A Phase I Study of Entrectinib in Combination With ASTX727 (35 mg Decitabine and 100 mg Cedazuridine) in Patients With Relapsed/Refractory TP53 Mutated Acute Myeloid Leukemia (AML)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 13
- 试验地点
- 2
- 主要终点
- Incidence of dose limiting toxicities (DLTs)
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of entrectinib when given with ASTX727 in treating patients with acute myeloid leukemia (AML) that has come back (relapsed) or that does not respond to treatment (refractory) and has a genetic change (mutation) in the TP53 gene. ASTX727 is a combination of cedazuridine and decitabine. Cedazuridine is in a class of medications called cytidine deaminase inhibitors. It prevents the breakdown of decitabine, making it more available in the body so that decitabine will have a greater effect. Decitabine is in a class of medications called hypomethylation agents. It works by helping the bone marrow produce normal blood cells and by killing abnormal cells in the bone marrow. Entrectinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps to stop or slow the spread of cancer cells. Giving ASTX727 and entrectinib together may kill more tumor cells in patients with AML.
详细描述
PRIMARY OBJECTIVE:
I. To determine the maximum tolerated dose (MTD) of decitabine and cedazuridine (ASTX727) combined with entrectinib in relapsed/refractory (R/R) AML patients with TP53 mutations.
SECONDARY OBJECTIVE:
I. To assess overall safety and preliminary anti-AML activity of combined ASTX727 and entrectinib regimen.
EXPLORATORY OBJECTIVE:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Must be able to understand and willing to sign an informed consent document.
- •Participants aged 18 years or older.
- •Morphologically documented AML in patients with relapsed/refractory disease, defined as having >= 20% blasts in bone marrow or peripheral blood.
- •Documented TP53 mutation as seen on standard diagnostics in AML.
- •Aspartate aminotransferase (AST) < 3 × upper limit of normal (ULN).
- •Alanine aminotransferase (ALT) < 3 × ULN.
- •Total bilirubin < 1.5 × ULN (except for patients with known Gilbert's syndrome).
- •Adequate renal function as defined by calculated creatinine clearance (according to the Cockcroft-Gault equation) > 40 mL/min OR serum creatinine < 1.5 × ULN.
- •Eastern Cooperative Oncology Group (ECOG) performance status (PS) =<
- •Must be able to take oral medication.
- •Individuals of childbearing potential (IOCBP) must agree to use highly-effective method(s) of contraception during the study and six months after the last dose of study drugs. IOCBP must have a negative pregnancy test prior to study enrollment.
- •Sperm producing individuals must agree to use an adequate method of contraception starting with the first dose of study therapy through 3 months after the last dose of study drugs.
- •Participants must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of their cancer.
排除标准
- •Isolated myeloid sarcoma (patients must have blood or marrow involvement with AML to enter the study).
- •Acute promyelocytic leukemia (M3).
- •Active central nervous system (CNS) involvement by AML.
- •Clinical signs/symptoms of leukostasis which has failed urgent therapy of at least 3 days duration, which may have included hydroxyurea or leukapheresis.
- •Known active human immunodeficiency virus (HIV), active hepatitis B or active hepatitis C infection.
- •Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis.
- •Patients who have received an investigational agent (for any indication) within 5 half-lives of the agent or who have agent-related toxicity that has not resolved to grade 1 or less. If the half-life of an investigational agent is unknown, patients must wait 1 week after discontinuing it before receiving the first dose of study treatment. An investigational agent is one for which there is no approved indication by the United States (US) Food and Drug Administration (FDA).
- •Prior entrectinib for other malignancies (prior decitabine therapy will not be excluded).
- •Patients with psychological, familial, social, or geographic factors that otherwise preclude them from giving informed consent, following the protocol, or potentially hamper compliance with study treatment and follow-up.
- •Patients who are otherwise felt unable to comply with the protocol, in the opinion of the investigator.
- •Any other significant medical condition, including psychiatric illness or laboratory abnormality, that would preclude the patient participating in the trial or would confound the interpretation of the results of the trial.
- •Patients with the following will be excluded: uncontrolled intercurrent illness including, but not limited to, symptomatic (New York Heart Association [NYHA] class III or IV) congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction at presentation of AML, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Patients with medical comorbidities that will preclude safety evaluation of the combination should not be enrolled.
- •Patients with uncontrolled infection shall not be enrolled until infection is treated and controlled.
- •Participants with prior documented history of malabsorption syndrome (e.g., short gut syndrome) that might limit the bioavailability of study medications will be excluded.
研究组 & 干预措施
Treatment (ASTX727, entrectinib)
Patients receive entrectinib PO QD on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Decitabine and Cedazuridine (Drug)
Treatment (ASTX727, entrectinib)
Patients receive entrectinib PO QD on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Treatment (ASTX727, entrectinib)
Patients receive entrectinib PO QD on days 1-28 and ASTX727 PO QD on days 1-5. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Entrectinib (Drug)
结局指标
主要结局
Incidence of dose limiting toxicities (DLTs)
时间窗: From first dose of study drug (day 1 of cycle 0) to end of cycle 1 (each cycle = 28 days)
Toxicities will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version \[v\] 5.0).
次要结局
- Overall survival (OS)(From first dose of study drug up to end of follow-up or death, assessed up to 6 months)
- Composite complete remission (CCR) rate(From first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant, end of study follow up, death (whichever is first), assessed up to 6 months)
- Overall response rate (ORR)(From first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months)
- Duration of response (DOR)(From first dose of study drug up to end of follow-up, loss of partial response (PR), progression or death (whichever is first), assessed up to 6 months)
- Incidence of treatment-related grade >= 3 adverse events(From first dose of study drug (day 1 of cycle 0) up to 30 days post end of therapy (each cycle = 28 days))
- Proportion transplanted(From first dose of study drug up to end of follow-up or death, assessed up to 6 months)
- Event free survival (EFS)(From first dose of study drug up to end of follow-up, relapse, progression, start of new cancer therapy, study drug discontinuation due to toxicity or death (whichever is first), assessed up to 6 months)
- Clinical benefit rate (CBR)(From first dose of study drug up to 2 weeks after last dose of study drug, start of new cancer therapy, or transplant (whichever is first), assessed up to 6 months)
研究者
Ronan Swords, M.D.
Principal Investigator
OHSU Knight Cancer Institute