Clinical trial NCT06193993: Effect of Low-dose 500 mg Abiraterone Acetate in Treatment of Metastatic Prostate Cancer Patients
Official title: Low-dose 500 mg Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer (mCRPC) and Metastatic Hormone-sensitive Prostate Cancer (mHSPC) Patients: a Phase I Proof-of-concept Clinical Study
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Prostate Cancer
Metastatic Cancer
Hormone Sensitive Prostate Cancer
Castration-resistant Prostate Cancer
Lead sponsor: National University Hospital, Singapore
Sponsor class: OTHER
Collaborators: name: National University of Singapore
First posted: 2024-01-08
Enrollment: 10
Sex: MALE
Minimum age (years): 21
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This will be an open label, Phase I study to assess the efficacy of a reduced 500 mg dose of abiraterone acetate in patients with metastatic prostate cancer. Eligible metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC) patients newly initiated on abiraterone acetate treatment will be recruited to receive a reduced 500 mg dose of abiraterone acetate plus prednisolone. The study treatment duration will span 12 weeks, after which patients being administered the reduced dose will be reverted to the standard 1000 mg dosing. Follow-up for mCRPC and mHSPC patients will last for 18 and 36 months respectively. The main question the study aims to answer is whether dose reduction of abiraterone acetate to 500 mg would achieve antitumor activity in mCRPC and mHPSC patients comparable to standard of care.

Detailed description: Primary Objectives:

As a preliminary Phase I trial, the primary objective of the study would be to evaluate the percentage change in prostate specific antigen (PSA) from baseline to 12 weeks.

Secondary Objectives:

1. determine the proportion of patients achieving PSA response (≥ 50% reduction in PSA after 12 weeks of therapy).
2. evaluate the pharmacokinetics associated with the 500 mg dose of abiraterone acetate.
3. investigate the correlation between plasma exposure of abiraterone and CP-I or CP-III in order to support their utility as a biomarker of OATP1B1/1B3 function.
4. assess the pharmacodynamic effects of the reduced 500 mg dose on the maximal percentage change in serum androgens (dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), testosterone, androstenedione) from baseline.

Eligibility criteria: Inclusion Criteria:

1. Histologically confirmed adenocarcinoma prostate
2. Age \>21 years
3. Diagnosis of metastatic castration-resistant prostate cancer (mCRPC) (chemotherapy naïve and chemotherapy pre-treated patients) or metastatic hormone-sensitive prostate cancer (mHSPC)
4. For mCRPC patients, evidence of castration resistance is defined as disease progression despite a testosterone level \<50ng/dL (or surgical castration)
5. Progressive disease was defined as either

   1. PSA progression according to Prostate Cancer Working Group (PCWG2) criteria15: PSA evidence for progressive prostate cancer consists of a minimum PSA level of at least 2 ng/ml, which has subsequently risen on at least 2 successive occasions, at least 1 week apart
   2. Radiographic progression according to RECIST 1.1 guidelines or
   3. 2 or more new lesions on bone scan
6. Newly initiated on abiraterone acetate therapy
7. Eastern Cooperative Oncology Group (ECOG) performance status grade of 0, 1 or 2.
8. Adequate hematologic, hepatic, and renal function would include:

   * hemoglobin ≥9.0 g/dL independent of transfusions
   * neutrophils ≥1.5 x 109/L
   * platelets ≥100 x 109/L
   * total bilirubin ≤1.5× upper limit of normal (ULN) \[except for subjects with documented Gilbert's disease in which case total bilirubin not to exceed 10× ULN\]
   * alanine (ALT) and aspartate (AST) aminotransferase ≤2.5X ULN
   * serum creatinine \<1.5× ULN or calculated creatinine clearance ≥30 mL/min
   * serum potassium ≥3.5 mmol/L
9. Ability to provide informed consent

Exclusion Criteria:

1. Patients with prior use of enzalutamide or other potent androgen pathway targeted therapies
2. Concurrent therapy with strong inhibitors or inducers of CYP3A4 due to concerning possible drug-drug interactions with abiraterone.
3. Concurrent therapy with strong inhibitors or inducers of OATP transporters (e.g., rifampicin, cyclosporine) due to concerning possible effects on CP-I and CP-III.
4. New York Heart Association (NYHA) class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure)
5. Uncontrolled hypertension (systolic blood pressure ≥160 mmHg or diastolic BP ≥95 mmHg). Subjects with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment
6. Patients who do not voluntarily consent to participate in the study

Primary outcomes:
measure: Percentage of patients with greater than or equal to 50 percent decrease in Prostate Specific Antigen (PSA) levels
timeFrame: Baseline up to Week 12
Secondary outcomes:
measure: Maximum Plasma Concentration (Cmax) of 500 mg dose of Abiraterone Acetate
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment)
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of 500 mg dose of Abiraterone Acetate
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment)
measure: Area under the plasma concentration time curve from time 0 to 6 hours (AUC0-6h) of 500 mg dose of Abiraterone Acetate
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment)
measure: Area under the plasma concentration time curve from time 0 to infinity time (AUC0-inf) of 500 mg dose of Abiraterone Acetate
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment). On Visits 2 (Week 4), 3 (Week 8) and 4 (Week 12) pre-dose
measure: Volume of distribution (Vd) of 500 mg dose of Abiraterone Acetate
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment). On Visits 2 (Week 4), 3 (Week 8) and 4 (Week 12) pre-dose
measure: Apparent oral clearance (CL/F) of 500 mg dose of Abiraterone Acetate
timeFrame: Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment). On Visits 2 (Week 4), 3 (Week 8) and 4 (Week 12) pre-dose
measure: Trough plasma concentrations at steady state (Ctrough) of 500 mg dose of Abiraterone Acetate
timeFrame: Baseline up to Week 12
measure: Plasma concentrations of testosterone
timeFrame: Baseline up to Week 12
measure: Plasma concentrations of androstenedione
timeFrame: Baseline up to Week 12
measure: Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S)
timeFrame: Baseline up to Week 12
measure: Plasma concentrations of cortisol
timeFrame: Baseline up to Week 12
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: National University Hospital
Study officials:
affiliation: National University Hospital, Singapore
name: Edmund Chiong, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
References: