Chronic Myelogenous Leukemia, CML Accelerated Phase, CML Chronic Phase
Conditions
Keywords
CML-CP/AP, HS-10382, Flumatinib, Allosteric inhibitor
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
Interventions
DRUGHS-10382+Flumatinib
Drug:HS-10382+Flumatinib HS-10382 is administered orally BID Drug:Flumatinib Flumatinib 400mg once daily
Sponsors
Jiangsu Hansoh Pharmaceutical Co., Ltd.
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum tolerated dose (MTD) for HS-10382 combined treatment | Up to day 28 from the first dose | MTD was defined as the previous dose level at which 2 out of 3 subjects or 2 out of 6 subjects experienced a DLT |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | From the first dose to disease progression or withdrawal from study, whichever came first,up to 24 months | 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) | From the first dose up to death or withdrawal from study, whichever came first, up to 24 months | OS is defined as the time from the date of first dose to the date of death from any cause. |
| Incidence and severity of treatment-emergent adverse events | Cycle 1 day 1 up to 28 days after the last dose | 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 |
| maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite ) after HS-10382 combination therapy | Cycle 1 day 1 up to 28 days after the last dose | Cmax is the maximum observed concentration. |
| Time to reach maximum plasma concentration of HS-10382 or Flumatinib(and its major metabolite) after HS-10382 combination therapy | Cycle 1 day 1 up to 28 days after the last dose | Tmax is defined as time to reach maximum observed plasma concentration |
| Event-free survival (EFS) | up to 24 months | 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 . |
| Area under the curve (AUC) of HS-10382 combination therapy | Cycle 1 day 1 up to 28 days after the last dose | The AUC is defined as the area under the plasma concentration-time curve |
| Hematologic Response of combination therapy with HS-10382 | up to 24 months | 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. |
| Cytogenetic Response of combination therapy with HS-10382 | up to 24 months | 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. |
| Molecular Response of combination therapy with HS-10382 | up to 24 months | To record and analyse the molecular response of subjects. Molecular response will be assessed by BCR-ABL1 transcript level as measured by RQ-PCR. |
| half-life (T1/2) of HS-10382 combination therapy | Cycle 1 day 1 up to 28 days after the last dose | half-life is the time measured for the concentration to decrease by one half |
Contacts
Primary ContactYu Hu, PhD
Outcome results
None listed