Study of HS-10382 Combination in Patients With Chronic Myeloid Leukemia (CML)

Официальное название

A Phase 1b, Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of HS-10382 Combination Therapy 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. Flumatinib is the first approved second generation TKI in China and a derivative of imatinib. The primary objective of this study is to evaluation the safety and tolerability and of HS-10382 combination therapy in patients with chronic myeloid leukemia (CML). The secondary objectives is to evaluate the PK profile, major metabolites and efficacy of HS-10382 in CML-CP/AP subjects after combination therapy, and to explore the kinase domain mutations associated with TKI resistance

Вмешательства

• Препарат HS-10382+Flumatinib
  Drug:HS-10382+Flumatinib HS-10382 is administered orally BID Drug:Flumatinib Flumatinib 400mg once daily

Первичные конечные точки

• Maximum tolerated dose (MTD) for HS-10382 combined treatment [Срок оценки: Up to day 28 from the first dose]

Вторичные конечные точки (11)

• Incidence and severity of treatment-emergent adverse events [Срок оценки: Cycle 1 day 1 up to 28 days after the last dose]
• maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite ) after HS-10382 combination therapy [Срок оценки: Cycle 1 day 1 up to 28 days after the last dose]
• Time to reach maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite) after HS-10382 combination therapy [Срок оценки: Cycle 1 day 1 up to 28 days after the last dose]
• half-life (T1/2) of HS-10382 combination therapy [Срок оценки: Cycle 1 day 1 up to 28 days after the last dose]
• Area under the curve (AUC) of HS-10382 combination therapy [Срок оценки: Cycle 1 day 1 up to 28 days after the last dose]
• Hematologic Response of combination therapy with HS-10382 [Срок оценки: up to 24 months]
• Cytogenetic Response of combination therapy with HS-10382 [Срок оценки: up to 24 months]
• Molecular Response of combination therapy with HS-10382 [Срок оценки: up to 24 months]
• Event-free survival (EFS) [Срок оценки: up to 24 months]
• Progression-free survival (PFS) [Срок оценки: From the first dose to disease progression or withdrawal from study, whichever came first,up to 24 months]
• Overall survival (OS) [Срок оценки: From the first dose up to death or withdrawal from study, whichever came first, 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 0-1 and no worsening within 2 weeks before the first dose.
• 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%.
• Myocardial infarction occurred within 6 months of the first scheduled dose of study drug.;
• Congestive heart failure occurred within 6 months of the first scheduled dose of study drug.;
• 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 study drug
• Inadequate other organ function.
• History of other malignancies.
• History of hypersensitivity to any active or inactive ingredient of HS-10382 and flumatinib.
• 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

Не применимо

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT06530810 · HS-10382-102

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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