A Study of ES101 (PD-L1x4-1BB Bispecific Antibody) in Patients With Advanced Malignant Thoracic Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, RP2D and PK/pharmacodynamic profile of ES101 monotherapy in patients with advanced NSCLC and to further evaluate the antitumor efficacy of ES101 in advanced malignant thoracic tumors, including NSCLC and SCLC.

Official Title
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An Open-label, Multicenter, Multicohort Phase 1b/2 Clinical Trial of ES101 in Patients With Advanced Malignant Thoracic Tumors

Conditions
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Thoracic Tumors, Non-small Cell Lung Cancer, Small Cell Lung Cancer

Intervention / Treatment
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* Drug: ES101


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand and the willingness to sign a written informed consent form. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. At least one measurable lesion is required (RECIST v1.1) Phase 1b: Subjects with pathologically or cytologically confirmed recurrent or metastatic NSCLC without known EGFR mutation and ALK and ROS1 gene rearrangements. Phase II: Subjects with pathologically or cytologically confirmed recurrent or metastatic malignant thoracic tumours who have received 1-2 lines of systemic anti-tumour therapy, including platinum regimens, and have failed, including at least 2 cycles of chemotherapy. Exclusion Criteria: Prior exposure to 4-1BB agonists. Receipt of any anticancer investigational product or any approved drug(s) or biological products (except hormone-replacement therapy, testosterone or oral contraceptives) within 4 weeks prior to the first dose of study drug. Previous exposure to oral fluorouracils or small molecular targeted drugs require a minimum washout period of 2 weeks or 5 half-lives prior to the first dose of study drug (whichever is longer). Previous exposure to mitomycin C or nitrosourea requires a minimum washout period of 6 weeks prior to the first dose of study drug. Receipt of PD-L1 therapy within 24 weeks prior to the first dose of study drug. Known allergies to CHO-produced antibodies, which in the opinion of the Investigator suggests an increased potential for an adverse hypersensitivity to ES101. Grade ≥ 3 immune-related adverse events (irAEs) or irAE that lead to discontinuation of prior immunotherapy. Some exceptions as defined per protocol apply. Subject has not recovered from all AEs of previous anticancer therapies to baseline or ≤ Grade 1 per CTCAE v5.0 before teh first dose of study drug. Certain exceptions as defined in protocol apply. Active autoimmune disease or documented history of autoimmune disease that required systemic steroids or other immunosuppressive medications. Certain exceptions as defined in protocol apply. Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or other immunosuppressive medications. Systemic anti-infectious drug treatments within 4 weeks prior to the first dose of study drug. Pregnant or nursing females.

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>ES101 is administered via intravenous infusion, 0.3mg/kg，once every 14 days, every 28 days as a treatment cycle. | Drug: ES101<br>* The active ingredient of ES101 is a recombinant, humanized, bispecific IgG antibody that targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor.<br>|
| Experimental: Cohort 2<br>ES101 is administered via intravenous infusion, 1mg/kg，once every 14 days, every 28 days as a treatment cycle. | Drug: ES101<br>* The active ingredient of ES101 is a recombinant, humanized, bispecific IgG antibody that targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor.<br>|
| Experimental: Cohort A1<br>ES101 is administered via intravenous infusion, RP2D (to be determined)，once every 14 days, every 28 days as a treatment cycle. | Drug: ES101<br>* The active ingredient of ES101 is a recombinant, humanized, bispecific IgG antibody that targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor.<br>|
| Experimental: Cohort A2<br>ES101 is administered via intravenous infusion, RP2D (to be determined)，once every 14 days, every 28 days as a treatment cycle. | Drug: ES101<br>* The active ingredient of ES101 is a recombinant, humanized, bispecific IgG antibody that targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor.<br>|
| Experimental: Cohort B<br>ES101 is administered via intravenous infusion, RP2D (to be determined)，once every 14 days, every 28 days as a treatment cycle. | Drug: ES101<br>* The active ingredient of ES101 is a recombinant, humanized, bispecific IgG antibody that targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor.<br>|
| Experimental: Cohort C<br>ES101 is administered via intravenous infusion, RP2D (to be determined)，once every 14 days, every 28 days as a treatment cycle. | Drug: ES101<br>* The active ingredient of ES101 is a recombinant, humanized, bispecific IgG antibody that targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Frequency and severity of adverse events of ES101 | Adverse events will be assessed and assigned by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. | 1-2 years | 
| Phase 1b: Recommended Phase 2 Dose (RP2D) of of ES101 | RP2D of ES101 will be determined. | 6 months | 
| Phase 2: Objective response rate (ORR) | Tumor response will be determined by the revised Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). | 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of ES101 | Tumor response will be determined by the revised Response Evaluation Criteria in Solid Tumors version 1.1 (RECISTv1.1). | 2-4 years | 
| PK profile of ES101 | Assess the relationship between ES101 exposure and efficacy/adverse events. | 2-4 years | 
| Immunogenicity of ES101 | Frequency of anti-drug antibodies (ADA) against ES101 will be determined. | 2-4 years | 
| Pharmacodynamic markers | Assess PD-L1 receptor occupancy and cytokines | 2-4 years | 
| PD-L1 expression | Assess PD-L1 expression status of tumor tissues | 2-4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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4-1BB, ES101, INBRX-105, PD-L1, PD-L1×4-1BB, PDL1, 41BB, Thoracic Tumor