A phase 1, first-in-human, open-label, dose escalation and dose expansion study of TST005 in patients with locally advanced or metastatic solid tumors.
Authors: Tolcher Anthony W. , Wu Xiaohua , Zhang Jian , Barve Minal A. , Gabrail Nashat Y. , Sommerhalder David , Rodriguez Rivera Ildefonso I , Wilks Sharon , Wu Yong , Liu Rujiao , Gao Shuiping , Valiyil Akhilkrishna , Sayi Ntombizodwa , Germa Caroline , Qi Charlie , Chen LEI , Yu Steven , Yao Jenny , Zhu Xuelian 
Published: June 2023

2531 Background: TST005 is a novel bi-functional fusion protein combining a high affinity PD-L1 mAb and a differentiated TGF-β trap with improved stability. In pre-clinical study, TST005 showed no antibody-dependent dependent cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC) activity. Methods: This is a Phase 1, dose escalation study with classic 3+3 design to evaluate the safety, tolerability, PK and pharmacodynamic and preliminary anti-tumor activity of TST005 and determine the maximum tolerated dose and/or the Recommended Phase 2 Dose (RP2D). Eligible solid tumor patients who have failed prior standard therapy(ies) and have received no more than one prior immune checkpoint inhibitor (ICI) treatment will be enrolled to receive TST005 intravenous (IV) infusion every 3 weeks until disease progression assessed by the Investigator per RECIST v1.1 and/or immune RECIST, or unacceptable toxicity. Results: The study is ongoing at 4 clinical centers in US and China. As of 31 Jan 2023, 18 eligible subjects have been enrolled into different TST005 dose levels: 2 at dose of 1mg/kg, 4 at 3 mg/kg, 4 at 10 mg/kg, 3 at 20 mg/kg, and 5 at the last dose level of 30 mg/kg. The enrollment is still ongoing. No DLT was observed so far. The most common treatment-emergent adverse events (TEAEs) ( > 10%) included: fatigue (38.9%), rash (22.2%), anemia (16.7%), myalgia (16.7%), and arthralgia, dehydration diarrhea, dry skin, hematuria, hypokalemia, pruritus, lymphocyte count decreased were 11.1%. 7 patients (38.9%) experienced ≥Grade 3 (G3) TEAEs according to CTCAE V5.0, 1 of whom were considered as related to TST005: it was an infusion related reaction (G3), and caused discontinuation of treatment. Two subjects experienced IRRs (G2 and G3 respectively), both at the dose of 3mg/kg cohort. One subject of 30mg/kg dose cohort presented a squamous cell carcinoma of skin, which is known as a classic side effect of TGF-β directed therapies. The subject was discontinued from study and to receive resection. No treatment-related deaths occurred. TST005 demonstrated a nonlinear PK profile between 1 to 20 mg/kg with calculated t1/2 of 4-9 days. ADA was observed in most ADA evaluable subjects, PK at doses ≥ 10mg/kg were not impacted by ADA. At 20mg/kg, the receptor occupancy increased to > 90% immediately after infusion and remain at this level up to C2D1. Start from 1mg/kg, serum TGF-β1 was depleted immediately after dosing, sustained to next dose of TST005. 11 subjects had at least one post treatment tumor assessment per RECIST 1.1. 7 subjects (63.6%) had best overall response of SD. No PR or CR had been observed. Conclusions: TST005 monotherapy demonstrated a good safety and tolerability, nonlinear PK characteristics and significant target engagement in patients with advanced solid tumors. Continue investigation of TST005 as monotherapy or in combination with other therapies are warranted. Clinical trial information: NCT04958434 .