Phase I/II Study of SP-2577 (Seclidemstat) in Combination With Azacitidine for Patients With Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 44
- 试验地点
- 1
- 主要终点
- Overall response rate
研究概览
简要总结
This phase I/II trial identifies the best dose of seclidemstat when given together with azacitidine in treating patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. Seclidemstat may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Azacitidine may help block the formation of growths that may become cancer. Giving seclidemstat and azacytidine may kill more cancer cells.
详细描述
PRIMARY OBJECTIVES:
I. To determine the safety, tolerability and maximum tolerable dose (MTD) of seclidemstat in combination with azacitidine.
II. To assess overall response rate (ORR) to seclidemstat in combination with azacitidine.
SECONDARY OBJECTIVES:
I. To assess overall survival (OS), duration of response (DOR), relapse-free survival (RFS), and leukemia-free survival (LFS) and safety profile.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age >= 18 years as myelodysplastic syndrome (MDS) is a very rare disease in the pediatric setting
- •Diagnosis of MDS or chronic myelomonocytic leukemia (CMML) according to World Health Organization (WHO) and:
- •MDS with int-1, int-2, or high risk by International Prognostic Scoring System (IPSS), or CMML-1/CMML-2 , myeloproliferative CMML (white blood cell [WBC] >= 13 x 10^9/L) or CMML-0 with high-risk molecular features (known mutations in ASXL1, SETBP1, RUNX1, NRAS, TP53 or more than 3 mutations).
- •No response after 6 cycles of azacitidine, decitabine, guadecitabine, ASTX030 or ASTX727 or relapse or progression after any number of cycles
- •Serum creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 50 ml/min for patients with creatinine levels > 1.5 x ULN
- •Adequate hepatic function with total bilirubin < 2 x ULN (will allow less than 5 x ULN if Gilbert's syndrome at investigator's discretion)
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 3 x ULN
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- •Patient (or patient's legally authorized representative) must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study
- •Prior hydroxyurea for control of leukocytosis or use of hematopoietic growth factors (e.g., granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], Procrit, Aranesp, thrombopoietins) is allowed at any time prior to or during study if considered to be in the best interest of the patient
排除标准
- •Uncontrolled infection not adequately responding to appropriate antibiotics
- •New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 50% by echocardiogram or multigated acquisition (MUGA) scan
- •History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
- •Baseline corrected QT interval by Fridericia formula (QTcF) (Fridericia) >= 450 msecs and long QT syndrome or family history of idiopathic sudden death or congenital long QT syndrome
- •Currently receiving any of the following substances and cannot be discontinued 14 days for CYP inhibitors prior to cycle 1 day 1:
- •Moderate or strong inhibitors or inducers of major CYP isoenzymes, including grapefruit, grapefruit hybrids, pomelos, star fruit and Seville oranges
- •Moderate or strong inhibitors or inducers of major drug transporters
- •Substrates of CYP3A4/5 with a narrow therapeutic index
- •Female patients who are pregnant or lactating
- •Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives [birth control pills], contraceptive injections, intrauterine devices [IUD], double-barrier method [spermicidal jelly or foam with condoms or diaphragm], contraceptive patch, or surgical sterilization) throughout the study
- •Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta human chorionic gonadotropin [HCG]) pregnancy test at screening
- •Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy
- •Evidence of graft versus host disease or prior allogeneic (allo)-stem cell transplantation within 6 months of cycle 1 day 1 or receiving immunosuppressants following a stem-cell procedure
- •Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Patients with history of human immunodeficiency virus (HIV) disease are also excluded from the study
研究组 & 干预措施
Treatment (azacitidine, seclidemstat)
Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7. Patients also receive seclidemstat PO QD on day 1 of cycle 1 and PO BID on days 2-28 of cycle 1 and on days 1-28 of all subsequent cycles. There are 6 planned dose levels for seclidemstat: 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg and 1500 mg. Successive cohorts of eligible patients will be treated with azacitidine. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Azacitidine (Drug)
Treatment (azacitidine, seclidemstat)
Patients receive azacitidine IV over 10-40 minutes or SC on days 1-7. Patients also receive seclidemstat PO QD on day 1 of cycle 1 and PO BID on days 2-28 of cycle 1 and on days 1-28 of all subsequent cycles. There are 6 planned dose levels for seclidemstat: 300 mg, 450 mg, 600 mg, 900 mg, 1200 mg and 1500 mg. Successive cohorts of eligible patients will be treated with azacitidine. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Seclidemstat (Drug)
结局指标
主要结局
Overall response rate
时间窗: Up to the end of four cycles of treatment (1 cycle = 28 days)
Will be defined as complete response, partial response, marrow complete response, or hematological improvement. Will be estimated for all patients along with the 95% confidence interval.
Incidence of adverse events
时间窗: Up to 1 year
The severity of the toxicities will be graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. The number and percent of subjects with treatment-emergent adverse events will be summarized according to intensity and drug relationship, and categorized by System Organ Class and preferred term by dose level/part. All reported adverse events that occur after signing informed consent will be included in the analysis of all reported adverse events. Exposure to study drug and reasons for discontinuation of study drug will be tabulated.
次要结局
- Overall survival(Time from treatment start till death or last follow-up, assessed up to 1 year)
- Duration of response(Time from the first documented onset of partial response or complete response to the date of progressive disease/relapse, assessed up to 1 year)
- Leukemia free survival(Time from treatment start to transformation to acute myeloid leukemia or death, whichever comes first, assessed up to 1 year)
- Relapse-free survival(Time from start of response to the date of event defined as the first documented progressive disease/relapse or death, whichever comes first, assessed up to 1 year)