This study represents the first time that PSCA has been used as a target for the treatment of cancer in humans. This is also the first time that AGS-PSCA has been used in humans. Despite the fact that AGS-PSCA can bind to ocular, ureteral and gastric tissue in human pathology specimens, toxic effects related to these organs were not observed. All grade 3 or higher AEs were considered not related to study treatment and other than occasional minor infusion reactions, we found no significant toxicity; no DLT was demonstrated and the MTD was not established. The phase II dose was determined on the basis PK properties only and not toxicity. No anti-AGS-PSCA antibodies were generated.
The combination of a 40-mg/kg loading dose followed by 20 mg/kg administered every 3 weeks achieved steady state levels that are at or above the target concentration within two to three doses, without apparent drug accumulation. This proposed phase II dose mitigates the limitations of both the 20-mg/kg dose, which results in a lengthy time to achieving steady state peak and trough target concentrations, and the 40-mg/kg dose, which results in drug accumulation as reflected by rapidly increasing peak and trough concentrations.
Although interpreting efficacy is difficult in the setting of a phase I trial given that cohorts are small and doses variable, we observed only limited antitumor activity in this study, even in the expansion cohort in which the 18 patients achieved putatively effective serum drug levels. No patient durably converted from an unfavorable CTC categorization to a favorable one. Even in the expansion cohort, no radiographic responses or confirmed PSA responses were seen, and therefore, the trial failed to meet the predefined efficacy end point.
There are several possible reasons why antitumor effects were not seen in this study. It is possible that the effective serum concentration based on preliminary animal data is too low for efficacy in humans. These animal data are presently being reassessed. Alternatively, it is possible that the target drug levels are accurate and achievable, but that the patients tested in this trial did not express PSCA on their cancers. A downside of this study is that tissue specimens were not analyzed for PSCA expression, and therefore, this question cannot be answered. Finally, it is possible that the naked antibody does not induce ADCC as was shown in preclinical models. In such a case, immune adjuvants may be necessary, as might chemoconjugated or radioconjugated antibodies. More immunogenic anti-PSCA antibodies are being developed, and a screening study to confirm PSCA targeting in humans using CTCs is planned.
This phase I/IIA study demonstrated for the first time the safety of using a monoclonal antibody directed against PSCA. Although antitumor effects using a naked antibody were limited in this trial, the PK profile of AGS-PSCA suggests that targeting PSCA with conjugates and other antibodies warrants further investigation. In addition, PSCA is expressed in bladder, renal cell and pancreas cancers [16
] and treating these populations at the recommended AGS-PSCA phase II dose may yield more favorable results.