Clinical Trial Finder

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.

Arms

Experimental: Single Agent Escalation

INBRX-105 will be escalated in patients with locally advanced or metastatic solid tumors.

Experimental: Expansion Cohort Non-small Cell Lung Cancer

Patients will be treated with single-agent INBRX-105 at either the MTD or RP2D.

Experimental: Expansion Cohort Melanoma

Patients will be treated with single-agent INBRX-105 at either the MTD or RP2D.

Experimental: Expansion Cohort PD-L1 Positive Basket

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.

Experimental: Expansion Cohort Nasopharyngeal or Oropharyngeal Carcinoma

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.

Experimental: INBRX-105 Escalation in Combination with Pembrolizumab

INBRX-105 will be escalated in combination with Pembrolizumab in pateitns with locally advanced or metastatic solid tumors.

Experimental: Combination Expansion Cohort Non-small Cell Lung Cancer

CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab.

Experimental: Combination Expansion Cohort Melanoma

CPI relapsed/refractory patients will be treated with INBRX-105 in combination with Pembrolizumab.

Experimental: Combination Expansion Cohort Cohort PD-L1 Positive Basket

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.

Experimental: Combination Expansion Cohort CPI Naive Non-small Cell Lung Cancer

CPI naive patients (PD-L1 IHC between 1 and 49%) will be treated with INBRX-105 in combination with Pembrolizumab.

Experimental: Combination Expansion Cohort CPI Naive HNSCC

CPI naive patients (PD-L1 IHC >50%) will be treated with INBRX-105 in combination with Pembrolizumab.

Interventions

Drug: - INBRX-105 - PDL1x41BB antibody

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.

Drug: - Pembrolizumab

Pembrolizumab 200 mg by intravenous (IV) infusion, given on Day 1 of each 21-day cycle.