Phase 1/2 Study of HS-10376 in Patients With Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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HS-10376 is an oral, highly selective, small molecular inhibitor of EGFR/HER2 Exon 20 insertion mutation. This study will evaluate the safety, tolerability, pharmacokinetics and clinical activity of HS-10376 in Chinese advanced Non-Small Cell Lung Cancer (NSCLC) patients.

Detailed Description
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This is a phase 1/2, first-in-human, open-label, multicenter study of HS-10376, this study has two parts: phase 1 and phase 2. The phase 1 portion consists of dose escalation and dose expansion, which is aimed to assess the safety and tolerability of HS-10376 in subjects with advanced NSCLC and evaluate the preliminary efficacy of HS-10376. Phase 2 will be conducted to evaluate the efficacy of HS-10376 in subjects with locally advanced or metastatic NSCLC with a EGFR Exon 20 insertion mutation.

Official Title
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A Phase 1/2, Multicenter Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of HS-10376 Monotherapy in Patients With Advanced Non-small-Cell Lung Cancer

Conditions
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Advanced Non-Small-Cell Lung Cancer

Intervention / Treatment
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* Drug: HS-10376


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, tumor tissue samples can be used to test EGFR/HER2 Exon 20 insertion mutation by central laboratory for 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 Exon 20 insertion inhibitors, HER2 Exon 20 insertion inhibitors or EGFR/HER2 Exon 20 insertion inhibitors Any cytotoxic chemotherapy, anticancer Chinese medicine and targeted small molecule inhibitors within 14 days of the first dose of HS-10376 Any investigational agents and large molecule antibodies within 28 days of the first dose of HS-10376 Local radiotherapy for palliation within 2 weeks of the first dose of HS-10376, or patients received more than 30% of the bone marrow irradiation, or large-scale radiotherapy within 4 weeks of the first dose of HS-10376 Major surgery (including craniotomy, thoracotomy, or laparotomy, etc.) within 4 weeks of the first dose of HS-10376 Inadequate bone marrow reserve or serious organ dysfunction Uncontrolled pleural, ascites or pericardial effusion Untreated, symptomatic or active central nervous system metastases Severe or poorly controlled hypertension Immunodeficiency disease and 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-10376 or to drugs with a similar chemical structure or drugs belonging to the same category of HS-10376 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-10376<br>Phase 1a：Dose Escalation：Subjects with advanced NSCLC will be enrolled in dose escalation cohorts. Dose escalation of HS-10376 will be done to determine maximum tolerated dose. Phase 1b：Dose Expansion：Depending on data obtained from the dose escalation part, dose expansion may proceed with multiple cohorts in subjects with advanced NSCLC having a EGFR/HER2 Exon 20 insertion mutation. Phase 2：Subjects with locally advanced or metastatic EGFR Exon 20 insertion NSCLC will be enrolled in phase 2 part to evaluate the efficacy and sufficient safety of HS-10376 as monotherapy. | Drug: HS-10376<br>* HS-10376 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 (total 28 days) | 
| To evaluate clinical activity/efficacy of HS-10376 by assessment of objective response rate-Phase Ib/II | Objective response rate (ORR) assessed by Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) | 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-10376 | In the study of single-dose, Cmax will be obtained following administration of a single oral dose of HS-10376 | From pre-dose to 120 hours after single dose on Day 1 | 
| Time to reach maximum plasma concentration (Tmax) after single dose of HS-10376 | In the study of single-dose, Tmax will be obtained following administration of a single oral dose of HS-10376 | From pre-dose to 120 hours after single dose on Day 1 | 
| Apparent terminal half-life (T1/2) after single dose of HS-10376 | 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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NSCLC, Non-Small Cell Lung Cancer, HS-10376, EGFR/HER2 Exon 20 insertion mutation