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Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 (Apalutamide) in Castration-Resistant Prostate Cancer (CRPC)

Primary Purpose

Prostate Cancer

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
ARN-509 (Phase 1)
ARN-509 (Phase 2)
Sponsored by
Aragon Pharmaceuticals, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostate Cancer focused on measuring Non-Metastatic, Rising PSA, Castration-Resistant, Treatment-Naive, Post-abiraterone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

NON-METASTATIC CRPC

Inclusion Criteria

  1. Histologically or cytologically proven prostate cancer with high risk for development of metastases, defined as either a PSA value >=8 ng/mL within the last 3 months or PSA Doubling Time <=10 months
  2. Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration)
  3. Castrate levels of serum testosterone of less than or equal to 50 ng/dL
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  5. A life expectancy of at least 3 months

Exclusion Criteria

  1. Distant metastases, including CNS and vertebral or meningeal involvement
  2. Prior treatment with MDV3100
  3. Prior treatment with abiraterone
  4. Prior treatment with ketoconazole
  5. Concurrent treatment with medications known to have seizure potential
  6. Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible.
  7. QTc > 450 msec
  8. History of seizure or condition that may predispose to seizure
  9. Evidence of severe or uncontrolled systemic disease or HIV infection

METASTATIC CRPC, TREATMENT-NAIVE

Inclusion Criteria

  1. Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression
  2. Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration)
  3. Castrate levels of serum testosterone of less than or equal to 50 ng/dL
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  5. A life expectancy of at least 3 months

Exclusion Criteria

  1. History of, or current metastases in the brain or untreated spinal cord compression
  2. Prior treatment with MDV3100
  3. Prior treatment with abiraterone
  4. Prior treatment with ketoconazole
  5. Concurrent treatment with medications known to have seizure potential
  6. Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible.
  7. QTc > 450 msec
  8. History of seizure or condition that may predispose to seizure
  9. Evidence of severe or uncontrolled systemic disease or HIV infection

METASTATIC CRPC, CHEMOTHERAPY-NAIVE, POST-ABIRATERONE

Inclusion Criteria

  1. Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression
  2. Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration)
  3. Castrate levels of serum testosterone of less than or equal to 50 ng/dL
  4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  5. A life expectancy of at least 3 months
  6. Patients must have received a minimum of 6 months of abiraterone treatment prior to disease progression

Exclusion Criteria

  1. History of, or current metastases in the brain or untreated spinal cord compression
  2. Prior treatment with MDV3100
  3. Prior treatment with ketoconazole
  4. Concurrent treatment with medications known to have seizure potential
  5. Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible.
  6. QTc > 450 msec
  7. History of seizure or condition that may predispose to seizure
  8. Evidence of severe or uncontrolled systemic disease or HIV infection

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Escalation Cohort (Phase 1)

Non-metastatic CRPC (Phase 2)

Treatment-naive metastatic CRPC (Phase 2)

Post-abiraterone metastatic CRPC (Phase 2)

Arm Description

ARN-509 will be administered at a starting dose of 30 milligram per day (mg/day), with escalations to 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 390 mg, and 480 mg daily. Once Recommended Phase 2 Dose (RP2D) has been selected, Phase 1 participants being treated at the lower dose levels will be allowed to escalate to the RP2D level at the discretion of the primary investigator.

Participants with non-metastatic, treatment-naive Castration-Resistant Prostate Cancer (CRPC) with rapidly rising Prostate Specific Antigen (PSA) will be enrolled. ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.

Participants with treatment-naive metastatic CRPC will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1.

Participants with metastatic CRPC that are chemotherapy-naive, but have been previously treated with abiraterone will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1.

Outcomes

Primary Outcome Measures

Phase 1 and 2: Percentage of Participants With Greater Than or Equal to (>=) 50 Percent (%) Reduction in Prostate-Specific Antigen (PSA) at Week 12
Percentage of participants with >=50% decrease in PSA compared to baseline were assessed at Week 12. PSA progression was defined by the protocol-specific Prostate Cancer Working Group 2 (PCWG2) criteria: PSA increase greater than or equal to [>=] 25 percent [%] and >=2 nanogram per milliliter [ng/mL] above the nadir confirmed >=3 weeks later; or >=25% and >=2 ng/mL above baseline PSA after 12 weeks.

Secondary Outcome Measures

Phase 1 and 2: Median Time to PSA Progression
Time to PSA progression was measured as the time interval from the date of the first dose to the date of PSA progression as defined by the PCWG2 criteria. PCWG2 criteria: For participants who achieved >=50% decrease from the baseline PSA, assessment of time to disease progression was when the PSA increased 25% and at a minimum of 2 ng/mL above the nadir at 3 or more weeks later. For participants without a PSA decrease, the time for progression was calculated at the time when the PSA progression was >=25% and >=2 ng/mL after 12 weeks.
Phase 2: Median Metastasis-Free Survival (MFS)
MFS was defined as the time from the start of treatment until new metastatic lesions were observed on Computed Tomography/ Magnetic Resonance Imaging (CT/MRI) scans or radionuclide bone scans (according to PCWG2 criteria: appearance of >=2 new lesions, and, for the first reassessment only, a confirmatory scan performed 6 or more weeks later that showed at least 2 or more additional new lesions) or death, whichever occurred first.
Phase 1 and 2: Progression-free Survival (PFS)
PFS was defined as the time from randomization to the radiographic disease progression or death, whichever occurred first. Radiographic progression defined by at least one of the following: a) Soft tissue progression by modified RECIST confirmed on repeat imaging >= 6 weeks later; b) Progression by bone scans: 1) first bone scan with >= 2 new lesions compared to baseline observed <12 weeks from start date and confirmed on a second bone scan >=6 weeks later that showed >=2 additional lesions (a total of >=4 new lesions compared to baseline); or 2) first bone scan with >=2 new lesions compared to baseline observed >=12 weeks from start date and the new lesions verified on the next bone scan >=6 weeks later (a total of >=2 new lesions compared to baseline).
Phase 1 and 2: Objective Response Rate
Objective Response Rate was defined as the percentage of participants with best overall response (OR) of confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). Where, CR defined as disappearance of all target lesions. Any pathological lymph nodes must had reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions. Confirmed responses were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response.

Full Information

First Posted
July 27, 2010
Last Updated
October 10, 2023
Sponsor
Aragon Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT01171898
Brief Title
Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 (Apalutamide) in Castration-Resistant Prostate Cancer (CRPC)
Official Title
An Open-Label, Phase 1/2, Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 in Patients With Progressive Advanced Castration-Resistant Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
July 26, 2010 (Actual)
Primary Completion Date
August 20, 2012 (Actual)
Study Completion Date
December 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Aragon Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to assess the safety and activity of ARN-509 in men with advanced castration resistant prostate cancer. Patients will first be enrolled into Phase 1 of the study to identify a tolerable dose for the Phase 2 portion of the study. In the Phase 2, 3 different cohorts of patients will be enrolled to evaluate the safety and activity of ARN-509.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostate Cancer
Keywords
Non-Metastatic, Rising PSA, Castration-Resistant, Treatment-Naive, Post-abiraterone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
127 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Escalation Cohort (Phase 1)
Arm Type
Experimental
Arm Description
ARN-509 will be administered at a starting dose of 30 milligram per day (mg/day), with escalations to 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 390 mg, and 480 mg daily. Once Recommended Phase 2 Dose (RP2D) has been selected, Phase 1 participants being treated at the lower dose levels will be allowed to escalate to the RP2D level at the discretion of the primary investigator.
Arm Title
Non-metastatic CRPC (Phase 2)
Arm Type
Experimental
Arm Description
Participants with non-metastatic, treatment-naive Castration-Resistant Prostate Cancer (CRPC) with rapidly rising Prostate Specific Antigen (PSA) will be enrolled. ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.
Arm Title
Treatment-naive metastatic CRPC (Phase 2)
Arm Type
Experimental
Arm Description
Participants with treatment-naive metastatic CRPC will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1.
Arm Title
Post-abiraterone metastatic CRPC (Phase 2)
Arm Type
Experimental
Arm Description
Participants with metastatic CRPC that are chemotherapy-naive, but have been previously treated with abiraterone will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1.
Intervention Type
Drug
Intervention Name(s)
ARN-509 (Phase 1)
Intervention Description
ARN-509 will be administered at a starting dose of 30 milligram per day (mg/day), with escalations to 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 390 mg, and 480 mg daily.
Intervention Type
Drug
Intervention Name(s)
ARN-509 (Phase 2)
Intervention Description
ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.
Primary Outcome Measure Information:
Title
Phase 1 and 2: Percentage of Participants With Greater Than or Equal to (>=) 50 Percent (%) Reduction in Prostate-Specific Antigen (PSA) at Week 12
Description
Percentage of participants with >=50% decrease in PSA compared to baseline were assessed at Week 12. PSA progression was defined by the protocol-specific Prostate Cancer Working Group 2 (PCWG2) criteria: PSA increase greater than or equal to [>=] 25 percent [%] and >=2 nanogram per milliliter [ng/mL] above the nadir confirmed >=3 weeks later; or >=25% and >=2 ng/mL above baseline PSA after 12 weeks.
Time Frame
Week 12
Secondary Outcome Measure Information:
Title
Phase 1 and 2: Median Time to PSA Progression
Description
Time to PSA progression was measured as the time interval from the date of the first dose to the date of PSA progression as defined by the PCWG2 criteria. PCWG2 criteria: For participants who achieved >=50% decrease from the baseline PSA, assessment of time to disease progression was when the PSA increased 25% and at a minimum of 2 ng/mL above the nadir at 3 or more weeks later. For participants without a PSA decrease, the time for progression was calculated at the time when the PSA progression was >=25% and >=2 ng/mL after 12 weeks.
Time Frame
Up to approximately 7 years
Title
Phase 2: Median Metastasis-Free Survival (MFS)
Description
MFS was defined as the time from the start of treatment until new metastatic lesions were observed on Computed Tomography/ Magnetic Resonance Imaging (CT/MRI) scans or radionuclide bone scans (according to PCWG2 criteria: appearance of >=2 new lesions, and, for the first reassessment only, a confirmatory scan performed 6 or more weeks later that showed at least 2 or more additional new lesions) or death, whichever occurred first.
Time Frame
Up to approximately 7 years
Title
Phase 1 and 2: Progression-free Survival (PFS)
Description
PFS was defined as the time from randomization to the radiographic disease progression or death, whichever occurred first. Radiographic progression defined by at least one of the following: a) Soft tissue progression by modified RECIST confirmed on repeat imaging >= 6 weeks later; b) Progression by bone scans: 1) first bone scan with >= 2 new lesions compared to baseline observed <12 weeks from start date and confirmed on a second bone scan >=6 weeks later that showed >=2 additional lesions (a total of >=4 new lesions compared to baseline); or 2) first bone scan with >=2 new lesions compared to baseline observed >=12 weeks from start date and the new lesions verified on the next bone scan >=6 weeks later (a total of >=2 new lesions compared to baseline).
Time Frame
Up to approximately 7 years
Title
Phase 1 and 2: Objective Response Rate
Description
Objective Response Rate was defined as the percentage of participants with best overall response (OR) of confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors, Version 1.0 (RECIST). Where, CR defined as disappearance of all target lesions. Any pathological lymph nodes must had reduction in short axis to less than 10 millimeter (mm). PR defined as at least 30 percent (%) decrease in sum of the diameters of the target lesions. Confirmed responses were those that persisted on repeat imaging study for at least 4 weeks after initial documentation of response.
Time Frame
Up to approximately 7 years

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
NON-METASTATIC CRPC Inclusion Criteria Histologically or cytologically proven prostate cancer with high risk for development of metastases, defined as either a PSA value >=8 ng/mL within the last 3 months or PSA Doubling Time <=10 months Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration) Castrate levels of serum testosterone of less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 A life expectancy of at least 3 months Exclusion Criteria Distant metastases, including CNS and vertebral or meningeal involvement Prior treatment with MDV3100 Prior treatment with abiraterone Prior treatment with ketoconazole Concurrent treatment with medications known to have seizure potential Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible. QTc > 450 msec History of seizure or condition that may predispose to seizure Evidence of severe or uncontrolled systemic disease or HIV infection METASTATIC CRPC, TREATMENT-NAIVE Inclusion Criteria Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration) Castrate levels of serum testosterone of less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 A life expectancy of at least 3 months Exclusion Criteria History of, or current metastases in the brain or untreated spinal cord compression Prior treatment with MDV3100 Prior treatment with abiraterone Prior treatment with ketoconazole Concurrent treatment with medications known to have seizure potential Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible. QTc > 450 msec History of seizure or condition that may predispose to seizure Evidence of severe or uncontrolled systemic disease or HIV infection METASTATIC CRPC, CHEMOTHERAPY-NAIVE, POST-ABIRATERONE Inclusion Criteria Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration) Castrate levels of serum testosterone of less than or equal to 50 ng/dL Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 A life expectancy of at least 3 months Patients must have received a minimum of 6 months of abiraterone treatment prior to disease progression Exclusion Criteria History of, or current metastases in the brain or untreated spinal cord compression Prior treatment with MDV3100 Prior treatment with ketoconazole Concurrent treatment with medications known to have seizure potential Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible. QTc > 450 msec History of seizure or condition that may predispose to seizure Evidence of severe or uncontrolled systemic disease or HIV infection
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aragon Pharmaceuticals, Inc Clinical Trial
Organizational Affiliation
Aragon Pharmaceuticals, Inc.
Official's Role
Study Director
Facility Information:
City
San Diego
State/Province
California
Country
United States
City
San Francisco
State/Province
California
Country
United States
City
Atlanta
State/Province
Georgia
Country
United States
City
Baltimore
State/Province
Maryland
Country
United States
City
Boston
State/Province
Massachusetts
Country
United States
City
Ann Arbor
State/Province
Michigan
Country
United States
City
Omaha
State/Province
Nebraska
Country
United States
City
New York
State/Province
New York
Country
United States
City
Raleigh
State/Province
North Carolina
Country
United States
City
Portland
State/Province
Oregon
Country
United States
City
Lancaster
State/Province
Pennsylvania
Country
United States
City
Myrtle Beach
State/Province
South Carolina
Country
United States
City
Dallas
State/Province
Texas
Country
United States
City
Seattle
State/Province
Washington
Country
United States
City
Madison
State/Province
Wisconsin
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
28633425
Citation
Rathkopf DE, Smith MR, Ryan CJ, Berry WR, Shore ND, Liu G, Higano CS, Alumkal JJ, Hauke R, Tutrone RF, Saleh M, Chow Maneval E, Thomas S, Ricci DS, Yu MK, de Boer CJ, Trinh A, Kheoh T, Bandekar R, Scher HI, Antonarakis ES. Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide. Ann Oncol. 2017 Sep 1;28(9):2264-2271. doi: 10.1093/annonc/mdx283.
Results Reference
derived
PubMed Identifier
27160947
Citation
Smith MR, Antonarakis ES, Ryan CJ, Berry WR, Shore ND, Liu G, Alumkal JJ, Higano CS, Chow Maneval E, Bandekar R, de Boer CJ, Yu MK, Rathkopf DE. Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort. Eur Urol. 2016 Dec;70(6):963-970. doi: 10.1016/j.eururo.2016.04.023. Epub 2016 May 6.
Results Reference
derived

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Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 (Apalutamide) in Castration-Resistant Prostate Cancer (CRPC)

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