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

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

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

Study Overview

• Status: Not yet recruiting
• Conditions: Chronic Myelogenous Leukemia; CML Chronic Phase; CML Accelerated Phase
• Intervention / Treatment: Drug: HS-10382+Flumatinib

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Yu Hu, PhD; Phone Number: 13986183871; Email: dr_huyu@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: HS-10382+Flumatinib; Subjects with resistant or intolerant CML CP/AP will be enrolled in dose-escalation stage.Dose escalation of HS-10382 combined flumatinib will be done to determine maximum tolerated dose(Part 1). Depending on data obtained from the dose-escalation stage,dose expansion may proceed with in subjects with newly diagnosed CML-CP.The safety and efficacy will be evaluated at the target dose.(Part 2)

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD) for HS-10382 combined treatment	MTD was defined as the previous dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT	Up to day 28 from the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	EFS is defined as the time from the date of first dose to the earliest occurrence of the following events: death due to any cause ; loss of CHR ,loss of PCyR ;loss of CCyR ; discontinuation of study treatment due to AE or treatment failure ; progression to AP/BC .	up to 24 months
Incidence and severity of treatment-emergent adverse events	Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, and NCI CTCAE v5.0	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	Cmax is the maximum observed concentration.	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	Tmax is defined as time to reach maximum observed plasma concentration	Cycle 1 day 1 up to 28 days after the last dose
half-life (T1/2) of HS-10382 combination therapy	half-life is the time measured for the concentration to decrease by one half	Cycle 1 day 1 up to 28 days after the last dose
Area under the curve (AUC) of HS-10382 combination therapy	The AUC is defined as the area under the plasma concentration-time curve	Cycle 1 day 1 up to 28 days after the last dose
Hematologic Response of combination therapy with HS-10382	To record and analyse the hematologic response of subjects. Hematologic response will be assessed by complete blood count (CBC) and physical examination at each visit.	up to 24 months
Cytogenetic Response of combination therapy with HS-10382	To record and analyse the cytogenetic response of subjects. Cytogenetic response (CyR) is based on the prevalence of Ph+ cells in metaphase from bone marrow (BM) sample.	up to 24 months
Molecular Response of combination therapy with HS-10382	To record and analyse the molecular response of subjects. Molecular response will be assessed by BCR-ABL1 transcript level as measured by RQ-PCR.	up to 24 months
Progression-free survival (PFS)	PFS is defined as the time from the date of first dose to the earliest occurrence of progression to AP/BC or death from any cause.	From the first dose to disease progression or withdrawal from study, whichever came first,up to 24 months
Overall survival (OS)	OS is defined as the time from the date of first dose to the date of death from any cause.	From the first dose up to death or withdrawal from study, whichever came first, up to 24 months

Collaborators and Investigators

• Sponsor: Jiangsu Hansoh Pharmaceutical Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Estimated): July 31, 2024
• Primary Completion (Estimated): May 8, 2026
• Study Completion (Estimated): May 8, 2028

Study Registration Dates

• First Submitted: July 19, 2024
• First Submitted That Met QC Criteria: July 26, 2024
• First Posted (Actual): July 31, 2024

Study Record Updates

• Last Update Posted (Actual): July 31, 2024
• Last Update Submitted That Met QC Criteria: July 26, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Flumatinib; Allosteric inhibitor; CML-CP/AP; HS-10382
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Chronic Disease; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; Flumatinib
• Other Study ID Numbers: HS-10382-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No