The safety and tolerability of TST001, a high affinity humanized IgG1 monoclonal antibody to CLDN18.2, is under investigation as a potential treatment option for patients with gastric/gastroesophageal junction (GEJ) cancer and other locally advanced or metastatic solid tumors as part of a phase 1 trial (NCT04396821).^1,2

CLDN18.2 expression showcases a unique tissue distribution pattern than other claudin family members. Specifically, the expression is restricted to the differentiated epithelial cells of healthy gastric mucosa, but undetectable or absent from other healthy tissues. CLDN18.2 expression has been found in select tumors such as gastric, esophageal, and pancreatic cancers.

Those with CLDN18-positive cancers typically experience poor clinical outcomes with available therapies, but CLDN18.2 has emerged as a potential therapeutic target, and several CLDN18.2 antibodies are under clinical development.

One such agent is TST001, and its Fab domain binds to distinct epitopes of CLDN18.2 compared with what other CLDN18.2 antibodies under development bind to, like zolbetuximab (IMAB362). The agent is developed through an optimized glycoengineering process to reduce fucose content and increase its affinity to FcR.

“The biological characteristics of CLDN18.2 suggest it is an ideal therapeutic target for cancer drug development,” Michael Shi, MD, executive vice president, head of global R&D, and chief medical officer of Transcenta Holding Limited, stated in a press release.³ “Data from patients treated with the current doses of either TST001 alone or in combination with chemotherapy supports that TST001 is safe.”

In an in vivo MKN45-CLDN18.2 mouse model with human peripheral blood mononuclear cells co-inoculated, investigators compared TST001 with a IMAB362-analog. Seven in the TST001 group (N1 = 10) experienced tumor clearance vs no clearance in the IMAB362-analog group (N2 = 10). In a CT26-CLDN18.2 model, synergic tumor growth inhibition was noted when TST001 was paired with atezolizumab (Tecentriq).

Investigators hypothesized that because the agent has high affinity from the specific binding to CLDN18.2 through Fab, and enhanced Fc-FcR recognition/binding onto natural killer cells, TST001 might have improved efficacy vs other CLDN18.2 antibodies under development.

The phase 1 trial, the design of which was shared as a “Trial in Progress” during the 2022 Gastrointestinal Cancers Symposium, enrolled patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors who had progressed following standard treatment, were intolerant of standard options, or who had a tumor type that did not have standard therapy available.

Patients had to be at least 18 years of age, 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. Those in part B needed to have CLDN18.2 expression determined by immunohistochemistry.

If patients had symptomatic central nervous system metastases; previously received anticancer treatment including chemotherapy, immunotherapy, biologic therapy, or targeted therapy within 5 half-lives of the agents or 4 weeks before C1D1 and related toxicities prior to the first dose of study treatment; previously received radiation therapy within 4 weeks before the first day of the first cycle of treatment; previously received treatment with an anti-CLDN18.2 agent, they were excluded.

Other key exclusion criteria included having undergone major surgery within 8 weeks before study entry or minor surgery within 2 weeks before study entry, gastrointestinal abnormalities like documented unresolved gastric outlet obstruction or persistent vomiting and uncontrolled peptic ulcer disease despite treatment in the past 3 months or having an allergy or sensitivity to TST001 to known allergies to antibodies produced from Chinese hamster ovary cells.

Part A of the trial is the dose-escalation portion of the research set out to enroll 3 to 6 participants to each dose level examined. TST001 was delivered intravenously at doses ranging from 1 mg/kg to 3 mg/kg, to 6 mg/kg, to 10 mg/kg. The agent was given either once every 2 weeks or every 3 weeks.

All patients in part B, the dose-expansion portion of the research, will be selected based on CLDN18.2 expression. This phase of the research plans to enroll 20 to 30 patients to 3 cohorts. Cohort A will comprise those with gastric cancer/GEJ cancer who 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 (Opdivo) in the second- or later-line setting. TST001 will be started at 1 dose level lower based on findings from part A of the trial, and then escalated 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 objectives of the research are to examine the safety and tolerability of TST001 monotherapy in patients with locally advanced or metastatic solid tumors, to identify the maximum tolerated dose and/or recommended phase 2 dose, and to examine the safety and tolerability of TST001 plus nivolumab in those with locally advanced or metastatic gastric/GEJ cancer.

Investigators also want to characterize the pharmacokinetic profile of TST001 and its exposure/response relationship for safety and efficacy, to characterize the immunogenicity of the agent, and to evaluate preliminary antitumor activity with TST001 as a single agent or with nivolumab in those with locally advanced or metastatic solid tumors.

Other exploratory objectives include assessing the ADCC/CDC activities induced by TST001 using blood samples, to evaluate 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 trial, which is being conducted in the United States, is completing the dose-escalation portion. As of January 8, 2022, 9 trial sites were open for enrollment and the current dose level of TST001 under examination was 10 mg/kg every 3 weeks.

References

1. 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

2. 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

3. Transcenta to present two phase I clinical trials of TST001 at upcoming ASCO GI and IGCC. News release. Transcenta Holding Limited; January 12, 2022. Accessed January 22, 2022. https://bit.ly/3fQx3E0 

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