A PhaseⅠStudy of HS-10381 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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HS-10381 is a small molecular, oral potent, SHP2 inhibitor. 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-10381 in Patients With Advanced Solid Tumors.

Detailed Description
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This is a Phase 1 open-label, multicenter study to evaluate the safety, tolerability, PK and preliminary efficacy of HS-10381 in patients with advanced solid tumors by using a 3+3 dose escalation.

Official Title
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A Phase I, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of HS-10381 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumor

Intervention / Treatment
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* Drug: HS-10381


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women aged more than or equal to (≥) 18 years Advanced solid tumor patients confirmed by histology or cytology for who that standard treatment is invalid, unavailable or intolerable Patients have at least one target lesion according to RECEST 1.1. The requirements for target lesions are: measurable lesions without local treatment such as irradiation, or with definite progress after local treatment, with the longest diameter ≥ 10 mm in the baseline period (in case of lymph nodes, the shortest axis ≥ 15 mm is required) ECOG performance status was 0-1 and did not deteriorate in the previous 2 weeks Estimated life expectancy greater than (>) 12 weeks Females should be using adequate contraceptive measures throughout the study; should not be breastfeeding at the time of screening, during the study and until 3 months after completion of the study; and must have evidence of non-childbearing potential Sign Informed Consent Form Exclusion Criteria: Treatment with any of the following: Previous or current treatment with drugs targeting SHP2 Any cytotoxic chemotherapy, investigational agents or anticancer drugs within 28 days of the first dose of study drug Radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study drug, or patients received more than 30% of the bone marrow irradiation, or large-scale radiotherapy within 4 weeks of the first dose. Major surgery (including craniotomy, thoracotomy, or laparotomy, etc.) within 4 weeks of the first dose of study drug. Known and untreated, or active central nervous system metastases. Existing abnormal CTCAE≥grade 2 resulted from previous treatment History of other malignancy Inadequate bone marrow reserve or organ function Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV), unless the hepatitis is considered to be cured, Known history of HIV History of hypersensitivity to any active or inactive ingredient of HS-10381. 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. Any disease or condition that, in the opinion of the investigator, would compromise the safety of the patient or interfere with study assessments.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I：Dose escalation<br>HS-10381 given orally QD of various dose strengths administered in 21 day dosing cycles. | Drug: HS-10381<br>* Each subject will receive a single dose(C0) of HS-10381 and then repeat doses(C1, C2…) for 21-day cycles. Participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria is met.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of HS-10381 | To determine the MTD of HS-10381 in subjects with advanced solid tumors. | 4 weeks after initiation of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events | The CTCAE criteria will be used to assess adverse events on this trial. | Baseline through study completion(28 days after last dose) | 
| Observed maximum plasma concentration (Cmax) after single dose of HS-10381 | Cmax will be obtained after single dose of HS-10381 on Cycle 0 Day 1. | From pre-dose to 120 hours after single dose on Cycle 0 Day 1. | 
| Observed maximum plasma concentration (Cmax ss) after multiple dose of HS-10381 | Cmax ss will be obtained on Cycle 2 Day 1. | From pre-dose to 24 hours after the dose on Cycle 2 Day 1 | 
| Apparent terminal half-life (t1/2) after single dose of HS-10381 | Apparent terminal half-life is the time measured for the concentration to decrease by one half. | From pre-dose to 120 hours after single dose on Cycle 0 Day 1 | 
| Area under plasma concentration versus time curve from zero to the 24-hour sampling time (AUC0-24) after single dose of HS-10381 | 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). | From pre-dose to 24 hours after single dose on Cycle 0 Day 1 | 
| Area under plasma concentration versus time curve from zero to last sampling time (AUC0-t) after single dose of HS-10381 | 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). | From pre-dose to 120 hours after single dose on Cycle 0 Day 1 | 
| Area under the plasma concentration versus time curve from time zero to infinity (AUC0-∞) after single dose of HS-10381 | 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. | From pre-dose to 120 hours after single dose on Cycle 0 Day 1 | 
| To further evaluation of the anti-tumor activity of HS-10381 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 21-Day cycles after the primary evaluation period, progression will be assessed after each 6 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. | 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，up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HS-10381, SHP2, Advanced Solid Tumor