A Phase I Study of Decitabine, Lisaftoclax, and Olverembatinib in Patients With Advanced Chronic Myeloid Leukemia and Philadelphia Chromosome-Positive Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 2
- 主要终点
- Safety and adverse events (AEs)
研究概览
简要总结
To find the recommended doses of lisaftoclax and olverembatinib that can be given in combination with decitabine to participants with advanced CML and Ph+ AML.
详细描述
Primary Objectives
• To establish the minimum safe and biologically-effective dose of lisaftoclax and olverembatinib in combination with decitabine
Secondary Objectives
- To determine the rate of conversion to CML-CP for participants with advanced phase CML or complete remission (CR)/CR with incomplete hematology recovery (CRi) for participants with Ph+ AML, within 4 cycles of combination therapy
- To assess other efficacy endpoints (CR rate, measurable residual disease negativity by flow cytometry, rates of CCyR, MMR, MR4 and MR4.5, relapse-free survival, overall survival)
- To assess proportion of participants proceeding to allogeneic hematopoietic stem cell transplantation
- To determine the safety of the combination regimen
Exploratory Objectives
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 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
- •a) Diagnosis: Age ≥18 years with CML-AP, CML-MBP, or Ph+ AML by WHO 2016 criteria.
- •Participants must have been intolerant or resistant to at least one prior BCR::ABL1 TKI
- •2. Performance status ≤3 (ECOG Scale).
- •3. Adequate liver, cardiac, renal and pancreatic function as defined by the following criteria:
- •Total serum bilirubin < 1.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
- •Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 3 x ULN, unless due to the underlying leukemia approved by the PI
- •Creatinine clearance ≥30 mL/min
- •Serum amylase or lipase < 1.5 x ULN
- •4. Ability to understand and the willingness to sign a written informed consent document
- •5. Willingness to use adequate contraception prior to study entry, for the duration of study participation, and for 6 months after completion of study participation. For women of child-bearing potential, adequate methods of contraception include: complete abstinence,, hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), intrauterine device (IUD), tubal Ligation or hysterectomy, subject/partner post vasectomy, implantable or injectable contraceptives, and condoms plus spermicide.
排除标准
- •Participants who have previously received lisaftoclax or olverembatinib
- •History of acute pancreatitis within 1 year of study or history of chronic pancreatitis
- •Active grade III-V cardiac failure as defined by the New York Heart Association Criteria
- •Clinically significant and uncontrolled cardiovascular disease, including but not restricted to:
- •i. Myocardial infarction (MI), stroke, revascularization, unstable angina, or transient ischemic attack within 6 months.
- •ii. Left ventricular ejection fraction (LVEF) less than lower limit of normal per local institutional standards prior to enrollment.
- •iii. Diagnosed or suspected congenital long QT syndrome. iv. Clinically significant atrial or ventricular arrhythmias (such as uncontrolled, clinically significant atrial fibrillation, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes) as determined by the treating physician.
- •v. Prolonged QTc interval on pre-entry electrocardiogram (> 480 msec) unless corrected after electrolyte replacement.
- •vi. History of venous thromboembolism including deep venous thrombosis or pulmonary embolism within the past 3 months, excluding line associated DVT of the upper extremity vii. Uncontrolled hypertension (diastolic blood pressure >100mmHg; and systolic >150mmHg).
- •Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment).
- •Active central nervous system leukemia
- •Known human immunodeficiency virus (HIV) seropositive, unless well-controlled on stable doses of anti-retroviral therapy.
- •Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection Note: Participants who have isolated positive hepatitis B core antibody (ie, in the setting of negative hepatitis B surface antigen and negative hepatitis B surface antibody) must have an undetectable hepatitis B viral load. Participants who have positive hepatitis C antibody may be included if they have an undetectable hepatitis C viral load.
- •Participants with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI
- •Consumed strong inducer of CYP3A or p-glycoprotein within 14 days of study enrollment, or 5 half-lives, whichever is longer. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wart
- •Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Prior recent treatment with corticosteroids, hydroxyurea, cytarabine (up to 2 g/m2 given for cytoreduction within the preceding 7 days) and/or an FDA-approved BCR::ABL1 TKI is permitted.
- •Inability to swallow
- •Pregnant or breastfeeding women will not be eligible
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to Decitabine, Lisaftoclax, and Olverembatinib or other agents used in study.
- •Participants with psychiatric illness/social situations that would limit compliance with study requirements.
研究组 & 干预措施
Phase 1
Participants enrolled in Phase I, the dose of lisaftoclax you receive will depend on when a participants join this study. Up to 2 dose levels of lisaftoclax will be tested. Between 3-12 participants will be enrolled at each dose level.
干预措施: Decitabine (Drug)
Phase 1
Participants enrolled in Phase I, the dose of lisaftoclax you receive will depend on when a participants join this study. Up to 2 dose levels of lisaftoclax will be tested. Between 3-12 participants will be enrolled at each dose level.
干预措施: Listaftoclax (Drug)
Phase 1
Participants enrolled in Phase I, the dose of lisaftoclax you receive will depend on when a participants join this study. Up to 2 dose levels of lisaftoclax will be tested. Between 3-12 participants will be enrolled at each dose level.
干预措施: Olverembatinib (Drug)
Phase 2
Participants enrolled in Phase II, participants will receive lisaftoclax at the recommended dose that was found in Phase I
干预措施: Decitabine (Drug)
Phase 2
Participants enrolled in Phase II, participants will receive lisaftoclax at the recommended dose that was found in Phase I
干预措施: Listaftoclax (Drug)
Phase 2
Participants enrolled in Phase II, participants will receive lisaftoclax at the recommended dose that was found in Phase I
干预措施: Olverembatinib (Drug)
结局指标
主要结局
Safety and adverse events (AEs)
时间窗: Through study completion; an average of 1 year
Incidence of Adverse Events, Graded According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version (v) 5.0
次要结局
未报告次要终点