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

Metastatic Castration-resistant Prostate Cancer (mCRPC) Clinical Trial

— UPWARD  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01977651
• Other study ID #: 9785-CL-0403
• Secondary ID: 2013-003022-92U1
• Status: Completed
• Phase: Phase 4
• Start date: September 25, 2013
• Est. completion date: January 11, 2019

Study information

• Verified date: October 2023
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 424
• Est. completion date: January 11, 2019
• Est. primary completion date: February 1, 2016
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Metastatic Castration-resistant Prostate Cancer (mCRPC)
• Prostatic Neoplasms
• Seizures

Intervention

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.

Locations

Country	Name	City	State
Argentina	Site AR54001	Berazategui	Buenos Aires
Argentina	Site AR54002	Buenos Aires	Caba
Argentina	Site AR54006	Ciudad Autonoma de BuenosAires	Buenos Aires
Argentina	Site AR54003	Cordoba
Argentina	Site AR54004	Santa Fe
Argentina	Site AR54005	Tucuman
Australia	Site AU61007	Adelaide	South Australia
Australia	Site AU61004	Ballarat	Victoria
Australia	Site AU61012	Kogarah	New South Wales
Australia	Site AU61002	Nambour	Queensland
Australia	Site AU61005	Randwick	New South Wales
Australia	Site AU61011	Sydney	New South Wales
Australia	Site AU61001	Tweed Heads	New South Wales
Belgium	Site BE32004	Anderlecht
Belgium	Site BE32001	Kortrijk
Belgium	Site BE32003	Liege
Canada	Site CA15005	Abbotsford	British Columbia
Canada	Site CA15004	Brampton	Ontario
Canada	Site CA15014	Halifax	Nova Scotia
Canada	Site CA15001	Quebec City	Quebec
Canada	Site CA15010	Scarborough	Ontario
Chile	Site CL56004	Santiago
Chile	Site CL56001	Temuco	IX Region
Chile	Site CL56002	Temuco
Chile	Site CL56003	Vina del Mar
Czechia	Site CZ42004	Praha 2
Czechia	Site CZ42002	Praha 6
Finland	Site FI35803	Helsinki
Finland	Site FI35801	Oulu
Finland	Site FI35802	Tampere
France	Site FR33002	Lyon Cedex 03
France	Site FR33004	Rouen Cedex
France	Site FR33005	Suresnes
Germany	Site DE49003	Berlin
Germany	Site DE49001	Munster
Germany	Site DE49009	Nürtingen	Baden-Württemberg
Hungary	Site HU36002	Sopron	Gyor-Moson Sopron
Israel	Site IL97201	Be'er Ya'akov
Israel	Site IL97203	Beer-Sheva
Israel	Site IL97205	Haifa
Israel	Site IL97204	Jerusalem
Israel	Site IL97202	Kfar Saba	HaMerkaz
Israel	Site IL97208	Nahariya
Israel	Site IL97206	Petah-Tiqva
Israel	Site IL97207	Ramat Gan
Italy	Site IT39002	Arezzo
Italy	Site IT39001	Cremona	Lombardia
Italy	Site IT39005	Meldola	Emilia-Romagna
Italy	Site IT39003	Roma
Korea, Republic of	Site KR82006	Seongnam-Si	Gyeonggi-do
Korea, Republic of	Site KR82001	Seoul
Korea, Republic of	Site KR82003	Seoul
Korea, Republic of	Site KR82004	Seoul
Korea, Republic of	Site KR82007	Seoul
New Zealand	Site NZ64001	Hamilton
Singapore	Site SG65002	Singapore
Spain	Site ES34003	Barcelona
Spain	Site ES34004	Barcelona
Spain	Site ES34007	Hospitalet de Llobregat	Barcelona
Spain	Site ES34006	Madrid
Spain	Site ES34001	Pamplona	Navarra
Spain	Site ES34005	Sabadell	Barcelona
Sweden	Site SE46001	Goteborg
Sweden	Site SE46002	Orebro
Taiwan	Site TW88601	Kaohsiung
Taiwan	Site TW88603	Taipei City
United Kingdom	Site GB44002	Sutton	Surrey
United States	Site US10005	Anchorage	Alaska
United States	Site US10026	Bronx	New York
United States	Site US10008	Dallas	Texas
United States	Site US10024	Detroit	Michigan
United States	Site US10016	Durham	North Carolina
United States	Site US10001	New York	New York
United States	Site US10014	New York	New York
United States	Site US10025	Seattle	Washington
United States	Site US10039	Syracuse	New York

Sponsors (2)

Lead Sponsor	Collaborator
Astellas Pharma Global Development, Inc.	Medivation LLC, a wholly owned subsidiary of Pfizer Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Canada,  Chile,  Czechia,  Finland,  France,  Germany,  Hungary,  Israel,  Italy,  Korea, Republic of,  New Zealand,  Singapore,  Spain,  Sweden,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)

External Links

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