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

Primary Purpose

CML, Chronic Phase, CML, Accelerated Phase

Status

Recruiting

Phase

Phase 1

Locations

China

Study Type

Interventional

Intervention

HS-10382(Part 1: Dose escalation)

HS-10382(Part 2: Dose expansion)

About this trial

This is an interventional treatment trial for CML, Chronic Phase focused on measuring CML-CP/AP, HS-10382, BCR-ABL TKI, Phase I, Allosteric inhibitor

Eligibility Criteria

18 Years - 74 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 0-2.
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.

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:
1. 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).
2. Any clinically important abnormalities in rhythm, conduction, or morphology of the resting ECG.
3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events,
4. Left ventricular ejection fraction (LVEF) ≤ 50%.
5. During screening period, ECG examination showed average heart rate <50 beats per minute.
6. Myocardial infarction occurred within 6 months of the first scheduled dose of HS-10382.;
7. Congestive heart failure occurred within 6 months of the first scheduled dose of HS-10382.;
8. 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.

Sites / Locations

Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and TechnologyRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

HS-10382 (Part 1: Dose escalation)

HS-10382 (Part 2: Dose expansion)

Arm Description

There are five escalation dose cohorts.

The recommended dose from the dose-escalation stage and other potential doses will be further explored.

Outcomes

Primary Outcome Measures

Part 1(Dose escalation): Maximum tolerated dose (MTD) for HS-10382

MTD was defined as the previous dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT.

Part 2(Dose expansion): Major cytogenetic response (MCyR) rate at 6 months

MCyR is the proportion of patients achieving Complete cytogenetic response (CCyR: defined as 0% Philadelphia chromosome-positive [Ph+] metaphases by cytogenetic analysis of bone marrow) and Partial Cytogenetic Response (PCyR: defined as >0% to 35% Ph+ metaphases by cytogenetic analysis of bone marrow).

Secondary Outcome Measures

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.

Observed maximum plasma concentration (Cmax) after single dose of HS-10382

From pre-dose to 120 hours after single dose on Day 1

Time to reach maximum plasma concentration (Tmax) after single dose of HS-10382

In the study of single-dose, Tmax will be obtained following administration of a single oral dose of HS-10382 on Day 1 to Day 6.

Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) after single dose of HS-10382

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

Hematologic response

Hematologic response will be assessed by complete blood count (CBC) and physical examination at each visit.

Molecular response

Molecular response will be assessed by BCR-ABL1 transcript level as measured by RQ-PCR.

Cytogenetic response

Cytogenetic response (CyR) is based on the prevalence of Ph+ cells in metaphase from bone marrow (BM) sample.

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 .

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.

Overall survival (OS)

OS is defined as the time from the date of first dose to the date of death from any cause.

Full Information

NCT ID

NCT05367700

First Posted

May 6, 2022

Last Updated

January 12, 2023

Sponsor

Jiangsu Hansoh Pharmaceutical Co., Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT05367700

Brief Title

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

Official Title

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.

Study Type

Interventional

2. Study Status

Record Verification Date

January 2023

Overall Recruitment Status

Recruiting

Study Start Date

April 28, 2022 (Actual)

Primary Completion Date

December 30, 2024 (Anticipated)

Study Completion Date

September 30, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Jiangsu Hansoh Pharmaceutical Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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. 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.

Detailed Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

CML, Chronic Phase, CML, Accelerated Phase

Keywords

CML-CP/AP, HS-10382, BCR-ABL TKI, Phase I, Allosteric inhibitor

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

108 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

HS-10382 (Part 1: Dose escalation)

Arm Type

Experimental

Arm Description

There are five escalation dose cohorts.

Arm Title

HS-10382 (Part 2: Dose expansion)

Arm Type

Experimental

Arm Description

The recommended dose from the dose-escalation stage and other potential doses will be further explored.

Intervention Type

Drug

Intervention Name(s)

HS-10382(Part 1: Dose escalation)

Intervention Description

Single or multiple dose(s) of HS-10382 once daily.

Intervention Type

Drug

Intervention Name(s)

HS-10382(Part 2: Dose expansion)

Intervention Description

HS-10382 is administered orally once daily.

Primary Outcome Measure Information:

Title

Part 1(Dose escalation): Maximum tolerated dose (MTD) for HS-10382

Description

MTD was defined as the previous dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT.

Time Frame

From the single dose to the last dose of the first cycle as 28days of multiple dosing (35days).

Title

Part 2(Dose expansion): Major cytogenetic response (MCyR) rate at 6 months

Description

Time Frame

6 months

Secondary Outcome Measure Information:

Title

Incidence and severity of treatment-emergent adverse events

Description

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.

Time Frame

From baseline until 28 days after the last dose.

Title

Observed maximum plasma concentration (Cmax) after single dose of HS-10382

Description

From pre-dose to 120 hours after single dose on Day 1

Time Frame

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.

Title

Time to reach maximum plasma concentration (Tmax) after single dose of HS-10382

Description

In the study of single-dose, Tmax will be obtained following administration of a single oral dose of HS-10382 on Day 1 to Day 6.

Time Frame

From pre-dose to 120 hours after single dose on Day 1

Title

Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) after single dose of HS-10382

Description

Time Frame

From pre-dose to 120 hours after single dose on Day 1

Title

Hematologic response

Description

Hematologic response will be assessed by complete blood count (CBC) and physical examination at each visit.

Time Frame

at screening and 28th day of cycle 1,2,3,4,5,6,9 and 12.

Title

Molecular response

Description

Molecular response will be assessed by BCR-ABL1 transcript level as measured by RQ-PCR.

Time Frame

at screening and 28th day of cycle 3, 6, 9 and 12.

Title

Cytogenetic response

Description

Cytogenetic response (CyR) is based on the prevalence of Ph+ cells in metaphase from bone marrow (BM) sample.

Time Frame

at screening and 28th day of cycle 3, 6, 9 and 12.

Title

Event-free survival (EFS)

Description

Time Frame

up to 24 months

Title

Progression-free survival (PFS)

Description

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.

Time Frame

up to 24 months

Title

Overall survival (OS)

Description

OS is defined as the time from the date of first dose to the date of death from any cause.

Time Frame

up to 24 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

74 Years

Accepts Healthy Volunteers

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 0-2. 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. 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%. 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Yu Hu

Phone

13986183871

dr_huyu@126.com

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Yu Hu

Organizational Affiliation

Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology

Official's Role

Principal Investigator

Facility Information:

Facility Name

Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology

City

Wuhan

State/Province

Hubei

ZIP/Postal Code

430022

Country

China

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Yu Hu

Phone

13986183871

dr_huyu@126.com

12. IPD Sharing Statement

Learn more about this trial

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

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