Myelofibrosis
Conditions
Interventions
Dose Escalation Phase:Gicaxitinib hydrochloride 100mg Bid, oral
Selinexor 20mg Biw starting dose, adjusted to 20mg Tiw or 20mg Qw based on tolerability (3+3 Design)
Efficacy Evaluation Phase:Gicaxitinib hydrochloride 100mg Bid, oral
Selinexor 20mg RP2D (Recommended Phase 2 Dose), oral
Sponsors
The First Affiliated Hospital, College of Medicine, Zhejiang University
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Inclusion criteria
Inclusion criteria: 1. Age >= 18, male or female; 2. Patients diagnosed with PMF according to the 2016 World Health Organization (WHO) criteria, or patients diagnosed with Post-PV-MF or Post-ET-MF according to the 2007 International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria; enrollment is allowed regardless of JAK2 mutation status; 3. Patients with myelofibrosis assessed as intermediate-1, intermediate-2, or high risk according to the DIPSS prognostic scoring system, or patients with myelofibrosis assessed as higher risk according to the NCCN guidelines prognostic scoring system (MIPSS-70: >=4 or MIPSS70+V2.0: >=4, DIPSS-Plus: >1, DIPSS: >2, MYSEC-PM: >=14); 4. Intolerant, refractory, or relapsed to ruxolitinib or other JAK inhibitors, or deemed unsuitable for existing treatment regimens by the investigator: (1) Intolerance: Received recommended dose treatment for at least 4 weeks, and any of the following occurred during treatment: 1) Hb decreased from baseline to below the lower limit of normal (LLN), or Hb decrease >10g/L, or two consecutive Hb decreases at intervals of 1~2 weeks; 2) Need to initiate red blood cell transfusion (transfusion considered if Hb50% and platelet count below LLN; 4) Occurrence of >= Grade 3 bleeding/hematoma; 5) Occurrence of >= Grade 3 organ function impairment. (2) Refractoriness: Received maximum tolerated dose treatment for at least 1 month, and any of the following occurred: 1) No spleen response: Reduction in palpable spleen length below the costal margin from pre-treatment =1 month: 1) Loss of spleen response: Reduction in palpable spleen length below the costal margin compared to pre-treatment = 5cm (Jia-Bing line), or spleen volume assessed by MRI/CT >=450 cm^3; 6. Peripheral blood blasts =10mg/day or glucocorticoids with equivalent biological potency, or erythropoiesis-stimulating agents (e.g., EPO) for improving anemia were used within 2 weeks before enrollment, they must be disconti
Exclusion criteria
Exclusion criteria: 1.Any significant clinical and laboratory abnormalities that the researchers consider to affect the safety evaluation, such as: (1) Uncontrolled diabetes (>250 mg/dL or >13.9mmol/L), (2) Suffering from hypertension and unable to lower it to the following range after combined antihypertensive treatment (systolic blood pressure <160 mmHg) (1) diastolic blood pressure <100 mmHg), (3) Peripheral neuropathy (NCICTC AE v5.0 standard grade 2 or above); 2.Patients with a current or history of autoimmune disease at screening. 3.Patients with severe retinopathy (e.g., cytomegalovirus retinitis, macular degeneration) or clinically relevant ophthalmologic diseases caused by diabetes or hypertension at screening. 4.Patients with inadequately controlled thyroid dysfunction at screening. 5.Patients with a history of congestive heart failure (NCI-CTCAE version 5.0, Grade 3 or higher), uncontrolled or unstable angina pectoris, myocardial infarction, cerebrovascular accident, or pulmonary embolism within 24 weeks prior to screening. 6.Patients who underwent surgical procedures within 4 weeks prior to screening and have not fully recovered. 7.Patients with arrhythmic disorders requiring treatment at screening (except digoxin). 8.Patients with any clinically symptomatic bacterial, viral, parasitic, or fungal infection requiring treatment at screening. 9.Patients with a prior diagnosis of active tuberculosis, or positive interferon-gamma release assay during screening who are confirmed as having active tuberculosis by the investigator. 10.confirmed as having active tuberculosis; 11.Patients with active pulmonary infection indicated by chest X-ray at screening. 12.Patients with a history of splenectomy, or who received splenic irradiation within 48 weeks prior to screening. 13.Patients with positive HIV test, active hepatitis B virus infection (positive HBsAg and positive HBV-DNA or above the normal reference range), or positive anti-HCV antibody with positive HCV-RNA at screening. 14.Patients with epilepsy or receiving psychotropic or sedative medications at screening (Note: Excluded are estazolam tablets, and olanzapine used for the prevention of chemotherapy-induced nausea during the first two cycles (28 days per cycle) after study initiation). 15.Female patients who are pregnant, breastfeeding, planning a pregnancy, or unable to use effective contraceptive methods throughout the trial;male patients who do not use condoms during dosing and for 2 days (approximately 5 half-lives) after the last dose. 16.Patients with a history of malignancy within the past 5 years (except cured basal cell carcinoma of the skin and carcinoma in situ of the cervix). 17.Patients with other severe comorbidities that, in the investigator’s judgment, may compromise patient safety or compliance. 18.Patients with suspected hypersensitivity to gicacitinib hydrochloride or to drugs of the same class. 19.Patients with suspected hypersensitivity to selinexor or to drugs of the same class. 20.Patients who participated in other investigational drugs or medical devices and received investigational medicinal products or used investigational devices within 12 weeks prior to screening. 21.Subjects receiving strong CYP3A4 inhibitors (according to the previous PK/PD study of gicacitinib, no dose adjustment is required when co-administered with CYP3A4 inducers).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Spleen response rate at week 24; | — |
Secondary
| Measure | Time frame |
|---|---|
| Symptom improvement related to myelofibrosis (>=50% reduction in MPN-SAF TSS score);Anemia improvement (transfusion independence or increase in hemoglobin level);Best response rate;Time to response;Duration of maintained spleen response (DoMSR);Adverse event incidence rate;Objective response rate (CR + PR);Temporal clonal dynamics of driver and non-driver genes;Molecular response rate for driver gene;Change in bone marrow fibrosis grade;Progression-free survival (PFS);Leukemia-free survival (LFS);Overall survival (OS); | — |
Countries
China
Contacts
Public ContactHuang Jian
The First Affiliated Hospital, College of Medicine, Zhejiang University
Outcome results
None listed