Clinical Trial of YH32367 in Patients With HER2 Positive Locally Advanced or Metastatic Solid Tumor

Study Overview
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Brief Summary
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This first-in-human study will be counducted to evaluate the safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of YH32367 in Patients with HER2-Positive Locally Advanced or Metastatic Solid Tumors.

Detailed Description
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YH32367, a novel HER2/4-1BB bispecific antibody (BsAb), simultaneously targets HER2 and h4-1BB and binds to both targets. YH32367 exhibits a strong 4-1BB signal activation as well as blocking of HER signaling in HER2-expressing tumor cells. YH32367 stimulats IFN-γ secretion from T cells and thereby inducing tumor cells lysis. This is a Phase 1/2, non-randomized, open-label, multicenter, first-in-human study of YH32367. This 2-part study will include both a Dose Escalation part, to identify the Maximum Tolerated Dose (MTD) or the RP2D of YH32367, and a Dose Expansion part, to confirm the safety, tolerability and efficacy of YH32367 at the RP2D.

Official Title
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A Phase 1/2, Non-randomized, Open-label, Multicenter, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Anti-tumor Activity of YH32367 in Patients With HER2-Positive Locally Advanced or Metastatic Solid Tumors

Conditions
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HER2-Positive Solid Tumor

Intervention / Treatment
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* Drug: YH32367


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: [Dose Escalation Part] Pathologically confirmed HER2-positive Mandatory provision of tumor tissue sample [Dose Expansion Part] Patients who have at least one measurable lesion Mandatory provision of tumor tissue sample Cohort 1: Pathologically confirmed HER2-positive breast cancer Cohort 2: Pathologically confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma Exclusion Criteria: Uncontrolled central nervous system (CNS) metastases Spinal cord compression Carcinomatous meningitis Acute coronary syndromes Heart failure Interstitial lung disease (ILD) Pneumonitis History of a second primary cancer Human immunodeficiency virus (HIV) Active chronic hepatitis B Hepatitis C Systemic steroid therapy Autoimmune disease

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YH32367<br>Dose Escalation Part: 8 Cohorts (Dose level: 0.3, 0.75, 1.5, 3, 6, 12, 20, and 30 mg/kg). In Dose Escalation part, patients are assigned to receive YH32367 at a starting dose of 0.3 mg/kg and the dose being escalated/de-escalated in adjacent dose cohorts will be 0.75, 1.5, 3, 6, 12, 20, and 30 mg/kg. Dose Expansion Part: 2 Cohorts (Cohort 1: Breast cancer, Cohort 2: Gastric cancer). Dose Expansion part will consist of multiple cohorts in patients who were treated with three or more prior lines of therapy including at least one trastuzumab-based regimen, HER2-positive, locally advanced or metastatic breast cancer(Cohort 1); in patients who were treated with two or more prior lines of therapy including at least one trastuzumab-based regimen, HER2-positive, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma(Cohort 2). | Drug: YH32367<br>* Dose Escalation Part: 8 Cohorts (Dose level: 0.3, 0.75, 1.5, 3, 6, 12, 20, and 30 mg/kg). In Dose Escalation part, approximately 30 patients will be enrolled and patients are assigned to receive YH32367 at a starting dose of 0.3 mg/kg and the dose being escalated/de-escalated in adjacent dose cohorts will be up to 30 mg/kg. Dose Expansion Part: 2 Cohorts (Cohort 1: Breast cancer, Cohort 2: Gastric cancer). Upon completion of the Dose Escalation part with the determination of MTD/RP2D, the Dose Expansion part will initiate. Dose Expansion part will consist of multiple cohorts in patients who were treated with three or more prior lines of therapy, HER2-positive breast cancer(Cohort 1); in patients who were treated with two or more prior lines of therapy, HER2-positive gastric or gastroesophageal junction adenocarcinoma(Cohort 2). Approximately 40 patients will be enrolled in each cohort. Additional cohorts may be added, taking into account available non-clinical or clinical data.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent adverse events (TEAEs) up to Day 21 | To assess the safety and tolerability of YH32367 | in dose escalation part, an average of 21 days | 
| Objective Response Rate (ORR) | To assess the ORR of YH32367 at the recommended Phase 2 dose (RP2D) according to RECIST v1.1 by blinded independent central reviews (BICR) | through dose expansion part completion, approximately 2.5 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum concentration-time curve from time 0 to the last quantifiable concentration (AUClast) | To characterize the PK of YH32367 | up to 66 weeks | 
| maximum observed serum concentration (Cmax) | To characterize the PK of YH32367 | up to 66 weeks | 
| time to reach Cmax (Tmax) | To characterize the PK of YH32367 | up to 66 weeks | 
| Presence and characterization of YH32367 ADA in serum including titer of ADA and neutralizing antibodies | To explore the immunogenicity of YH32367 | through study completion, approximately 3.5 year | 
| Objective Response Rate (ORR) | To assess the anti-tumor efficacy according to RECIST v1.1 by Investigator assessment | through study completion, approximately 3.5 year | 
| Duration of Response (DoR) | To assess the anti-tumor efficacy according to RECIST v1.1 by Investigator assessment | through study completion, approximately 3.5 year | 
| Disease Control Rate (DCR) | To assess the anti-tumor efficacy according to RECIST v1.1 by Investigator assessment | through study completion, approximately 3.5 year | 
| Depth of Response | To assess the anti-tumor efficacy according to RECIST v1.1 by Investigator assessment | through study completion, approximately 3.5 year | 
| Time to Response | To assess the anti-tumor efficacy according to RECIST v1.1 by Investigator assessment | through study completion, approximately 3.5 year | 
| Progression-free survival (PFS) | To assess the anti-tumor efficacy according to RECIST v1.1 by Investigator assessment | through study completion, approximately 3.5 year | 
| TEAEs | To assess the safety and tolerability of YH32367 at the RP2D | through dose expansion part completion, approximately 2.5 year | 
| Overall Survival (OS) | To assess overall survival of YH32367 | through study completion, approximately 3.5 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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YH32367, HER2/4-1BB bispecific antibody, Solid tumor, Breast cancer, Gastric cancer, HER2-positive