Combination Study of AZD5069 and Enzalutamide.

ACE is a multi-centre proof of concept Phase I/II trial of the CXCR2 antagonist AZD5069, administered in combination with enzalutamide, in patients with metastatic castration resistant prostate cancer(mCRPC). The investigators will be investigating the safety and toxicity of the combination.

The purpose of this study is to find out the side effects and safety of a combination of the CXCR2 antagonist, AZD5069 in combination with the androgen receptor antagonist, enzalutamide in patients with metastatic castration resistant prostate cancer and to determine the most appropriate dose of this combination. During the phase I study, patients will receive AZD5069 orally twice daily (BD) in combination with enzalutamide at 160mg orally once daily continuously. The starting dose of AZD5069 will be 40mg BD (dose level 1): other doses to be evaluated will include 80mg BD (dose level 2), 120mg BD (dose level 3), 160mg BD (dose level 4) and 320mg BD (dose level 5) in order to determine the MTD and RP2D to take forward to a Phase II reversal of resistance cohort. Intermediate dose levels such as 240mg BD may also be evaluated. During dose levels 1 to 4, patients will start with AZD5069 monotherapy for two weeks before commencing the combination. At all other dose levels, the two agents will be started concurrently. In addition, if agreed by the SRC, intermediate dose levels such as 240 mg taken BD will be explored. 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. In the Phase I part of the study, the AZD5069 is started first and will be taken twice daily as an oral tablet at Cycle 1, Day -14 for 14 days. Two weeks later on Cycle 1 Day 1, patients will start taking 160mg enzalutamide once a day in addition to the AZD5069. The starting dose of AZD5069 will be 40mg taken orally twice daily with single dose escalations to 80mg, 120mg and 160mg taken orally twice daily to determine the MTD to take forward to a Phase II reversal of resistance cohort. The Phase II reversal of enzalutamide resistance study will explore whether the addition of AZD5069 to enzalutamide reverses resistance to enzalutamide alone. In the phase II reversal of enzalutamide resistance study patients will start taking the AZD5069 at the dose established in the Phase I safety run in part of the study in combination with 160mg of enzalutamide once a day and at the same time from Cycle 1 Day 1 onwards. If the MTD of AZD5069 is greater than 160 mg BD, two different dose levels may be taken forward to the phase II study to determine efficacy. Only patients who have experienced disease progression after at least 12 weeks of treatment with enzalutamide, apalutamide or darolutamide will be eligible for this trial. Those patients who progressed on enzalutamide, apalutamide or darolutamide (at least 12 weeks of therapy) greater than 6 months prior to starting the IMP will enter the Phase II enzalutamide resistance run in cohort to confirm resistance to enzalutamide; once progression on enzalutamide is confirmed they will enter the Phase II reversal of enzalutamide resistance cohort. Up to approximately 86 patients will be enrolled into this phase I/II trial, with up to 36 patients in the phase I safety run in cohort depending on number of patients required to determine the RP2D and up to 50 patients in the phase II study. We predict around 50% of these patients will enter the phase II enzalutamide resistance run in cohort first. The anticipated accrual rate for this trial is 3-6 patients per month across 4 centres.