Global Studies Evaluate Safety/Efficacy of TST001 for Locally Advanced or Metastatic Solid Tumors

The combination of TST001 and nivolumab (Opdivo) for the treatment of patients with unresectable locally advanced or metastatic gastric cancer or gastroesophageal junction cancer (GC/GEJ) will be evaluated in multiple phase 1/2 studies, according to a press release by Transcenta.¹

"TST001 is a high affinity humanized monoclonal antibody targeting CLDN18.2. It has shown to be safe in ongoing trials as monotherapy or in combination with chemotherapy and displayed encouraging anti-tumor activity signals in gastric cancer and other solid tumor patients expressing CLDN18.2. TST001 works through NK cell mediated antibody dependent cellular cytotoxicity to exert its anti-tumor activity, and the addition of PD-1 inhibitor and chemotherapy have resulted in synergistic effects in preclinical models. We are excited to test the combination of TST001 with Opdivo For the treatment of metastatic gastric/gastroesophageal junction cancer as a new potential treatment option for these patients." said Michael Shi, MD, executive vice president, head of global R&D and chief marketing officer of Transcenta, in a press release.

This collaboration includes 2 global phase 1/2 open-label, multi-center studies to evaluate the safety, tolerability, and anti-tumor efficacy of TST001 in combination with nivolumab in patients with unresectable locally advanced or metastatic CLDN18.2 expressing GC/GEJ with or without previous treatment.

Poor clinical outcomes with available therapies are often experienced by patients with CLDN18-positive cancer. CLDN18.2 has emerged as a potential therapeutic target, and several CLDN18.2 antibodies are under clinical development, including TST001, an investigational humanized monoclonal antibody targeting CLDN18.2.^2,3

A phase 1 trial of TST001 enrolled patients aged 18 years and older with histologically or cytologically confirmed locally advanced or metastatic solid tumors who had progressed following standard treatment. Patients were intolerant of standard options or had a tumor type that did not have standard therapy available. Other requirements included an ECOG performance status of 0 or 1, a life expectancy of at least 3 months, at least 1 measurable lesion per RECIST v1.1 criteria, and acceptable hepatic, kidney, and hematologic function. For participants in part B, CLDN18.2 expression determined by immunohistochemistry was needed.

Part A of the trial consisted of a dose-escalation portion of research which set out to enroll 3 to 6 participants for each dose level. TST001 was given intravenously every week, 2 weeks or 3 weeks, ranging from doses of 1 mg/kg to 3 mg/kg, to 6 mg/kg, to 10 mg/kg.

In part B of the study, which plans to enroll 20-30 patients to 3 cohorts, all patients will be selected based on CLDN18.2 expression. Cohort A will consist of individuals with gastric cancer/GEJ cancer and each will receive TST001 as a single agent in the third- or later-line setting.

Cohort B will also include patients with gastric cancer/GEJ cancer, who will receive the agent in combination with nivolumab in the second- or later-line setting. Based on the findings from part A, TST001 will be started at 1 dose level lower, and then escalate to the suggested dose level from part A if no dose-limiting toxicity is observed. Nivolumab will be given at a dose of 240 mg on day 1 every 2 weeks or 360 mg on day 1 every 3 weeks.

Cohort C will include those with pancreatic cancer or biliary tract cancer who will receive TST001 as a monotherapy in the second- or later-line setting.

The primary end point of the research includes examining the safety and tolerability of TST001 monotherapy in patients with locally advanced or metastatic solid tumors, identifying the maximum tolerated dose and/or recommended phase 2 dose, and examining the safety and tolerability of TST001 plus nivolumab in those with locally advanced or metastatic gastric/GEJ cancer.

Other end points include characterizing the pharmacokinetic profile of TST001 and its exposure/response relationship for safety and efficacy, characterizing the immunogenicity of the agent, and evaluating preliminary antitumor activity with TST001 as a single agent or with nivolumab in those with locally advanced or metastatic solid tumors.

Additional exploratory objectives include assessing the ADCC/CDC activities induced by TST001 using blood samples, in order to examine the pharmacodynamics and related biomarkers for TST001 in peripheral blood and/or tumor tissue, and to evaluate correlations between CLDN18.2 expression, pharmacokinetics, and pharmacodynamics, and clinical readouts of the agent.

The second trial is also a phase 1, open-label study (NCT04495296), to evaluate the safety and tolerability, pharmacokinetics, and preliminary efficacy of TST001 in patients with advanced or metastatic solid tumors who progressed on or after standard treatments.⁴

There are two parts in the study which include part A, the monotherapy, dose escalation, and dose expansion part of the study, and Part B, the dose escalation and dose expansion study of combination therapy. For part A, dose escalation will be conducted using 3+3 dose escalation method eitheronce every 2 weeks once every 3 weeks.

The study plans to enroll between 165-210 participants aged 18-75 with advanced unresectable or metastatic malignant local solid tumors confirmed by histological diagnosis. Other requirements for eligibility include an ECOG score 0-1 and an expected survival ≥ 3 months.

Primary end points include safety, maximum tolerated dose, recommended phase 2 dose, and the incidence and case number of dose limiting toxicity. Secondary objectives include the assessment of pharmacokinetic parameters, immunogenicity, and preliminary anti-tumor activity.

References:

1. Transcenta announces global clinical collaboration with Bristol Myers Squibb to evaluate TST001 in combination with opdivo in patients with locally advanced or metastatic gastric/gastroesophageal junction cancer. News release. Transcenta Holding Limited; March 21, 2022. Accessed March 23, 2022. https://prn.to/3ukoQPn

2. Gabrail NY, Tolcher A, Alese OB, et al. A phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of TST001 in patients with locally advanced or metastatic solid tumors. J Clin Oncol. 2022;40(suppl 4):TPS375. doi:10.1200/JCO.2022.40.4_suppl.TPS375

3. A trial to evaluate safety and tolerability of TST001 in advanced or metastatic solid tumors. ClinicalTrials.gov. Updated June 9, 2020. Accessed January 22, 2022. https://clinicaltrials.gov/ct2/show/NCT04396821

4. A Trial to Evaluate Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of TST001 in Advanced or Metastatic Solid Tumors. Clinicaltrials.gov. Accessed March 23, 2022. https://clinicaltrials.gov/ct2/show/NCT04495296?term=NCT04495296&draw=2&rank=1