Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Micronutrients

All Drugs and Chemicals

Anti-Infective Agents

Antineoplastic Agents

Vitamins

Ascorbic Acid

Metronidazole

Amoxicillin

Vancomycin

Ciprofloxacin

Anti-Bacterial Agents

Antibiotics, Antitubercular

Antiprotozoal Agents

Antiparasitic Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Vitamin C

Phase I:

The evaluation of the safety and tolerability of the combinations of amoxicillin plus metronidazole, and ciprofloxacin plus vancomycin with enzalutamide.

Phase II:

Determination of the anti-tumour activity of the combinations of amoxicillin plus metronidazole, and ciprofloxacin plus vancomycin with enzalutamide.

Enzalutamide is presented in 40mg yellow film-coated tablets. They are supplied in a cardboard wallet incorporated a PVC/PCTFE/aluminium blister pack which holds 28 tablets. Each carton contains 4 wallets (112 tablets in total)

Enzalutamide 40mg

Red / Buff coloured size '0' capsules containing white to off white powder printed with 'AMOXY 500 ' in black ink

OR

White to off-white granular powder filled in hard gelatine capsule shells size '0'. Scarlet colour cap, buff colour body printed with 'AMOXY' on cap and '500' on body

OR

White/Maroon size '0' capsules containing white to yellowish granular powder

Amoxicillin 500mg

Yellow, circular (11mm), biconvex, film-coated tablets with '400' debossed on one side and plain on other side

OR

White to off white coloured, caplet shaped (17.00 x 6.00 mm) film-coated tablets, debossed "400" on one side and plain on other side

OR

Off-white coloured, round, biconvex uncoated tablets engraved "MZ 400" \& break line on one side and plain on other

Metronidazole 400mg

Grey/pink 17.8 ± 0.40 mm hard capsules each containing 125mg, containing white to off white congealed liquid mixture as solid mass

OR

Dark blue and brown hard capsules, imprinted with 3125 in red ink

OR

Brown 21.4 ± 0.40 mm hard capsule, containing white to off white congealed liquid mixture as solid mass

Vancomycin 125mg

White to off white, capsule shaped, film coated tablets, with a score line on one side and debossed with 'F22' on the other side. The tablet can be divided into equal doses. The size is 18.2 mm x 8.1 mm

OR

White, caplet shaped film-coated tablets debossed with '500' on one side and plain on the other side

OR

White to off-white, capsule shape, biconvex with bevelled edge, film coated tablet with inscription 'CI' on one side and plain on the other side

OR

White, oval shaped film-coated tablets debossed 'C500' on one side and breakline on other side

Ciprofloxacin 500g

Hannah Badham, MSc

Alison Turner, PhD

Ilaria Colombo

Johann S De Bono, MD

Khobe Chandran, MD

Johann De Bono, MD

PROMIZE is an open-label, multi-centre, single-arm, Phase I/II clinical trial, evaluating the safety, tolerability and anti-tumuor efficacy of an antibiotic combination and enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC).

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.

Patients with histologically or cytologically confirmed mCRPC who have previously progressed on at least one line of taxane chemotherapy (or not fit or not willing to receive a taxane) and a next generation antiandrogen (e.g. enzalutamide, apalutamide, darolutamide, abiraterone acetate)

Combination Study of Antibiotics With Enzalutamide (PROMIZE)

PROMIZE: A Phase I/II Trial to Assess the Safety, Tolerability and Preliminary Anti-tumour Activity of Oral Combination Antibiotic Therapy to Modulate the Microbiome in Combination With Enzalutamide With Metastatic Castration Resistant Prostate Cancer (mCRPC).

Serial peripheral white blood cell immunophenotyping.

Serial whole blood transcriptome analyses.

Determine a dose at which no more than one patient out of up to 6 patients experiences a highly probable or probably drug-related DLT, during the 28-day DLT period.

Causality and grading severity of each adverse event related to the investigational agents according to the NCI CTCAE v5.0.

Anti-tumour activity will be defined by response rate on the basis of the following outcomes. If any of the following occur, patients will be considered to have responded:

* PSA decline ≥ 50% criteria confirmed 4 weeks or later, and/or
* Confirmed soft tissue objective response by RECIST (v1.1) in patients with measurable disease.

Antitumour activity will be defined by response rate on the same basis as that used for the primary objective of the Phase II component.

PFS will be measured from the date of antibiotic commencement to the date of progression as determined by radiological criteria (RECIST v 1.1, PCWG3 bone scan criteria) or unequivocal clinical progression necessitating drug discontinuation (e.g. worsening pain, spinal cord compression, need for other anticancer therapy).

PFS will be measured from the date of antibiotic commencement to:

* The date of progression as determined by radiological criteria (RECIST v1.1, PCWG3 bone scan criteria) and/or
* Unequivocal clinical progression necessitating drug discontinuation (e.g. worsening pain, spinal cord compression, need for other anticancer therapy).

This is an estimate of the biochemical anti-tumour activity of the combination of amoxicillin plus metronidazole (2-weeks) followed by ciprofloxacin plus vancomycin (2-weeks) along with enzalutamide.

The duration of PSA decline by ≥ 50% is an estimate of the biochemical anti-tumour activity of the combination of amoxicillin plus metronidazole (2-weeks) followed by ciprofloxacin plus vancomycin (2-weeks) along with enzalutamide.

Radiologic PFS (rPFS) measured from the date of of antibiotic commencement to:

* Progression of soft tissue/visceral disease by RECIST (v1.1) and/or,
* Progression of bone disease by PCWG3 bone scan criteria
* And/or death from any cause

Time to radiologic progression defined from the date of antibiotic commencement to radiologic progression by RECIST v1.1 and/or PCWG3 criteria.

OS will be measured from the date of antibiotic commencement to date of death (whatever the cause).

Causality and grading severity of each adverse event related the investigational agents according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 (v5.0)

Biomarkers of response include tumour genomics and immunologic characteristics in tumour biopsies from responders and non-responders

NLR at baseline and on-treatment for:

* Baseline NLR as a determinant of response
* Percentage change in NLR between baseline and NLR nadir between responders versus non-responders

Spots Global Cancer Trial Database for enzalutamide 40mg