Background: NT219 is a small molecule, dual inhibitor of insulin receptor substrates (IRS) 1/2 and signal transducer and activator of transcription 3 (STAT3), effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. Patient derived xenograft (PDX) models have shown that inhibition of both IRS and STAT3 is essential to overcome targeted epidermal growth factor receptor inhibitor (EGFRi) resistance, and NT219 has demonstrated efficacy as monotherapy and in combination with immune oncology therapies. Particularly, both pathways have been found to be relevant in resistance to cetuximab in head and neck squamous cell carcinoma (HNSCC) PDX models. Methods: This phase 1/2 study (Clinical trial: NCT04474470) began in September 2020. The phase 1 component has a dose escalation arm of NT219 as a single agent at doses ranging between 3mg/kg and 50mg/kg in adult subjects with recurrent and/or metastatic solid tumors enrolled in sequential dose cohorts of 3 to 6 subjects, in a conventional 3+3 design aiming to establish the safety of single agent NT219. Following the conclusion of follow up on the third dose cohort, an additional dose-escalation arm of NT219 in combination with standard dose cetuximab will be opened in patients with recurrent and/or metastatic HNSCC and colorectal cancer, aiming to establish the safety of NT219 when combined with cetuximab. In the expansion phase, 29 patients will be enrolled at the recommended phase 2 dose in combination with standard dose cetuximab in patients with recurrent/metastatic HNSCC. The primary objectives of the trial are safety, tolerability, MTD, and RP2D and preliminary efficacy of NT219 alone and in combination with cetuximab. Measurements of STAT3 and IRS1/2 phosphorylation in biopsy specimens and TILs will be evaluated as potential biomarkers. NT219 provides a first-in-class treatment for patients with resistant neoplastic disease. The current trial will provide important data in patients with recurrent/metastatic cancers, particularly, HNSCC on the effects of the inhibition of STAT3 and IRS1/2 pathways as a novel therapeutic approach. Clinical trial information: NCT04474470