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

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.

Figure 1.

TEAE (≥20% incidence). Includes all patients from the total study population.

Figure 2.

Mean serum concentration–time profiles of AGS15E ADC (A), MMAE (B), and TAb (C) after single (day 1) and multiple (day 15) dosing in cycle 1 by dose group (semi-log scale plot) PK analysis set. LLOQ, lower limit of quantification.

Figure 3.

A, Maximum percent reduction from baseline in total tumor burden by BOR (parts A, B, and C; FAS). All patients who consented and received at least one infusion of AGS15E (FAS). H-score is shown above or below the BOR. Maximum reduction is defined as patient's best response in sum of target lesion diameters from baseline, based on radiological evidence of measurable disease. Bars below 0 represent tumor burden reduction. BOR of SD with a minimum duration of 7 weeks from cycle 1, day 1 is required. Patients with no postbaseline radiologic disease assessment or measurement of tumor burden (at baseline or postbaseline) are excluded from the graph. Patients with nonevaluable BOR are also excluded from the graph. Investigator's assessment of BOR is annotated for each patient according to RECIST v.1.1. B, Duration of treatment (parts A, B, and C; FAS). All patients who consented and received at least one infusion of AGS15E (FAS). Duration of treatment is defined as (date the decision is made to end treatment or data cutoff date if patient is still on treatment) – (first dose date + 1 day)/7. BL, bladder; BOR, best overall response; CR, complete response; DLT, dose-limiting toxicity; FAS, full analysis set; OS, other site; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; RP, renal pelvis; SD, stable disease; UA, urethra; UR, ureter.