Effect of Low-dose 500 mg Abiraterone Acetate in Treatment of Metastatic Prostate Cancer Patients

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Prostate Cancer; Metastatic Cancer; Castration-resistant Prostate Cancer; Hormone Sensitive Prostate Cancer
• Intervention / Treatment: Drug: Abiraterone Acetate

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Abiraterone Acetate; 500 mg dose of Abiraterone Acetate plus prednisolone	Drug: Abiraterone Acetate; Upon successful registration, patients would be initiated on 500 mg once daily (two 250 mg tablets), plus prednisolone 5 mg twice daily orally for mCRPC and 5mg once daily orally for mHSPC.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of patients with greater than or equal to 50 percent decrease in Prostate Specific Antigen (PSA) levels	Baseline up to Week 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Maximum Plasma Concentration (Cmax) of 500 mg dose of Abiraterone Acetate	Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment)
Time to Reach the Maximum Plasma Concentration (Tmax) of 500 mg dose of Abiraterone Acetate	Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment)
Area under the plasma concentration time curve from time 0 to 6 hours (AUC0-6h) of 500 mg dose of Abiraterone Acetate	Pre-dose and 0.5, 1, 2, 3, 4 and 6 hours post-dose on Visit 1 (Week 2 from start of treatment)
Area under the plasma concentration time curve from time 0 to infinity time (AUC0-inf) of 500 mg dose of Abiraterone Acetate	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
Volume of distribution (Vd) of 500 mg dose of Abiraterone Acetate	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
Apparent oral clearance (CL/F) of 500 mg dose of Abiraterone Acetate	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
Trough plasma concentrations at steady state (Ctrough) of 500 mg dose of Abiraterone Acetate	Baseline up to Week 12
Plasma concentrations of testosterone	Baseline up to Week 12
Plasma concentrations of androstenedione	Baseline up to Week 12
Plasma concentrations of dehydroepiandrosterone-sulfate (DHEA-S)	Baseline up to Week 12
Plasma concentrations of cortisol	Baseline up to Week 12

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: National University of Singapore
• Investigators: Principal Investigator: Edmund Chiong, MBBS, PhD, National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start (Actual): November 30, 2021
• Primary Completion (Actual): September 5, 2023
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: December 5, 2023
• First Submitted That Met QC Criteria: January 4, 2024
• First Posted (Estimated): January 8, 2024

Study Record Updates

• Last Update Posted (Estimated): January 8, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Hypersensitivity; Prostatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Steroid Synthesis Inhibitors; Abiraterone Acetate
• Other Study ID Numbers: NUH-DSRB-2020/00258

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No