A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide (UPWARD)

A Multicenter, Single-arm, Open-label, Postmarketing Safety Study to Evaluate the Risk of Seizure Among Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide Who Are at Potential Increased Risk of Seizure

The objective of this study was to evaluate the incidence of seizures and monitor the safety of enzalutamide treatment in participants with metastatic castration-resistant prostate cancer (mCRPC) known to have risk factor(s) for seizure.

Study Overview

• Status: Completed
• Conditions: Metastatic Castration-resistant Prostate Cancer (mCRPC)
• Intervention / Treatment: Drug: Enzalutamide

Detailed Description

This was a multicenter, single-arm, open-label, postmarketing safety study to evaluate the risk of seizure among patients with mCRPC treated with enzalutamide who were at potential increased risk of seizure.

Participants who met all inclusion and none of the exclusion criteria were enrolled into the study and participated in a 4-month treatment period, during which once daily dosing of enzalutamide (160 mg/day) occurred. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment were allowed to continue in the extension period where participants continued to receive enzalutamide until 1 of the following criteria was met:

1. The participant experienced bone disease progression per Prostate Cancer Working Group 2 (PCWG2) guidelines or soft tissue disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
2. The participant initiated treatment with another anticancer therapy or, in the opinion of the investigator, continued dosing would have led to undue risk to the patient
3. The participant met a discontinuation criterion
4. The sponsor terminated the study

Participants who continued to receive clinical benefit from treatment with enzalutamide and did not meet any discontinuation criteria may have transitioned to an open label roll-over extension study upon approval of the study protocol at the institution where they were receiving treatment.

Participants who did not continue in the extension period or who met a discontinuation criterion were discontinued from enzalutamide therapy and completed a follow-up visit 30 days from the last dose of enzalutamide or prior to the initiation of another anticancer therapy, whichever occurred first.

For participants who continued on treatment after the 12-month extension period, data collection was limited to dosing information, concomitant medications, and all adverse events (AEs) including serious adverse events (SAEs).

• Study Type: Interventional
• Enrollment (Actual): 424
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, 5000
    • Site AR54003
  • Santa Fe, Argentina, S3000FFU
    • Site AR54004
  • Tucuman, Argentina, 4000
    • Site AR54005
  • Buenos Aires
    • Berazategui, Buenos Aires, Argentina, B1880BBF
      • Site AR54001
    • Ciudad Autonoma de BuenosAires, Buenos Aires, Argentina, C1426ANZ
      • Site AR54006
  • Caba
    • Buenos Aires, Caba, Argentina, C1120AAT
      • Site AR54002
• Australia
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • Site AU61012
    • Randwick, New South Wales, Australia, 2031
      • Site AU61005
    • Sydney, New South Wales, Australia, 2109
      • Site AU61011
    • Tweed Heads, New South Wales, Australia, 2485
      • Site AU61001
  • Queensland
    • Nambour, Queensland, Australia, 4560
      • Site AU61002
  • South Australia
    • Adelaide, South Australia, Australia, 5042
      • Site AU61007
  • Victoria
    • Ballarat, Victoria, Australia, 3350
      • Site AU61004
• Belgium
  • Anderlecht, Belgium, 1070
    • Site BE32004
  • Kortrijk, Belgium, 8500
    • Site BE32001
  • Liege, Belgium, B-4000
    • Site BE32003
• Canada
  • British Columbia
    • Abbotsford, British Columbia, Canada, V2S 3N5
      • Site CA15005
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Site CA15014
  • Ontario
    • Brampton, Ontario, Canada, L6T 4S5
      • Site CA15004
    • Scarborough, Ontario, Canada, M1S 4V5
      • Site CA15010
  • Quebec
    • Quebec City, Quebec, Canada, G1R3S1
      • Site CA15001
• Chile
  • Santiago, Chile, 8420383
    • Site CL56004
  • Temuco, Chile, 4781156
    • Site CL56002
  • Vina del Mar, Chile, 2540364
    • Site CL56003
  • IX Region
    • Temuco, IX Region, Chile, 4810469
      • Site CL56001
• Czechia
  • Praha 2, Czechia, 12000
    • Site CZ42004
  • Praha 6, Czechia, 16000
    • Site CZ42002
• Finland
  • Helsinki, Finland, 00290
    • Site FI35803
  • Oulu, Finland, 90220
    • Site FI35801
  • Tampere, Finland, 33520
    • Site FI35802
• France
  • Lyon Cedex 03, France, 69437
    • Site FR33002
  • Rouen Cedex, France, 76031
    • Site FR33004
  • Suresnes, France, 92151
    • Site FR33005
• Germany
  • Berlin, Germany, 12200
    • Site DE49003
  • Munster, Germany, 48149
    • Site DE49001
  • Baden-Württemberg
    • Nürtingen, Baden-Württemberg, Germany, 72622
      • Site DE49009
• Hungary
  • Gyor-Moson Sopron
    • Sopron, Gyor-Moson Sopron, Hungary, 9400
      • Site HU36002
• Israel
  • Be'er Ya'akov, Israel, 70300
    • Site IL97201
  • Beer-Sheva, Israel, 84101
    • Site IL97203
  • Haifa, Israel, 31096
    • Site IL97205
  • Jerusalem, Israel, 91120
    • Site IL97204
  • Nahariya, Israel, 21000
    • Site IL97208
  • Petah-Tiqva, Israel, 49100
    • Site IL97206
  • Ramat Gan, Israel, 52621
    • Site IL97207
  • HaMerkaz
    • Kfar Saba, HaMerkaz, Israel, 44281
      • Site IL97202
• Italy
  • Arezzo, Italy, 52100
    • Site IT39002
  • Roma, Italy, 00144
    • Site IT39003
  • Emilia-Romagna
    • Meldola, Emilia-Romagna, Italy, 47014
      • Site IT39005
  • Lombardia
    • Cremona, Lombardia, Italy, 26100
      • Site IT39001
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Site KR82007
  • Seoul, Korea, Republic of, 135-710
    • Site KR82003
  • Seoul, Korea, Republic of, 135-720
    • Site KR82001
  • Seoul, Korea, Republic of, 137-701
    • Site KR82004
  • Gyeonggi-do
    • Seongnam-Si, Gyeonggi-do, Korea, Republic of, 013620
      • Site KR82006
• New Zealand
  • Hamilton, New Zealand, 3204
    • Site NZ64001
• Singapore
  • Singapore, Singapore, 119228
    • Site SG65002
• Spain
  • Barcelona, Spain, 08035
    • Site ES34004
  • Barcelona, Spain, 08025
    • Site ES34003
  • Madrid, Spain, 28050
    • Site ES34006
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Site ES34007
    • Sabadell, Barcelona, Spain, 08208
      • Site ES34005
  • Navarra
    • Pamplona, Navarra, Spain, 31008
      • Site ES34001
• Sweden
  • Goteborg, Sweden, 41345
    • Site SE46001
  • Orebro, Sweden, 701 85
    • Site SE46002
• Taiwan
  • Kaohsiung, Taiwan, 81362
    • Site TW88601
  • Taipei City, Taiwan, 10048
    • Site TW88603
• United Kingdom
  • Surrey
    • Sutton, Surrey, United Kingdom, SM2 5PT
      • Site GB44002
• United States
  • Alaska
    • Anchorage, Alaska, United States, 99503
      • Site US10005
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Site US10024
  • New York
    • Bronx, New York, United States, 10461
      • Site US10026
    • New York, New York, United States, 10065
      • Site US10001
    • New York, New York, United States, 10065
      • Site US10014
    • Syracuse, New York, United States, 13210
      • Site US10039
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Site US10016
  • Texas
    • Dallas, Texas, United States, 75231
      • Site US10008
  • Washington
    • Seattle, Washington, United States, 98109
      • Site US10025

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject has histologically confirmed metastatic adenocarcinoma of the prostate.
• Subject has ongoing androgen deprivation therapy with a Gonadotropin-releasing hormone (GnRH) analogue (agonist or antagonist) or bilateral orchiectomy (i.e., surgical or medical castration).

• Subject has disease progression by at least one of the following:

  1. Prostate-Specific Antigen (PSA) progression defined by a minimum of 2 rising PSA levels with an interval of at least 1 week between each draw;
  2. Bone disease progression as defined by Prostate Cancer Working Group 2 guidelines (at least 2 new lesions) on bone scan; or
  3. Soft tissue disease progression as defined by RECIST 1.1
• For subjects who have not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue therapy for the duration of the study.
• Subject must have failed at least one course of androgen deprivation therapy (ADT), i.e., treatment with GnRH analogues.
• Subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.

• Subject has been evaluated by a local neurologist prior to study entry who has determined the subject has at least one risk factor for seizure including:

  1. past history of seizure due to any cause except a single febrile seizure in childhood. Patients with a history of seizures should not have had a seizure within 12 months of Screening and must have had no anticonvulsants for 12 months prior to Screening,
  2. history of cerebrovascular accident (CVA) or transient ischemic attack (TIA),
  3. history of traumatic brain or head injury with loss of consciousness
  4. unexplained loss of consciousness within the last 12 months,
  5. presence of a space occupying lesion in the brain including previously treated brain metastasis(es) or primary central nervous system (CNS) tumor,
  6. history of arteriovenous malformations of the brain,
  7. history of brain infection (i.e., abscess, meningitis, or encephalitis),
  8. current use of medication that may lower seizure threshold
  9. presence of Alzheimer's disease, meningioma, leptomeningeal disease from prostate cancer.
• Subject is able to swallow the study drug and comply with study requirements.
• Subject agrees not to participate in another interventional study while on treatment.

• Male subject and his female partner who is of childbearing potential must use two acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at Screening and continuing throughout the study period and for 3 months after final study drug administration.

  1. Two acceptable forms of birth control include:

  1. Condom (barrier method of contraception), AND

  2. One of the following acceptable forms of contraception is required:

     1. Established use of oral, injected or implanted hormonal methods of contraception.
     2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
     3. Barrier methods of contraception: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository).
     4. Vasectomy or surgical castration at least 6 months prior to Screening.
• Male subject must use a condom, if having sex with a pregnant woman.
• Male subject must not donate sperm starting at Screening and throughout the study period and for at least 3 months after final drug administration.

Exclusion Criteria:

• Subject with a history of exposure to enzalutamide.
• Subject has severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment.
• Subject is currently being treated with anti-epileptics.
• Subject has a history of seizure within the past 12 months of Screening as assessed by neurology examination and history.
• Subject with rapidly progressing visceral disease who has not received and is thought to be able to tolerate cytotoxic chemotherapy. (However, subject who has previously received cytotoxic chemotherapy is permitted).
• Subject has clinical signs suggestive of high or imminent risks for pathological fracture, spinal cord compression and/or cauda equina syndrome.
• Subject's absolute neutrophil count is < 1500/microliter (µL), platelet count is < 100,000/µL) or hemoglobin is < 5.6 millimoles(mmol)/liter (L) (9 grams (g)/deciliter (dL) at Screening.
• Subject's total bilirubin is ≥ 1.5 x upper limit of normal (ULN) (except for subjects with documented Gilbert's disease) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is ≥ 2.5x upper limit of normal (ULN) at Screening.
• Subject's estimated creatinine clearance (Cer) is less than 30 milliliter (mL)/minute (min) by the Cockcroft and Gault formula (Creatinine Clearance (mL/min) = (140 - age)(weight (wt) kilogram (kg) / 72 x serum creatinine (milligram (mg)/100 mL) [Cockcroft, 1976] at Screening.
• Subject has uncontrolled hypertension as indicated by a resting systolic blood pressure > 160 millimeter of mercury (mmHg) or diastolic blood pressure > 100 millimeter of mercury (mmHg) at Screening.
• Subject has received an investigational agent within 4 weeks or 5 half lives whichever is longer prior to Day 1.
• Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Enzalutamide 160 mg; Participants received 160 mg of enzalutamide orally once a day, for 4 months. At the end of the 4-month treatment period, participants who were assessed as deriving benefit from enzalutamide treatment continued in the extension period. The total study drug treatment duration for the extended period depended on individual clinical benefit. If a participant experienced a Grade 3 or higher toxicity that was attributed to enzalutamide and could not be ameliorated by the use of adequate medical intervention, treatment with enzalutamide was allowed to be interrupted for 1 week or until the toxicity grade improved to Grade 2 or lower severity. Subsequently, enzalutamide was restarted at the original dose 160 mg per day or a reduced dose 120 or 80 mg per day in consultation with the medical monitor.

Drug: Enzalutamide; Participants received 4 capsules (40 mg each) of enzalutamide orally once a day, for a total daily dose of 160 mg. Treatment was given with or without food and as close as possible to the same time each day.; Other Names: Xtandi; MDV3100

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC)	Percentage of evaluable participants with at least one confirmed seizure as adjudicated by the IAC during the first 4 months of treatment were reported.	Day 1 up to week 17 (end of 4-month treatment period)

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
• Investigators: Study Director: Sr. Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

Helpful Links

• Link to results on the Astellas Clinical Study Results website.

Study record dates

Study Major Dates

• Study Start (Actual): September 25, 2013
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): January 11, 2019

Study Registration Dates

• First Submitted: October 31, 2013
• First Submitted That Met QC Criteria: October 31, 2013
• First Posted (Estimated): November 7, 2013

Study Record Updates

• Last Update Posted (Actual): December 6, 2024
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Xtandi; MDV3100; enzalutamide; Central Nervous System; metastatic castration-resistant prostate cancer (mCRPC); seizure
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Neurologic Manifestations; Nervous System Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Prostatic Neoplasms; Seizures
• Other Study ID Numbers: 9785-CL-0403; 2013-003022-92 (EudraCT Number); U1111-1157-0224 (Registry Identifier: World Health Organization (WHO))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Clinical Study Report (CSR)