A Phase 1/2 Study with Open-Label, Dose Escalation Phase Followed by Single-Arm Expansion At the Maximum Tolerated Dose to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of NT219 Injection Alone and in Combination with ERBITUX® (Cetuximab) in Adults with Advanced Solid Tumors and Head and Neck Cancer

This is a phase 1/2, multi-center study with an open-label, dose escalation phase followed by a single-arm expansion phase to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 alone and in combination with ERBITUX® (cetuximab) in adults with recurrent and/or metastatic solid tumors.

Start Date03 Sep 2020

Sponsor / Collaborator

Tyrnovo Ltd.

100 Clinical Results associated with Tyrnovo Ltd.

0 Patents (Medical) associated with Tyrnovo Ltd.

Literatures (Medical) associated with Tyrnovo Ltd.

01 Jun 2022·Journal of Clinical Oncology

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

Author: Schickler, Michael ; Weinberg, Benjamin Adam ; Bessudo, Alberto ; Gutierrez, Rodolfo ; Cohen, Ezra E.W. ; Reuveni, Hadas ; Johnson, Daniel H. ; Liang, Bertrand C. ; Rosenberg, Ari ; Ulahannan, Susanna Varkey

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.

09 Aug 2021·Neuro-Oncology Advances

BSCI-03. Adaptation of colorectal cancer cells to the brain microenvironment: The role of IRS2

Author: Liang, Bertrand ; Reuveni, Hadas ; Klein, Anat ; Wolf, Ido ; Sokol, Ethan ; Ofek, Paula ; Satchi-Fainaro, Ronit ; Grossman, Rachel ; Yeini, Eilam ; Rubinek, Tami ; Greenberg, Inbal

AbstractColorectal cancer (CRC) reflects the fourth most frequent etiology of brain metastasis (BM). Yet, molecular mechanisms supporting it are unknown. We aimed to explore drivers enabling adaptation of CRC cells to the brain and decipher mechanisms facilitating the process.We analyzed the FoundationOne database, which contains genomic alterations data of cancer-related genes in over 16,000 human CRC primary and metastasis samples. Increased prevalence of IRS2 gene amplification was observed in 13% of BM, compared to only 3% of primary tumors or other metastatic sites. IRS2 is a cytoplasmic adaptor mediating effects of insulin and IGF-1 receptors and is involved in more aggressive behavior of different cancer types. In agreement with the genomic data, immunohistochemistry of human clinical samples showed increased expression of IRS2 protein in BM. We constructed an in-vitro system mimicking the brain microenvironment using cultured human astrocytes or their conditioned media. Under these conditions, IRS2-overexpressed CRC cells survived better and formed larger 3D spheres. IRS2-silenced CRC cells showed a mirror image. Moreover, in an intracranial CRC BM mouse model, IRS2-overexpressed cells generated larger brain lesions, while silencing IRS2 dramatically decreased tumor outgrowth and extended survival. Interestingly, transcriptomic analysis revealed enrichment of oxidative phosphorylation (OXPHOS) and Wnt/β-catenin pathways by IRS2. Indeed, IRS2-expressing cells showed increased mitochondrial activity and glycolysis-independent viability. Furthermore, IRS2-expressing cells had increased β-catenin transcriptional activity. Interestingly, β-catenin or IRS2 inhibition (using NT219) in IRS2-expressing cells decreased their viability, β-catenin transcriptional activity, and OXPHOS gene expression, suggesting involvement of IRS2 in modulating OXPHOS through β-catenin. β-catenin is known to confer 5-FU resistance; consequently, we showed that combination of 5-FU and NT219 worked in synergy, inhibited the formation of BM, and extended animal survival.These data reveal the unique genomic profile of CRC BM and suggest IRS2 inhibition as a novel target for treatment of these patients.

20 May 2021·Journal of Clinical Oncology

A phase 1/2 study with open-label, dose escalation phase followed by single-arm expansion at the maximum tolerated dose to assess the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of NT219 injection alone and in combination with cetuximab in adults with advanced solid tumors and head and neck cancer.

Author: Bessudo, Alberto ; Liang, Bertrand C. ; Stemmer, Salomon M. ; Gutierrez, Rodolfo ; Cohen, Ezra E.W. ; Sukari, Ammar ; Johnson, Daniel H. ; Weinberg, Benjamin Adam ; Reuveni, Hadas ; Rosenberg, Ari ; Schickler, Michael

TPS3156 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.

100 Deals associated with Tyrnovo Ltd.

100 Translational Medicine associated with Tyrnovo Ltd.

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Drug(Targets)	Indications	Global Highest Phase

NT-219 ( IRS-1 x IRS2 x STAT3 )	Metastatic Solid Tumor More	Phase 2 Clinical
NT-157 ( IGF-1R x IRS-1 x IRS2 )	Prostatic Cancer More	Pending

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