A multi-cohort phase I/IIa clinical trial to evaluate the safety, tolerability, and pharmacokinetics of TST001 administered as a monotherapy, with nivolumab or standard of care in patients with locally advanced or metastatic solid tumors: TransStar101.
Authors: Janjigian Yelena Y. , Sun Weijing , Rocha Lima Caio Max Sao Pedro , Shah Satish , Scott Aaron James , Monga Dulabh K. , Kundranda Madappa N. , Sher Amna Falak , Gold Philip Jordan , Berlin Jordan , Patel Manish R. , Alese Olatunji B. , Hamilton Erika P. , Cecchini Michael , Van Tine Brian Andrew , George Ben , Mehta Rutika , Xia Zhenzhong , Germa Caroline , Gabrail Nashat Y. 
Published: June 2023

TPS4176 Background: Gastric cancer (GC) remains the 4th leading cause of cancer death worldwide, accounting for about 7.7% of all cancer related mortality. Despite recent approval of nivolumab in combination with chemotherapy, the median survival of treatment naïve Gastric Cancer/gastroesophageal junction cancer (G/GEJ) cancer is only approximately 14 months, even in patients with high CPS PD-L1. Targeting claudin 18.2 (CLDN18.2) in combination with chemotherapy is a clinically validated approach for patients with CLDN18.2 expressing advanced G/GEJ cancer. TST001 is a humanized monoclonal antibody with improved affinity to human CLDN18.2 and enhanced antibody-dependent cellular cytotoxicity (ADCC). In pre-clinical studies, TST001 treatment upregulates PD-L1 expression on CLDN18.2-positive tumor cells. The in vivo analysis showed anti-tumor efficacy of TST001 combined with anti-PD-1 antibody and chemotherapy was superior to combination of anti-PD-1 antibody with chemotherapy or combination of TST001 with chemotherapy. Promising anti-tumor activities have been observed in patients with advanced G/GEJ cancer who have been treated with TST001 alone or in combination with chemotherapy, making the combination of TST001, nivolumab and chemotherapy attractive. Methods: This is a multi-cohort, open-label, multi-center phase I/II first in human (FIH) study of TST001 administered as single agent, in combination with nivolumab or standard of care in the treatment of patients with locally advanced or metastatic solid tumors. Primary endpoints include characterization of TST001 safety profile and the maximum tolerated dose / recommended phase 2 dose. Secondary endpoints include pharmacokinetics, immunogenicity, pharmacodynamics, and efficacy. The study includes two parts. Part A (completed) is a dose escalation of TST001 as a monotherapy. Part B (ongoing) consists of three independent cohorts: cohort A includes combination TST001 + nivolumab+ leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin (mFOLFOX6) as 1st line treatment for G/GEJ cancer; cohort B includes TST001 in combination with nivolumab in advanced pre-treated G/GEJ cancer; cohort C includes combination therapy of TST001, gemcitabine, and nanoparticle albumin-bound paclitaxel as 1st line treatment for advanced/metastatic pancreatic cancer. Multiple doses and schedules will be assessed during Part B. Conclusions: Combination of TST001 with nivolumab and chemotherapy has the potential to improve the outcomes of patients with advanced or metastatic CLDN18.2 expressing G/GEJ cancer. Data from this trial will support the selection of the optimal dose and dose regimen of TST001 in these combinations. Enrollment in the trial is ongoing. Clinical trial information: NCT04396821 .