EUCTR2018-001672-38-CZ进行中（未招募）1 期
A Two-Part, Randomized, Open-label, Multicenter, Phase 2a/2b Study of the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared to Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera
适应症
相关药物
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 320
研究概览
简要总结
暂无简介。
研究设计
- 研究类型
- Interventional clinical trial of medicinal product
入排标准
- 性别
- All
入选标准
- •1. Adults > 18 years of age
- •2. Documentation that the patient has met the World Health Organization (WHO) criteria for the diagnosis of PV
- •3. Subjects must be phlebotomy dependent. The definition of phlebotomy dependent is:
- •Hematocrit is 40–45% with two phlebotomies or more spaced at least 4 weeks apart within 24 weeks before Screening
- •Hematocrit level is higher than 45% with at least one phlebotomy within 16 weeks before Screening
- •4. In Part A, subjects with splenomegaly (defined as spleen volume =450 cubic centimeters cm3) and without splenomegaly by MRI (or CT) are eligible. In Part B, only subjects with splenomegaly by MRI or CT are eligible.
- •5. Previous treatment with hydroxyurea (HU) (Part A and B), or interferon (Part A only). If previously treated with HU, subject must be resistant to/intolerant of HU according to the following criteria:
- •HU resistance is defined as a dose =2 g/day or a maximum tolerated dose <2 g/day for a minimum of 12 weeks, resulting in need for phlebotomy to maintain hematocrit <45% or platelet count >400 x109 /L and white blood cell (WBC) count >10 x 109 /L
- •HU intolerance is defined as:
- •ANC <1.0 x109/L or platelet count <100 x109/L or hemoglobin <100 g/L (i.e., 10 g/dL) at the lowest dose of HU required to achieve a response (hematocrit <45% without phlebotomy and/or all 3 of a platelet count = 400 x109/L, a WBC count =10 x109/L, and a nonpalpable spleen)
- •Presence of leg ulcers or other unacceptable HU-related nonhematologic toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis, or fever at any dose of HU), defined as:
- •Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3–4 adverse event (AE) or
- •>1 week of CTCAE version 5.0 grade 2 AE or Permanent discontinuation of HU or Interruption of HU until toxicity resolved or Hospitalization due to HU toxicity
- •6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- •7. 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 includes either vasectomy or use of condoms. Effective birth control for females includes (a) combined, estrogen and progestogen containing, hormonal
- •contraception (oral, intravaginal, transdermal); (b) progestogen-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d) intrauterine hormone-releasing system; (e) bilateral tubal
- •occlusion; and (f) sexual abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- •Are the trial subjects under 18? no
- •Number of subjects for this age range:
- •F.1.2 Adults (18-64 years) yes
- •F.1.2.1 Number of subjects for this age range 100
- •F.1.3 Elderly (>=65 years) yes
- •F.1.3.1 Number of subjects for this age range 220
排除标准
- •1. Meets the criteria for post-PV myelofibrosis, as defined by the International Working Group-
- •Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
- •2. >10% blasts
- •3. Clinically significant thrombosis within 3 months of screening
- •4. Inadequate liver or renal function:
- •a. Renal impairment (estimated creatinineclearance <30 mL/min by Cockcroft Gault)
- •b. Known history of hepatocellular disease (for example, hepatitis B or C, cirrhosis or other hepatocellular disease)
- •c. Total bilirubin = 2 X upper limit of laboratory normal (ULN) unless Gilbert’s Syndrome
- •d. Alanine aminotransferase (ALT) > 2.5x ULN
- •5. Part B only: Previous treatment with a JAK inhibitor
- •6. Part B only: Patients with a history of progressive multifocal leukoencephalopathy (PML)
- •7. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors
- •8. Patients previously treated with MDM2 antagonist therapies, p53-directed therapies, or patients receiving interferon-alpha or anagrelide within 28 days or approximately 5 half-lives, or hydroxyurea within 1 day, or patients receiving any other cytoreductive or investigational agents within 28 days or 5 half lives of initial KRT-232 dose. Patients being treated with ruxolitinib (or other JAK inhibitor) should be tapered and discontinued from ruxolitinib therapy prior to starting KRT-232 as per the tapering guidelines. Aspirin is permitted per treatment guidelines for PV unless medically contraindicated.
- •9. Absolute neutrophil count < 1.5 × 109/L prior to dosing on Cycle 1 Day 1
- •10. Platelet count =150 × 109/L prior to dosing on Cycle 1 Day 1
- •11. Splenic radiation within 3 months prior to first dose of KRT-232
- •12. Women who are pregnant or breastfeeding
- •13. History of major organ transplant
- •14. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; known history of human immunodeficiency virus (HIV)- positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
- •15. 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.
- •16. 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
- •17. Grade 2 or higher QTc prolongation (>480 milliseconds, per NCI CTCAE criteria, version 5.0)
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