Trial Title:
Combination Study of Antibiotics With Enzalutamide (PROMIZE)
NCT ID:
NCT06126731
Condition:
Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Conditions: Official terms:
Prostatic Neoplasms
Amoxicillin
Metronidazole
Vancomycin
Ciprofloxacin
Conditions: Keywords:
Microbiome
Antibiotic
Enzalutamide
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
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)
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Enzalutamide 40mg
Description:
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)
Arm group label:
mCRPC patients dose with a combination of enzalutamide and antibiotics
Other name:
Xtandi
Intervention type:
Drug
Intervention name:
Amoxicillin 500mg
Description:
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
Arm group label:
mCRPC patients dose with a combination of enzalutamide and antibiotics
Intervention type:
Drug
Intervention name:
Metronidazole 400mg
Description:
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
Arm group label:
mCRPC patients dose with a combination of enzalutamide and antibiotics
Intervention type:
Drug
Intervention name:
Vancomycin 125mg
Description:
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
Arm group label:
mCRPC patients dose with a combination of enzalutamide and antibiotics
Intervention type:
Drug
Intervention name:
Ciprofloxacin 500g
Description:
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
Arm group label:
mCRPC patients dose with a combination of enzalutamide and antibiotics
Summary:
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).
Detailed description:
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.
Criteria for eligibility:
Criteria:
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 systemic disease including active
uncontrolled infection.
14. Clinically significant history of liver disease consistent with Child-Pugh Class B
or C, including viral or other hepatitis, current alcohol abuse, or cirrhosis.
15. Known to be serologically positive for hepatitis B, hepatitis C or human
immunodeficiency 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 cardiac
disease (New York Heart Association [NYHA] - refer to Appendix 5), prior
history 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 other
forms of systemic immunosuppression.
19. Patient is a participant or plans to participate in another interventional clinical
trial, whilst taking part in this study. Participation in an observational trial
would be acceptable.
20. Any other condition which in the Investigator's opinion would not make the patient a
good candidate for the clinical trial.
21. Malignancy other than prostate cancer within 3-years of trial entry with the
exception of adequately treated basal cell carcinoma. Cancer survivors, who have
undergone potentially curative therapy for a prior malignancy must have no evidence
of that disease for at least-3 years and be deemed at negligible risk for
recurrence, are deemed eligible.
22. Symptoms of COVID-19 and/or current documented COVID-19 infection.
Gender:
Male
Gender based:
Yes
Gender description:
Male
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Oncolgy Institute of Southern Switzerland (IOSI)
Address:
City:
Bellinzona
Country:
Switzerland
Status:
Not yet recruiting
Contact:
Last name:
Ilaria Colombo
Email:
Ilaria.colombo@eoc.ch
Facility:
Name:
The Royal Marsden NHS Foundation Trust
Address:
City:
London Borough of Sutton
Zip:
SM2 5PT
Country:
United Kingdom
Status:
Recruiting
Contact:
Last name:
Johann S De Bono, MD
Phone:
020 8722 4028
Email:
johann.debono@icr.ac.uk
Contact backup:
Last name:
Khobe Chandran, MD
Phone:
020 3437 6150
Email:
khobe.chandran@ic.ac.uk
Start date:
November 2, 2023
Completion date:
July 31, 2025
Lead sponsor:
Agency:
Institute of Cancer Research, United Kingdom
Agency class:
Other
Collaborator:
Agency:
Prostate Cancer Foundation
Agency class:
Other
Source:
Institute of Cancer Research, United Kingdom
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06126731
