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Dexamethasone with and without Metronidazole in Combination with Abiraterone to Restore Sensitivity to Abiraterone for the Treatment of Progressive Metastatic Castration Resistant Prostate Cancer
Trial Status: active
This phase II trial compares the effect of dexamethasone with and without metronidazole in combination with abiraterone on resistance to abiraterone in treating patients with prostate cancer that is growing, spreading, or getting worse (progressive), and that has spread from where it first started (primary site) to other places in the body (metastatic) and that grows and continues to spread despite the surgical removal of the testes or medical intervention to block androgen production (castration resistant). Prostate cancer is the second most common cause of cancer death in men in the United States. Androgen deprivation therapy (ADT), such as abiraterone, is the usual treatment for metastatic prostate cancer. ADT blocks the growth of hormone sensitive prostate tumor cells. While ADT is initially very effective, most tumors adapt to the low hormone environment and become resistant to ADT. This is thought to be due to androgen (a type of hormone) production by the bacteria in the gut. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Metronidazole, an antibacterial, antiprotozoal, and anthelmintic, is a drug used to treat infection. It may block the tumor-associated bacteria in the gut and may help improve response to treatment. Abiraterone, a type of anti-androgen, lowers the amount of testosterone made by the body. This may help stop the growth of tumor cells that need testosterone to grow. Giving dexamethasone with or without metronidazole in combination with abiraterone may reverse resistance to abiraterone in patients with progressive metastatic castration resistant prostate cancer.
Inclusion Criteria
Willing and able to provide signed informed consent
Males aged 18 years of age and above
Diagnosis of prostate adenocarcinoma. Since abiraterone/prednisone is standard of care in multiple disease states, we will allow for participants with progression on abiraterone in any of these settings
Absolute PSA ≥ 2.0 ng/mL at screening
PSA progression (any numerical increase, confirmed on a second reading) after having been on abiraterone and prednisone for at least 12 weeks
There is no limit on the maximum number or types of prior hormonal therapies received
Must be maintained on a gonadotrophin releasing hormone (GnRH) analogue or have undergone bilateral orchiectomy
Participants must have a life expectancy ≥ 6 months
Ability to swallow study medication tablets
Willing to abstain from alcohol during and for 14 days after treatment since alcohol use is not recommended while on metronidazole
Willing and able to collect urine and stool samples per protocol
Exclusion Criteria
Active infection or other medical condition that would make dexamethasone use contraindicated
Any chronic medical condition requiring a higher systemic dose of corticosteroid (steroid dose equivalent to greater than 10mg of prednisone)
Pathological finding consistent with small cell carcinoma of the prostate
Chronic liver disease with Child-Pugh class C cirrhosis
Bilirubin > 3 x upper limit of normal (ULN) or aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 5 x ULN
Uncontrolled diabetes (hemoglobin A1c > 10%) or increasing doses of insulin within the past 4 weeks due to poorly controlled glucoses
Administration of an investigational therapeutic or invasive surgical procedure (not including surgical castration) within 30 days of cycle 1 day 1 or currently enrolled in an investigational drug study
Any other serious illness or medical condition that would, in the opinion of the investigator, make this protocol unreasonably hazardous, including, but not limited to:
* Any uncontrolled major infection
* Crohn’s disease or ulcerative colitis
* Known or suspected toxic megacolon and/or known small bowel ileus
* Known allergy to any of the compounds under investigation
On antibacterial therapy within 30 days prior to administration of study treatment
Any condition or situation which, in the opinion of the investigator, would put the subject at risk, or interfere with the subject’s participation in this study
Additional locations may be listed on ClinicalTrials.gov for NCT06616597.
I. To estimate the prostate specific antigen (PSA) response rate (PSA^30) within 24 weeks in patients with castration resistant prostate cancer.
SECONDARY OBJECTIVES:
I. To estimate the PSA^30 response rate at 12 and 24 weeks of treatment.
II. To estimate the proportion of patients with PSA progression-free survival (PSA-PFS), defined as the time from initiation of dexamethasone +/- metronidazole until PSA increase of 25%, confirmed with another measurement at least 4 weeks later, and rise greater than 2ng/ml (Prostate Cancer Clinical Trials Working Group 3 [PCWG3]) at 24 weeks.
III. To estimate the proportion of patients without progression (progression-free survival [PFS]), defined as the time to radiographic or clinical progression or death, whichever comes first.
CORRELATIVE/EXPLORATORY OBJECTIVES:
I. To measure changes in fecal desmolase quantification by quantitative polymerase chain reaction (PCR) prior to glucocorticoid switch in both trial arms and at baseline, 1 week after glucocorticoid switch, and then every 6 weeks for 24 weeks or until PSA progression.
II. To measure changes in androgen metabolites (including delta1-adrenosterone [AT], 11beta-hydroxyandrost-4-ene-3,17-dione [11OHAD], testosterone [T], dihydrotestosterone [DHT], androstenedione [AD], dehydroepiandrosterone [DHEA], and progesterone) in fecal, serum, and urine samples at baseline, 1 week after glucocorticoid switch, and then every 6 weeks for 24 weeks or until PSA progression.
III. To measure changes in abiraterone acetate (abiraterone) metabolites in fecal, serum, and urine samples at baseline, 1 week after glucocorticoid switch, and then every 6 weeks for 24 weeks or until PSA progression.
IV. To characterize fecal microbiota profile at baseline, 1 week, 6-week, and 24-week time points.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM 1: Patients receive abiraterone orally (PO) once daily (QD), dexamethasone PO QD for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo urine and blood sample collection, computed tomography (CT), nuclear medicine (NM) bone scan, and/or prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/CT throughout the study.
ARM 2: Patients receive abiraterone PO QD, dexamethasone PO QD for up to 24 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive metronidazole PO thrice daily (TID) on days 1-5 of cycle 1. Additionally, patients undergo urine and blood sample collection, CT, NM bone scan, and/or PSMA PET/CT throughout the study.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationJohns Hopkins University/Sidney Kimmel Cancer Center
