Combination Study of Antibiotics With Enzalutamide (PROMIZE)

Patients with histologically confirmed metastatic castration-resistant adenocarcinoma of the prostate refractory to conventional therapy (or for which no conventional therapy exists or is declined by the patient), that have progressed after at least 1 line of taxane based chemotherapy (or not fit or not willing to receive a taxane) and a NAAT are eligible for the study. The Phase I will evaluate the safety and tolerability of the combination of amoxicillin plus metronidazole (2 weeks) followed by ciprofloxacin plus vancomycin (2 weeks) administered for 2 cycles (i.e., 8 weeks) in addition to enzalutamide (160 mg daily). Enzalutamide will continue beyond the completion of the antibiotic combination until disease progression, intolerance, or withdrawal from the study. The DLT period is 4 weeks and commences at the time of combination treatment with antibiotics plus enzalutamide. Each cycle of treatment will be 4 weeks in length. The design permits the safety monitoring of DLT regularly throughout the 2 phases. During the Phase I study, if 2 or more patients experience a DLT out of up to 6 patients, the schedule will be deemed intolerable, and a decision will be made by the SRC to modify the schedule depending on the timing and nature of toxicity observed and its causality. For any modified schedule, a further 6 patients will be treated, and the new dose and schedule will only be deemed tolerable if no more than 1 out of 6 patients experience a DLT. The Phase II study will employ a 2-stage design. It will recruit a maximum of 33 patients with a desirable response level of 30% and an undesirable response rate of 10%. Patients enrolled to the Phase I who are treated at the RP2D and are evaluable for response will contribute to the Phase II study. Patients will receive the same dose and schedule deemed to be safe in the Phase I. In the phase II study, the first stage will enrol 15 patients who are evaluable for response. If at least one patient responds during stage 1, a further 18 patients will be recruited (stage 2). The decision to proceed to stage 2 can be made once one response has been observed after thorough review of the cases where objective response was observed by the SRC. The trial will be terminated with the conclusion that the treatment is futile if no responses are observed in the first 15 patients. The second stage of the trial will enrol 18 patients who are evaluable for response. If \>6 patients respond across the 2 stages, the study will have met its efficacy threshold. Further details of the Simon 2-stage design are specified in section 13. If \<7 patients respond across the 2 stages, all samples will be analysed to identify predictive biomarkers of response. If a robust biomarker is identified, the study may be expanded in a biomarker-selected cohort following protocol amendment. Further safety analysis of safety (at least 2 further interim looks) will occur throughout the phase II trial. Approximately 6 patients will be enrolled to the Phase I and up to a total of 33 response evaluable patients will be enrolled to the Phase II study. Patients in the Phase I study who are treated with the RP2D and are evaluable for response can contribute to the Phase II study. Based on this, up to 39 response evaluable patients will be recruited across the 2 phases. Based on a recruitment rate of 3 patients per month across the 2 sites, recruitment will be completed within 24 months.