Pharmacokinetic Food-effect Study of Abiraterone Acetate (AA) in Castration Resistant Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
ABIFOOD study is a randomized open-labelled, phase I study to evaluate food effect in the pharmacokinetic parameters of abiraterone acetate (AA) at reduced doses, versus AA in fasting conditions at conventional doses, in castration resistant prostate cancer (mCRPC) patients who have progressed to docetaxel.

Detailed Description
-----------------
Abiraterone acetate (AA) has been approved for the treatment of mCRPC after docetaxel progression at doses of 1.000 mg per day taken in fasting conditions. However, it has been described both the significant food-effect on bioavailability up to 5 to 10 times folder increase depending on the fat content of the diet. These data come from the analysis of a small number of patients in phase I studies conducted in the early stages of drug development and some exploratory study in healthy subjects. There is not prospective randomized study that has analyzed the real impact of the normal diet in the bioavailability of the drug (not a fatty diet like has been used in initial studies). Given the particular epidemiology of mCRPC (relatively frequent pathology), and taking into account recent data which indicates positive results of AA treatment in patients who had not previously received chemotherapy, a significant use of this drug is anticipated in the uro-oncology community in the coming years. The precise definition of dose according to the food-effect on bioavailability may be critical not only from a purely medical perspective and / or pharmacological but even for its socioeconomic impact in our health system. The hypothesis for this study is to prove that AA administered in reduced doses with standard diet presents a suitable pharmacokinetic profile which would achieve therapeutic levels in blood, so that regimens lower than currently approved in association with food can be used in future studies on efficacy.

Official Title
-----------------
Pharmacokinetic Food-effect Study of Abiraterone Acetate (A.A) in Patients With Metastatic Castration Resistant Prostate Cancer (mCRPC)

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: AA Reduced dose-normal diet (A)
* Drug: AA reduced dose-fat diet (B)
* Drug: AA normal dose-fasting conditions (C)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with histologically or cytologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or with no small cell histology. At least one, but no more than two regimens of cytotoxic chemotherapy for metastatic castration-resistant prostate cancer. At least one regimen must have contained docetaxel. Men 18 years old or more. Criteria for progression according to the recommendations of the Prostate Cancer Working Group. Androgen deprivation present with testosterone levels <50 ng / dl or <2.0 nmol / l). ECOG (Eastern Cooperative Oncology Group) performance status <2. Adequate organ function Accept the use of barrier methods of contraception throughout the study Signature of informed consent to participate in the study consent. Exclusion Criteria: Inability or unwillingness to swallow tablets. Known brain metastases Significant chronic gastrointestinal disorder with diarrhea as the main symptom (Crohn's disease, ulcerative colitis, malabsorption, or grade ≥ 2 diarrhea of any etiology at baseline). Local prostate surgery or intervention within 30 days prior to the first dose. Further, any clinically relevant sequel to surgery should be resolved before the 1st of cycle 1. Radiotherapy, chemotherapy or immunotherapy within 30 days before or single fraction of palliative radiotherapy within 14 days prior to the administration of the day 1of Cycle 1. Patients with uncontrolled hypertension, clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, heart failure Class III or IV of the New York Heart Association or cardiac ejection fraction <50%, active or symptomatic viral hepatitis, chronic liver failure, clinically significant adrenal or pituitary dysfunction. (Patients with hypertension controlled with drugs are allowed) Any acute toxicity due to chemotherapy and / or prior radiotherapy has not been resolved to ≤ grade 1 NCI CTCAE (version 4). Alopecia and grade 2 peripheral neuropathy induced by chemotherapy are allowed. Previous treatment with abiraterone acetate.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AA Reduced dose-normal diet (A)<br>Abiraterone acetate at reduced dose of 250 mg po daily in cycles of 28 days administered with a standard breakfast | Drug: AA Reduced dose-normal diet (A)<br>* Cycles of 28 days length of AA at reduced doses (250 mg) administered with a pre-defined normal diet, described with specific caloric and fat content.<br>* Other names: Abiraterone acetate 250 mg normal diet;|
| Experimental: AA reduced dose-fat diet (B)<br>Abiraterone acetate at reduced dose of 250 mg po daily in cycles of 28 days administered with a fat breakfast | Drug: AA reduced dose-fat diet (B)<br>* Cycles of 28 days length of AA at reduced doses (250 mg) administered with a pre-defined fat diet, described with specific caloric and fat content.<br>* Other names: Abiraterone acetate 250 mg fat- diet;|
| Active Comparator: AA normal dose-fasting conditions (C)<br>Abiraterone acetate at approved dose of 1000 mg po daily in cycles of 28 days administered in fasting conditions | Drug: AA normal dose-fasting conditions (C)<br>* Cycles of 28 days length of AA at approved doses (1000 mg) administered in fasting conditions.<br>* Other names: Abiraterone acetate 1000 mg fasting conditions;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under curve (AUC) | Area under curve at time t and infinite, compared with abiraterone acetate administered a standard dose fasting in the times specified: 1, 2, 3, 4, 5, 6, 8, 12, y 24 hours post dose | 1, 2, 3, 4, 5, 6, 8, 12, y 24 hours post dose in day 1 of cycle 1 (28 days long) , day 10-14 of cycle 1 and day 1 of cycle 5(28 days long) | 
| Peak Plasma Concentration (Cmax) | Peak Plasma Concentration (Cmax) of acetate administered at low doses with meals, compared with abiraterone acetate administered a standard dose fasting in the times specified: 1, 2, 3, 4, 5, 6, 8, 12, y 24 hours post dose | 1, 2, 3, 4, 5, 6, 8, 12, y 24 hours post dose in day 1 of cycle 1 (28 days long) , day 10-14 of cycle 1 and day 1 of cycle 5(28 days long) | 
| Time to reach peak plasma concentration (Tmax) | Time to reach peak plasma concentration (Tmax) of acetate administered at low doses with meals, compared with abiraterone acetate administered a standard dose fasting in the times specified: 1, 2, 3, 4, 5, 6, 8, 12, y 24 hours post dose | 1, 2, 3, 4, 5, 6, 8, 12, y 24 hours post dose in day 1 of cycle 1 (28 days long) , day 10-14 of cycle 1 and day 1 of cycle 5(28 days long) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA (Prostate Specific Antigen) levels | Basal PSA levels and monitoring until disease progression | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Response rate | Response rate according to RECIST 1.1 | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Pain intensity | Pain intensity measured by the Brief Pain Inventory-Short Form scale (BPI-SF) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Use of analgesics | Type of analgesics used for pain treatment. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 
| Total daily dose of analgesics | Total daily dose of analgesics will be recorded. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pharmacokinetics, food-effect, fat diet, abiraterone acetate