Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab in Subjects With Locally Advanced or Metastatic Solid Tumors (Hexavalent OX40 Agonist)

Study Overview
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Brief Summary
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This is a Phase 1/2, open-label, non-randomized, 4-part Phase 1 trial to determine the safety profile and identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of INBRX 106 administered as a single agent or in combination with the anti-PD-1 checkpoint inhibitor (CPI) pembrolizumab (Keytruda).

Official Title
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An Open-Label, Multicenter, First-in-Human, Dose-Escalation, Multicohort, Phase 1/2 Study of INBRX-106 and INBRX-106 in Combination With Pembrolizumab in Subjects With Locally Advanced or Metastatic Solid Tumors

Conditions
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Solid Tumor, Non-Small Cell Lung Cancer, Melanoma, Head and Neck Cancer, Gastric Cancer, Renal Cell Carcinoma, Urothelial Carcinoma

Intervention / Treatment
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* Drug: INBRX-106 - Hexavalent OX40 agonist antibody
* Drug: Pembrolizumab 200 mg
* Drug: Pembrolizumab 400 mg


Participation Criteria
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Eligibility Criteria
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Select Inclusion Criteria: Males or females aged ≥18 years. Parts 1 and 3 (escalation cohorts): Subjects with locally advanced or metastatic non resectable solid tumors, whose disease has progressed despite all standard therapies or for whom no further standard or clinically acceptable therapy exists. Part 2 (single-agent expansion cohort): Subjects with NSCLC, melanoma, HNSCC, G/GEA, RCC, or TCC, with locally advanced or metastatic, non-resectable disease, which has progressed despite all standard therapies including CPI or for whom no standard or clinically acceptable therapy exists. Part 4 (expansion cohorts in combination with pembrolizumab): Subjects with melanoma (all types), HNSCC, G/GEA, RCC, TCC, NSCLC, or MSI-high, TMB-high, MMR-deficient tumors, with locally advanced or metastatic, non resectable disease, which is either CPI-naive (melanoma, HNSCC, NPC) or progressed despite all standard therapies including CPI (NSCLC, RCC, TCC, uveal melanoma, MSI-high, TMB-high, or MMR-deficient solid tumors) or for whom no standard or clinically acceptable therapy exists. All subjects with non-squamous NSCLC must have documentation of absence of tumor activating EGFR mutations and absence of ALK gene rearrangements. PD-L1 by IHC (22C3): Parts 1 and 3: IHC optional. Part 2: IHC result mandatory but any score allowed. Part 4: Combined Positive Score (CPS) ≥ 1% (or Tumor Proportion Score ≥50% for NSCLC; for TMB-high tumors, any TPS% is allowed). Adequate hematologic, coagulation, hepatic and renal function and ECOG score as defined per protocol. Select Exclusion Criteria: Prior exposure to OX40 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 with certain exceptions. Hematologic malignancies (e.g., ALL, AML, MDS, CLL, CML, NHL, Hodgkin's 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-106. 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) infection for Parts 1 and 3. 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. Additional in- and exclusion criteria per protocol.

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: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 INBRX-106 Escalation<br>INBRX-106 will be escalated in subjects with locally advanced or metastatic solid tumors. | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>|
| Experimental: Part 3 INBRX-106 Escalation in Combination with Pembrolizumab<br>INBRX-106 will be escalated, in combination with pembrolizumab, in subjects with locally advanced or metastatic solid tumors. | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>Drug: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Part 4 INBRX-106 Expansion in Combination with Pembrolizumab<br>Subjects with melanoma (any type), head and neck squamous cell carcinoma (non-nasopharyngeal), nasopharyngeal carcinoma, MSI-high, TMB-high or MMR-deficient tumors, will be treated with INBRX-106 in combination with 200mg pembrolizumab IV every 3 weeks. | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>Drug: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Active Comparator: Part 4 Pembrolizumab Expansion Arm, Randomized<br>Subjects with non-small cell lung cancer will be treated with 200 mg pembrolizumab IV every 3 weeks | Drug: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Part 4 INBRX-106 Expansion in Combination with Pembrolizumab in NSCLC, Randomized<br>Subjects with non-small cell lung cancer will be treated with alternating every 6 weeks dosing of INBRX-106 0.3 mg/kg Q6W and 400 mg pembrolizumab IV | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>Drug: Pembrolizumab 400 mg<br>* Pembrolizumab 400 mg by IV infusion given on Day 1 of alternating 21-day cycles (every 6 weeks)<br>* Other names: Keytruda;|
| Experimental: Part 4 INBRX-106 Expansion in Combination with Pembrolizumab in NSCLC; Randomized<br>Subjects with non-small cell lung cancer will be given a 0.3 mg/kg priming dose of INBRX-106 in cycle 1, followed by 0.1 mg/kg INBRX-106 and 200 mg pembrolizumab IV every 3 weeks in subsequent cycles | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>Drug: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Part 2 INBRX-106 Escalation in NSCLC<br>Subjects with non-small cell carcinoma relapsed or refractory to prior checkpoint inhibitor (CPI) therapy will be treated with INBRX-106 | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>|
| Experimental: Part 2 INBRX-106 Escalation in Various Solid Tumor Types<br>Subjects with melanoma (any type), head and neck squamous cell carcinoma, renal cell carcinoma, urothelial carcinoma or MSI/TMB-high tumors that are relapsed or refractory to prior checkpoint inhibitor (CPI) therapy will be treated with INBRX-106 | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>|
| Experimental: Part 4 INBRX-106 Expansion with Pembrolizumab in Uveal Melanoma<br>Subjects with ocular (uveal) melanoma who are relapsed or refractory to checkpoint inhibitor (CPI) therapy will be treated with INBRX-106 and 200 mg pembrolizumab IV every 3 weeks | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>Drug: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|
| Experimental: Part 4 INBRX-106 Expansion with Pembrolizumab in MSI-high, TMB-high or MMR-deficient tumors<br>Subjects with solid tumors that have confirmed MSI-high, TMB-high or MMR-deficient states who are relapsed or refractory to checkpoint inhibitor (CPI) therapy will be treated with INBRX-106 and 200 mg pembrolizumab IV every 3 weeks | Drug: INBRX-106 - Hexavalent OX40 agonist antibody<br>* The active ingredient of INBRX-106 is a recombinant, humanized, hexavalent IgG antibody that targets the human OX40 receptor (TNFRSF4).<br>Drug: Pembrolizumab 200 mg<br>* Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events of INBRX-106 as single agent and in combination with pembrolizumab | Adverse events will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 | 2-4 years | 
| Severity of adverse events of INBRX-106 as single agent and in combination with pembrolizumab | Adverse events will be assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 | 2-4 years | 
| MTD and/or RP2D of INBRX-106 as single agent and in combination with pembrolizumab | Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) of INBRX-106 and INBRX-106 in combination with pembrolizumab | 2-4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the serum concentration time curve (AUC) of INBRX-106 | Area under the serum concentration time curve (AUC) of INBRX-106 as a single agent and in combination with pembrolizumab will be determined. | 2-4 years | 
| Maximum observed serum concentration (Cmax) of INBRX-106 | Maximum observed serum concentration (Cmax) of INBRX-106 as a single agent and in combination with pembrolizumab will be determined. | 2-4 years | 
| Trough observed serum concentration (Ctrough) of INBRX-106 | Trough observed serum concentration (Ctrough) of INBRX-106 as a single agent and in combination with pembrolizumab will be determined. | 2-4 years | 
| Time to Cmax (Tmax) of INBRX-106 | Time to Cmax (Tmax) of INBRX-106 as a single agent and in combination with pembrolizumab will be determined. | 2-4 years | 
| Immunogenicity of INBRX-106 | Frequency of anti-drug antibodies (ADA) against INBRX-106 as a single agent and in combination with pembrolizumab will be determined. | 2-4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1 and Phase 2, Phase 1 and Phase 2 Clinical Trial, Solid Tumors, Melanoma, Head and Neck Cancer, Stomach Cancer, Gastric Cancer, Lung Cancer, Non-Small Cell Lung Cancer, Kidney Cancer, Renal Cell Carcinoma, Bladder Cancer, Urothelial Carcinoma, OX40, PD-1, Pembrolizumab, Keytruda