A Phase I Clinical Study of HS-20117 in Participants With Advanced Solid Tumors

Study Overview
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Brief Summary
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HS-20117 is a fully-human EGFR-MET immunoglobulin G1(IgG1)-like bispecific antibody. The purpose of study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of HS-20117 as a monotherapy for participants with advanced solid tumors.

Detailed Description
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This is a multicenter, open-label, Phase I clinical study of HS-20117 to evaluate the safety, tolerability, PK, immunogenicity and efficacy in participants with advanced solid tumors. The study consists of phase Ia (dose escalation) and phase Ib (dose expansion). The dose-escalation study will be performed to evaluate the safety, tolerability, PK profile, immunogenicity, and efficacy of HS-20117 in participants with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. The subsequent dose-expansion study will be performed to evaluate the efficacy of HS-20117 in participants with locally advanced or metastatic NSCLC who have progressed after prior platinum-based chemotherapy or are intolerant to platinum-based chemotherapy with EGFR exon 20 insertion mutations, and to explore the efficacy of HS-20117 in participants with other advanced solid tumors.

Official Title
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A Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of HS-20117 in Participants With Advanced Solid Tumors

Conditions
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Non-Small Cell Lung Cancer, Solid Tumor

Intervention / Treatment
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* Drug: HS-20117


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females aged 18 - 75 years (inclusive). For the phase Ia study: Participants with locally advanced or metastatic NSCLC (stage IIIB/IIIC/IV) with EGFR-activating mutations who have progressed after or are intolerant to or not available to standard of care (SoC). For the phase Ib study: Cohort A: Participants with locally advanced or metastatic NSCLC (stage IIIB/IIIC/IV) with EGFR exon 20ins mutations who have progressed after prior platinum-based chemotherapy or are intolerant to platinum-based chemotherapy. Cohort B: Participants with other advanced solid tumors who have progressed after prior SoC or are intolerant to SoC. Agree to provide fresh or archival tumor tissue. At least one target lesion per the RECIST v1.1. ECOG performance status of 0-1. Minimum life expectancy > 12 weeks. Males or Females should be using adequate contraceptive measures throughout the study. Females must not be pregnant at screening or have evidence of non-childbearing potential. Have signed Informed Consent Form. Exclusion Criteria: Received or are receiving the following treatments: For the phase Ib study Cohort A: Previous or current treatment with EGFR exon 20ins targeted therapy. Traditional Chinese medicine indicated for tumors within 2 weeks prior to the first dose of HS-20117. Cytotoxic chemotherapies, investigational drugs or other systematic anti-tumor therapies within 3 weeks prior to the first dose of HS-20117. Antibodies within 4 weeks prior to the first dose of HS-20117. Local radiotherapy within 2 weeks prior to the first dose of HS-20117, more than 30% of bone marrow irradiation or large-area radiotherapy within 4 weeks before the first dose of HS-20117. Presence of pleural effusion/ascites requiring clinical intervention; presence of pericardial effusion. Major surgery within 4 weeks prior to the first dose of HS-20117. Presence of Grade ≥ 2 toxicities due to prior anti-tumor therapy. History of other primary malignancies. Untreated, or active central nervous system metastases. Inadequate bone marrow reserve or organ functions. Severe, uncontrolled or active cardiovascular disorders. Severe or uncontrolled systemic diseases. Severe bleeding symptoms or bleeding tendencies within 1 month prior to the first dose of HS-20117. Severe arteriovenous thrombosis occurred within 3 months prior to the first dose of HS-20117 Serious infection within 4 weeks prior to the first dose of HS-20117. Active infectious diseases. Interstitial lung disease (ILD). Serious neurological or mental disorders. History of hypersensitivity to any component of HS-20117 or similar drugs. Participants with any condition that compromises the safety of the participant or interferes with the assessment of the study, as judged by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HS-20117<br>Participants will receive IV infusion of HS-20117 once during cycle 1 and once every 2 weeks during subsequent cycles (The duration of each treatment cycle is 28 days) | Drug: HS-20117<br>* Phase Ia: patients will receive HS-20117 starting at 400 mg, and subsequent cohorts will test escalating doses, if tolerated, until a maximum tolerated dose (MTD) or maximum applicable dose (MAD) is defined. Phase Ib: patients will receive HS-20117 at MED or MAD<br>* Other names: PM1080;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| [Phase 1a] Maximum tolerated dose (MTD) of HS-20117 | MTD is defined as the previous dose level at which 2 or more out of 2-6 subjects experienced a DLT. | Cycle 1 (28 days) | 
| [Phase 1a] Maximum applicable dose (MAD) of HS-20117 | MAD is defined as follows: a) based on PK data, it is anticipated that at this dose level, the dose-exposure plateau has been reached, b) based on existing safety data, it is judged that dose escalation following this dose level will have a large safety risk or subject intolerance, or c) based on the PK-PD model, it suggested that the optimal target concentration of safety and efficacy has been explored. | Cycle 1 (28 days) | 
| [Phase 1b] Efficacy of HS-20117: Objective response rate (ORR) | ORR is defined as the percentage of participants with BOR of confirmed CR or confirmed PR per RECIST v1.1 | From the date of first dose until the date of disease progression or withdrawal from study, approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| [phase 1a and 1b] Incidence and severity of treatment-emergent adverse events | Adverse event (assessed according to NCI CTCAE v5.0) is defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. | From the date of first dose until 90 days after the final dose. A cycle is 28 days | 
| [phase 1a and 1b] PK parameters: Maximum serum concentration (Cmax) of HS-20117 | The Cmax is the maximum observed serum concentration of HS-20117. | From the date of first dose until 30 days after the final dose. A cycle is 28 days. | 
| [phase 1a and 1b] PK parameters: Trough serum concentration (Ctrough) of HS-20117 | Ctrough is the observed serum concentration immediately prior to the next administration. | From the date of first dose until 30 days after the final dose. A cycle is 28 days. | 
| [phase 1a and 1b] PK parameters: Time to reach maximum observed serum concentration (Tmax) of HS-20117 | The Tmax is defined as time to reach maximum observed serum concentration of HS-20117. | From the date of first dose until 30 days after the final dose. A cycle is 28 days | 
| [phase 1a] PK parameters: Area under the curve from time Zero to end of dosing interval (AUCtau) of HS-20117 | The AUCtau is defined as the area under the serum concentration-time curve during a dose interval time period (tau). | From the date of first dose until 30 days after the final dose. A cycle is 28 days. | 
| [phase 1a] PK parameters: Terminal elimination half-life (t1/2) of HS-20117 | The t1/2 is defined as the time it takes for the concentration levels to fall to 50% of their value. | From the date of first dose until 30 days after the final dose. A cycle is 28 days. | 
| [phase 1a] Efficacy of HS-20117: ORR | ORR is defined as the percentage of participants with BOR of confirmed CR or confirmed PR per RECIST v1.1. | From the date of first dose until the date of disease progression or withdrawal from study, approximately 2 years. | 
| [phase 1a and 1b] Efficacy of HS-20117: disease control rate (DCR) | DCR is deﬁned as the percentage of patients who have a best overall response (confirmed CR, PR, or stable disease for at least 6 weeks) per RECIST v1.1. | From the date of first dose until the date of disease progression or withdrawal from study, approximately 2 years. | 
| [phase 1a and 1b] Efficacy of HS-20117: duration of response (DoR) | DoR only applies to participants whose best overall response is CR or PR based on assessment per RECIST v1.1. The start date is the date of first documented response of CR or PR (i.e. the start date of observed response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying disease. | From the date of CR, PR until the date of disease progression or death, approximately 2 years. | 
| [phase 1a and 1b] Efficacy of HS-20117: progression free survival (PFS) | PFS is defined as the time from the date of randomization or first dose (if randomization is not needed) to the date of the first documented progression or death due to any cause. PFS will be assessed per RECIST v1.1. | From the date of randomization or first dose (if randomization is not needed) until the date of disease progression or death, approximately 2 years. | 
| [phase 1b] Efficacy of HS-20117: overall survival (OS) | OS is defined as the time from the date of randomization or first dose (if randomization is not needed) to the date of death due to any cause. For each participant who is not known to have died as of the cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive. | From the date of randomization or first dose (if randomization is not needed) until the documentation of death from any cause, approximately 4 years | 
| [phase 1a and 1b] Immunogenicity of HS-20117 | Immunogenicity will be measured by the number of participants that are ADA positive. | Cycle 1 Day 1: predose through EOT or follow up period (90 days after the last dose). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-Small Cell Lung Cancer, Solid Tumor, HS-20117, Epidermal Growth Factor Receptor, c-Mesenchymal-Epithelial Transition, Bispecific Antibody, EGFR exon 20 insertion