Clinical study to evaluate the safety and efficacy of an antibiotic therapy in combination with enzalutamide in metastatic hormone-resistant prostate cancer

Switzerland, United Kingdom (ICTRP)

ICTRP Studien-ID
NCT06126731 (ICTRP)

Offizieller Titel (Genehmigt von der Ethikkommission)
Studio di fase I/II per valutare la sicurezza, la tollerabilità e l'attività antitumorale preliminare di una terapia antibiotica combinata orale per modulare il microbioma in combinazione con enzalutamide nel carcinoma prostatico metastatico resistente alla castrazione (mCRPC) (BASEC)

Wissenschaftlicher Titel
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). (ICTRP)

Öffentlicher Titel
Combination Study of Antibiotics With Enzalutamide (PROMIZE) (ICTRP)

Untersuchte Krankheit(en)
Metastatic Castration-Resistant Prostate Cancer (mCRPC) (ICTRP)

Untersuchte Intervention
Drug: Vancomycin 125mgDrug: Enzalutamide 40mgDrug: Amoxicillin 500mgDrug: Metronidazole 400mgDrug: Ciprofloxacin 500g (ICTRP)

Studientyp
Interventional (ICTRP)

Studiendesign
Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Ein-/Ausschlusskriterien
Inclusion Criteria:

1. Histologically or cytologically proven metastatic castration-resistant prostate
cancer or adenocarcinoma refractory to conventional treatment, or for which no
conventional 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:

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

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

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

4. Clinical progression with worsening pain and need for palliative radiotherapy
for bone metastases.

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

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

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

6. Life expectancy of at least 12-weeks.

7. Able to swallow tablets.

8. Archival tumour tissue must be available for analyses.

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

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

11. Haematological and biochemical indices within the ranges shown below. These
measurements must be performed within one week (Day -7 to Day 1) prior to the
patient'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 which
case up to 5 x ULN is permissible

Aspartate aminotransferase (AST): = 2.5 x (ULN) unless raised due to tumour in which
case 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

12. 18 years or over

13. Written (signed and dated) informed consent and be capable of co-operating with
treatment and follow-up

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

Exclusion criteria:

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

- Patients receiving enzalutamide immediately preceding the trial will be able to
continue on enzalutamide without washout.

- Prior flutamide treatment during previous 4-weeks. N.B. Patients whose PSA did
not decline in response to antiandrogens given as a second line or later
intervention will only require a 14-day washout

- Prior bicalutamide (Casodex) and nilutimide (Nilandron) treatment during
previous 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 alopecia
or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDU
should 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 section
including strong inducers and inhibitors of CYP450 (please refer to
http://medicine.iupui.edu/clinpharm/ddis/table.aspx). Seville orange or grapefruit
products and any herbal medications should be avoided for 4 weeks prior to starting
trial treatment.

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

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

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

10. History of clinically significant hearing loss including but not limited to
congenital hearing loss, need for hearing aids, ongoing acute or chronic ear
infection, history of tympanic membrane perforation, tinnitus, vertigo, Meniere
disease, cerebrovascular ischemia.

11. Patients with partners of child-bearing potential (unless they agree to use a
barrier method of contraception [condom plus spermicide] or to sexual abstinence
effective from the first administration of any of the investigational agents,
throughout the trial and for 6 months afterwards. Patients with partners of
child-bearing potential must also be willing to ensure that their partner uses an
effective method of contraception for the same duration for example, hormonal
contraception, intrauterine device, diaphragm with spermicidal gel or sexual
abstinence). Patients with pregnant or lactating partners must be advised to use
barrier method contraception (for example, condom plus spermicidal gel) to prevent
exposure of the foetus or neonate.

NB. Abstinence is only considered to be an acceptable method of contraception when
this is in line with the preferred and usual lifestyle of the subject. Periodic
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception

12. Any condition that would increase enteral absorption in the opinion of the
investigator, including but not limited to malabsorption syndromes, impaired GI
motility, 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 syst (ICTRP)

nicht verfügbar

Primäre und sekundäre Endpunkte
Confirm the safety and tolerability of the combination of amoxicillin plus metronidazole (2 weeks) followed by ciprofloxacin plus vancomycin (2 weeks) along with enzalutamide in Phase I in mCRPC patients.;Describe the safety profile of the antibiotic combinations along with enzalutamide in Phase I.;Determine the response rate of the antibiotic combinations in patients with mCRPC in Phase II. (ICTRP)

To document possible anti-tumour activity in patients in Phase I.;To evaluate progression-free survival (PFS) in mCRPC patients receiving the antibiotic combinations in Phase I.;To evaluate PFS in mCRPC patients receiving the antibiotic combinations along with enzalutamide in Phase II.;To determine the time to PSA progression from the date of antibiotic commencement;To determine the duration of PSA decline as 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.;To determine the maximum percentage and absolute PSA decline from baseline;To determine the radiologic PFS (rPFS) of the combination of antibiotics and enzalutamide in Phase II.;To determine the time to radiologic progression to the combination of antibiotics and enzalutamide in Phase II.;To estimate the OS in mCRPC patients receiving the antibiotic combinations along with enzalutamide in Phase II.;To further characterise the safety and tolerability profile of the antibiotic combinations with enzalutamide in Phase II.;To identify biomarkers of response to the antibiotic combinations and of anti-tumour activity in Phase II.;To evaluate the peripheral circulation neutrophil-to-lymphocyte ratio (NLR) as a determinant of response to to treatment in Phase II. (ICTRP)

Registrierungsdatum
25.10.2023 (ICTRP)

Einschluss des ersten Teilnehmers
nicht verfügbar

Sekundäre Sponsoren
Prostate Cancer Foundation (ICTRP)

Weitere Kontakte
Johann De Bono, MDHannah Badham, MSc, hannah.badham@icr.ac.uk, 02087224497, National Health Service, United Kingdom (ICTRP)

Sekundäre IDs
CCR5461 (ICTRP)

Angaben zur Verfügbarkeit von individuellen Teilnehmerdaten
nicht verfügbar

Weitere Informationen zur Studie
https://clinicaltrials.gov/ct2/show/NCT06126731 (ICTRP)