Abiraterone Acetate in Combination With Tildrakizumab

The purpose of this study is to find out the side effects and safety of a combination of the anti-IL23 targeting monoclonal antibody tildrakizumab in combination with abiraterone acetate in men with metastatic castration resistant prostate cancer and to determine the most appropriate dose of this combination. In the Phase I part of this study small groups of patients will be treated with increasing doses of tildrakizumab in combination with a fixed dose of abiraterone acetate (500mg once daily). Once Phase I has been completed the combination with the optimum safety and pharmacokinetic/pharmacodynamic profile will be taken forward to the Phase II part of the study. The Phase II part of the study will evaluate the optimized dose/schedule identified in Phase I of the study in patients with metastatic castration resistant prostate cancer.

The trial will be divided into 2 parts: Phase I and Phase II. The Phase I study will adopt a Bayesian Continual Reassessment Method. Patients will receive single-agent abiraterone run-in of 500 mg orally, once daily (continuous dosing) along with prednisolone at 5 mg BD until PSA progression on abiraterone monotherapy is confirmed. This run-in will not be required if patients have been treated with abiraterone in the previous 6 months. Upon confirmation of PSA progression, tildrakizumab IV will be started and given once every 4-weeks in combination with the fixed dose abiraterone (and prednisolone). The starting dose of tildrakizumab will be 100mg, with single dose escalations to 300mg and 600mg to determine the RP2D to take forward to the Phase II study. Depending on the number of responses observed, dose levels that are deemed tolerable may be expanded to up to a total of 10 patients who are evaluable for response. The Phase II study will employ a two-stage Minimax design, recruiting up to 25 patients. During the first stage, 15 evaluable patients will be enrolled and followed for a minimum of 2 cycles each. If there are one or more responses confirmed at least 4-weeks later, an additional 10 evaluable patients will be recruited. If 4 or more responses are seen in the 25 patients evaluable for response, the combination will be deemed successful, warranting further evaluation in subsequent phases of testing. In the phase II study, patients will start taking 500mg abiraterone as an oral tablet once daily along with 5mg of prednisolone twice daily until PSA progression on abiraterone monotherapy is confirmed. This run-in will not be required if patients have been treated with abiraterone in the previous 6 months. Upon confirmation of PSA progression, the tildrakizumab will be given as an intravenous infusion at the dose established in the Phase I safety part of the study in combination with the abiraterone (and prednisolone) from combination Cycle 1 Day 1 onwards.