PRIMARY OBJECTIVE:
I. Determine the efficacy of agenT-797, botensilimab and balstilimab in combination with ramucirumab and paclitaxel as second-line therapy in patients with advanced unresectable or metastatic esophagogastric cancer, as measured by overall response rate (ORR) (defined as the percentage of patients who achieve either an objective complete response [CR] + partial response [PR]).
SECONDARY OBJECTIVES:
I. Establish the safety and tolerability of this regimen (including when all agents are given together and as well as in sequence as in the induction cycles).
II. Determine the disease control rate (DCR) (defined as percentage of patients who have best response of either stable disease [SD], partial response [PR], or complete response [CR]) as well as other measures of efficacy, including duration of response (DOR), progression free survival (PFS) (median, 6-month, 1-year), and overall survival (OS) (median, 1-year).
EXPLORATORY OBJECTIVES:
I. Evaluate the increase in systemic and local anti-tumor response and clonal T-cell expansion, and persistence of agenT-797 in periphery in all patients and in each cohort (agenT-797 alone as induction cycle, agenT-797 with botensilimab and balstilimab as induction cycle, and no induction cycle).
II. Describe the evolution of the anti-tumor immune response by performing T-cell receptor (TCR) sequencing, quantitative multiplex immunohistochemistry (IHC), and flow cytometry on serial tissue biopsies and plasma samples, and define the association with outcomes in all patients and in each cohort (agenT-797 alone as induction cycle, agenT-797 with botensilimab and balstilimab as induction cycle, and no induction cycle).
III. Evaluate the response at 4 weeks in patients who receive an induction cycle and compare outcomes (best response, PFS, OS, circulating tumor deoxyribonucleic acid [ctDNA] clearance) in each cohort (agenT-797 alone as induction cycle, agenT-797 with botensilimab and balstilimab as induction cycle, and no induction cycle).
IV. Correlate clinical outcomes with tumor mutational burden assessed by whole exome sequencing of available tumor tissue and matching blood.
V. Correlate gene expression signatures tested by ribonucleic acid (RNA) sequencing with clinical outcomes on therapy.
VI. Use circulating tumor DNA (ctDNA) and peripheral blood mononuclear cells (PBMCs) collected during the course of the study to explore the mechanisms of response and acquired resistance and determine relationship of clearance of ctDNA to response, PFS, and OS.
VII. Determine metabolic response with fluorodeoxyglucose (FDG) positron emission tomography (PET) in patients with evaluable disease, defined per RECIST v1.1.
VIII. Explore PD-L1 expression as measured by combined positive score (CPS) as a predictive biomarker.
IX. Bank tumor and blood material at screening, on treatment, and at time of progression for future correlative analysis.
X. Send 1 of 4 PBMC’s collected at baseline and 1 of 4 PBMCs collected at timepoints throughout the course of the study to Agenus. The other 3 of 4 PBMCs collected at each time point will be dedicated to Memorial Sloan Kettering Cancer Center. Memorial Sloan Kettering Cancer Center and Agenus will explore the mechanisms of response and acquired resistance and determine relationship of clearance of ctDNA to response, PFS, and OS.
OUTLINE:
Patients receive agenT-797 intravenously (IV), over 10 to 30 minutes, on day 1 of cycle 1 and balstilimab IV, over 30 minutes, and ramucirimab IV, over 60 minutes, on day 1 and 15 and paclitaxel IV, over 60 minutes, on days 1, 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive botensilumab IV, over 30 minutes, on day 1 of each cycle, for 3 doses in the absence of disease progression or unacceptable toxicity. Patients undergo urine sample collection during screening, computed tomography (CT) or magnetic resonance imaging (MRI) and blood sample collection throughout the study and may undergo endoscopy and positron emission tomography (PET) on study.
After completion of study treatment, patients are followed up every 3 months thereafter.
