedratinib
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