Combination Study of Antibiotics With Enzalutamide (PROMIZE)

Inclusion Criteria:

1. Histologically or cytologically proven metastatic castration-resistant prostatecancer or adenocarcinoma refractory to conventional treatment, or for which noconventional therapy exists or is declined by the patient.

2. Documented prostate cancer progression as assessed by the investigator with RECIST (v1.1) and PCWG3 criteria with at least one of the following criteria:

3. Progression of soft tissue/visceral disease by RECIST (v1.1) and/or,

4. Progression of bone disease by PCWG3 bone scan criteria and/or,

5. Progression of PSA by PCWG3 PSA criteria and/or

6. Clinical progression with worsening pain and need for palliative radiotherapyfor bone metastases.

7. Phase I: Patients that have progressed after at least 12 weeks of treatment with aNAAT within the previous 6 months Phase II: Patients that have progressed after atleast 12 weeks of treatment with a NAAT within the previous 6 months (forcombination treatment) or more than 6 months prior to trial entry (for enzalutamidealone resistance run-in).

8. Previously progressed on at least one line of taxane chemotherapy (or not fit or notwilling to receive a taxane).

9. Ongoing androgen deprivation maintaining serum testosterone of less than 50 ng/dL (less than 2.0 nM) is mandatory.

10. Life expectancy of at least 12-weeks.

11. Able to swallow tablets.

12. Archival tumour tissue must be available for analyses.

13. Willing to have pre- and post-treatment biopsies if biopsy is feasible.

14. World Health Organisation (WHO) performance status of 0-2 (Appendix 1).

15. Haematological and biochemical indices within the ranges shown below. Thesemeasurements must be performed within one week (Day -7 to Day 1) prior to thepatient's first dose of IMP. Haemoglobin (Hb): ≥ 9.0 g/dL Absolute neutrophil count: ≥ 1.5 x 109/L Platelet count: ≥ 75 x 109/L Serum bilirubin: ≤ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT): ≤ 2.5 x (ULN) unless raised due to tumour in whichcase up to 5 x ULN is permissible Aspartate aminotransferase (AST): ≤ 2.5 x (ULN) unless raised due to tumour in whichcase up to 5 x ULN is permissible Serum creatinine / calculated creatinine clearance: ≤ 1.5 x upper limit of normal (ULN) / GFR ≥ 50 mL/min (uncorrected value) Serum albumin: >25 g/L

16. 18 years or over

17. Written (signed and dated) informed consent and be capable of co-operating withtreatment and follow-up

18. Willing and able to comply with the study requirement including the collection ofblood, fresh tumour biopsy, urine, rectal swab and stool samples.

Exclusion criteria:

1. Surgery, radiotherapy, chemotherapy, or other anti-cancer therapy within 4-weeksprior to trial entry into the study (6 weeks for bicalutamide). The use ofbisphosphonates or RANK ligand inhibitors in patients with known osteopenia orosteoporosis or bone metastases is permitted. Prior antiandrogenic treatmentexclusions as follows:

• Patients receiving enzalutamide immediately preceding the trial will be able tocontinue on enzalutamide without washout.

• Prior flutamide treatment during previous 4-weeks. N.B. Patients whose PSA didnot decline in response to antiandrogens given as a second line or laterintervention will only require a 14-day washout;

• Prior bicalutamide (Casodex) and nilutimide (Nilandron) treatment duringprevious 6-weeks;

• Prior progesterone, medroxyprogesterone, progestins, cyproterone acetate,tamoxifen, and 5-alpha reductase inhibitors during previous 2-weeks (14-days).

2. Ongoing toxic manifestations of previous treatments. Exceptions to this are alopeciaor certain Grade 1 toxicities, which in the opinion of the Investigator and the DDUshould not exclude the patient.

3. Previous treatment with any systemic antibiotic within 12 weeks of study entry.

4. Known hypersensitivity reaction or intolerance to any penicillin, amoxicillin,metronidazole, vancomycin, ciprofloxacin or enzalutamide.

5. History of tendon disorder secondary to quinolones

6. Use of drugs that are listed in the prohibited concomitant medications sectionincluding strong inducers and inhibitors of CYP450 (please refer tohttp://medicine.iupui.edu/clinpharm/ddis/table.aspx). Seville orange or grapefruitproducts and any herbal medications should be avoided for 4 weeks prior to startingtrial treatment.

7. Concurrent treatment with prohibited medications which include medications thatcauses ototoxicity, neurotoxicity, and nephrotoxicity.

8. Known or suspected leptomeningeal metastases or untreated brain metastasis. Patientswith brain metastases that have been treated and have been shown to beradiologically stable for more than 6 months may be considered for the trial.

9. History of stroke, epilepsy or current excessive alcohol intake. History ofclinically significant hearing loss including but not limited to congenital hearingloss, need for hearing aids, ongoing acute or chronic ear infection, history oftympanic membrane perforation, tinnitus, vertigo, Meniere disease, cerebrovascularischemia.

10. History of clinically significant hearing loss including but not limited tocongenital hearing loss, need for hearing aids, ongoing acute or chronic earinfection, history of tympanic membrane perforation, tinnitus, vertigo, Menieredisease, cerebrovascular ischemia.

11. Patients with partners of child-bearing potential (unless they agree to use abarrier method of contraception [condom plus spermicide] or to sexual abstinenceeffective from the first administration of any of the investigational agents,throughout the trial and for 6 months afterwards. Patients with partners ofchild-bearing potential must also be willing to ensure that their partner uses aneffective method of contraception for the same duration for example, hormonalcontraception, intrauterine device, diaphragm with spermicidal gel or sexualabstinence). Patients with pregnant or lactating partners must be advised to usebarrier method contraception (for example, condom plus spermicidal gel) to preventexposure of the foetus or neonate. NB. Abstinence is only considered to be an acceptable method of contraception whenthis is in line with the preferred and usual lifestyle of the subject. Periodicabstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) andwithdrawal are not acceptable methods of contraception

12. Any condition that would increase enteral absorption in the opinion of theinvestigator, including but not limited to malabsorption syndromes, impaired GImotility, chronic pancreatitis, partial or complete gastric and/or bowel resections,history of clinically significant gastrointestinal bleeding in the last 6 months,history of mesenteric ischemia or bowel obstruction, chronic diarrhoea (≥Grade 2),inflammatory bowel disease (Crohn's disease, ulcerative colitis).

13. At high medical risk because of non-malignant systemic disease including activeuncontrolled infection.

14. Clinically significant history of liver disease consistent with Child-Pugh Class Bor C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.

15. Known to be serologically positive for hepatitis B, hepatitis C or humanimmunodeficiency virus (HIV).

16. Any of the following cardiac criteria:

• Clinically important abnormalities including rhythm, conduction or ECG changes (left bundle branch block, third degree heart block).

• Factors predisposing to QT prolongation including congenital long QT syndrome;family history of prolonged QT syndrome, unexplained sudden death (under 40);concomitant medications known to prolong QT interval.

• Concurrent congestive heart failure, prior history of class III/ IV cardiacdisease (New York Heart Association [NYHA] - refer to Appendix 5), priorhistory of cardiac ischaemia or prior history of cardiac arrhythmia.

• QTcF (corrected using Fredericia formula) of ≥460 ms.

17. Prior bone marrow transplant or have had extensive radiotherapy to greater than 25%of bone marrow within eight weeks.

18. Active or uncontrolled autoimmune disease requiring corticosteroid therapy or otherforms of systemic immunosuppression.

19. Patient is a participant or plans to participate in another interventional clinicaltrial, whilst taking part in this study. Participation in an observational trialwould be acceptable.

20. Any other condition which in the Investigator's opinion would not make the patient agood candidate for the clinical trial.

21. Malignancy other than prostate cancer within 3-years of trial entry with theexception of adequately treated basal cell carcinoma. Cancer survivors, who haveundergone potentially curative therapy for a prior malignancy must have no evidenceof that disease for at least-3 years and be deemed at negligible risk forrecurrence, are deemed eligible.

22. Symptoms of COVID-19 and/or current documented COVID-19 infection.