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

NCT ID: NCT01977651

Last Updated: 2024-12-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 424 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-09-25
• Study Completion Date: 2019-01-11

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).

Conditions

Metastatic Castration-resistant Prostate Cancer (mCRPC)

Keywords

enzalutamide; Xtandi; seizure; Central Nervous System; MDV3100; metastatic castration-resistant prostate cancer (mCRPC)

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Enzalutamide

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

Xtandi; MDV3100

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.

• Eligible Sex: MALE
• Accepts Healthy Volunteers: No

Sponsors

Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

INDUSTRY

Sponsor Role: collaborator

Astellas Pharma Global Development, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sr. Medical Director

Role: STUDY_DIRECTOR

Astellas Pharma Global Development, Inc.

Locations

Site US10005

Anchorage, Alaska, United States

Site US10024

Detroit, Michigan, United States

Site US10001

New York, New York, United States

Site US10014

New York, New York, United States

Site US10039

Syracuse, New York, United States

Site US10026

The Bronx, New York, United States

Site US10016

Durham, North Carolina, United States

Site US10008

Dallas, Texas, United States

Site US10025

Seattle, Washington, United States

Site AR54001

Berazategui, Buenos Aires, Argentina

Site AR54006

Ciudad Autonoma de BuenosAires, Buenos Aires, Argentina

Site AR54002

Buenos Aires, Buenos Aires F.D., Argentina

Site AR54003

Córdoba, , Argentina

Site AR54005

San Miguel de Tucumán, , Argentina

Site AR54004

Santa Fe, , Argentina

Site AU61012

Kogarah, New South Wales, Australia

Site AU61005

Randwick, New South Wales, Australia

Site AU61011

Sydney, New South Wales, Australia

Site AU61001

Tweed Heads, New South Wales, Australia

Site AU61002

Nambour, Queensland, Australia

Site AU61007

Adelaide, South Australia, Australia

Site AU61004

Ballarat, Victoria, Australia

Site BE32004

Anderlecht, , Belgium

Site BE32001

Kortrijk, , Belgium

Site BE32003

Liège, , Belgium

Site CA15005

Abbotsford, British Columbia, Canada

Site CA15014

Halifax, Nova Scotia, Canada

Site CA15004

Brampton, Ontario, Canada

Site CA15010

Scarborough Village, Ontario, Canada

Site CA15001

Québec, Quebec, Canada

Site CL56001

Temuco, Región de la Araucanía, Chile

Site CL56004

Santiago, , Chile

Site CL56002

Temuco, , Chile

Site CL56003

Viña del Mar, , Chile

Site CZ42004

Prague, , Czechia

Site CZ42002

Prague, , Czechia

Site FI35803

Helsinki, , Finland

Site FI35801

Oulu, , Finland

Site FI35802

Tampere, , Finland

Site FR33002

Lyon, , France

Site FR33004

Rouen, , France

Site FR33005

Suresnes, , France

Site DE49009

Nürtingen, Baden-Wurttemberg, Germany

Site DE49003

Berlin, , Germany

Site DE49001

Münster, , Germany

Site HU36002

Sopron, Győr-Moson-Sopron, Hungary

Site IL97202

Kfar Saba, Central District, Israel

Site IL97203

Beersheba, , Israel

Site IL97201

Be’er Ya‘aqov, , Israel

Site IL97205

Haifa, , Israel

Site IL97204

Jerusalem, , Israel

Site IL97208

Nahariya, , Israel

Site IL97206

Petah Tikva, , Israel

Site IL97207

Ramat Gan, , Israel

Site IT39005

Meldola, Emilia-Romagna, Italy

Site IT39001

Cremona, Lombardy, Italy

Site IT39002

Arezzo, , Italy

Site IT39003

Roma, , Italy

Site NZ64001

Hamilton, , New Zealand

Site SG65002

Singapore, , Singapore

Site KR82006

Seongnam-si, Gyeonggi-do, South Korea

Site KR82007

Seoul, , South Korea

Site KR82003

Seoul, , South Korea

Site KR82001

Seoul, , South Korea

Site KR82004

Seoul, , South Korea

Site ES34007

L'Hospitalet de Llobregat, Barcelona, Spain

Site ES34005

Sabadell, Barcelona, Spain

Site ES34001

Pamplona, Navarre, Spain

Site ES34003

Barcelona, , Spain

Site ES34004

Barcelona, , Spain

Site ES34006

Madrid, , Spain

Site SE46001

Gothenburg, , Sweden

Site SE46002

Örebro, , Sweden

Site TW88601

Kaohsiung City, , Taiwan

Site TW88603

Taipei, , Taiwan

Site GB44002

Sutton, Surrey, United Kingdom

Countries

Greece; Hong Kong; United States; Argentina; Australia; Belgium; Canada; Chile; Czechia; Finland; France; Germany; Hungary; Israel; Italy; New Zealand; Singapore; South Korea; Spain; Sweden; Taiwan; United Kingdom

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://astellasclinicalstudyresults.com/study.aspx?ID=349

Link to results on the Astellas Clinical Study Results website.

Other Identifiers

2013-003022-92

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1157-0224

Identifier Type: REGISTRY

Identifier Source: secondary_id

9785-CL-0403

Identifier Type: -

Identifier Source: org_study_id