Flonoltinib maleate tablets for adults with JAK-inhibitor refractory or intolerant myelofibrosis

Flonoltinib Maleate for the Treatment of Patients With Intermediate- or High-risk Myelofibrosis Who Are Refractory, Relapsed, or Intolerant to JAK Inhibitors a Single-arm, Open-label, Multicenter Phase IIb Clinical Trial Evaluating Efficacy and Safety

This trial will try once-daily flonoltinib maleate tablets, taken on an empty stomach, in adults with moderate-to-high risk myelofibrosis whose disease returned, did not respond to, or who could not tolerate JAK inhibitor therapy.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 64 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: Chengdu Zenitar Biomedical Technology Co., Ltd (Industry-sponsored)
• Drugs / interventions: radiation, prednisone, flonoltinib
• Locations: 2 sites (Chengdu, Sichuan and 1 other locations)
• Trial ID: NCT07443306 on ClinicalTrials.gov

What this trial studies

This is a single-arm, open-label, multicenter Phase 2 trial planning to enroll about 64 adults with intermediate-2 or high-risk myelofibrosis (or symptomatic intermediate-1 disease) who are refractory, relapsed, or intolerant to prior JAK inhibitor treatment. Eligible participants will be allocated to flonoltinib maleate tablets with dosing stratified by platelet counts observed during screening and will take the drug once daily on an empty stomach until predefined withdrawal criteria are met. The protocol is being run at two specialized hematology centers in China and monitors participants for safety and clinical response while on treatment. Detailed primary and secondary endpoints were not provided in the available trial summary.

Who should consider this trial

Good fit: Adults aged 18–80 with primary or post–polycythemia vera/post–essential thrombocythemia myelofibrosis who are intermediate-2 or high-risk (or symptomatic intermediate-1 with hepatosplenomegaly), have prior JAK inhibitor refractory/relapsed/intolerant disease, ECOG 0–2, expected survival >24 weeks, and palpable splenomegaly ≥5 cm are the intended participants.

Not a fit: Patients with low-risk myelofibrosis, very short expected survival, severe comorbidities, inadequate performance status, or who do not meet the trial's platelet or prior JAK inhibitor failure criteria are unlikely to benefit from participation.

Why it matters

Potential benefit: If effective, flonoltinib could offer a new oral treatment option for patients whose myelofibrosis no longer responds to or who cannot tolerate JAK inhibitors.

How similar studies have performed: Other second-line and JAK-pathway targeted agents for JAK-inhibitor refractory myelofibrosis have shown mixed results, so using flonoltinib in this setting represents a relatively novel approach with limited published data.

Eligibility criteria

Inclusion Criteria:

1. Age range of 18-80 years old (including threshold), gender not limited;
2. Patients diagnosed with primary myelofibrosis (PMF) according to WHO criteria (2016 edition) or patients diagnosed with post polycythemia vera myelofibrosis (PPV-MF) or post thrombocytopenia myelofibrosis (PET-MF) according to IWG-MRT criteria;
3. Patients with myelofibrosis assessed as intermediate-2 or high-risk according to the dynamic international prognostic scoring system (DIPSS) prognostic classification criteria;or patients with intermediate-1 myelofibrosis who exhibit hepatosplenomegaly and require treatment;
4. MF patients who have received JAK inhibitor treatment in the past and meet the criteria of refractory/recurrent/intolerant;
5. Expected survival period greater than 24 weeks;
6. ECOG score 0-2 points;
7. Splenomegaly: Palpation of the splenic margin reaching or exceeding 5cm below the rib (distance from the intersection of the left clavicle midline and left rib margin to the farthest point of the spleen); Or due to physical reasons (such as obesity), it may not be palpable, but MRI/CT spleen evaluation during screening confirms a volume of \>= 450 cm\^3;
8. Peripheral blood and bone marrow blasts \<=10%;
9. Within 7 days prior to randomization, ANC \>=1.0 × 10\^9/L, platelet count \>=100 × 10\^9/L, HGB\>60 g/L ;
10. Within 7 days prior to randomization, the main organ functions were generally normal, meeting the following criteria: ALT and AST \<= 2.5 × ULN; TBIL\<=2.0×ULN; Serum creatinine \<=1.5 × ULN or serum creatinine clearance rate (Ccr)\>50 mL/min; INR, PT, and APTT \<= 1.5 × ULN;
11. Can understand and voluntarily sign an informed consent form..

Exclusion Criteria:

1. The toxic reactions of previous anti-cancer treatments have not recovered to grade 1 or below (excluding hair loss), or have not fully recovered from previous surgeries(such as undergoing major surgery within 4 weeks);
2. Allergy to experimental drugs and their excipients;
3. For any significant clinical and laboratory abnormalities, the researchers believe that they affect the safety evaluators, such as: a. uncontrollable diabetes - fasting blood glucose\>250 mg/dL (13.9 mmol/L), b. hypertension and cannot be reduced to the following range after treatment with two or more antihypertensive drugs (systolic blood pressure\<160 mmHg, diastolic blood pressure\<100 mmHg), c. peripheral neuropathy;
4. Patients with a history of congestive heart failure (NYHA grade III or above), unstable angina or myocardial infarction, cerebrovascular accidents or thromboembolism within the first 6 months of screening;
5. Individuals with impaired cardiac function (those with ejection fraction\<45% detected by echocardiography, congenital ventricular arrhythmia, QTcF\>450 ms on electrocardiogram (males), QTcF\>470 ms on electrocardiogram (females), or those with arrhythmia requiring treatment at the time of screening);
6. Patients with congenital or acquired bleeding disorders or unstable thrombotic diseases requiring anticoagulant therapy;
7. Any active infections requiring systemic treatment (oral, intravenous, subcutaneous, intramuscular, etc.) within 14 days prior to enrollment;
8. Individuals who have experienced active tuberculosis infection within the 48 weeks prior to screening or those who have been diagnosed with latent tuberculosis infection during the screening period (those diagnosed with latent tuberculosis infection must complete preventive anti tuberculosis treatment for at least 3 months before they can be enrolled);
9. Patients who have undergone splenectomy in the past or those who have received splenic radiation therapy within the 12 months prior to their first dose;
10. Active infection of hepatitis B virus (HBV) or hepatitis C virus (HCV), except for the following patients: a) HBV infection: patients who are positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and undergo peripheral blood HBV-DNA testing, with the lower limit of HBV-DNA detection value (i.e. the upper limit of normal value in the laboratory of each research center) can be enrolled; If the baseline HBsAg is positive, continuous antiviral treatment is required after enrollment, and HBV-DNA testing should be conducted every 12 weeks and at EOT visits; b) Patients who are positive for HCV serology but negative for HCV-RNA can be included in the study;
11. Patients who are positive for human immunodeficiency virus antibodies (HIV Ab) or anti Treponema pallidum antibodies (TP Ab) (Treponema pallidum antibodies positive);
12. Patients with epilepsy or those taking psychotropic or sedative drugs during screening;
13. Pregnant or lactating female patients, female/male patients with fertility who refuse to use contraceptive measures during the trial period and within 6 months after the trial ends;
14. Patients who have suffered from other malignant tumors within the past 5 years before the first administration (excluding cured carcinoma in situ and basal cell carcinoma of the skin);
15. Patients with swallowing difficulties, chronic diarrhea, or oral absorption disorders;
16. Combining other serious illnesses, researchers believe may affect patient safety or compliance;
17. Patients who have participated in clinical trials of other new drugs or medical devices within one month before the first administration and have taken the study drug or used the study device;
18. Select patients who have used JAK inhibitors within the previous 4 weeks or 5 half lives (whichever is longer);
19. Patients who have used any MF drug (including traditional Chinese patent medicines and simple preparations with anti-tumor indications), androgen, any immunomodulator (such as thalidomide), any immunosuppressant, prednisone\>10 mg/day or glucocorticoid with the same biological effect intensity within 2 weeks or 5 half-life periods (whichever is the elder) before screening;
20. Researchers believe that there are other factors that are not suitable for participating in the experiment.

Where this trial is running

Chengdu, Sichuan and 1 other locations

• West China Hospital Sichuan University — Chengdu, Sichuan, China (Recruiting)
• Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences (IHCAMS) — Tianjin, Tianjin Municipality, China (Recruiting)

Study contacts

• Principal investigator: Xiao Zhijian — Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences (IHCAMS)
• Study coordinator: Wang Fangmei

Conditions MF