NEW YORK – Triumvira Immunologics on Monday said it began dosing patients in a Phase I/II trial of an autologous T-cell antigen coupler (TAC) therapy, TAC101-CLDN18.2, targeting claudin 18.2 (CLDN18.2)-positive solid tumors.
At the same time, in an effort to optimize finite resources, the Austin, Texas-based company has paused clinical development of its HER2-targeted TAC agent, TAC100-HER2 (formerly TAC01-HER2), and is focusing instead on the CLDN18.2 program, said Robert Williamson, Triumvira's president and chief operating officer. TAC100-HER2 had shown activity in an early data readout last year in HER2-positive gastric cancer, but it also caused cytokine release syndrome and pneumonitis in some patients.
CLDN18.2 is a member of the family of claudin proteins, which are present in tight junctions. Alterations in claudin expression that disrupt tight junctions have been implicated in the development of gastric, liver, biliary tract, breast, kidney, and other cancers. CLDN18.2 is commonly expressed in many cancers but is not expressed in healthy tissues, except in the gastric mucosa. Approximately 40 percent of patients with gastric cancers in the US are believed to be CLDN18.2-positive.
In the TACTIC-3 trial, Triumvira researchers will evaluate the safety, maximum-tolerated dose, pharmacokinetics, and efficacy of TAC101-CLDN18.2 in about 113 patients with CLDN18.2-positive gastric, esophageal, pancreatic, colorectal, bile duct, ovarian, gall bladder, and non-small cell lung cancer who have received at least two but no more than four prior lines of therapy. That includes patients with pancreatic ductal adenocarcinoma who have received one prior line of antineoplastic therapy.
In the Phase I portion of the trial, patients will be given escalating doses of TAC101-CLDN18.2 to establish a recommended Phase II dose and a maximum-tolerated dose. In the Phase II portion, researchers will carry out a dose-expansion study in three patient groups. Group A will include patients with gastric and esophageal cancer; group B will involve patients with pancreatic cancer; and group C will comprise patients with mucinous ovarian cancer and NSCLC.
The researchers will track patients' overall response rate, overall survival, disease control rate, progression-free survival, and treatment-emergent adverse events on TAC101-CLDN18.2 as primary outcome measures in the trial.
Triumvira's TACs are multi-domain chimeric molecules that bind to an antigen on the tumor cell and recruit T cells to attack the tumor. However, unlike other T-cell receptor therapies, the TAC includes a co-receptor domain that can activate or silence the T cell depending on the presence of the cancer antigen.
"Compared to [TACs], a CAR T-cell therapy is a much simpler approach to redirecting a T cell," Williamson said. "We tried to mimic the natural T-cell receptor, which allows us to have characteristics we think are better than a [CAR T-cell therapy]."
Those characteristics include better control over the release of cytokines, leading to less cytokine release syndrome in patients. "We see some [cytokine release syndrome] in our patients" treated with TAC101-CLDN18.2, Williamson said. "But nothing really dramatic."
There are currently no approved therapies targeting CLDN18.2, but many drugmakers are developing treatments that target this protein. For example, Astellas was seeking approval for its CLDN18.2-targeted IgG1 monoclonal antibody zolbetuximab as a treatment for advanced, HER2-negative, CLDN18.2-positive gastric cancer, but it recently received a complete response letter from the US Food and Drug Administration for that application.
Phanes Therapeutics is developing a CLDN18.2/CD47-targeted bispecific antibody and in August 2023 began a Phase I trial of the product in combination with Merck's checkpoint inhibitor Keytruda (pembrolizumab) in patients with CLDN18.2-positive gastric or gastroesophageal junction cancers. There are CLDN18.2-targeted cell therapy products in development, too, such as Carsgen Therapeutics' CAR T-cell therapy CT041, which it is testing alone in gastric and pancreatic cancer patients and in combination with Moderna's CLDN18.2-targeted off-the-shelf mRNA cancer vaccine.
Triumvira believes TAC101-CLDN18.2 has an edge over the competition when it comes to tolerability. Williamson noted that Triumvira's cell therapy technology has demonstrated good tolerability in clinical trials of its TAC101-HER2. "We're looking forward to seeing that benefit again in our claudin18.2 program," he said.
Among potential competitors, while Carsgen's CT041 has shown "really compelling efficacy," according to Williamson, there's room for [TAC101-CLDN18.2] to have "better efficacy and certainly better tolerability."
In a Phase I trial of CT041 in previously treated, CLDN18.2-positive gastric cancers, Carsgen reported an overall response rate of 48.6 percent and a disease control rate of 73.0 percent. Six months after treatment, 81.2 percent of patients were still alive. In terms of safety, out of 37 patients treated with CT041, 94.6 percent of patients had grade 1 or 2 cytokine release syndrome, lasting a median six days.
Triumvira is also developing both autologous and allogeneic TACs against several other targets including HER2, guanylyl cyclase 2C (GUCY2C), and GPC2, but currently all of those programs are on hold because the company lacks the funds at present to advance them. The company raised $100 million in a Series A financing round in May 2022 and $26 million in a Series B round last year. Williamson said the company continues to explore financing options.
"The funding environment for cancer cell therapies remains difficult even as other biotechnology areas, such as radiopharma, heat up," Williamson said. "Publicly traded cell therapy companies remain poorly valued, and this impacts the private markets. We have also experienced significant interest in our claudin 18.2 program, so prioritizing that made a lot of sense."
With the money raised to date, the company began the Phase II portion of the TACTIC-2 trial of its prior lead agent TAC100-HER2 alone and in combination with Keytruda in HER2-positive gastric and gastroesophageal junction cancers in May 2023. In a preliminary readout from the dose-escalation portion of this trial last November, two patients had partial responses to TAC100-HER2 monotherapy with a 100 percent and 35 percent reduction in measurable disease, respectively. Out of 20 patients treated, one patient had grade 3 pneumonitis linked to TAC100-HER2 treatment, and 11 experienced cytokine release syndrome. Of those, seven events were grade 1, six were grade 2, and one was grade 3.
Williamson said that while the HER2 program is now paused, he still believes there's an opportunity for it. "But the investors are much more interested in claudin 18.2, and we had to pick one," he said.
Triumvira is expecting its first data readout from the TACTIC-3 trial in the first half of 2025.