Prostate Neoplasms
Conditions
Keywords
Prostate neoplasms, Hormone refractory prostate cancer, Abiraterone acetate, CB7630
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.
Interventions
DRUGAbiraterone acetate
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.
DRUGprednisone/prednisolone or dexamethasone
prednisone/prednisolone (5 mg twice daily) or dexamethasone (0.5 mg once daily) concurrent with abiraterone acetate
Sponsors
Janssen Research & Development, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Maximum Tolerated Dose (MTD) of Abiraterone Acetate | Up to Cycle 12 | The MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects. |
| Phase 2: Participants With Greater Than or Equal to 50 Percent Decline in Prostate Specific Antigen (PSA) | Up to 12 weeks from start of treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | 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 | 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). |
| Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | 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 | 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). |
| Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | 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 | 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). |
| Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | 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 | 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). |
| Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | 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 | 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). |
| Phase 2: Radiographic Progression Free Survival (RAD-PFS) | Up to 12 weeks from start of treatment | 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. |
| Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | 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. | 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). |
| Phase 2: Radiographic Objective Response Rate (RAD-ORR) | Up to 12 weeks from start of treatment | 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. |
| Phase 2: Time to PSA Progression | Up to 12 weeks from start of treatment | 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. |
| Phase 2: Duration of PSA Response | Up to 12 weeks from start of treatment | 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. |
| Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Up to 12 weeks from start of treatment | 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. |
| Phase 2: Overall Survival | Up to Month 60 | 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. |
| Phase 2: Duration of Objective Response | Up to 12 weeks from start of treatment | 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. |
| Phase 2: PSA Progression Free Survival (PSA-PFS) | Up to 12 weeks from start of treatment | 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. |
| Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | 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 | 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) |
Countries
United States
Participant flow
Recruitment details
The study was conducted between 10 July 2006 and 22 December 2012.
Pre-assignment details
66 participants participated in the study, including 33 participants enrolled in Phase 1 of the study, and 33 participants enrolled in Phase 2 of the study.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 250 MG/DAY Abiraterone acetate | 6 |
| Phase 1 500 MG/DAY Abiraterone acetate | 9 |
| Phase 1 750 MG/DAY Abiraterone acetate | 6 |
| Phase 1 1000 MG/DAY Abiraterone acetate | 12 |
| Phase 2 1000 MG/DAY Abiraterone acetate | 33 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 (Phase 1) | Adverse Event | 1 | 0 | 0 | 0 | 0 |
| Period 1 (Phase 1) | Progressive Disease | 5 | 6 | 6 | 10 | 0 |
| Period 1 (Phase 1) | Reason not specified | 0 | 1 | 0 | 0 | 0 |
| Period 1 (Phase 1) | Symptomatic Deterioration | 0 | 1 | 0 | 0 | 0 |
| Period 1 (Phase 1) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 |
| Period 2 (Phase 2) | Adverse Event | 0 | 0 | 0 | 0 | 3 |
| Period 2 (Phase 2) | Death | 0 | 0 | 0 | 0 | 1 |
| Period 2 (Phase 2) | Progressive Disease | 0 | 0 | 0 | 0 | 20 |
| Period 2 (Phase 2) | Reason not specified | 0 | 0 | 0 | 0 | 3 |
Baseline characteristics
| Characteristic | Phase 1 250 MG/DAY | Phase 1 500 MG/DAY | Phase 1 750 MG/DAY | Phase 1 1000 MG/DAY | Phase 2 1000 MG/DAY | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 66.7 years STANDARD_DEVIATION 6.19 | 67.6 years STANDARD_DEVIATION 6.5 | 73.2 years STANDARD_DEVIATION 8.18 | 72.9 years STANDARD_DEVIATION 8.3 | 70.3 years STANDARD_DEVIATION 8.51 | 70.3 years STANDARD_DEVIATION 8.05 |
| Region of Enrollment United States | 6 participants | 9 participants | 6 participants | 12 participants | 33 participants | 66 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 6 Participants | 12 Participants | 33 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 9 / 9 | 6 / 6 | 12 / 12 | 33 / 33 |
| serious Total, serious adverse events | 1 / 6 | 2 / 9 | 0 / 6 | 0 / 12 | 10 / 33 |
Outcome results
Primary
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.
Time frame: Up to Cycle 12
Population: Safety population included all enrolled participants who received any study drug. MTD of abiraterone acetate was not reached because the doses administered appear to be well tolerated with no Dose Limiting Toxicity (DLT) even at 1000 milligram per day (mg/day \[recommended maximum dose for phase 1\]) and 1000 mg/day was taken as test dose in phase 2.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Maximum Tolerated Dose (MTD) of Abiraterone Acetate | NA mg/day | 0 |
Primary
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.
Time frame: Up to 12 weeks from start of treatment
Population: Intent-to-treat (ITT) population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Dose Escalation | Phase 2: Participants With Greater Than or Equal to 50 Percent Decline in Prostate Specific Antigen (PSA) | Confirmed | 26 participants |
| Phase I Dose Escalation | Phase 2: Participants With Greater Than or Equal to 50 Percent Decline in Prostate Specific Antigen (PSA) | Not Confirmed | 2 participants |
| Phase I Dose Escalation | Phase 2: Participants With Greater Than or Equal to 50 Percent Decline in Prostate Specific Antigen (PSA) | Total | 28 participants |
Secondary
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).
Time frame: 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
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fasted | 1411.268 hr*nmol/L | Standard Deviation 697.183 |
| Phase I Dose Escalation | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fed | 1386.939 hr*nmol/L | Standard Deviation 290.24 |
| Phase I Dose Escalation (500mg) | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fed | 3839.804 hr*nmol/L | Standard Deviation 1080.853 |
| Phase I Dose Escalation (500mg) | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fasted | 1781.374 hr*nmol/L | Standard Deviation 986.77 |
| Phase I Dose Escalation (750mg) | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fasted | 1665.454 hr*nmol/L | Standard Deviation 704.551 |
| Phase I Dose Escalation (750mg) | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fed | 9358.743 hr*nmol/L | Standard Deviation 3338.601 |
| Phase I Dose Escalation (1000mg) | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fasted | 3478.385 hr*nmol/L | Standard Deviation 2012.176 |
| Phase I Dose Escalation (1000mg) | Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate | Fed | 14404.387 hr*nmol/L | Standard Deviation 5971.041 |
Secondary
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).
Time frame: 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
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fasted | 1329.178 hr*nmol/L | Standard Deviation 699.977 |
| Phase I Dose Escalation | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fed | 1310.715 hr*nmol/L | Standard Deviation 311.041 |
| Phase I Dose Escalation (500mg) | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fed | 3624.781 hr*nmol/L | Standard Deviation 1041.927 |
| Phase I Dose Escalation (500mg) | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fasted | 1625.059 hr*nmol/L | Standard Deviation 930.364 |
| Phase I Dose Escalation (750mg) | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fasted | 1565.659 hr*nmol/L | Standard Deviation 661.289 |
| Phase I Dose Escalation (750mg) | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fed | 8920.790 hr*nmol/L | Standard Deviation 3060.457 |
| Phase I Dose Escalation (1000mg) | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fasted | 3039.937 hr*nmol/L | Standard Deviation 1902.697 |
| Phase I Dose Escalation (1000mg) | Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate | Fed | 13695.482 hr*nmol/L | Standard Deviation 5623.185 |
Secondary
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).
Time frame: 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.
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fasted | 283.000 nanomoles per liter (nmol/L) | Standard Deviation 142.265 |
| Phase I Dose Escalation | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fed | 421.000 nanomoles per liter (nmol/L) | Standard Deviation 75.809 |
| Phase I Dose Escalation (500mg) | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fed | 676.000 nanomoles per liter (nmol/L) | Standard Deviation 147.866 |
| Phase I Dose Escalation (500mg) | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fasted | 330.633 nanomoles per liter (nmol/L) | Standard Deviation 204.889 |
| Phase I Dose Escalation (750mg) | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fasted | 289.533 nanomoles per liter (nmol/L) | Standard Deviation 126.646 |
| Phase I Dose Escalation (750mg) | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fed | 1552.000 nanomoles per liter (nmol/L) | Standard Deviation 458.082 |
| Phase I Dose Escalation (1000mg) | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fasted | 509.500 nanomoles per liter (nmol/L) | Standard Deviation 366.452 |
| Phase I Dose Escalation (1000mg) | Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate | Fed | 2194.250 nanomoles per liter (nmol/L) | Standard Deviation 1096.914 |
Secondary
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).
Time frame: 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
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fasted | 5.284 hour (hr) | Standard Deviation 1.676 |
| Phase I Dose Escalation | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fed | 5.125 hour (hr) | Standard Deviation 1.039 |
| Phase I Dose Escalation (500mg) | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fed | 6.913 hour (hr) | Standard Deviation 5.72 |
| Phase I Dose Escalation (500mg) | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fasted | 10.591 hour (hr) | Standard Deviation 6.337 |
| Phase I Dose Escalation (750mg) | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fasted | 7.066 hour (hr) | Standard Deviation 3.431 |
| Phase I Dose Escalation (750mg) | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fed | 7.939 hour (hr) | Standard Deviation 2.633 |
| Phase I Dose Escalation (1000mg) | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fasted | 14.361 hour (hr) | Standard Deviation 7.655 |
| Phase I Dose Escalation (1000mg) | Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate | Fed | 12.454 hour (hr) | Standard Deviation 1.218 |
Secondary
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)
Time frame: 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
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fasted | 2.000 hour (hr) | Standard Deviation 0 |
| Phase I Dose Escalation | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fed | 2.044 hour (hr) | Standard Deviation 0.077 |
| Phase I Dose Escalation (500mg) | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fed | 2.667 hour (hr) | Standard Deviation 1.155 |
| Phase I Dose Escalation (500mg) | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fasted | 1.500 hour (hr) | Standard Deviation 0.548 |
| Phase I Dose Escalation (750mg) | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fasted | 2.033 hour (hr) | Standard Deviation 0.058 |
| Phase I Dose Escalation (750mg) | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fed | 2.000 hour (hr) | Standard Deviation 0 |
| Phase I Dose Escalation (1000mg) | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fasted | 1.833 hour (hr) | Standard Deviation 0.408 |
| Phase I Dose Escalation (1000mg) | Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate | Fed | 4.000 hour (hr) | Standard Deviation 0 |
Secondary
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).
Time frame: 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
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fasted | 4288.456 liter per hour (l/hr) | Standard Deviation 1319.322 |
| Phase I Dose Escalation | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fed | 529.606 liter per hour (l/hr) | Standard Deviation 99.532 |
| Phase I Dose Escalation (500mg) | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fed | 391.046 liter per hour (l/hr) | Standard Deviation 99.118 |
| Phase I Dose Escalation (500mg) | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fasted | 5440.949 liter per hour (l/hr) | Standard Deviation 4844.515 |
| Phase I Dose Escalation (750mg) | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fasted | 1518.748 liter per hour (l/hr) | Standard Deviation 822.714 |
| Phase I Dose Escalation (750mg) | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fed | 246.643 liter per hour (l/hr) | Standard Deviation 72.97 |
| Phase I Dose Escalation (1000mg) | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fasted | 2649.954 liter per hour (l/hr) | Standard Deviation 4617.049 |
| Phase I Dose Escalation (1000mg) | Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate | Fed | 231.383 liter per hour (l/hr) | Standard Deviation 97.746 |
Secondary
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).
Time frame: 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
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase I Dose Escalation | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fasted | 653.745 Liter (L) | Standard Deviation 447.316 |
| Phase I Dose Escalation | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fed | 3940.400 Liter (L) | Standard Deviation 1275.408 |
| Phase I Dose Escalation (500mg) | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fed | 3418.280 Liter (L) | Standard Deviation 1934.384 |
| Phase I Dose Escalation (500mg) | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fasted | 10252.077 Liter (L) | Standard Deviation 12268.787 |
| Phase I Dose Escalation (750mg) | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fasted | 13688.367 Liter (L) | Standard Deviation 4265.429 |
| Phase I Dose Escalation (750mg) | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fed | 2739.655 Liter (L) | Standard Deviation 1084.694 |
| Phase I Dose Escalation (1000mg) | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fasted | 25494.398 Liter (L) | Standard Deviation 18670.215 |
| Phase I Dose Escalation (1000mg) | Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate | Fed | 4068.885 Liter (L) | Standard Deviation 1462.613 |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: Thirteen evaluable participants with measurable disease at baseline were evaluated for radiographic duration of objective response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalation | Phase 2: Duration of Objective Response | NA days |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalation | Phase 2: Duration of PSA Response | 477 days |
Secondary
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.
Time frame: Up to Month 60
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalation | Phase 2: Overall Survival | NA days |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Baseline ECOG 0 | 20 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Baseline ECOG 1 | 13 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Baseline ECOG 2 | 0 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Baseline ECOG 3 | 0 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Baseline ECOG 4 | 0 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Best Post-Baseline ECOG 0 | 28 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Best Post-Baseline ECOG 1 | 5 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Best Post-Baseline ECOG 2 | 0 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Best Post-Baseline ECOG 3 | 0 participants |
| Phase I Dose Escalation | Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score | Best Post-Baseline ECOG 4 | 0 participants |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalation | Phase 2: PSA Progression Free Survival (PSA-PFS) | 473 days |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: Thirteen evaluable participants with measurable disease at baseline were evaluated for radiographic objective response rate.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I Dose Escalation | Phase 2: Radiographic Objective Response Rate (RAD-ORR) | Confirmed | 9 participants |
| Phase I Dose Escalation | Phase 2: Radiographic Objective Response Rate (RAD-ORR) | Not Confirmed | 1 participants |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: ITT population included all participants who were enrolled into the study. RAD-PFS was not analyzed because of insufficient data to provide a meaningful estimate of the median and associated confidence interval (CI)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalation | Phase 2: Radiographic Progression Free Survival (RAD-PFS) | NA days |
Secondary
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.
Time frame: Up to 12 weeks from start of treatment
Population: ITT population included all participants who were enrolled into the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I Dose Escalation | Phase 2: Time to PSA Progression | 497 days |