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Study of Abiraterone Acetate Without Exogenous Glucocorticoids in Men With Castration-resistant 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: NCT02025010
Recruitment Status : Active, not recruiting
First Posted : December 31, 2013
Results First Posted : November 8, 2022
Last Update Posted : November 8, 2022
Sponsor:
Collaborator:
Janssen Research & Development, LLC
Information provided by (Responsible Party):
Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute

Brief Summary:
This study is comparing the safety and effectiveness of abiraterone acetate alone, followed by the addition of prednisone (when the participant's disease worsens or the physician feels it would lessen symptoms of toxicity) versus the current approved treatment regimen which involves the concomitant use of prednisone in conjunction with abiraterone acetate. Additionally, this study is also examining why participants stop responding to treatment with abiraterone acetate by evaluating blood and tissue.

Condition or disease Intervention/treatment Phase
Castration-resistant Prostate Cancer Drug: abiraterone acetate Phase 2

Detailed Description:

Participants will be treated with abiraterone acetate (AA) in 28-day cycles. Participants will be monitored (weekly for the first two cycles, then on Day 1 of each subsequent cycle) for symptoms of persistent or severe mineralocorticoid excess (including hypertension, hypokalemia).

For participants who experience symptoms of persistent or severe hypertension or hypokalemia as detailed in the above schema, prednisone 5 mg by mouth twice daily will be added. We will monitor for other symptoms of AA toxicity to include fluid retention and fatigue.

For participations who tolerate AA monotherapy without the addition of prednisone to manage symptoms of persistent or severe mineralocorticoid excess, prednisone 5 mg by mouth twice daily will be added at Prostate Specific Antigen (PSA) progression. Participants will be continued on study until symptomatic or radiographic progression or taken off study for another reason as detailed in protocol.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 60 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Clinical Trial of Abiraterone Acetate Without Exogenous Glucocorticoids in Men With Castration-resistant Prostate Cancer With Correlative Assessment of Hormone Intermediates.
Actual Study Start Date : January 27, 2014
Actual Primary Completion Date : December 2021
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: abiraterone acetate

Participants will be treated with four 250 mg tablets (1,000 mg) of abiraterone acetate (AA) orally on 28-day cycles. For participants who experience persistent or severe mineralocorticoid excess or have PSA progression, prednisone 5 mg by mouth twice daily will be added.

Patients will be treated until radiographic disease progression and unacceptable AE or taken off study for other reason.

Drug: abiraterone acetate
Abiraterone acetate is a selective and irreversible inhibitor of CYP17 which has demonstrated clinical efficacy in patients with CRPC. Currently, AA is administered with concomitant prednisone.
Other Name: JNJ21208




Primary Outcome Measures :
  1. Number of Participants With Toxicities That Required the Addition of Prednisone to Manage Symptoms of Persistent or Severe Mineralocorticoid Excess [ Time Frame: Patients were on abiraterone acetate up to 57 months and toxicities of mineralocorticoid excess were monitored each cycle (1cycle = 28 days). ]
    Patients requiring prednisone to manage toxicities such as COU-302 any grade or COU-301 grade 3-4 hypertension, hypokalemia and edema per CTCAE v. 4.0 were summarized using frequency and percentage.


Secondary Outcome Measures :
  1. Safety and Tolerability Associated With AA Monotherapy and the Addition of Prednisone to AA. [ Time Frame: Adverse events were assessed continuously on treatment and up to 30 days after going off treatment (up to 55 months). ]
    Grade 3 or higher toxicities attribution to AA monotherapy with or without prednisone were summarized descriptively.

  2. Number of Participants Requiring the Addition of Prednisone to Manage Symptoms of Severe Fatigue. [ Time Frame: Patients were on abiraterone acetate up to 57 months. ]
    Participants initiated treatment with prednisone for ≥grade 3 fatigue were summarized using frequency and percentage.

  3. Changes in Serum Concentrations of Corticosteroid Intermediates Between the First and Second Assessment Visits. [ Time Frame: 1 month ]
    Percent change in corticosterone level between the first visit and the second visit was summarized by whether patients initiated prednisone for hypertension and hypokalemia.

  4. Changes in Serum Concentrations of ACTH Between Cycle 1 and Cycle 2. [ Time Frame: 1 month ]
    Changes in serum concentrations of ACTH at second assessment referent to the value at the first visit were summarized descriptively.

  5. Percent Changes in Serum Concentrations of Androgen (Including Testosterone, DHT and Androgen Precursors) Between Cycle 1 and Cycle 2. [ Time Frame: 1 month ]
    Change in corticosterone level between cycle 2 and cycle 1 was summarized by whether patients initiated prednisone for hypertension and hypokalemia.

  6. Changes in BMI Between Cycle 1 and Next Cycle [ Time Frame: 1 month ]
    Changes in BMI between cycle 1 and cycle 2 were summarized descriptively.

  7. Changes in Hemoglobin-A1c Between Cycle 1 and Next Cycle (Cycle 4) [ Time Frame: 3 months ]
    Changes in HbA1c at cycle 1 and next measurement at cycle 4 were summarized descriptively.

  8. PSA Response and Its Duration to AA Monotherapy. [ Time Frame: PSA was measured every cycle (up to 25 months) ]
    PSA response was defined per PCWG2 criteria (PSA reduction of ≥50%) and duration of PSA response is defined as time from PSA response to PSA progression or death, whichever occurs first.

  9. PSA Response and Its Duration to Addition of Prednisone to AA at Time of PSA Progression on AA Monotherapy. [ Time Frame: PSA was measured every cycle (up to 25 months) ]
    Among those who initiated prednisone due to PSA progression, duration of PSA response was calculated as time from PSA response (PSA reduction ≥50%) to PSA progression or death, whichever occurs first.

  10. Response of Measurable Disease to AA Monotherapy. [ Time Frame: Imaging was performed every 12 weeks up to 23 months. ]

    Radiographic response of measurable disease is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease.

    Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm.

    Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

    Response is tabulated descriptively.


  11. Number of Patients Who Received AA Monotherapy and Progressed With Measurable Disease at Pre-study [ Time Frame: Imaging was performed every 12 weeks up to 23 months. ]
    Radiographic disease progression is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease (2 or more new lesions on bone scan and for the first 12-week assessment, defining disease progression requires a confirmatory scan performed 6 or more weeks later which shows a minimum of 2 additional new lesions).

  12. Response of Measurable Disease to Addition of Prednisone to AA at Time of PSA Progression on AA Monotherapy. [ Time Frame: Imaging was performed every 12 weeks up to 23 months. ]

    Radiographic response of measurable disease is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease.

    Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes must have reduction in short axis to <10 mm.

    Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

    Response is tabulated descriptively.


  13. Number of Patients Who Progressed With Measurable Disease at Pre-study Among Those Who Were Added of Prednisone to AA at Time of PSA Progression on AA Monotherapy. [ Time Frame: Imaging was performed every 12 weeks up to 23 months. ]
    Radiographic response of measurable disease is defined using RECIST v 1.1 for soft-tissue and visceral disease and PCWG2 for bone disease. Due to small number patients, patients who experienced progressive disease were summarized using frequency and time to progression using Kaplan-Meier method was not calculated.

  14. Subsequent Lines of Therapy [ Time Frame: Data not collected. ]
    Subsequent lines of therapy following study drug discontinuation were not collected for this trial.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • Participants must meet the following criteria on screening examination to be eligible to participate in the study:
  • Be a male ≥ 18 years of age.
  • Participants must have histologically or cytologically confirmed adenocarcinoma of the prostate without >50% neuroendocrine differentiation or small cell histology.
  • Participants must have progressive disease as defined by one or more of the following:
  • Castrate resistant disease as defined by Prostate cancer working Group (PCWG).[30] Participants must have a rise in PSA on two successive determinations at least one week apart and PSA levels ≥ 2 ng/ml (only the screening PSA needs to be ≥ 2 ng/ml) and testosterone levels < 50 ng/dL.
  • Soft tissue progression defined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1.
  • Bone disease progression defined by Prostate Cancer Clinical Trials Working Group 2 (PCWG2) with two or more new lesions on bone scan.[30]
  • Castration-resistant prostate cancer (CRPC) with metastatic disease with at least one site of metastatic disease must be amenable to needle biopsy. Soft tissue biopsy sites include: lymph node or visceral metastases. Bone sites include lumbar vertebrae, pelvic bones and long bones. Excluded sites are thoracic, cervical vertebrae, skull and rib lesions. Biopsy site will be selected with guidance of interventional radiologist determining best site to optimize balance of obtaining useful tissue for analysis and minimizing risk.
  • Participants without orchiectomy must be maintained on Luteinizing hormone-releasing hormone (LHRH) agonist/antagonist therapy.
  • Participants may have had any number of previous hormonal therapies (antiandrogens including enzalutamide, steroids, estrogens, finasteride, dutasteride, ketoconazole) provided these were discontinued ≥ 4 weeks before starting the trial.
  • Participants may have had up to two previous cytotoxic therapeutic regimens provided these were discontinued ≥ 4 weeks before starting the trial.
  • At least a 4 week interval from previous prostate cancer treatment other than LHRH agonist/antagonist therapy or bisphosphonates to the start of protocol therapy.
  • Participants receiving bisphosphonates therapy can be maintained on this therapy. If participants have not started bisphosphonates, it is recommended that they start treatment after the first biopsy.
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky >60%, see Appendix A).

Participants must have normal organ and marrow function as defined below:

  • Platelets > 50,000/microliter (mcL)
  • Serum potassium ≥ 3.5 mmol/L (independent of potassium supplementation)
  • Serum albumin ≥ 3.0 g/dL
  • Aspartate transaminase (AST), Alanine transaminase (ALT), and total bilirubin ≤ 1.5 x Institutional Upper Limit of Normal (ULN).
  • Partial thromboplastin time (PTT) ≤ 60, International Normalized Ratio (INR) ≤ 1.5 Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy)
  • Controlled blood pressure (systolic blood pressure < 140 and diastolic blood pressure <90) on no more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation.
  • EKG showing a normal QTc interval (QTc < 450 msec).
  • Left ventricular ejection fraction ≥ 50%.
  • Have signed an informed consent document indicating that the subjects understands the purpose of and procedures required for the study and are willing to participate in the study.
  • Be willing/able to adhere to the prohibitions and restrictions specified in this protocol.
  • Written Authorization for Use and Release of Health and Research Study Information (US sites only) has been obtained.
  • Able to swallow the study drug whole as a tablet.
  • Willing to take AA on an empty stomach; no food should be consumed at least two hours before and for at least one hour after the dose AA is taken.
  • Participants who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the PI during the treatment period and for 1 week after last dose of AA.

Exclusion Criteria:

  • Participants who exhibit any of the following conditions at screening will not be eligible for admission into the study.
  • Uncontrolled illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or would make prednisone/prednisolone (corticosteroid) use contraindicated.
  • Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class III or IV heart disease or cardiac ejection fraction measurement of < 50 % at baseline.
  • Thromboembolism within 6 months of Cycle 1, Day 1.
  • Severe hepatic impairment (Child-Pugh Class C).
  • History of pituitary or adrenal dysfunction.
  • Poorly controlled diabetes.
  • History of gastrointestinal disorders (medical disorders or extensive surgery) which may interfere with the absorption of the study drug.
  • Have a pre-existing condition that warrants long-term corticosteroid use.
  • Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: superficial bladder cancer, basal cell or squamous cell carcinoma of the skin.
  • Known brain metastasis.
  • Prior therapy with AA.
  • Have known allergies, hypersensitivity, or intolerance to AA or prednisone or their excipients.
  • Surgery or local prostatic intervention within 30 days of the first dose. In addition, any clinically relevant issues from the surgery must have resolved prior to Cycle 1, Day 1.
  • Major surgery or radiation therapy within 4 weeks of Cycle 1, Day 1.
  • Strontium-89 or samarium-153 therapy within 4 weeks of Cycle 1, Day 1.
  • Radiotherapy, chemotherapy or immunotherapy within 4 weeks, or single fraction of palliative radiotherapy within 14 days of administration of Cycle 1, Day 1.
  • Current enrollment in an investigational drug or device study or participation in such a study within 30 days of Cycle 1, Day 1.
  • Any acute toxicities due to prior chemotherapy and/or radiotherapy that have not resolved to a NCI Common Toxicity Criteria for Adverse Effects (CTCAE) version 4 grade of ≤ 1. Chemotherapy induced alopecia and grade 2 peripheral neuropathy are allowed.
  • Condition or situation which, in the investigator's opinion, may put the participant at significant risk, may confound the study results, or may interfere significantly with participant's participation in the study.
  • Individuals not willing to comply with the procedural requirements of this protocol.
  • HIV-positive individuals on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AA.

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): NCT02025010


Locations
Layout table for location information
United States, Massachusetts
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
United States, New Jersey
Memorial Sloan Kettering Cancer Center Basking Ridge
Basking Ridge, New Jersey, United States, 07920
United States, New York
Memorial Sloan Kettering Cancer Center Commack
Commack, New York, United States, 11725
Memorial Sloan Kettering Cancer Center West Harrison
Harrison, New York, United States, 10604
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
Memorial Sloan Kettering Cancer Center Rockville Centre
Rockville Centre, New York, United States, 11510
Memorial Sloan Kettering Cancer Center Sleepy Hollow
Sleepy Hollow, New York, United States, 10591
Sponsors and Collaborators
Dana-Farber Cancer Institute
Janssen Research & Development, LLC
Investigators
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Principal Investigator: Mary-Ellen Taplin, MD Dana-Farber Cancer Institute
  Study Documents (Full-Text)

Documents provided by Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Mary-Ellen Taplin, MD, Principal Investigators, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier: NCT02025010    
Other Study ID Numbers: 13-449
First Posted: December 31, 2013    Key Record Dates
Results First Posted: November 8, 2022
Last Update Posted: November 8, 2022
Last Verified: October 2022
Keywords provided by Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute:
Castration-resistant Prostate Cancer
Abiraterone Acetate
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Abiraterone Acetate
Antineoplastic Agents
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Cytochrome P-450 Enzyme Inhibitors