CARsgen Hopes to Show Continued GI Cancer Control in ELIMYN18.2 Trial

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The trial is assessing satri-cel CAR T-cell therapy, which is currently on clinical hold due to CMC concerns.

As cell therapy programs begin to dip into the field of solid tumors, one of the leading solid tumor indications being investigated is gastrointestinal (GI) cancers. One company developing a cell therapy program for GI cancers is CARsgen, whose chimeric antigen receptor (CAR) T-cell therapy satricabtagene autoleucel (satri-cel; CT041; CARsgen) is being assessed in patients with in patients with heavily pretreated Claudin18.2 (CLDN18.2)-positive advanced gastric/gastroesophageal (GC/GEJ) or pancreatic cancer (PC).

Satri-cel is an autologous, CLDN18.2-targeted CART-cell therapy that has received regenerative medicine advanced therapeutic and orphan drug designation (ODD) from the FDA for GC/GEJ cancers and PRIorityMEdicines and ODD designations from the European Medicines Agency.

“This is worldwide the first CLDN18.2 program that has received multiple countries’ investigational new drug (IND) clearance... the program is also the first solid tumor CAR-T program that has received multiple designations [from regulatory agencies,” Hong Ma, MD, Sr. Vice President of Clinical Development for Cancer Immunotherapy, CARsgen, told CGTLive.

The ELIMYN18.2 trial is evaluating the safety and efficacy of satri-cel in patients with advanced GC/GEJ or PC whose disease had progressed or was unresponsive to at least 2 prior lines (GC/GEJ) or 1 prior line (PC) of systemic therapy. The study followed a modified 3+3 dose escalation/de-escalation scheme with 5 dose levels (DL). Participants received a preconditioning regimen of fludarabine, cyclophosphamide, and nab-paclitaxel before receiving 1-3 cycles of satri-cel.

WATCH NOW: Maria Pia Morelli, MD, PhD, on Considerations for Cell Therapy in GI Cancers

The trial’s primary endpoints are the incidence of adverse events (AEs) and identification of maximum tolerated dose and dose-limiting toxicities in the phase 1b portion and objective response rate (ORR) in the phase 2 part. Secondary outcome measures are ORR in the phase 1b portion; duration of response, disease control rate, progression free survival, overall survival, utilization of hospital resources, health related quality of life, pharmacokinetics and biodistribution, CLDN18.2 ICH assay, anti-CT041 antibodies, cytokine expression level in blood in both portions; and incidence of AEs in the phase 2 portion.

The most recent data from ELIMYN18.2 were presented at the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers (GI) Symposium, held January 18-20, in San Francisco, California, by Gregory P. Botta, MD, PhD, associate professor of medicine, University of California San Diego.

Data were presented from 19 patients, 7 with GC/GEJ and 12 with PC, with a median of 4 (range, 2-10; GC/GEJ) and 7 (range, 1-5; PC) lines of treatment, and a median of 29.3 (range, 13.7-74.7; GC/GEJ) and 20.6 (range, 7.7-97.7; PC) months since diagnosis. Participants received a median of 2 infusions of satri-cel (range, 1-3).

Investigators found that the safety profile of satri-cel was manageable, although all patients had at least grade 3 treatment-emergent adverse events (AEs) and there were 4 serious treatment-emergent AEs related to satri-cel. The related TEAEs of at least grade 3 were cytokine release syndrome, hypotension, increased liver enzymes, hypoxia, and increased lipase. There was 1 case of grade 1 immune effector cell-associated neurotoxicity syndrome.

Participants had a median follow-up of 8.9 months (range, 1.5-18.7) and were treated at DL1 (250-300x106, n = 6), DL2 (375-400x106, n = 6), or DL3 (600x106, n = 7). Objective response rate was 42.9% (n = 3) in GC/GEJ, 16.7% (n = 2) in PC, and 42.9% overall in DL3, which was selected as the recommended phase 2 dose (RP2D). There was 1 complete response (CR) in GC/GEJ in DL3, 2 partial responses (PRs) in GC/GEJ, and 2 PRs in PC in DL3. Clinical benefit rate (CBR) was 57.1% (n = 4) in GC/GEJ, 33.3% in PC (n = 4), and 71.4% in DL3. Median duration of response (DOR) was 6.9 months in GC/GEJ (range, 2.6-not estimable [ES]), 3.4 months (range, 3.0-NE) in PC, and 3.7 months (range, 3.0-NE) in DL3.

“The next step, for gastric cancer, we shouldn't consider whether it can be moved to the early line, because solid tumors is very difficult to treat and gastric cancer is probably one of the most difficult to treat cancers. The results are promising but it is last line, and we hope the early line we want to test and see if there's a potential to cure the cancer,” Ma said.

Satri-cel is currently on clinical hold along with 2 other of CARsgen’s clinical stage CAR T-cell therapies, CT053, also known as zevorcabtagene autoleucel (zevor-cel), and CT071, over chemistry, manufacturing, and controls-related concerns that arose after an FDA inspection of the company’s manufacturing facility in Durham, North Carolina.2

CARsgen is planning to conduct a comprehensive review and improve its Current Good Manufacturing Practices (cGMP) at the facility and is “committed to working closely with the FDA to address the findings to ensure the smooth progress and production quality for clinical trials and launching applications.

Satri-cel has also been assessed in the confirmatory phase 2 clinical trial (CT041-ST-01; NCT04581473) in China in advanced gastric cancer.3 The therapy is also set to be evaluated in conjunction with Moderna’s mRNA cancer vaccine as announced in August 2023.4

REFERENCES
1. Botta GP, Kelly RJ, Jin Z, et al. CLDN18.2 chimeric antigen receptor T cell therapy for patients with advanced gastric and pancreatic adenocarcinoma: Results of ELIMYN18.2 phase 1b clinical trial. Presented at: 2024 ASCO GI; January 18-20; San Francisco, California. Abstract #356
2. Inside information announcement clinical hold in the U.S. due to CMC related questions. CARsgen. Letter.
3. CARsgen 2022 interim results: Innovative CAR t-cell technologies and robust pipeline. News release. CARsgen. August 24, 2022. https://www.prnewswire.com/news-releases/carsgen-2022-interim-results-innovative-car-t-cell-technologies-and-robust-pipeline-301611224.html
4. CARsgen collaborates with Moderna to evaluate CT041 in combination with an mRNA cancer vaccine. News release. CARsgen. August 21, 2023. https://www.carsgen.com/en/news/2023-08-21/
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