Abiraterone Acetate Dose-Escalation Study in Hormone Refractory Prostate Cancer

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to evaluate the safety, pharmacokinetics, pharmacodynamics, and anti-tumor activities of abiraterone acetate (also referred to as CB7630) in patients with hormone refractory prostate cancer (HRPC).

Detailed Description
-----------------
This is an open-label (identity of assigned study drug will be known) study to evaluate the safety, pharmacokinetics (study of what the body does to a drug), pharmacodynamics (study of what a drug does to the body), and anti-tumor activities of abiraterone acetate (also known as CB7630) in patients with HRPC. The study will be conducted in 2 phases (Phase 1 and Phase 2). In the first part of the study (Phase 1), the maximum tolerated dose (MTD) of abiraterone acetate will be determined for use in the second part of the study (Phase 2) where the number of patients who achieve at least a 50% decrease in prostate specific antigen (PSA) during treatment with abiraterone acetate will be assessed (MTD from Phase 1). Abiraterone acetate will be taken orally (by mouth) in fed and fasted patients once daily. Doses of abiraterone acetate (starting at 250 mg up to a maximum of 2000 mg) will be taken for 28-day treatment periods to determine the MTD. Patients will take MTD of abiraterone acetate for up to twelve 28 day cycles (12 months; patients will be given the option of staying on abiraterone acetate treatment if they are deriving benefit). In Phase 2, prednisone or dexamethasone will be administered concurrently with abiraterone acetate. Serial pharmacokinetic and pharmacodynamic samples will be collected and safety will be monitored throughout the study.

Official Title
-----------------
Phase I/II Open Label Dose Escalation Study of the 17α-Hydroxylase/ C17,20-Lyase Inhibitor, Abiraterone Acetate in Hormone Refractory Prostate Cancer

Conditions
-----------------
Prostate Neoplasms

Intervention / Treatment
-----------------
* Drug: Abiraterone acetate
* Drug: Abiraterone acetate
* Drug: prednisone/prednisolone or dexamethasone


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Phase 1 Histologically confirmed adenocarcinoma of the prostate No prior therapy with chemotherapy for prostate cancer Ongoing gonadal androgen deprivation therapy with luteinizing hormone-releasing hormone (LHRH) analogues or orchiectomy Testosterone <50 ng/dL Progressive disease after androgen deprivation The presence of objective metastatic disease is NOT required for study eligibility Demonstrate disease progression after antiandrogen withdrawal Eastern Cooperative Oncology Group (ECOG) performance status score = 0-1 Laboratory values within protocol-defined parameters Systolic blood pressure <160 mmHg and diastolic blood pressure <110mmHg documented on at least 3 different days Baseline adrenocorticotropic hormone (ACTH) stimulation test demonstrating a peak cortisol >18 µg/dL Agrees to protocol-defined use of effective contraception Life expectancy of >=12 weeks Phase 2 Same as Phase 1 criteria with addition of following criteria Neoadjuvant or adjuvant chemotherapy is only allowed if the last dose is >1 year from Cycle 1 Day 1 Target or non-target abnormalities must be present either on screening bone scan, computed tomography or magnetic resonance imaging No prior treatment with ketoconazole for the management of androgen independent prostate cancer Exclusion Criteria: Phase 1 Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) any herbal product known to decrease prostate specific antigen (PSA) levels (eg, saw palmetto and PC-SPES), or any systemic corticosteroid within 4 weeks prior to first dose of study drug Initiation of bisphosphonate therapy within 4 weeks prior to first dose of study drug Therapy with supplements or complementary medicines/botanicals within 4 weeks of first dose of study drug, except for any combination of the following: conventional multivitamin supplements, selenium, lycopene, soy supplements Prior radiation therapy completed <4 weeks prior to enrollment Prior chemotherapy for hormone refractory prostate cancer Any currently active second malignancy, other than non-melanoma skin cancer Systolic blood pressure >=160 mmHg or diastolic blood pressure >=110 mmHg measured on at least 2 occasions NYHA Class III or IV congestive heart failure Myocardial infarction within the 6 months prior to the first dose of study drug Serious intercurrent infections or nonmalignant medical illnesses that are uncontrolled Active psychiatric illnesses/social situations that would limit compliance with protocol requirements Active or uncontrolled autoimmune disease that may require corticosteroid therapy during study Phase 2 Same as phase 1 with the following addition Abnormal electrocardiogram, including any finding which would interfere with assessment of intervals (patients with long QT syndrome, bundle branch blocks or hemiblocks are prohibited)

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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Escalation<br> | Drug: Abiraterone acetate<br>* The first cohort was a abiraterone acetate 250 mg/day orally (by mouth), once daily for 28-day treatment periods , if no dose limiting toxicity (DLT) was documented at this dose, the dose will be escalated to next dose levels 500, 750, and 1000 mg/day. The dose escalation will continue to a maximum of 1000mg/day until Maximum Tolerated Dose (MTD) and a recommended Phase II dose was established.<br>|
| Experimental: Phase II Dose Treatment<br> | Drug: Abiraterone acetate<br>* Abiraterone acetate 1000 mg daily under fasted conditions upto 10 cycles of therapy.<br>Drug: prednisone/prednisolone or dexamethasone<br>* prednisone/prednisolone (5 mg twice daily) or dexamethasone (0.5 mg once daily) concurrent with abiraterone acetate<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Tolerated Dose (MTD) of Abiraterone Acetate | The MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects. | Up to Cycle 12 | 
| Phase 2: Participants With Greater Than or Equal to 50 Percent Decline in Prostate Specific Antigen (PSA) | Number of participants with greater than or equal to 50 percent decrease in PSA levels were assessed. PSA decline was evaluated according to (Prostate Specific Antigen Working Group) PSAWG criteria. Decrease in PSA levels represented improvement. | Up to 12 weeks from start of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose). | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3. | 
| Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose) | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3 | 
| Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose). | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3 | 
| Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose). | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3 | 
| Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose). | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3 | 
| Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose). | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3 | 
| Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Volume of distribution is normally calculated by using equation volume of distribution =dose/initial concentration. Blood samples for pharmacokinetic (PK) measurements was taken on Day -7 at hour 0 (predose), at hours 1, 2, 4, 6, 8, and 12 (postdose). On Day -6 at 24 hour (postdose) and Day -5 at 48 hour (postdose). On Days 1, 8, 15, 22 of Cycle 1 and Day 1 of Cycles 2 and 3 (Predose). | At hours 1, 2, 4, 6, 8, 12, 24 and 48 post dose and pre-dose on day 1, day 8, day 15 and day 22 cycle 1, day 1 cycle 2 and day 1 cycle 3 | 
| Phase 2: Radiographic Progression Free Survival (RAD-PFS) | RAD-PFS is the time interval from the date of first dose of abiraterone acetate therapy to the date of death or radiographic disease progression according to the RECIST (Response Evaluation Criteria In Solid Tumors) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 12 weeks from start of treatment | 
| Phase 2: PSA Progression Free Survival (PSA-PFS) | PSA-PFS is the time interval from the date of first dose of abiraterone acetate therapy to the date of death or the PSA progression as defined by the Prostate Specific Antigen Working Group (PSAWG) criteria. | Up to 12 weeks from start of treatment | 
| Phase 2: Radiographic Objective Response Rate (RAD-ORR) | The objective response rate is defined as the proportion of participants with measurable lesions achieving a Complete Response (CR) or Partial Response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 12 weeks from start of treatment | 
| Phase 2: Time to PSA Progression | The time interval from the date of first dose of abiraterone acetate therapy to the date of the PSA progression as defined by the PSAWG criteria. | Up to 12 weeks from start of treatment | 
| Phase 2: Duration of PSA Response | Duration of PSA response was defined as the duration between the date of confirmed PSA response and subsequent PSA progression date as defined by the PSAWG criteria. | Up to 12 weeks from start of treatment | 
| Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | ECOG performance status score ranges from 0 to 5 where 0=fully active, perform all pre-disease activities without restriction. 1=restricted in physically strenuous activity but ambulatory, carry out work of a light or sedentary nature. 2=ambulatory, capable of self-care, unable to carry out any work activities, up and about more than (>) 50% of waking hours. 3=capable of limited self-care, confined to bed or chair >50% of waking hours. 4=completely disabled, not capable of any self-care, totally confined to bed or chair. 5=dead. | Up to 12 weeks from start of treatment | 
| Phase 2: Overall Survival | Overall survival is the time interval from the date of first dose (cycle 1 day 1) of abiraterone acetate therapy to the date of death from any cause. | Up to Month 60 | 
| Phase 2: Duration of Objective Response | Duration of objective response was assessed only in participants who achieved a CR or PR, and measured from the first documented date of response to the first documented date of disease progression according to the RECIST criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 12 weeks from start of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CB7630, Prostate neoplasms, Hormone refractory prostate cancer, Abiraterone acetate