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Abiraterone Acetate Dose-Escalation Study in Hormone Refractory Prostate Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00473746
Recruitment Status : Completed
First Posted : May 15, 2007
Results First Posted : April 29, 2014
Last Update Posted : April 29, 2014
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Description
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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).

Condition or disease Intervention/treatment Phase
Prostate Neoplasms Drug: Abiraterone acetate Drug: prednisone/prednisolone or dexamethasone Phase 1 Phase 2

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.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 66 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : June 2006
Actual Primary Completion Date : December 2012
Actual Study Completion Date : December 2012

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Arms and Interventions
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Arm Intervention/treatment
Experimental: Phase I Dose Escalation Drug: Abiraterone 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.
Experimental: Phase II Dose Treatment Drug: Abiraterone acetate
Abiraterone acetate 1000 mg daily under fasted conditions upto 10 cycles of therapy.

Drug: prednisone/prednisolone or dexamethasone
prednisone/prednisolone (5 mg twice daily) or dexamethasone (0.5 mg once daily) concurrent with abiraterone acetate


Outcome Measures
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Primary Outcome Measures :
  1. Phase 1: Maximum Tolerated Dose (MTD) of Abiraterone Acetate [ Time Frame: Up to Cycle 12 ]
    The MTD is the highest dose of a drug or treatment that does not cause unacceptable side effects.

  2. Phase 2: Participants With Greater Than or Equal to 50 Percent Decline in Prostate Specific Antigen (PSA) [ Time Frame: 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 Outcome Measures :
  1. Phase 1: Maximum Plasma Concentration (Cmax) of Abiraterone Acetate [ 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. ]
    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).

  2. Phase 1: Time to Reach the Maximum Plasma Concentration (Tmax) of Abiraterone Acetate [ 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 ]
    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)

  3. Phase 1: Area Under the Plasma-Concentration-Time Curve From Time 0 to the Last Quantifiable Concentration (AUClast) of Abiraterone Acetate [ 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 ]
    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).

  4. Phase 1: Area Under the Plasma-Concentration-time Curve From Time 0 to Infinite Time (AUCINF_obs) of Abiraterone Acetate [ 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 ]
    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).

  5. Phase 1: Terminal Half-life (HL_Lambda_z) of Abiraterone Acetate [ 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 ]
    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).

  6. Phase 1: Total Body Clearance (Cl_F_obs) of Abiraterone Acetate [ 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 ]
    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).

  7. Phase 1: Volume of Distribution (Vz_F_obs) of Abiraterone Acetate [ 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 ]
    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).

  8. Phase 2: Radiographic Progression Free Survival (RAD-PFS) [ Time Frame: 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.

  9. Phase 2: PSA Progression Free Survival (PSA-PFS) [ Time Frame: 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.

  10. Phase 2: Radiographic Objective Response Rate (RAD-ORR) [ Time Frame: 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.

  11. Phase 2: Time to PSA Progression [ Time Frame: 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.

  12. Phase 2: Duration of PSA Response [ Time Frame: 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.

  13. Phase 2: Participants With Change in Eastern Cooperative Oncology Group (ECOG) Performance Status Score [ Time Frame: 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.

  14. Phase 2: Overall Survival [ Time Frame: 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.

  15. Phase 2: Duration of Objective Response [ Time Frame: 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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)
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00473746


Locations
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United States, California
San Francisco, California, United States
United States, Massachusetts
Boston, Massachusetts, United States
United States, Texas
Houston, Texas, United States
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
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Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT00473746    
Other Study ID Numbers: CR016969
COU-AA-002 ( Other Identifier: Janssen Research & Development, LLC )
First Posted: May 15, 2007    Key Record Dates
Results First Posted: April 29, 2014
Last Update Posted: April 29, 2014
Last Verified: March 2014
Keywords provided by Janssen Research & Development, LLC:
Prostate neoplasms
Hormone refractory prostate cancer
Abiraterone acetate
CB7630
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Dexamethasone
Prednisone
Prednisolone
Abiraterone Acetate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
 Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Cytochrome P-450 Enzyme Inhibitors