About the Phase 2 Trial of AgenT-797
Trial Name: A Phase II Study of agenT-797 (Invariant Natural Killer T Cells), Botensilimab, a Novel Fc-enhanced CTLA-4 Inhibitor, Plus Balstilimab (Anti-PD-1) With Ramucirumab and Paclitaxel for Patients With Previously Treated, Advanced Esophageal, Gastric, or Gastro-esophageal Junction Adenocarcinoma
ClinicalTrials.gov Identifier: NCT06251973
Sponsor: Memorial Sloan Kettering Cancer Center
Recruitment Contact: Yelena Janjigian, MD, 646-888-4186, janjigiy@mskcc.org, and Geoffrey Ku, MD, 646-888-4588, kug@mskcc.org
Completion Date: August 1, 2027
The first patient has been treated in a phase 2 investigator-sponsored study (NCT06251973) evaluating agenT-797, botensilimab, balstilimab, ramucirumab (Cyramza), and paclitaxel in the second-line setting for the treatment of gastric, esophageal, and gastroesophageal junction (GEJ) cancer.1,2
“There has been a lot of interest in the study. We enrolled and treated our first patient and so far, it has been feasible and safe. We have not seen any major issues come up. AgenT-797 is an allogeneic [invariant natural killer T (iNKT)] cell product, so to be able to give this to patients safely in the second-line setting, we are hopeful that we can then continue enrollment and show efficacy,” Yelena Y. Janjigian, MD, told Targeted OncologyTM, in an interview.
Previously, a phase 1 study of the allogeneic, off-the-shelf, iNKT cell, agenT-797, given alone or in combination with pembrolizumab (Keytruda) or nivolumab (Opdivo) without lymphodepletion led to durable clinical benefit in 34 patients.3 Patients with microsatellite instability-high (MSI-h) third-line gastric cancer displayed a notable clinical response subsequent to experiencing failure on pembrolizumab and nivolumab/FOLFOX regimens. Ten patients had long-term disease stabilization, including patients with testicular cancer with stable disease (SD) exceeding 10 months and anti-PD-1 relapsed/refractory non–small-cell lung cancer with SD surpassing 8 months.
AgenT-797 also produced a tolerable safety profile with no dose-limiting toxicities reported and the absence of any grade exceeding 3 neurotoxicity or cytokine release syndrome. These findings underscore the potential efficacy and safety of this therapeutic approach in managing patients with MSI-h gastric cancer who have experienced prior treatment failures.
“Despite the progress in the first-line setting with biomarker selection and targeted therapy, in the second-line setting, the standard that remains is ramucirumab plus paclitaxel. Although it has not been a very exciting option, particularly since it's not biomarker-selected and it has relatively plateaued with its efficacy pretty quickly, we have not been able to improve on it. explained Janjigian, a medical oncologist and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center.
“The harsh reality though is most of our patients eventually, in the first-line setting, progress, and although we are reporting 4- and 5-year survival data, the way we keep our patients alive and well is if we give it is we give them more second- and third-line options to continue to respond to treatment.”
Now, the phase 2 study, led by Janjigian, builds on findings from the phase 1 trial and is investigating the combination of agenT-797 with botensilimab, balstilimab, ramucirumab, and paclitaxel in patients with previously treated gastric, esophageal, and GEJ adenocarcinoma.2 Enrollment is open to patients with measurable disease and who have evaluable disease as defined by RECIST v1.1.2
“Patients who have received prior chemotherapy, and usually immunotherapy, are treated in a single-arm fashion with a combination of iNKT cells plus botensilimab plus balstilimab chemotherapy, which is taxol and ramucirumab. There is a component to the study to try to understand the contributions of different components in terms of the addition of PD-1, CTLA4 blockade to iNKT cells. In the study, we start with chemotherapy-free run-in, and subsequently add chemotherapy and ramucirumab later,” added Janjigian.
The study aims to enroll approximately 38 patients with advanced, unresectable, or metastatic forms of these cancers who have experienced disease progression on 1 prior line of therapy for metastatic disease and will evaluate the primary end point of overall response rate. Patients must also be aged 18 years and older with an ECOG performance status of 0 to 1 and adequate organ function.
Those who have previously received therapy with ramucirumab at any time; those who have undergone paclitaxel or docetaxel-based therapy within 6 months of study enrollment; those with a history of grade >3 immune-related adverse events due to anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 therapy at any time; patients with immunodeficiency or who have received systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment (excluding replacement therapy for adrenal or pituitary insufficiency); and patients with a history of gastrointestinal perforation or fistulae will be excluded from the study. Patients with a known active Bacillus tuberculosis infection; known active central nervous system metastases and/or carcinomatous meningitis; and those with a history of or evidence of active, non-infectious pneumonitis will also be excluded.
Patients with peripheral neuropathy that limits activities of daily living, those with a known history of human immunodeficiency virus, known active hepatitis B or hepatitis C infection, those who have received a live vaccine within 30 days of the planned start of study therapy, those with known psychiatric or substance abuse disorders that would interfere with cooperation with the trial requirements, and patients who are pregnant or breastfeeding or are expecting to conceive or father children within the projected duration of the trial starting from the prescreening or screening visit through 5 months after the last dose of trial treatment will also be ineligible for enrollment in the study.
“If [this study] shows promise, I think other researchers will come to that area and it will reignite their interest. And if promising phase 2 then leads to promising phase 3, that is how successful stories go. They bring in new trials, new options, and new standards of care to patients” added Janjigian.
REFERENCES:
1. First refractory gastric cancer patient dosed in phase 2 trial with novel combination of MiNK’s allogeneic INKT cell therapy and Agenus’ botensilimab and balstilimab. News release.MiNK Therapeutics, Inc. February 14, 2024. Accessed February 14, 2024.
2. A Study of agenT-797 in combination with botensilimab, balstilimab, ramucirumab, and paclitaxel for people with esophageal, gastric, or gastro-esophageal junction cancer. News release. Updated February 9, 2024. Accessed February 14, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06251973?term=AgenT-797&draw=2&rank=4
3. Hadfield MJ, Safran H, Purbhoo MA, Grossman JE, Buell JS, Carneiro BA. Overcoming resistance to programmed cell death protein 1 (PD-1) blockade with allogeneic invariant natural killer T-cells (iNKT). Oncogene. Published online January 29, 2024. doi:10.1038/s41388-024-02948-y
