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.
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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
108
Single or multiple dose(s) of HS-10382 once daily.
HS-10382 is administered orally once daily.
Union Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology
Wuhan, Hubei, China
RECRUITINGPart 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.
Time frame: From the single dose to the last dose of the first cycle as 28days of multiple dosing (35days).
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).
Time frame: 6 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.
Time frame: From baseline until 28 days after the last dose.
Observed maximum plasma concentration (Cmax) after single dose of HS-10382
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.
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.
Time frame: From pre-dose to 120 hours after single dose on Day 1
Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) after single dose of HS-10382
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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.
Time frame: From pre-dose to 120 hours after single dose on Day 1
Hematologic response
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.
Molecular response
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.
Cytogenetic response
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.
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 .
Time frame: 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.
Time frame: 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.
Time frame: up to 24 months