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.
Brief Title
A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer (mCRPC) Patients Treated With 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).
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).
Categories
Completion Date
Completion Date Type
Actual
Conditions
Metastatic Castration-resistant Prostate Cancer (mCRPC)
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.
* 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.
Inclusion 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.
* 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.
Gender
Male
Gender Based
false
Keywords
enzalutamide
Xtandi
seizure
Central Nervous System
MDV3100
metastatic castration-resistant prostate cancer (mCRPC)
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
NCT Id
NCT01977651
Org Class
Industry
Org Full Name
Astellas Pharma Inc
Org Study Id
9785-CL-0403
Overall Status
Completed
Phases
Phase 4
Primary Completion Date
Primary Completion Date Type
Actual
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
Primary Outcomes
Outcome Description
Percentage of evaluable participants with at least one confirmed seizure as adjudicated by the IAC during the first 4 months of treatment were reported.
Outcome Measure
The Percentage of Evaluable Participants With at Least One Confirmed Seizure as Adjudicated by the Independent Adjudication Committee (IAC)
Outcome Time Frame
Day 1 up to week 17 (end of 4-month treatment period)
Secondary Ids
Secondary Id
2013-003022-92
Secondary Id
U1111-1157-0224
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Child
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
0
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sanjay Goel
Investigator Email
sgoel@montefiore.org
Investigator Phone
718-405-8404
Categories Mesh Debug
Brain, Spinal Cord & Nervous System --- NEUROLOGIC MANIFESTATIONS
Headaches & Migraine --- NEUROLOGIC MANIFESTATIONS
Substance Use and Addiction --- NEUROLOGIC MANIFESTATIONS
Brain, Spinal Cord & Nervous System --- NERVOUS SYSTEM DISEASES
Brain, Spine & Nerve Cancers --- NERVOUS SYSTEM DISEASES
MeSH Terms
SEIZURES
NEUROLOGIC MANIFESTATIONS
NERVOUS SYSTEM DISEASES
SIGNS AND SYMPTOMS
PATHOLOGICAL CONDITIONS, SIGNS AND SYMPTOMS
ENZALUTAMIDE