A Study of HS-10382 in Patients With Chronic Myeloid Leukemia.

Официальное название

A Phase I, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Single and Multiple Doses of Oral Administration of HS-10382 in Patients With Chronic Myeloid Leukemia.

Обзор

HS-10382 is a small molecular, oral potent, allosteric inhibitor. By binding a myristoyl site of the BCR-ABL1 protein, HS-10382 locks BCR-ABL1 into an inactive conformation. The purpose of this study is to investigate the safety/tolerability and the pharmacokinetic(PK) profile of HS-10382 in patients with chronic myeloid leukemia (CML). Anti-CML activity will also be investigated in this study.

Подробное описание

This is an open-label, multicenter, dose-escalation and expansion, first-in-human study in participants of CML with T315I mutation or without T315I mutation in chronic phase/accelerate phase(CP/AP). This study will consist of two parts: A part 1 dose escalation stage and a part 2 dose expansion stage. The objectives of this study are to evaluate the safety, tolerability, PK and preliminary anti-CML activity, describe the dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) or maximum applicable dose (MAD) of HS-10382. Participants with CML-CP/AP are eligible for dose escalation study if they had resistance to or unacceptable side effect from BCR-ABL1 TKIs. After determination of the MTD or the MAD for CML patients, dose expansion will be undertaken to further evaluate the efficacy and safety of HS-10382 in patients with CML-CP. All patients will be carefully followed for adverse events during the study treatment and for 28 days after the last dose of study drug. Subjects of this study will be permitted to continue therapy with assessments for progression if the product is well tolerated and the subject has stable disease or better.

Вмешательства

• Препарат HS-10382(Part 1: Dose escalation)
  Single or multiple dose(s) of HS-10382 once daily.
• Препарат HS-10382(Part 2: Dose expansion)
  HS-10382 is administered orally once daily.

Первичные конечные точки

• Part 1(Dose escalation): Maximum tolerated dose (MTD) for HS-10382 [Срок оценки: From the single dose to the last dose of the first cycle as 28days of multiple dosing (35days).]
• Part 2(Dose expansion): Major cytogenetic response (MCyR) rate at 6 months [Срок оценки: 6 months]

Вторичные конечные точки (10)

• Incidence and severity of treatment-emergent adverse events [Срок оценки: From baseline until 28 days after the last dose.]
• Observed maximum plasma concentration (Cmax) after single dose of HS-10382 [Срок оценки: In the study of single-dose, Cmax will be obtained following administration of a single oral dose of HS-10382 on Day 1 to Day 6.]
• Time to reach maximum plasma concentration (Tmax) after single dose of HS-10382 [Срок оценки: From pre-dose to 120 hours after single dose on Day 1]
• Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) after single dose of HS-10382 [Срок оценки: From pre-dose to 120 hours after single dose on Day 1]
• Hematologic response [Срок оценки: at screening and 28th day of cycle 1,2,3,4,5,6,9 and 12.]
• Molecular response [Срок оценки: at screening and 28th day of cycle 3, 6, 9 and 12.]
• Cytogenetic response [Срок оценки: at screening and 28th day of cycle 3, 6, 9 and 12.]
• Event-free survival (EFS) [Срок оценки: up to 24 months]
• Progression-free survival (PFS) [Срок оценки: up to 24 months]
• Overall survival (OS) [Срок оценки: up to 24 months]

Критерии участия

Критерии включения

• Signed informed consent form.
• Men or women aged more than or equal to (≥) 18 years, and less than (<) 75 years.
• CML-CP/AP patients with the Ph chromosome or BCR-ABL1 fusion genes.
• Patient with CML-CP/AP who are resistant to or intolerant to previous TKIs therapy.
• ECOG performance status of 0-2.
• Life expectancy ≥ 12 weeks.
• Men or women should be using adequate contraceptive measures throughout the study; Females should not be breastfeeding at the time of screening, during the study and until 6 months after completion of the study.
• Females must have evidence of non-childbearing potential.

Критерии исключения

• CML-CP patients who have acquired CCyR and have not lost it.
• Patients with CML-CP who have progressed to AP or blast phase(BP.)
• Patients with CML-AP who have obtained CHR or no evidence of CML in peripheral blood.
• Patients with CML-AP who have progressed to BP.
• Previous treatment with a BCR-ABL1 TKI allosteric inhibitor .
• Impaired cardiac function including any one of the following:

• Resting corrected QT interval (QTc) > 470 ms obtained from electrocardiogram (ECG), using the screening clinic's ECG machine and Fridericia's formula for QT interval correction (QTcF).
• Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG.
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events,
• Left ventricular ejection fraction (LVEF) ≤ 50%.
• During screening period, ECG examination showed average heart rate <50 beats per minute.
• Myocardial infarction occurred within 6 months of the first scheduled dose of HS-10382.;
• Congestive heart failure occurred within 6 months of the first scheduled dose of HS-10382.;
• Uncontrollable angina.
• History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
• Any severe or uncontrolled systemic diseases (i.e. uncontrolled hypertension or diabetes).
• Clinically severe gastrointestinal dysfunction that may affect drug intake, transport or absorption.
• Severe infection within 4 weeks prior to the first scheduled dose of HS-10382.
• History of significant congenital or acquired bleeding disorders unrelated to CML.
• Inadequate other organ function.
• History of other malignancies.
• History of hypersensitivity to any active or inactive ingredient of HS-10382.
• History of neuropathy or mental disorders, including epilepsy and dementia.
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and — Ухань

Идентификаторы

NCT: NCT05367700 · HS-10382-101

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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