Clinical trial NCT06530810: Study of HS-10382 Combination in Patients With Chronic Myeloid Leukemia (CML)
Official title: 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
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Chronic Myelogenous Leukemia
CML Chronic Phase
CML Accelerated Phase
Keywords: CML-CP/AP
HS-10382
Flumatinib
Allosteric inhibitor
Lead sponsor: Jiangsu Hansoh Pharmaceutical Co., Ltd.
Sponsor class: INDUSTRY
First posted: 2024-07-31
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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


Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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

Primary outcomes:
measure: Maximum tolerated dose (MTD) for HS-10382 combined treatment
timeFrame: Up to day 28 from the first dose
Secondary outcomes:
measure: Incidence and severity of treatment-emergent adverse events
timeFrame: Cycle 1 day 1 up to 28 days after the last dose
measure: maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite ) after HS-10382 combination therapy
timeFrame: Cycle 1 day 1 up to 28 days after the last dose
measure: Time to reach maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite) after HS-10382 combination therapy
timeFrame: Cycle 1 day 1 up to 28 days after the last dose
measure: half-life (T1/2) of HS-10382 combination therapy
timeFrame: Cycle 1 day 1 up to 28 days after the last dose
measure: Area under the curve (AUC) of HS-10382 combination therapy
timeFrame: Cycle 1 day 1 up to 28 days after the last dose
measure: Hematologic Response of combination therapy with HS-10382
timeFrame: up to 24 months
measure: Cytogenetic Response of combination therapy with HS-10382
timeFrame: up to 24 months
measure: Molecular Response of combination therapy with HS-10382
timeFrame: up to 24 months
measure: Event-free survival (EFS)
timeFrame: up to 24 months
measure: Progression-free survival (PFS)
timeFrame: From the first dose to disease progression or withdrawal from study, whichever came first,up to 24 months
measure: Overall survival (OS)
timeFrame: From the first dose up to death or withdrawal from study, whichever came first, up to 24 months
Other outcomes:
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