Clinical trial NCT01977651: A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With Enzalutamide
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Metastatic Castration-resistant Prostate Cancer (mCRPC)
Keywords: enzalutamide
Xtandi
seizure
Central Nervous System
MDV3100
metastatic castration-resistant prostate cancer (mCRPC)
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
Collaborators: name: Medivation LLC, a wholly owned subsidiary of Pfizer Inc.
First posted: 2013-11-07
Enrollment: 424
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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).

Eligibility criteria: 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.

Primary outcomes:
measure: The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC)
timeFrame: Day 1 up to week 17 (end of 4-month treatment period)
Secondary outcomes:
Other outcomes:
Locations:
city: Anchorage
country: United States
facility: Site US10005
state: Alaska
city: Detroit
country: United States
facility: Site US10024
state: Michigan
city: Bronx
country: United States
facility: Site US10026
state: New York
city: New York
country: United States
facility: Site US10001
state: New York
city: New York
country: United States
facility: Site US10014
state: New York
city: Syracuse
country: United States
facility: Site US10039
state: New York
city: Durham
country: United States
facility: Site US10016
state: North Carolina
city: Dallas
country: United States
facility: Site US10008
state: Texas
city: Seattle
country: United States
facility: Site US10025
state: Washington
city: Berazategui
country: Argentina
facility: Site AR54001
state: Buenos Aires
city: Ciudad Autonoma de BuenosAires
country: Argentina
facility: Site AR54006
state: Buenos Aires
city: Buenos Aires
country: Argentina
facility: Site AR54002
state: Caba
city: Cordoba
country: Argentina
facility: Site AR54003
city: Santa Fe
country: Argentina
facility: Site AR54004
city: Tucuman
country: Argentina
facility: Site AR54005
city: Kogarah
country: Australia
facility: Site AU61012
state: New South Wales
city: Randwick
country: Australia
facility: Site AU61005
state: New South Wales
city: Sydney
country: Australia
facility: Site AU61011
state: New South Wales
city: Tweed Heads
country: Australia
facility: Site AU61001
state: New South Wales
city: Nambour
country: Australia
facility: Site AU61002
state: Queensland
city: Adelaide
country: Australia
facility: Site AU61007
state: South Australia
city: Ballarat
country: Australia
facility: Site AU61004
state: Victoria
city: Anderlecht
country: Belgium
facility: Site BE32004
city: Kortrijk
country: Belgium
facility: Site BE32001
city: Liege
country: Belgium
facility: Site BE32003
city: Abbotsford
country: Canada
facility: Site CA15005
state: British Columbia
city: Halifax
country: Canada
facility: Site CA15014
state: Nova Scotia
city: Brampton
country: Canada
facility: Site CA15004
state: Ontario
city: Scarborough
country: Canada
facility: Site CA15010
state: Ontario
city: Quebec City
country: Canada
facility: Site CA15001
state: Quebec
city: Temuco
country: Chile
facility: Site CL56001
state: IX Region
city: Santiago
country: Chile
facility: Site CL56004
city: Temuco
country: Chile
facility: Site CL56002
city: Vina del Mar
country: Chile
facility: Site CL56003
city: Praha 2
country: Czechia
facility: Site CZ42004
city: Praha 6
country: Czechia
facility: Site CZ42002
city: Helsinki
country: Finland
facility: Site FI35803
city: Oulu
country: Finland
facility: Site FI35801
city: Tampere
country: Finland
facility: Site FI35802
city: Lyon Cedex 03
country: France
facility: Site FR33002
city: Rouen Cedex
country: France
facility: Site FR33004
city: Suresnes
country: France
facility: Site FR33005
city: Nürtingen
country: Germany
facility: Site DE49009
state: Baden-Württemberg
city: Berlin
country: Germany
facility: Site DE49003
city: Munster
country: Germany
facility: Site DE49001
city: Sopron
country: Hungary
facility: Site HU36002
state: Gyor-Moson Sopron
city: Kfar Saba
country: Israel
facility: Site IL97202
state: HaMerkaz
city: Be'er Ya'akov
country: Israel
facility: Site IL97201
city: Beer-Sheva
country: Israel
facility: Site IL97203
city: Haifa
country: Israel
facility: Site IL97205
city: Jerusalem
country: Israel
facility: Site IL97204
city: Nahariya
country: Israel
facility: Site IL97208
city: Petah-Tiqva
country: Israel
facility: Site IL97206
city: Ramat Gan
country: Israel
facility: Site IL97207
city: Meldola
country: Italy
facility: Site IT39005
state: Emilia-Romagna
city: Cremona
country: Italy
facility: Site IT39001
state: Lombardia
city: Arezzo
country: Italy
facility: Site IT39002
city: Roma
country: Italy
facility: Site IT39003
city: Seongnam-Si
country: Korea, Republic of
facility: Site KR82006
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Site KR82007
city: Seoul
country: Korea, Republic of
facility: Site KR82003
city: Seoul
country: Korea, Republic of
facility: Site KR82001
city: Seoul
country: Korea, Republic of
facility: Site KR82004
city: Hamilton
country: New Zealand
facility: Site NZ64001
city: Singapore
country: Singapore
facility: Site SG65002
city: Hospitalet de Llobregat
country: Spain
facility: Site ES34007
state: Barcelona
city: Sabadell
country: Spain
facility: Site ES34005
state: Barcelona
city: Pamplona
country: Spain
facility: Site ES34001
state: Navarra
city: Barcelona
country: Spain
facility: Site ES34003
city: Barcelona
country: Spain
facility: Site ES34004
city: Madrid
country: Spain
facility: Site ES34006
city: Goteborg
country: Sweden
facility: Site SE46001
city: Orebro
country: Sweden
facility: Site SE46002
city: Kaohsiung
country: Taiwan
facility: Site TW88601
city: Taipei City
country: Taiwan
facility: Site TW88603
city: Sutton
country: United Kingdom
facility: Site GB44002
state: Surrey
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Sr. Medical Director
role: STUDY_DIRECTOR
References: