Study of INBRX-105 and INBRX-105 With Pembrolizumab in Patients With Solid Tumors Including Head and Neck Cancer

Study Overview
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Brief Summary
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This is a first-in-human, open-label, nonrandomized, four-part trial to determine the safety profile and identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of INBRX-105 and INBRX-105 in combination with Pembrolizumab. INBRX-105, a next generation bispecific antibody, targets the human programmed death-ligand 1 (PD-L1) receptor and the human 4-1BB receptor. INBRX-105 provides localized conditional T-cell co-stimulation through 4-1BB agonism.

Official Title
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An Open-Label, Multicenter, First-in-Human, Dose-Escalation, Phase 1 / 2 Study of INBRX-105 and INBRX-105 in Combination With Pembrolizumab in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Metastatic Solid Tumors, Non-small Cell Lung Cancer, Melanoma, Head and Neck Squamous Cell Carcinoma, Gastric Adenocarcinoma, Renal Cell Carcinoma, Esophageal Adenocarcinoma, Nasopharyngeal Carcinoma, Oropharyngeal Carcinoma

Intervention / Treatment
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* Drug: INBRX-105 - PDL1x41BB antibody
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parts 1 and 3 (escalation cohorts; completed): Patients with locally advanced or metastatic non-resectable solid tumors, whose disease has progressed despite standard therapy and for whom no further standard therapy exists. Part 2 (expansion cohorts): Patients with non-small cell lung cancer, cutaneous melanoma, head and neck squamous cell carcinoma or solid tumors amenable to paired biopsies, with locally advanced or metastatic, non-resectable disease, which has progressed despite standard therapy or for whom no standard or clinically acceptable therapy exists. Part 4 relapsed or refractory to CPI cohorts: NSCLC, cutaneous melanoma, HNSCC, MSI/TMB-high or MMRd solid tumors Part 4 CPI naive cohorts: locally advanced or metastatic, non-resectable NSCLC or HNSCC Refractory or relapsed to anti-PD-1 or anti-PD-L1, and anti-CTLA4 if applicable (NOTE: For all tumor types with checkpoint inhibitor approvals) with exception of the treatment naive NSCLC cohort. PD-L1 positivity by immunohistochemistry (IHC): Parts 1 and 3 (escalation cohorts) PD-L1 positivity is not required. Parts 2 and 4 (expansion cohorts): Combined Positive Score (CPS) or Tumor Proportion Score (TPS) above certain thresholds as defined per protocol. Adequate hematologic, coagulation, hepatic and renal function as defined per protocol. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Exclusion Criteria: Prior exposure to 4-1BB agonists. Receipt of any investigational product or any approved anticancer drug(s) or biological product(s) within 4 weeks prior to the first dose of study drug. Exceptions: Hormone replacement therapy, testosterone, or oral contraceptives. NOTE: Previous exposure to anti-PD-L1 checkpoint inhibitor requires a minimum washout period of 24 weeks prior to the first dose of study drug. Hematologic malignancies (e.g., ALL, AML, MDS, CLL, CML, NHL, Hodgkin lymphoma and multiple myeloma). Prior or concurrent malignancies. Exception: Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessments of INBRX-105. Known or active primary central nervous system (CNS) tumors, leptomeningeal disease and CNS metastases. Exception: Subjects with previously treated, asymptomatic, and clinically stable CNS metastases may be allowed study entry if certain criteria apply. Grade ≥ 3 immune-related adverse events (irAEs) or irAE that lead to discontinuation of prior immunotherapy. Some exceptions as defined per 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. Treatment with systemic immunosuppressive medications within 4 weeks prior to the first dose of study drug. Certain exceptions as defined in protocol apply. History of hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). Exceptions as defined in protocol for expansion cohorts will apply. History of hepatitis or cirrhosis (e.g., non-alcohol steatohepatitis, alcohol or drug-related, autoimmune, hepatitis B, or hepatitis C). Exceptions as defined in protocol for expansion cohorts will apply. Active interstitial lung disease (ILD) or pneumonitis or a history of ILD or pneumonitis requiring treatment with steroids or other immunosuppressive medications. Clinically significant cardiac condition, including myocardial infarction, uncontrolled angina, cerebrovascular accident, or other acute uncontrolled heart disease < 3 months; left ventricular ejection fraction (LVEF) < 50%; New York Heart Association (NYHA) Class III or IV congestive heart failure; or uncontrolled hypertension. Active, hemodynamically significant pulmonary embolism within 3 months prior to enrollment on this trial. Major surgery within 4 weeks prior to enrollment on this trial. Anti-infectious drug treatments (i.e., antibiotics) within 4 weeks prior to the first dose of study drug. Prior organ allograft transplantations or allogeneic peripheral blood stem cell (PBSC) or bone marrow (BM) transplantation.

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Agent Escalation<br>INBRX-105 will be escalated in patients with locally advanced or metastatic solid tumors. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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: Expansion Cohort Non-small Cell Lung Cancer<br>Patients will be treated with single-agent INBRX-105 at either the MTD or RP2D. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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: Expansion Cohort Melanoma<br>Patients will be treated with single-agent INBRX-105 at either the MTD or RP2D. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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: Expansion Cohort PD-L1 Positive Basket<br>Patients with gastric or gastro-esophageal junction adenocarcinoma, renal cell carcinoma, and urothelial (transitional) cell carcinoma will be treated with single-agent INBRX-105 at either the MTD or RP2D. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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: Expansion Cohort Nasopharyngeal or Oropharyngeal Carcinoma<br>Patients with head and neck squamous cell carcinoma (NPC or OPC) will be treated with single-agent INBRX-105 at either the MTD or RP2D. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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: INBRX-105 Escalation in Combination with Pembrolizumab<br>INBRX-105 will be escalated in combination with Pembrolizumab in pateitns with locally advanced or metastatic solid tumors. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Combination Expansion Cohort Non-small Cell Lung Cancer<br>CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Combination Expansion Cohort Melanoma<br>CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Combination Expansion Cohort Cohort PD-L1 Positive Basket<br>CPI-relapsed/refractory patients with head and neck squamous cell carcinoma, gastro-esophageal junction adenocarcinoma, renal cell carcinoma, and urothelial (transitional) cell carcinoma will be treated with INBRX-105 in combination with Pembrolizumab. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Combination Expansion Cohort CPI Naive Non-small Cell Lung Cancer<br>CPI naive patients (PD-L1 IHC between 1 and 49%) will be treated with INBRX-105 in combination with Pembrolizumab. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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>Drug: Pembrolizumab<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Combination Expansion Cohort CPI Naive HNSCC<br>CPI naive patients (PD-L1 IHC >50%) will be treated with INBRX-105 in combination with Pembrolizumab. | Drug: INBRX-105 - PDL1x41BB antibody<br>* The active ingredient of INBRX-105 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 |
| --- | --- | --- |
| Frequency of adverse events of INBRX-105 | Adverse events will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. | Up to 2-3 years | 
| Severity of adverse events of INBRX-105 | Severity of adverse events will be assessed and assigned by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0. | Up to 2-3 years | 
| Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of INBRX-105 | The MTD and/or RP2D of INBRX-105 will be determined. | Up to 2-3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum concentration time curve (AUC) of INBRX-105 | Area under the serum concentration time curve (AUC) of INBRX-105 will be determined. | Up to 2-3 years | 
| Maximum observed serum concentration (Cmax) of INBRX-105 | Maximum observed serum concentration (Cmax) of INBRX-105 will be determined. | Up to 2-3 years | 
| Trough observed serum concentration (Ctrough) of INBRX-105 | Trough observed serum concentration (Cmax) of INBRX-105 will be determined. | Up to 2-3 years | 
| Time to Cmax (Tmax) of INBRX-105 | Time to Cmax (Tmax) of INBRX-105 will be determined. | Up to 2-3 years | 
| Immunogenicity of INBRX-105 | Frequency of anti-drug antibodies (ADA) against INBRX-105 will be determined. | Up to 2-3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cancer, Phase 2, Phase 2 Clinical Trial, Solid Tumors, Lung Cancer, Melanoma, Head and Neck Cancer, Stomach Cancer, Gastric Cancer, Kidney Cancer, Renal cell carcinoma, Urothelial Carcinoma, PDL1, 41BB, PD-L1, 4-1BB, Pembrolizumab, Keytruda, Nasopharyngeal carcinoma, Oropharyngeal carcinoma