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

Overview

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

Interventions

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

Primary outcome measures

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

Secondary outcome measures (11)

• Incidence and severity of treatment-emergent adverse events [Time frame: 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 [Time frame: 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 [Time frame: Cycle 1 day 1 up to 28 days after the last dose]
• half-life (T1/2) of HS-10382 combination therapy [Time frame: Cycle 1 day 1 up to 28 days after the last dose]
• Area under the curve (AUC) of HS-10382 combination therapy [Time frame: Cycle 1 day 1 up to 28 days after the last dose]
• Hematologic Response of combination therapy with HS-10382 [Time frame: up to 24 months]
• Cytogenetic Response of combination therapy with HS-10382 [Time frame: up to 24 months]
• Molecular Response of combination therapy with HS-10382 [Time frame: up to 24 months]
• Event-free survival (EFS) [Time frame: up to 24 months]
• Progression-free survival (PFS) [Time frame: From the first dose to disease progression or withdrawal from study, whichever came first,up to 24 months]
• Overall survival (OS) [Time frame: From the first dose up to death or withdrawal from study, whichever came first, up to 24 months]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06530810 · HS-10382-102

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗