临床试验/NCT03850574

NCT03850574招募中1 期

A Phase 1/2 Open Label, Multicenter, Dose Escalation and Expansion Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HM43239 in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML)

Aptose Biosciences Inc.34 个研究点分布在 6 个国家目标入组 240 人开始时间: 2019年3月11日最近更新: 2025年8月26日

适应症

干预措施

试验速览

阶段: 1 期
状态: 招募中
发起方: Aptose Biosciences Inc.
入组人数: 240
试验地点: 34
主要终点: Frequency and severity of drug-related adverse events

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验相关资讯

研究概览

简要总结

A Phase 1/2, Open-label, Multicenter, Dose Escalation and Expansion Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Tuspetinib (HM43239) in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)

详细描述

This is a Phase 1/2, open-label, multi-center study designed to assess the efficacy, safety, tolerability, and pharmacokinetics, including determining the recommended Phase 2 dose (RP2D) of tuspetinib (HM43239) in subjects with relapsed or treatment-refractory acute myeloid leukemia (AML).

Part C: This portion of the study will evaluate tuspetinib (HM43239) as monotherapy in patients with relapsed or refractory (R/R) AML, focusing on safety, tolerability, pharmacokinetics, and preliminary efficacy (Aptivate).

Part D: This portion of the study will evaluate the safety, tolerability, and PK parameters of tuspetinib (HM43239) in combination with venetoclax and azacitidine when administered to newly diagnosed AML patients who are ineligible for induction chemotherapy (Tuscany).

研究设计

研究类型: Interventional
分配方式: Randomized
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

•Patient is defined as having morphologically documented primary or secondary AML by the World Health Organization (WHO) criteria (2016) and fulfills one of the following:
•Refractory to at least 1 cycle of prior therapy
•Relapsed after achieving remission with a prior therapy
•Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤
•Patient's interval from prior treatment to time of study drug administration is at least 2 weeks for cytotoxic agents (except hydroxyurea given for controlling blast cells), at 4 weeks for biologic or cellular immunotherapies, or at least 5 half-lives for prior experimental agents or noncytotoxic agents, including immunosuppressive therapy post hematopoietic stem cell transplantation (HSCT). (upon discussion with the Medical Monitor, shorter than stated washout period may be considered provided that the patient has recovered from any clinically relevant safety issue and recovered to Grade ≤ 1 toxicity from prior therapies)
•Patient must meet the following criteria as indicated on the clinical laboratory tests
•Serum aspartate aminotransferase(AST) and alanine aminotransferase(ALT) ≤ 2.5× institutional upper limit normal (ULN)
•Total serum bilirubin ≤ 1.5× institutional ULN
•Serum creatinine ≤ 1.5× institutional ULN or an estimated glomerular filtration rate (eGFR) of > 45 ml/min as calculated by the Modification of Diet in Renal Disease (MDRD) equation.
•Patient is suitable for oral administration of study drug and has minimum life expectancy (≥ 3 months)
•Female patient must be either:
•Of non-child bearing potential
•Post-menopausal (defined as at least 1 year without any menses) prior to screening, or
•Documented surgically sterile or status post hysterectomy (at least 1 month prior to screening)
•Or, if of childbearing potential,
•Must have a negative serum or urine pregnancy test at screening (within 72 hours prior to start of treatment), and
•Must use highly effective contraception starting at screening and throughout the study period and for 90 days after the final study drug administration.
•Female patient must not be breastfeeding at screening and during the study period, and for 90 days after the final study drug administration
•Female patient must not donate ova starting at screening and throughout the study period, and for 90 days after the final study drug administration.
•Male patient and their female spouse/partners who are of childbearing potential must be using highly effective contraception starting at screening and continue throughout the study period and for 90 days after the final study drug administration.
•Male patient must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.
•Patient agrees not to participate in another interventional study while on treatment

排除标准

•Patients must not enter the study if any of the following exclusion criteria are fulfilled.
•Patient was diagnosed as acute promyelocytic leukemia (APL)
•Patient has BCR-ABL-positive leukemia
•Patient has an active malignancy other than AML, or Myelodysplastic Syndrome (MDS).
•Patient has persistent non-hematological toxicities of ≥ Grade 2 (CTCAE v4.03), with symptoms and objective findings, from prior AML treatment (including chemotherapy, kinase inhibitors, immunotherapy, experimental agents, radiation, or surgery)
•Patient has had hematopoietic stem cell transplant (HSCT) and meets any of the following:
•Has undergone HSCT within the 2 month period prior to the first study dose
•Has clinically significant graft-versus-host-disease(GVHD) requiring treatment
•Has ≥ Grade 2 persistent non-hematological toxicity related to the transplant
•Has a donor lymphocytes infusion (DLI) ≤ 30 days prior to the first study dose or during the first two cycle of treatment on the study.
•Patient has meningeal or central nervous system (CNS) involvement with leukemia or other CNS disease related to underlying and secondary effects of malignancy.
•Patient has disseminated intravascular coagulation abnormality (DIC).
•Patient has had major surgery within 4 weeks prior to the first study dose.
•Patient has had radiation therapy within 4 weeks prior to the first study dose.
•Patient has congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patient with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multigated acquisition (MUGA) scan performed within 3 months prior to study entry results in a left ventricular ejection fraction (LVEF) that is ≥ 45%.
•Any of the following cardiac abnormalities of history
•Patient has any clinically important abnormalities in rhythm, conduction or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, or PR interval > 250 milliseconds (ms).
•Patient has a mean QT interval (QTc) by Friderica's method (QTcF) > 450ms in three successive Screening measurements.
•Patient has any factors that increase the risk of QTc prolongation or risk of arrhythmic events, such as congenital long QT, syndrome, family history of long QT syndrome.
•Patient is unable or unwilling to discontinue concomitant use of drugs that are known to prolong the QT interval.
•Patient is known to have active infection including any identified active COVID-19 infection.
•Patient is known to have human immunodeficiency virus infection.
•Patient has known active hepatitis B or C, or other active hepatic disorder.
•Patient has any condition which, in the investigator's opinion, makes the patient unsuitable for study participation.
•Patient has a history of Grade 3 or 4 non-hematologic toxicity related to tyrosine kinase inhibitor.

研究组 & 干预措施

Part A Dose Escalation [COMPLETED]

Experimental

Part A dose escalation of tuspetinib as a single agent is planned for up to 6 dose levels. If a study participant in dose escalation at any dose level achieves clinical response, then the dose level will continue to enroll in Part B. If one DLT or less is observed in the 6 participants (<1/6 DLT observed) in Part A, up to 20 evaluable participants can be enrolled in Part B at that dose level.

干预措施: Tuspetinib (Drug)

Part B Dose Exploration [ACTIVE, NOT RECRUITING]

Experimental

Part B dose exploration of tuspetinib as a single agent is planned for up to 4 dose levels.

干预措施: Tuspetinib (Drug)

Part C Dose Expansion (tuspetinib as a single agent) [COMPLETE]

Experimental

Part C dose expansion of tuspetinib as a single agent is planned for 2 dose levels. Study participants will be randomly assigned to either arm based on the number of slots available. The initial tuspetinib dose will be 120 mg.

干预措施: Tuspetinib (Drug)

Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]

Experimental

Part C dose expansion of tuspetinib in combination with venetoclax is planned for 2 dose levels. The initial tuspetinib dose will be 80 mg.

干预措施: Tuspetinib (Drug)

Part C Dose Expansion (tuspetinib plus venetoclax) [COMPLETE]

Experimental

Part C dose expansion of tuspetinib in combination with venetoclax is planned for 2 dose levels. The initial tuspetinib dose will be 80 mg.

干预措施: Venetoclax Oral Tablet (Drug)

Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

Experimental

Part D dose exploration of tuspetinib in combination with venetoclax and azacitidine is planned for up to 6 dose levels. The initial tuspetinib dose will be 40 mg.

干预措施: Tuspetinib (Drug)

Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

Experimental

Part D dose exploration of tuspetinib in combination with venetoclax and azacitidine is planned for up to 6 dose levels. The initial tuspetinib dose will be 40 mg.

干预措施: Venetoclax Oral Tablet (Drug)

Part D Dose Exploration (tuspetinib plus venetoclax and azacitidine) [ACTIVE, RECRUITING - US Sites]

Experimental

Part D dose exploration of tuspetinib in combination with venetoclax and azacitidine is planned for up to 6 dose levels. The initial tuspetinib dose will be 40 mg.

干预措施: Azacitidine for Intravenous Infusion (Drug)

结局指标

主要结局

Frequency and severity of drug-related adverse events

时间窗: 4 years

Maximum tolerated dose (MTD) of tuspetinib

时间窗: 4 years

The MTD will be determined as the dose at which no more than 1 out of 6 study participants experiences a dose-limiting toxicity (DLT). Alternatively, the safety of a clinically effective dose below the MTD will be established if the MTD is not reached in study participants.

Maximum plasma concentration (Cmax)