The goal of this clinical trial is to learn which of three different doses of Flonoltinib Maleate taken by mouth daily works best to treat adult patients with myelofibrosis in whom the most common approved therapy has failed to adequately control the disease. It will also learn about the safety of the three different daily doses of Flonoltinib Maleate. The main questions it aims to answer are:
Which dose is the best at controlling the symptoms and signs of organ damage caused by myelofibrosis? What medical problems do participants have when taking the three different doses of Flonoltinib Maleate? Researchers will compare the three different doses of Flonoltinib Maleate to see which dose is best to treat patients with myelofibrosis.
Participants will:
Take Flonoltinib Maleate every day for as long as it seems to be of benefit to them in terms of controlling myelofibrosis.
Visit the clinic for checkups and tests after giving fully informed written consent confirming that they would like to consider entering the study.
Visit the clinic for checkups and tests when on the study once every 2 weeks for the first 2 months, every 4 weeks after that, and when coming off study therapy.
Keep a diary of their symptoms.
Inclusion Criteria:
All participants must:
Exclusion Criteria:
Participants must not:
Have failure to recover from toxic effects of prior anticancer therapy to Grade 1 or below (except alopecia), or failure to fully recover from prior surgery (major surgery within 4 weeks);
Have known hypersensitivity to the investigational product or its excipients;
Have any significant clinical or laboratory abnormality that would interfere with accurate safety evaluation on study, including:
Have a history of congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism within the 6 months prior to screening;
Have impaired cardiac function including any of the following conditions as determined by echocardiogram or electrocardiogram (ECG): left ventricular ejection fraction less than 45%, or complete left bundle branch block with ST-segment depression greater than 1 mm or T-wave inversion across 2 or more leads. Other criteria include congenital ventricular arrhythmias, clinically significant tachycardia (greater than 100 beats per minute), bradycardia (less than 50 beats per minute) with accompanying clinical symptoms, heart rate less than 60 beats per minute with symptoms, an ECG Corrected QT Interval (QTc) interval greater than 450 ms, or clinically significant cardiac conditions such as unstable angina, congestive heart failure, or myocardial infarction occurring within the last 6 months. Patients with heart failure who meet New York Heart Association class III and IV definitions are ineligible for this study;
Have an active serious infection requiring treatment at the time of screening;
Have undergone splenectomy or who have received splenic irradiation within 6 months prior to screening;
Have Human Immunodeficiency Virus (HIV) positive, active Hepatitis B (Hepatitis B Surface Antigen [HBsAg] positive and Hepatitis B Virus [HBV]-DNA ≥1000 copies/mL), or positive for Hepatitis C Virus (HCV) antibodies or HCV-RNA at screening;
Have epilepsy or are taking psychotropic or sedative medications at screening;
Be women of childbearing potential (WOCBP): who are unwilling or unable to practice highly effective contraception before the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include:
i) Stable use of combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles before screening; ii) Intrauterine device; intrauterine hormone-releasing system; iii) Sexual abstinence; iv) Intercourse with a vasectomized partner (the male vasectomized partner is the sole sexual partner of the WOCBP study patient, the vasectomized partner has obtained medical assessment of surgical success for the procedure);
Be sexually active male patients with WOCBP partners who are unwilling to use 1 of the following forms of medically acceptable birth control at the start of the first treatment, during the study, and for at least 6 months after the last dose:
i) Vasectomy with medical assessment of surgical success or consistent use of a condom; ii) Male Participants must also agree not to donate sperm while receiving the investigational product and for at least 6 months after the last dose;
Have a history of malignancy within the 3 years prior to study screening (except for successfully treated basal cell carcinoma of the skin or carcinoma in situ of the cervix);
Have any other severe illnesses that the investigator feels may jeopardize Participant safety or compliance;
Have participated in an investigational agent or medical device study within 1 month prior to screening;
Have prior or concomitant treatment with any of the following: any myelofibrosis therapy (except hydroxyurea that may be stopped one day before first dose; prior JAKi is allowed with a ≥14 day washout); any immunomodulators (e.g., thalidomide); any immunosuppressants; androgenic steroids systemic corticosteroids ≥10 mg/day prednisone equivalent; or any growth factor (e.g., EPO) within 5 half lives or 2 weeks before enrollment (whichever is longer);
Have received potent or moderate cytochrome P450 (CYP)3A4 inhibitors (including but not limited to ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin) or potent CYP3A4 inducers (including but not limited to rifampin and St. John's wort) within 2 weeks before the first dose;
Have received concomitant QT-prolonging medications that cannot be discontinued or appropriately managed in accordance with the QTc Monitoring Plan;
Have received concomitant strong inhibitors/inducers of P-gp or Breast Cancer Resistance Protein (BCRP)；
Have congenital or acquired bleeding disorders;
Be alcohol dependent or drug abusers;
Consume grapefruit, starfruit, or their products within 48 hours of the first dose of study medication, or be unwilling to abstain from such products while on study as these substances may affect drug absorption, distribution, metabolism, or excretion;
Have any other severe and/or uncontrolled concomitant medical condition that in the opinion of the investigator could compromise participation in the study or analysis of study data.
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frank.giles@zenitar.cn
This study arm will include 35 fully eligible and evaluable participants with myelofibrosis, including 14 JAKi-naïve and 63 JAKi-resistant, who are randomized to receive 50mg of oral Flonoltinib daily. Participants will receive continuous treatment until unacceptable toxicities, progressive disease or meeting other stopping criteria. The key safety endpoints and clinical efficacy endpoints will be evaluated at the end of 6 cycles (24 weeks). Other efficacy and safety evaluations will be conducted every 3 to 6 cycles. Safety follow-up will be conducted up to 30 days after the last dose and all participants will be followed up for adverse events, serious adverse events, and concomitant medication (including any new therapy) for 30 days following last Flonoltinib dose.
This study arm will include 35 fully eligible and evaluable participants with myelofibrosis, including 14 JAKi-naïve and 63 JAKi-resistant, who are randomized to receive 75mg of oral Flonoltinib daily. Participants will receive continuous treatment until unacceptable toxicities, progressive disease or meeting other stopping criteria. The key safety endpoints and clinical efficacy endpoints will be evaluated at the end of 6 cycles (24 weeks). Other efficacy and safety evaluations will be conducted every 3 to 6 cycles. Safety follow-up will be conducted up to 30 days after the last dose and all participants will be followed up for adverse events, serious adverse events, and concomitant medication (including any new therapy) for 30 days following last Flonoltinib dose.
This study arm will include 35 fully eligible and evaluable participants with myelofibrosis, including 14 JAKi-naïve and 63 JAKi-resistant, who are randomized to receive 100mg of oral Flonoltinib daily. Participants will receive continuous treatment until unacceptable toxicities, progressive disease or meeting other stopping criteria. The key safety endpoints and clinical efficacy endpoints will be evaluated at the end of 6 cycles (24 weeks). Other efficacy and safety evaluations will be conducted every 3 to 6 cycles. Safety follow-up will be conducted up to 30 days after the last dose and all participants will be followed up for adverse events, serious adverse events, and concomitant medication (including any new therapy) for 30 days following last Flonoltinib dose.
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