A phase 1/2 study evaluating the safety and efficacy of autologous TAC T cells in subjects with claudin 18.2+ advanced solid tumors

Authors

Ecaterina E. Dumbrava, Syma Iqbal, Simon Turcotte, Gregory Botta, Benjamin Schlechter, Geoffrey Ku, Peter Hosein, Sam Saibil, Miriam Gavriliuc, Maria Apostolopoulou, Mobolaji Giwa, Heather MacGregor, Kara Moss, Eli Panna, Swaminathan Murugappan, Davendra Sohal

Institutions

The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; University of Southern California Health Sciences, Los Angeles, California, USA; Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada; University of California, San Diego Health, San Diego, California, USA; Dana Farber Cancer Institute, Boston, Massachusetts, USA; Memorial Sloan Kettering Cancer Center, New York, New York, USA; University of Miami, Coral Gables, Florida, USA; Princess Margaret/University Health Network, Toronto, Ontario, CA; Triumvira Immunologics, Inc., Austin, Texas, USA; University of Cincinnati, Cincinnati, Ohio, USA.

INTRODUCTION

• The T cell antigen coupler (TAC) is a novel, proprietary chimeric receptor that facilitates the re-direction of T cells to tumor cells and activates T cells by co-opting the endogenous T cell receptor complex, aiming to elicit a safe and durable anti-tumor response. In preclinical models, TAC-engineered T cells effectively eradicate tumor cells in vitro and in vivo without toxicities typically associated with engineered T cell products. TAC01-CLDN18.2 is an autologous T cell product comprising T cells expressing the CLDN18.2 TAC, which specifically recognize CLDN18.2+ cells.

• TACTIC-3 (NCT05862324) is an open-label, multicenter phase I/II study that aims to establish safety, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetic profile, and efficacy of TAC01-CLDN18.2 in patients with CLDN18.2 positive solid tumors by immunohistochemistry (i.e. gastric, GEJ, esophageal adenocarcinoma, PDAC, colorectal cancer, cholangiocarcinoma, ovarian mucinous cancer, gallbladder cancer and NSCLC) who have been exposed to at least 2 prior anti-cancer therapies.

TAC SCIENCE

TAC achieves TCR activation via a CD3 binding domain while tightly binding the target of interest, CLDN18.2. TAC thus co-opts natural TCR function and provides intracellular co-receptor signaling via Lymphocyte-specific Protein Tyrosine Kinase (LCK), mimicking physiologic TCR activation.

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Phase I (Dose Escalation)

Eligibility Criteria

Patients with advanced, metastatic, unresectable solid tumors which express CLDN18.2 after at least 2 lines of therapy (1 for PDAC), at least 1 measurable lesion per RECIST version 1.1, ECOG performance score 0-1, grade 1 or baseline for any prior treatment related toxicities.

The classic 3+3 dose escalation design will be employed to efficiently determine the maximum tolerated dose (MTD) and RP2D using well-defined DL T criteria. N = 9-24 subjects.

Phase II (Dose Expansion)

Note: Required specific tumor types for phase 1 include: gastric, GEJ, esophageal adenocarcinoma, PDAC, colorectal cancer, cholangiocarcinoma, ovarian mucinous cancer, gallbladder cancer and NSCLC.

Groups A and C:

• Approach: Simon 2-stage design.
• Objective: Assess efficacy (ORR).

Group B:

• Initial Approach: Evaluate ORR after 10 PDAC treatments.
• Future: Adopt Simon 2-stage based on outcomes.

Demographics and Tumor Intrinsic Characteristics (n=13)

In both phases, a second dose is allowed if subjects meet predefined clinical and safety criteria, with modified or no lymphodepleting chemotherapy (LDC).

Preferred LDC:

3 consecutive days of fludarabine (Flu) IV (30 mg/m2) and cyclophosphamide (Cy) IV (300 mg/m2) +/- Mesna IV, and a single dose of nab-paclitaxel (100mg/m2) on the second day of LDC.

Secondary Endpoints

RP2D, PK, Efficacy (ORR, DoR, OS, TCR, PFS)

PHASE I TRIAL PROGRESS

Primary Endpoints

Safety: DLTs, AEs

High (H) CLDN18.2 expression subjects in this study are those with samples where 50% or more of tumor cells express CLDN18.2 with intensity of 2+ or 3+. All others are termed low (L) expression.

TUMOR ASSESSMENT: SUBJECT RESPONSE

• One subject experienced Grade 3 gastritis and gastric hemorrhage, both resolving within 4 days.

Subject 0112-0040

• 57 year old female with CLDN18.2+ (high expression) stage IV metastatic pancreatic cancer.
• Previously treated with 3 lines of therapy.
• The subject did not receive bridging therapy.

Follow-up

• All subjects are still in follow-up.

• The subject had stable disease at first tumor assessment, which turned to a partial response 3 months after TAC infusion. The partial response has been confirmed and is ongoing (for 6 months as of data cut date). The subject received a second TAC infusion 5 months after the first and is still on treatment (for 9 months as of data cut date). The subject’s non-target lesions met complete response criteria during their last scan.

RECIST 1.1 Tumor Response Assessments (Measurable Disease)

• Baseline (19 mm)

TAC01-CLDN18.2 PK AND CYTOKINE ANALYSIS

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TAC copies detected in the blood of subjects at the indicated days post-treatment. Red, blue and green lines indicate DL1, DL2 and DL3 subjects, respectively. TAC concentration after the second dose (black outline) was lower than similar time points after the first dose. TAC T cells still persist in the circulation of most subjects at D29, and even 3 months after infusion (D90; DL1 and DL2 data only available). Biopsies, where available, indicate a higher concentration of TAC cells in the tumor bed compared to blood samples taken at the same time.

Safety

• Interim results from the Phase I TACTIC-3 study suggest that TAC01-CLDN18.2 has manageable toxicity. Two Grade 3 treatment-related events of gastritis and gastric hemorrhage were observed, but resolved within 4 days. One Grade 1 ICAN event was observed, which resolved without intervention within 24 hours. Three low-grade CRS events were reported, which resolved with standard interventions.

| Subject / Dose Level | Biopsy Day | Blood | TAC copies pg/mL |

| --- | --- | --- | --- | | 0044 / 1.3tC/Tac/kg | Day 11 (A) | 165 | 338 | | 0044 / 1.3tC/Tac/kg | Day 11 (B) | 165 | 364 | | 0044 / 1.3*tC/Tac/kg | Day 29 (A) | BLOD | 64.44 | | 0000 / 6-8eT/Cac/kg | Day 29 | 17.3 | 218.5 |

Acknowledgements

Clinical Trial Sites and Apheresis Unit staffs, as well as the patients and their families.