HS-10352 is a highly potent and selective small molecule inhibitor of phosphoinositide 3-kinase (p110α). In preclinical studies, it demonstrated strong activity against PI3K p110α in vitro and in vivo, and inhibited tumor cell growth. The first-in-human trial is conducted to assess the maximum tolerated dose (MTD) and dose limiting toxicity (DLT), to evaluate the pharmacokinetics, safety and preliminary anti-tumor activity of HS-10352 at single dose and multiple doses.
This is a phase I, open-label, multicenter study to evaluate safety, tolerability, pharmacokinetics, and efficacy of single and multiple doses of oral administration of HS-10352 in patients with locally advanced or metastatic breast cancer with hormone receptor (HR) positive and epidermal growth factor receptor 2 (HER2) negative who have progressed following prior therapy. There is a dose-escalation study, which is designed to evaluate the safety, tolerability, and pharmacokinetics of single dose and multiple doses of HS-10352 given once every day (QD). An alternative dosing schedule of twice every day (BID) may be investigated if the drug clearance of HS-10352 is faster than anticipated. 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 once every 8 weeks, if the product is well tolerated and the subject has stable disease or better. As the disease progresses, survival follow-up is recommended bimonthly.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
54
Participants will receive single dose of HS-10352 on Day 1 of Cycle 1 followed by once daily from Day 8 of Cycle 1. (Cycle length: 35 days for Cycle 1 and 28 days for all other cycles). Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.
SUN YAT-SEN Memorial Hospital
Guanzhou, Guangdong, China
RECRUITINGHunan Cancer Hospital
Changsha, Hunan, China
RECRUITINGFudan University Shanghai Cancer Center
Shanghai, Shanghai Municipality, China
RECRUITINGNumber of subjects with any dose limiting toxicity (DLT)
DLT is defined as one of the following HS-10352 related adverse event (AE) that occurs during the DLT period, excluding AE assessed by investigator exclusively related to subject's underlying disease or medical condition (graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0):
Time frame: From the single dose to the last dose of the first cycle defined as 28 days of multiple dosing (35 days).
To determine the maximum tolerated dose (MTD)
MTD was defined as the previous dose level at which 2 of 2 subjects or 2 out of 6 subjects experienced a DLT.
Time frame: From the single dose to the last dose of the first cycle defined as 28 days of multiple dosing (35 days).
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, RECIST1.1, 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-10352
In the study of single-dose, Cmax will be obtained following administration of a single oral dose of HS-10352 on Day 1 to Day 6.
Time frame: From pre-dose to 120 hours after single dose on Day 1
Observed maximum plasma concentration (Cmax ss) after multiple dose of HS-10352
At multiple-dose, Cmax ss will be obtained on Day 1 of dosing in the second 28-Day cycle of therapy.
Time frame: From pre-dose to 24 hours after the first dose of multiple dosing on Day 1 of the second 28-Day cycle of therapy
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time to reach maximum plasma concentration (Tmax) after single dose of HS-10352
In the study of single-dose, Tmax will be obtained following administration of a single oral dose of HS-10352 on Day 1 to Day 6.
Time frame: From pre-dose to 120 hours after single dose on Day 1
Time to reach maximum plasma concentration (Tmax) after multiple dose of HS-10352
At multiple-dose, Tmax will be obtained on Day 1 of dosing in the second 28-Day cycle of therapy.
Time frame: From pre-dose to 24 hours after the first dose of multiple dosing on Day 1 of the second 28-Day cycle of therapy
Apparent terminal half-life (t1/2) after single dose of HS-10352
Apparent terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz.
Time frame: From pre-dose to 120 hours after single dose on Day 1
Area under plasma concentration versus time curve from zero to the 24-hour sampling time (AUC0-24) after single dose of HS-10352
Area under the plasma concentration versus time curve from time zero to the 24-hour sampling time at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-24 was to be calculated according to the mixed log-linear trapezoidal rule.
Time frame: From pre-dose to 24 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-10352
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
Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞) after single dose of HS-10352
AUC0-∞ was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the LLQ and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: From pre-dose to 120 hours after single dose on Day 1
To further evaluation of the anti-tumor activity of HS-10352 by assessment of objective response rate (ORR)
Anti-tumor efficacy will be assessed by best radiographic response based on Response Evaluation Criteria in Solid Tumors at baseline (Day -28 to -1). For patients that continue on repeating 28-Day cycles after the primary evaluation period, progression will be assessed after each 8 weeks of therapy. ORR is defined as the percentage of patients with a complete response (CR) or partial response (PR) that was confirmed at a subsequent scan at least 4 weeks later, as assessed according to RECIST version 1.1.
Time frame: From the date of first occurrence of complete response (CR) or partial response (PR) on 2 consecutive occasions (≥4 weeks), until the date of disease progression or withdrawal from study, approximately 3 years
Disease control rate of HS-10352
Objective response was assessed by RECIST 1.1 thereby to evaluate disease control rate. Disease control was defined as the percentage of patients who have a best overall response (confirmed CR, PR, or stable disease for at least 6 weeks).
Time frame: From the first occurrence of confirmed CR or PR or SD until the date of disease progression or withdrawal from study, approximately 3 years
Deepness of response of HS-10352
Objective response was assessed by RECIST 1.1 thereby to evaluate deepness of response. Depth of response was defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions, or progression of non-target lesions compared with baseline.
Time frame: From the date of enrollment until the date of disease progression or death, approximately 3 years
Progression-free survival of HS-10352
Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival. Progression-free survival was defined as the time from date of first dose until the documentation of objective disease progression (PD) or death from any cause in the absence of progression (whichever occurred first), regardless of whether they subsequently received non-study anti-cancer therapy.
Time frame: From the date of enrollment until the date of disease progression or death from any cause, approximately 3 years
Overall survival of HS-10352
Overall survival was defined as the time from date of first dose until the documentation of death from any cause.
Time frame: From the date of enrollment until the date of death from any cause, approximately 5 years