Phase 1 Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients With Metastatic Urothelial Carcinoma

Mené sur 93 patients atteints d'un carcinome urothélial de stade métastatique, cet essai multicentrique de phase I détermine la dose maximale tolérée de AGS15E (un conjugué anticorps-médicament ciblant SLITRK6) et analyse ses caractéristiques pharmacocinétiques

Clinical Cancer Research, sous presse, 2023, résumé

Résumé en anglais

Purpose: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADCs) 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 1 dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at 6 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 (DLTs) and the recommended phase 2 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 CPIs. 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 DLTs occurred from 0.50‒1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORRs in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively.

Conclusion: DLTs with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.