Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma

Clinical Cancer Research · 17 authors, 16 centres

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FIDELITY 100%

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TL;DR

This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in 93 patients with metastatic urothelial carcinoma. The recommended phase II dose was 1.00 mg/kg, with an objective response rate of 35.7% at that dose level and 18.3% in the total population.

Full summary

354 CHARS

Five dose-limiting toxicities occurred from 0.50 to 1.25 mg/kg, establishing the recommended phase II dose at 1.00 mg/kg. Peripheral neuropathy and ocular toxicities occurred at doses of 0.75 mg/kg or higher. The objective response rate was 35.7% at 1.00 mg/kg and 18.3% overall. Pharmacokinetics showed dose-proportional increases with low accumulation.

STUDY TYPE

RCT

SPECIALTY

oncology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10767306

Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma

Clinical Cancer Research

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ABSTRACT

Abstract Purpose: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody–drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. Patients and Methods: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC ( NCT01963052 ). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. Results: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. Conclusions: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.

CITATION EXPORT

Daniel P. Petrylak, Bernhard J. Eigl, Saby George et al.. Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma. Clinical Cancer Research. (2024). https://doi.org/10.1158/1078-0432.CCR-22-3627

AUTHORS

17 · 16 CENTRES

Daniel P. Petrylak, Bernhard J. Eigl, Saby George, Elisabeth I. Heath, Sebastien J. Hotte, David D. Chism, Lisle M. Nabell, Joel Picus, Susanna Y. Cheng, Leonard J. Appleman, Guru P. Sonpavde, Alicia K. Morgans, Pourya Pourhosseini, Ruishan Wu, Laura Standley, Ruslan Croitoru, Evan Y. Yu

1Yale School of Medicine, New Haven, Connecticut.
2BC Cancer, Vancouver, British Columbia, Canada.
3Roswell Park Cancer Institute, Buffalo, New York.
4Karmanos Cancer Institute, Detroit, Michigan.
5Department of Oncology, McMaster University, Hamilton, Ontario, Canada.
6Thompson Cancer Survival Center, Knoxville, Tennessee.
7O'Neal Comprehensive Cancer Center, Birmingham, Alabama.
8Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri.
9Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
10UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
11Advent Health Cancer Institute, Orlando, Florida.
12University of Central Florida, Orlando, Florida.
13Dana-Farber Cancer Institute, Boston, Massachusetts.
14Seagen, Woodinville, Washington.
15Astellas Pharma Global Development, Inc., Northbrook, Illinois.
16Division of Medical Oncology, Seattle Cancer Care Alliance, Seattle, Washington.