Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors.

3096 Background: NT219 is a small molecule, 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. A Phase 1/2 study (NCT04474470) includes a dose escalation of NT219 administered weekly for the treatment of relapsed and/or refractory cancer patients. Methods: In the dose escalation part of the study involving a conventional 3+3 design, patients with recurrent and/or metastatic solid tumors were administered intravenously with NT219 at 3, 6, 12 and 24mg/kg. Safety was assessed according to CTCAE v5 and anti-tumor activity was assessed by the investigators according to RECISTv1.1 using CT/MRI. The primary objectives of this part of the study are to evaluate safety, tolerability, PK and determine the recommended Phase 2 dose (RP2D). The study includes evaluation of potential biomarkers including measurements of STAT3, IRS1/2 phosphorylation, and TILs in biopsy specimens. Results: As of data cutoff date of February 8, 2022, a total of 13 patients were enrolled to 4 NT219 dose levels (3 - 24mg/kg) in the dose escalation phase, of which 11 were evaluable for dose limiting toxicity (DLT) determination, including 4 with colorectal cancer (CRC), 2 with pancreatic cancer, 2 with breast cancer, and one of each of the following cancers: gastroesophageal junction (GEJ), esophageal, appendiceal, papillary thyroid, and mesothelioma. Median number of prior treatment regimens for metastatic disease was 4 (2-11). Six Grade 3 adverse events (AEs) were observed, including alkaline phosphatase increase, aspartate aminotransferase increase, toxic encephalopathy, worsening back pain, abdominopelvic ascites, closed displaced fracture of right femoral neck, with the first 2 considered as possibly related to NT219. No Grade 4 AEs or treatment related deaths were reported. For the 11 evaluable patients, best overall response included one confirmed PR (GEJ patient, 5.5 months duration of response), and 3 SD (3 of 4 CRC patients; duration of 5.2, 4, and 2 months with ongoing follow up) with two patients awaiting follow up MRI/CT scans. As of the cutoff date, 9/11 patients that completed the DLT period are either on treatment or in follow up (range 1.1 to 14.7 months). Conclusions: Interim analysis of safety results obtained in 4 NT219 dose levels found NT219 to be well tolerated without DLTs in advanced cancer patients. The observed durable PR in a GEJ patient and SDs in 3 CRC patients are an encouraging initial signal of efficacy. Combination treatment of cetuximab with escalating NT219 doses in patients with recurrent/metastatic CRC and squamous cell carcinoma of the head and neck (SCCHN) has begun. An expansion cohort in patients with recurrent/metastatic SCCHN will be initiated at the conclusion of this part. Clinical trial information: NCT04474470.