EUCTR2020-002392-35-FR招募中1 期
An Open-Label, Multicenter, Phase 1b/2 Study of the Safety and Efficacy of KRT-232 with TL-895 in Subjects with Relapsed/Refractory Myelofibrosis and of KRT-232 in Janus-associated Kinase Inhibitor-Intolerant Myelofibrosis
适应症
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 116
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional
入排标准
- 性别
- All
入选标准
- •For Cohort 1, Cohort 2, and Cohort 3:
- •Subjects in all Cohorts must meet the following criteria in order to be eligible for the study:
- •1. Adults =18 years of age
- •2. Confirmed diagnosis of primary MF, post-PV MF, or post-ET MF, as assessed by treating physician according to the World Health Organization (WHO) criteria
- •3. Subjects with TP53 WT MF, defined as tumors that do not harbor deleterious alteration in TP53
- •4. Palpable spleen measuring =5 cm below the left lower costal margin or spleen volume of =450 cm3 by MRI or CT scan assessment
- •5. MF symptoms as defined by having at least 2 symptoms with a score of at least 1 each on the MFSAF v4.0
- •6. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS) and DIPSS-PLUS
- •7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 according to ECOG performance status criteria
- •8. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of study treatment)
- •a. Hematologic:
- •i. Absolute neutrophil count (ANC) =1.0×109/L (Note: ANC eligibility is based on values obtained in the absence of growth factors, ie, 7 days for granulocyte colony-stimulating factor (G-CSF) or 14 days for pegfilgrastim)
- •ii. Platelet count =50×109/L
- •iii. Peripheral blood blast count <10%
- •b. Hepatic:
- •i. Total bilirubin within normal limits if total bilirubin is >upper limit of normal (ULN), then subjects are eligible if the direct bilirubin is =2.0×ULN
- •ii. Aspartate transaminase/serum glutamic oxaloacetic transaminase and alanine transaminase/serum glutamic pyruvic transaminase =2.5×ULN
- •i. Estimated creatinine clearance (eCcr) =30 mL/min by Cockcroft Gault.
- •9. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, male subjects must continue to use contraception for 3 months and 1 week after the last dose of study drug and female subjects must continue to use contraception for 1 month and 1 week after the last dose of study drug. Effective birth control for males is the use of condoms. Effective birth control for females includes the following:
- •a. Combined, estrogen and progestogen containing hormonal contraception (PO, intravaginal, or transdermal)
- •b. Intrauterine device combined with a barrier method
- •c. Intrauterine hormone-releasing system combined with a barrier method
- •d. Bilateral tubal occlusion or ligation
- •e. Vasectomized partner
- •f. Sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, and post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- •For Cohort 1 and Cohort 2 only:
- •Must have R/R MF following JAK inhibitor treatment that meets either criterion (1) or (2) below:
- •1. Relapsed defined by one of the following:
- •a. Spleen volume increase by =25% by radiographic imaging from nadir
- •b. =100% increase in palpable distance below the left lower costal margin (LLCM), for Baseline splenomegaly of 5 to 10 cm
- •c. =50% increase in palpable distance below the LLCM, for Baseline splenomegaly of >10 cm
- •d. Regrowth after achieving complete response
- •2. Refractory defined by one of the following after receiving =12 weeks of JAK inhibitor treatment:
- •a. <10% spleen volume reduction by radiographic imagi
排除标准
- •For Cohort 1, Cohort 2, and Cohort 3:
- •Subjects in all cohorts who meet any of the following criteria will not be eligible for the study:
- •1. Treatment with a JAK inhibitor within 21 days of the Screening MRI/CT
- •2. Prior MDM2 inhibitor therapy or TP53-directed therapy
- •3. Prior treatment with a BTK, BMX, BCR-ABL, phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR), bromodomain and extraterminal domain (BET), histone deacetylase (HDAC), or spleen tyrosine kinase (Syk) inhibitor
- •4. Major surgery, chemotherapy, immunomodulating therapy, biologic therapy, or radiation therapy within 28 days prior to the first dose of study treatment; hydroxyurea may be taken within 1 day prior to the first dose of study treatment
- •5. Participation in another interventional clinical study within the past 28 days of the first dose of study treatment (participation in observational studies is permitted)
- •6. Prior splenectomy
- •7. Splenic irradiation within 12 weeks prior to the first dose of study treatment
- •8. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation in the opinion of the Investigator; subjects that refuse a transplant are eligible for enrollment in this study.
- •9. Women who are pregnant or breastfeeding
- •Page 20 of 127
- •10. History of major organ transplant
- •11. Uncontrolled intercurrent illness including, but not limited to, clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; unstable ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
- •12. Subjects with active hepatitis B virus or hepatitis C virus
- •13. Subjects with known history of human immunodeficiency virus (HIV)
- •14. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
- •15. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
- •16. Grade 2 or higher QTc prolongation (>480 milliseconds per National Cancer Institute Common Terminology of Adverse Events [NCI-CTCAE] version 5.0 criteria)
- •17. Major hemorrhage or intracranial hemorrhage within 6 months prior to the first dose of study treatment
- •18. Having history of difficulty swallowing, gastric or small bowel surgery with history of malabsorption, or other chronic gastrointestinal disease or conditions that may hamper compliance and/or absorption of the TL-895 or KRT-232
- •For Cohort 1 and Cohort 2 only
- •1. Requires treatment with proton-pump inhibitors (PPIs; eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving PPIs who switch to H2-receptor antagonists or antacids prior to Cycle 1 Day 1 are eligible for enrollment in this study
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