Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results
- Study type
- Clinical trial
- Study name
- CT041-CG4006
- Phase
- Phase 1
- Design
- Single-arm, open-label trial with a dose-escalation phase and a dose-expansion phase in four different cohorts
- Sample size
- 98 patients infused with satri-cel (dose escalation: 15 patients; dose expansion: 83 patients in total)
- Source
- Nat Med · 2024
- Trial registration
- NCT03874897
In plain words
In this study, a type of cell therapy called satri-cel, which is made from the patient's own immune cells and targets a protein called Claudin18.2 on cancer cells, was tested in 98 patients with advanced cancer of the digestive system. The tumour shrank in about 39% of patients and the disease was brought under control in about 92%. Side effects were mostly mild to moderate and no treatment-related deaths were reported. This is an early (phase 1) study and the treatment is not yet considered standard.
Key results
Treatment arms and regimens
Modified "3+3" dose escalation/de-escalation design with a single IV infusion of satri-cel (satricabtagene autoleucel / CT041; autologous CLDN18.2-targeted CAR T cells) at one of the levels 2.5 × 108, 3.75 × 108 or 5.0 × 108 CAR T cells; after a grade 4 gastrointestinal haemorrhage at the 5.0 × 108 level, a dose of 2.5 × 108 was recommended for the expansion phase. Of all 98 patients, 89 received 2.5 × 108, six 3.75 × 108 and three 5.0 × 108 CAR T cells.
Conditioning (lymphodepletion): fludarabine 25 mg/m² on days −4 and −3, cyclophosphamide 250 mg/m² on days −4, −3 and −2, and nab-paclitaxel 100 mg (or gemcitabine 1000 mg) on day −3 (the paper gives these two doses without "per m²"); cell infusion within 7 days of completing conditioning, with an NSAID and an antihistamine half an hour before infusion. Bridging therapy was allowed during cell manufacture (suggested FOLFIRI regimen: fluorouracil 2400 mg/m² and irinotecan 180 mg/m²). Re-infusion with a second course of conditioning was allowed if the response was at least stable disease, severe toxicities had resolved to grade 1 or lower and CAR copies were undetectable in peripheral blood.
61 patients with gastrointestinal cancer refractory to standard chemotherapy; satri-cel monotherapy at the recommended expansion dose (2.5 × 108 CAR T cells) with the same conditioning and re-infusion rules as the dose-escalation phase.
15 patients with gastrointestinal cancer refractory to standard chemotherapy; satri-cel (2.5 × 108 CAR T cells with the same conditioning) plus an anti-PD-1 antibody (in the trial registry: toripalimab). The dose and schedule of the anti-PD-1 drug are not stated in the available sources.
5 patients with gastric or gastro-oesophageal junction cancer; satri-cel (2.5 × 108 CAR T cells with the same conditioning) as sequential treatment after physician's-choice first-line systemic therapy. The first-line regimen and doses are not stated in the available sources.
2 patients with gastric cancer refractory to an anti-CLDN18.2 monoclonal antibody; satri-cel monotherapy (2.5 × 108 CAR T cells with the same conditioning).
Source of the regimen details: Interim report of the same trial (Nat Med 2022; PMC9205778) for conditioning, dose levels and re-infusion rules; abstract of the final report and ClinicalTrials.gov NCT03874897 for the expansion cohorts. The full text of the final report was not available, and the dose of the anti-PD-1 drug is not stated in these sources
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients aged 18 to 75 years with histologically confirmed advanced gastrointestinal cancer (gastric or gastro-oesophageal junction, pancreatic or other gastrointestinal malignancies) who had failed at least one line of therapy; CLDN18.2 expression on immunohistochemistry of 2+ or greater intensity in at least 40% of tumour cells; life expectancy over 12 weeks; measurable or non-measurable disease per RECIST 1.1; ECOG 0 to 1. Exclusion criteria included prior CAR-T or TCR-T cell therapy, untreated or symptomatic brain metastases and systemic glucocorticoids of 15 mg/day or more within 7 days before apheresis. In the dose-expansion phase, cohorts 1 and 2 comprised patients refractory to standard chemotherapy, cohort 3 sequential treatment after first-line therapy and cohort 4 patients with gastric cancer refractory to an anti-CLDN18.2 monoclonal antibody.
Endpoints
Primary endpoint: safety. Secondary endpoints: efficacy, pharmacokinetics and immunogenicity.
Safety and side effects
No dose-limiting toxicity, treatment-related death or immune effector cell-associated neurotoxicity syndrome (ICANS) was reported. Cytokine release syndrome (CRS) occurred in 96.9% of patients, all grade 1 to 2. Gastric mucosal injury was observed in eight patients (8.2%).
Clinical significance and place in guidelines
These final phase 1 results show that CLDN18.2-targeted CAR T cell therapy in patients with CLDN18.2-positive advanced gastrointestinal cancer has a manageable safety profile and signs of efficacy. Because of the single-arm, early-phase design, these findings do not yet establish a change in standard care. Regulatory approval status and the place of this therapy in clinical guidelines should be checked separately.
Limitations
The study was phase 1, single-arm and open-label without a control group, so direct comparison with standard care is not possible. The expansion cohorts differed greatly in size (from 2 to 61 patients) and the population included various types of gastrointestinal cancer. Most patients received the same dose level.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.