Hase 1/2 Study of HS-10375 in Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer(NSCLC)

Study Overview
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Brief Summary
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HS-10375 is an oral, highly selective, small molecular inhibitor of EGFR C797S. This study will evaluate the safety, tolerability, pharmacokinetics and clinical activity of HS-10375 in Chinese advanced or metastatic NSCLC.

Official Title
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A Phase 1/2, Open-label, Multicenter Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of HS-10375 Monotherapy in Patients With Advanced or Metastatic Non-Small-Cell Lung Cancer(NSCLC)

Conditions
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Advanced or Metastatic NSCLC

Intervention / Treatment
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* Drug: HS-10375


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women greater than or equal to 18 years. Locally advanced or metastatic NSCLC patients confirmed by histology or cytology, for which standard treatment is invalid, unavailable or intolerable . Pathological, NSCLC tissue samples can be used to test EGFR C797S mutation by central laboratory for Phase 1b and Phase II subjects. At least one measurable lesion in accordance with RECIST 1.1. Eastern Cooperative Oncology Group (ECOG) performance status: 0 1. Estimated life expectancy >12 weeks. Reproductive-age women agree to use adequate contraception and cannot breastfeed while participating in this study and for a period of 6 months after the last dose. Likewise, men also consent to use adequate contraceptive method within the same time limit. Females must have the evidence of non-childbearing potential. Signed and dated Informed Consent Form. Exclusion Criteria: Treatment with any of the following: Previous or current treatment with EGFR C797S inhibitors. Any cytotoxic chemotherapy, anticancer Chinese medicine and targeted small molecule inhibitors within 14 days of the first dose of HS-10375. Any investigational agents and large molecule antibodies within 28 days of the first dose of HS-10375. Local radiotherapy for palliation within 2 weeks of the first dose of HS-10375, or patients received more than 30% of the bone marrow irradiation, or large-scale radiotherapy within 4 weeks of the first dose of HS-10375. Major surgery (including craniotomy, thoracotomy, or laparotomy, etc.) within 4 weeks of the first dose of HS-10375. Inadequate bone marrow reserve or serious organ dysfunction. Uncontrolled pleural, ascites or pericardial effusion. Known and untreated, or active central nervous system metastases. Active autoimmune diseases or active infectious disease. Refractory nausea, vomiting, or chronic gastrointestinal diseases, or inability to swallow oral medications. History of hypersensitivity to any active or inactive ingredient of HS-10375 or to drugs with a similar chemical structure or drugs belonging to the same category of HS-10375. The subject who is unlikely to comply with study procedures, restrictions, or requirements judged by the investigator. The subject whose safety cannot be ensured or study assessments would be interfered judged by the investigator. Pregnant women, breastfeeding women or woman who has a child-bearing plan during the study. History of neuropathy or mental disorders, including epilepsy and dementia.

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: HS-10375<br>Experimental: HS-10375（Phase 1a：Dose Escalation） Subjects with advanced or metastatic NSCLC will be enrolled in dose escalation cohorts. Dose escalation of HS-10375 will be done to determine maximum tolerated dose. Experimental: HS-10375（Phase 1b：Dose Expansion） Depending on data obtained from the dose escalation part, dose expansion may proceed with multiple cohorts in subjects with advanced or metastatic NSCLC having a EGFR C797S mutation. Experimental: HS-10375（Phase 2） Subjects with locally advanced or metastatic EGFR C797S mutant NSCLC will be enrolled in phase 2 part to evaluate the efficacy and sufficient safety of HS-10375 as monotherapy. | Drug: HS-10375<br>* HS-10375 will be administered orally once daily in a continuous regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the maximum tolerated dose (MTD)-Part Ia | Number of participants with dose limiting toxicity | From the single dose to the last dose of the first cycle defined as 21 days of multiple dosing (28 days) | 
| To evaluate clinical activity/efficacy of HS-10375 by assessment of objective response rate-Part Ib/II | Objective response rate (ORR) assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) | Time Frame: up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment related adverse events | Number of participants with treatment related adverse events | From baseline until 28 days after the last dose | 
| Observed maximum plasma concentration (Cmax) after single dose of HS-10375 | In the study of single-dose, Cmax will be obtained following administration of a single oral dose of HS-10375 | From pre-dose to 120 hours after single dose on Day 1 | 
| Time to reach maximum plasma concentration (Tmax) after single dose of HS-10375 | In the study of single-dose, Tmax will be obtained following administration of a single oral dose of HS-10375 | From pre-dose to 120 hours after single dose on Day 1 | 
| Apparent terminal half-life (T1/2) after single dose of HS-10375 | 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 | From pre-dose to 120 hours after single dose on Day 1 | 
| Duration of response (DOR) | DOR assessed by RECIST 1.1 criteria | 24 months | 
| Disease Control Rate (DCR) | DCR assessed by RECIST 1.1 criteria | 24 months | 
| Progression-free survival (PFS) | PFS assessed by RECIST 1.1 criteria | 24 months | 
| Overall survival (OS) |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced or metastatic NSCLC, EGFR C797S mutation, HS-10375