Enzalutamide (MDV3100) ISN 9785-CL-0401 Prostate … · SYNOPSIS Title of Study: A Multicenter, Single-arm, ... its safety in patients with progressive CRPC previously treated with

Enzalutamide (MDV3100) ISN 9785-CL-0401Prostate CancerCONFIDENTIAL

Name of Sponsor/Company: Astellas Pharma

Global Development, Inc.

Name of Finished Product: Not applicable

Name of Active Ingredient: Enzalutamide

Jun 2014 Astellas Synopsis Page 1 of 22

SYNOPSIS

Title of Study: A Multicenter, Single-arm, Open Label Treatment Protocol to Provide Expanded Access to

Enzalutamide (MDV3100) and Monitor Its Safety in Patients with Progressive Castration-Resistant Prostate

Cancer Previously Treated with Docetaxel-Based Chemotherapy

Signing Investigator: , MBBS, PhD

Study Centers: 80 study centers: 61 in the United States and 19 in Canada

Publication Based on the Study: None to date.

Study Period: Q2 2012 to Q4 2013

Study Initiation Date (Date of First Enrollment): 21 May 2012

Study Completion Date (Date of Last Evaluation): 07 Oct 2013

Phase of Development: Expanded Access Program

Objective: The purpose of this treatment protocol is to provide expanded access to enzalutamide and monitor

its safety in patients with progressive CRPC previously treated with docetaxel-based chemotherapy.

Methodology: This multi-center, single-arm, open-label study was conducted to provide expanded access to

enzalutamide and monitor its safety in approximately 500 male patients with progressive CRPC previously

treated with docetaxel-based chemotherapy and for whom, in the judgment of the investigator, there was no

comparable or satisfactory alternative therapy. Patients who met all of the inclusion and none of the exclusion

criteria were enrolled into the study. (Note: the protocol provided separate eligibility criteria for patients being

enrolled into the study who initiated enzalutamide via the Special Access Programme in Canada.) The study

was conducted while the sponsor was actively pursuing marketing approval of enzalutamide based on data from

the phase 3 AFFIRM study.

Patients were to complete visits on day 1, week 4, week 12 and every subsequent 12 weeks until discontinued

from the study. The safety of enzalutamide was to be assessed through evaluation of adverse events (AEs),

serious AEs (SAEs), blood pressure, heart rate, and laboratory measurements. Efficacy data were not collected

during this study; however, it was recommended in the protocol that disease assessment be performed at least

every 12 weeks and include clinical, radiographic, and/or prostate specific antigen (PSA) assessment.

When enzalutamide became commercially available in a given country, enrollment in that country was stopped

and patients were discontinued from this expanded access study.

An end of study visit was performed 30 days after the last dose of investigational product, prior to the initiation

of the commercially supplied enzalutamide, or prior to the initiation of another anticancer therapy, whichever

occurred first. Patients who transitioned to commercially supplied enzalutamide after their end of study visit

had safety monitored by the treating physician, with spontaneous reporting of AEs in the post-marketing period.







Number of Patients (Planned, Enrolled and Analyzed): Approximately 500 patients; 508 enrolled,

508 analyzed

Diagnosis and Main Criteria for Inclusion:

A histological or cytological confirmation of adenocarcinoma of the prostate was required for study enrollment.

Patient must have had ongoing androgen deprivation therapy (ADT) with a gonadotropin-releasing hormone

(GnRH) analogue (agonist or antagonist) or orchiectomy (i.e., surgical or medical castration), patients who have

not had orchiectomy had to plan to maintain effective GnRH-analogue therapy for the duration of the study. In

addition, the patient must have had at least 1 prior chemotherapy regiment for metastatic CRPC, with at least

1 regimen containing docetaxel, progressive disease evidenced by prostate specific antigen (PSA) rise or

radiographic or clinical worsening of disease, no known or suspected brain metastasis, ECOG performance

status of 0 to 2 and must have agreed to use a double barrier method of birth control during the study and for at

least 3 months after study drug was discontinued. A country-specific amendment permitted patients who

initiated enzalutamide treatment vial the Special Access Programme in Canada to enroll in this study (as

recommended by Health Canada).

Subjects were excluded from the study if they were eligible for enrollment in another ongoing clinical study of

enzalutamide, had severe concurrent disease, infection or comorbidity that the investigator considered was

inappropriate for enrollment; if the subject had abnormal laboratory values at baseline (neutrophil count

< 1000/µL, platelet count < 50,000/µL, hemoglobin < 5.6 µmol/L (9 g/dL), total bilirubin > 1.5 times the upper

limit of normal [ULN], alanine aminotransferase [ALT], aspartate aminotransferase [AST] > 2.5 x ULN or

creatinine clearance was < 30 mL/min. Subjects were excluded if they recently received hormonal therapy,

chemotherapy, or biologic therapy for prostate cancer (other than bone targeted agents such as bisphosphonates

or denosumab, GnRH analogue therapy, or glucocorticoids, which were allowed) or radiation therapy, had a

history of seizures or any condition predisposed to seizures, or history of a loss of consciousness or transient

ischemic attack within 12 months. Subjects were also excluded if they had clinical sings suggestive of high or

imminent risk for pathological fracture, spinal cord compression and/or cauda equine syndrome, had

uncontrolled hypertension, recently received an investigational agent, recently underwent major surgery or

showed a hypersensitivity reaction to any components of the study drug. Patients were excluded if they

participated in a previous clinical study with enzalutamide for which the primary endpoint had not yet been

reported.

Test Product, Dose and Mode of Administration, Batch Numbers: Enzalutamide was provided as 40 mg

(active pharmaceutical ingredient) soft gelatin oral capsules in high-density polyethylene bottles with

child-resistant induction seal closure (batch numbers: , , ,

and ).

Duration of Treatment: Subjects received enzalutamide in the expanded access treatment protocol until they

were no longer deriving benefit in the judgment of the investigator, they initiated treatment with another







anticancer therapy or they met 1 of the discontinuation criteria. When enzalutamide became commercially

available in a given country, enrollment in that country was stopped and subjects were discontinued from the

expanded access treatment protocol.

Reference Product, Dose and Mode of Administration, Batch Numbers: None.

Criteria for Evaluation:

Safety:

● Vital signs (blood pressure and pulse rate)

● Adverse events (AEs) and serious adverse events (SAEs)

● Physical examination

● Laboratory measurements

Statistical Methods:

The full analysis set (FAS) consisted of all registered patients (including patients from the Canadian Special

Access Programme who subsequently registered in this expanded access program). The FAS was used for

summaries of demographic and baseline characteristics.

The safety analysis set (SAF) consisted of all patients who took at least one dose of study drug during this study.

The SAF was used for summaries of all safety variables.

Demographics and other baseline characteristics were obtained at screening and were summarized for the FAS

using descriptive statistics. Medical history was coded using MedDRA (v12.0) and provided in tables and

listings.

Previous and concomitant medications were coded with World Health Organization Drug Reference List. All

previous and concomitant medications data were provided in a listing.

Safety

The SAF included all patients who received any amount of enzalutamide. Adverse events (AEs) were coded

using MedDRA (v 12.0) and the National Cancer Institute-Common Terminology Criteria for Adverse Events

(NCI-CTCAE). The number and percentage of subjects with treatment-emergent adverse events (TEAEs),

drug-related TEAEs, serious TEAEs and TEAEs that led to dose reduction, interruption, or discontinuation were

summarized for each treatment by system organ class and preferred term. A drug-related TEAE was defined as

any TEAE with a relationship category of possible or probably to study drug or missing relationship.

Overviews of TEAEs and TEAEs by NCI-CTCAE grade were provided.

Descriptive statistics were used to summarize clinical laboratory variables and their corresponding changes

from baseline by treatment.







Summary of Results/Conclusions: A total of 588 patients were screened for study enrollment; 80 patients

(13.6%) failed screening. The primary reason for screening failure was ‘other’ 70 patients [11.9%]. The most

common reasons for patients to be classified as ‘other’ were because their laboratory values did not met

protocol specifications (20/70 patients, 28.6%) or they did not meeting inclusion or exclusion criteria – not

specified (14/70 patients, 20.0%)). Additional reasons for screening failure included: withdrawal by patient in

7 patients (1.2%), SAE in 2 patients (0.3%) and lost to follow-up in 1 patient (0.2%) [Figure 1].

A total of 508 patients were enrolled into the study. Of the patients enrolled, 507 patients (99.8%) received at

least 1 dose of enzalutamide and were included in the SAF. One enrolled patient had previously received

enzalutamide as they had participated in the CRPC2 (AFFIRM) study but discontinued for needed surgery with

no evidence of disease progression. Also, 8 patients who had previously received enzalutamide via the

Canadian Special Access Programme were registered in this Expanded Access Program. A total of 237 patients

(46.7%) were on study drug at the time enzalutamide became commercially available and the sponsor halted

enrollment in that country (completer). All completers were offered the option to transition to commercially

supplied enzalutamide, 227 patients (95.8%) transitioned to commercially supplied enzalutamide. The most

common reasons for patients discontinuing study treatment were progressive disease (171 patients, 33.7%), AE

(41 patients, 8.1%), and withdrawal by patient (30 patients, 5.9%) [Table 1].

Baseline Demographics and Disease Status/History

The median patient age was 71.0 years; with 39.4% of patients (200) between 65 and 74 years of age

(inclusive). The majority of patients were white (448 patients, 88.2%) and had a baseline Eastern Cooperative

Oncology Group (ECOG) performance status of 1 (285 patients, 56.1%) [Table 2].

The median duration of disease at baseline was 88.9 months (range: 9.5 – 301.8 months). The median number

of prior unique anti-neoplastic therapies per patient was 5 therapies (range: 1 – 18 therapies) and the median

number of prior unique chemotherapy therapies per patient was 1 therapy (range: 0 – 10 therapies). The

majority of patients had with prior abiraterone exposure (386 patients, 76.0%) and 126 patients had prior

abiraterone and cabazitaxel exposure (24.8%). The median number of cycles of prior docetaxel exposure per

patient was 8 cycles (range: 1 – 76 cycles). At baseline, the majority of patients had a total Gleason Score of

medium (201 patients, 39.6%) or high (269 patients, 53.0%) Table 3 . The patients had significant past

medical history, with more than 25% reporting cardiac disorders, 72% reporting vascular disorders, 56.6%

reporting hypertension, and 50.9% reporting fatigue [Table 3 and Table 4].

All patients received prior taxane therapy (i.e., docetaxel); however, 2 patients received docetaxel in

combination with other agents were coded as receiving either other therapeutic products or other antineoplastic

agents. Other common prior prostate cancer therapies (ATC 4th level chemical name) included gonadotropin

releasing hormone analogues (481 patients, 94.9%), anti-androgens (444 patients, 87.6%) and other hormone

antagonists and related agents (404 patients, 79.7%).







Concomitant Medications

All patients used concomitant medications (507 patients, 100%). The most common drugs (ATC 4th level

chemical name) taken during the study were natural opium alkaloids (308 patients, 60.7%), glucocorticoids

(249 patients, 49.1%), anilides (239 patients, 47.1%), vitamin D and analogues (229 patients, 45.2%), and

proton pump inhibitors (210 patients, 41.4%). A concomitant medication protocol deviation was reported in

1 patient, but no patients permanently discontinued study drug as a result of concomitant medication use.

Study Drug Exposure

A total of 507 patients took at least 1 dose of 160 mg enzalutamide once daily. The median exposure to

enzalutamide was 2.60 months in 502 patients Table 5 . The majority of patients (286 patients, 56.4%) took

study drug for 1 to < 3 months during this study. Exposure data are limited in their interpretability as they only

indicate the time on drug during the study period and did not include exposure after the transition to commercial

drug.

Safety Results: Key findings included:

TEAEs reported in at least 10% of treated patients were: fatigue (39.1% [198 patients]), nausea (22.7%

[115 patients]), anorexia (14.8% [75 patients]), anemia (11.8% [60 patients]), peripheral edema (11.4%

[58 patients]), back pain (10.3% [52 patients]), vomiting (10.3% [52 patients]), and arthralgia (10.1%

[51 patients]) Table 7 .

SAEs reported in at least 1.0% of treated patients were: disease progression (7.9% [40 patients]),

pneumonia (2.0% [10 patients]), asthenia (1.8% [9 patients]), anemia (1.6% [8 patients]), and back

pain (1.4% [7 patients]); also abdominal pain, bone pain, pleural effusion, spinal cord compression and

vomiting were each reported at (1% [5 patients]) Table 12 .

Drug-related SAEs that occurred in more than 1 patient were events of seizure (0.8% [4 patients]),

asthenia (0.6% [3 patients]), and vomiting (0.4% [2 patients]).

Grade 3 and greater TEAEs occurred in approximately 43% of patients; the most common events with

an incidence rate of at least 2% were: fatigue (9.9% [50 patients]), malignant neoplasm progression

(7.7% [39 patients]), anemia (6.5% [33 patients]), asthenia (3.6% [18 patients]), back pain (2.8%

[14 patients]), bone pain (2.4% [12 patients]), nausea (2.4% [12 patients]) and pneumonia (2.0%

[10 patients]) Table 9 . Among these severe events, the following were reported as drug-related with

an incidence rate of at least 1%: fatigue (5.9% [30 patients], asthenia (1.4% [7 patients]), nausea (1.4%

[7 patients]) and anemia (1.0% [5 patients]) Table 10 .

TEAEs leading to dose reduction occurred in 3.4% of patients Table 6 ; the most common reasons for

dose reduction were fatigue (1.6% [8 patients]) and nausea (0.6% [3 patients]).

TEAEs leading to dose interruption occurred in 11.8% of patients Table 6 ; the most commonly

reported events leading to dose interruption were: fatigue (1.8% [9 patients]), nausea (1.4%







[7 patients]), asthenia (1.2% [6 patients]), vomiting (0.8% [4 patients]), diarrhea (0.6% [3 patients]),

pain (0.6% [3 patients]), and pneumonia (0.6% [3 patients]).

Drug-related TEAEs leading to treatment discontinuation occurred in 3.7% of patients; those that

occurred in more than 1 patient were: fatigue (0.8% [4 patients]), events of seizure (0.6% [3 patients])

and dyspnoea (0.4% [2 patients]).

TEAEs leading to death occurred in 9.9% (50 patients) of the patients; the most commonly reported

TEAE leading to death was malignant neoplasm progression (7.7% [39 patients]). Other fatal events

included: embolic stroke, metastases to central nervous system, anaemia, death NOS, wound sepsis,

congestive cardiac failure, hepatic failure, gastrointestinal perforation, cardiac arrest and lower

gastrointestinal hemorrhage. These events were assessed as unrelated to study drug and each was

reported in 1 patient. Drug-related TEAEs leading to death occurred in 4 patients; 3 of these events

were considered possibly drug-related (cerebrovascular accident; acute myocardial infarction and

myocardial infarction) and 1 event did not have relatedness reported (death NOS) Table 11 .

The following targeted medical events were reported [Table 14].

o Cognitive/memory impairment (7.7% [39 patients])

o Falls (2.4% [12 patients])

o Hypertension (2.4% [12 patients])

o Hallucinations (1.6% [8 patients])

o Neutrophil count decrease (1.4% [7 patients])

o Non-pathological fractures (1.4% [7 patients])

o Seizure (0.8% [4 patients])

In summary, enzalutamide was well-tolerated in this study population and demonstrated a safety profile

consistent with that observed in AFFIRM.

CONCLUSIONS: This multi-center, single-arm, open-label study was conducted to provide expanded access

to enzalutamide and monitor its safety in approximately 500 male patients with progressive CRPC previously

treated with docetaxel-based chemotherapy and for whom, in the judgment of the investigator, there was no

comparable or satisfactory alternative therapy. The study enrolled 508 patients of whom 507 received at least

1 dose of open label enzalutamide. The majority of patients were white (88.2%) with a median age of 71 years

and 39.4% of patients were 65 to 74 years of age. Baseline ECOG performance score of 1 was reported in

56.1% of patients. Prior prostate cancer treatments included abiraterone (76.0%), and cabazitaxel (28.6%);

24.8% of patients received both prior abiraterone and cabazitaxel. The patients who received enzalutamide had

significant past medical history, with more than 25% reporting cardiac disorders, 72% reporting vascular







disorders, and 56.6% reporting hypertension; the majority of patients were on multiple concomitant

medications.

The median exposure to study drug was 2.6 months. Nearly half (46.7%, 227 patients) of the patients were on

study drug at the time enzalutamide became commercially available; duration on the subsequent commercial

drug was not collected. Hence, interpretation of study drug exposure data is limited because it does not include

exposure following transition to commercial drug.

Enzalutamide was well-tolerated in the study. Fatigue was the most common TEAE (39.1%) and was also the

most common TEAE considered to have a possible or probable relationship to study drug by the investigator

(28.8%). The most common (≥ 10%) TEAEs were fatigue, nausea, anorexia, anemia, peripheral edema, back

pain, vomiting, and arthralgia. SAEs occurred in 28.2% of patients, with malignant neoplasm progression being

the most common; other common SAEs, with an incidence of at least 2.0%, were pneumonia, asthenia, anemia,

and back pain. Drug-related SAEs occurred in 3.9% of patients and those that occurred in more than 1 patient

were events of seizure, asthenia, and vomiting. Grade ≥ 3 TEAEs occurred in approximately 43% of patients;

the most common events (≥ 2 %) were fatigue, malignant neoplasm progression, anemia, asthenia, back pain,

bone pain, nausea and pneumonia. Drug-related TEAEs leading to discontinuation occurred in 3.7% of patients

and the events leading to discontinuation in more than 1 patient were fatigue, events of seizure and dyspnea.

TEAEs leading to death occurred in 9.9% of the patients (50 patients), the most common TEAE reported was

malignant neoplasm progression (7.7%, 39 patients). Drug-related TEAEs leading to death occurred in

4 patients; 3 events (cerebrovascular accident, acute myocardial infarction, and myocardial infarction) were

considered possibly drug-related, and 1 event (death NOS) did not have relatedness reported due to insufficient

information.

The frequencies of the targeted medical events (cognitive/memory impairment, falls, hypertension,

hallucinations, neutrophil count decreased, pathological fractures, and events of seizure) observed in this study

were comparable to those observed in the CRPC2 study. Seizures were reported in 4 patients (0.8%), 2 were

found to have brain metastases and 1 was found to have encephalomalacia consistent with hemorrhagic

contusions. The study excluded patients with risk factors for seizure and prohibited the use of medications

known to lower the seizure threshold. The incidence of seizures observed in this study is consistent with that

seen in the CRPC2 study (<1%).

In conclusion, enzalutamide 160 mg once daily was safe and well-tolerated in this heavily-pretreated expanded

access population. The safety profile was consistent with that seen in the CRPC2 study and no new safety

signals were identified.

Date of Report: 19 Jun 2014



Figure 1 Disposition of Subjects

Assessed for Eligibility(n = 588)

Enrolled (n = 508)

EnrolledNot enrolled (n = 80)

Withdrawal by patient (n = 7)Adverse event (n = 2)Lost to follow-up (n = 1)Other reasons (n = 70)

Enzalutamide 160 mg daily (n = 507)Received Treatment (n = 507)Not Treated (n = 1)

Lost to follow-up (n = 7)Discontinued treatment (n = 271)

Completed Study (n = 237)

Source: 9785-CL-0401 CSR, End-of-Text Tables 12.1.1.2 and 12.1.1.3



Table 1 Patient Disposition

Parameter Category

TotalEnzalutamide 160 mg qd

(n = 508)n (%)

Analysis SetFull Analysis Set 508 (100)

Safety Analysis Set 507 (99.8)Completed Study Treatment

Transitioning to Commercially Supplied Enzalutamide‡

No 271 (53.3)Yes 237 (46.7)Yes 227 (44.7)No 10 (2.0)

Primary Reason for Study Treatment Discontinuation†

Completed‡ 237 (46.7)Registered but never

received/dispensed study drug1 (0.2)

Adverse event 41 (8.1)Death 17 (3.3)

Lost to follow-up 7 (1.4)Progressive disease 171 (33.7)Protocol violation 1 (0.2)

Withdrawal by patient§ 30 (5.9)Other 3 (0.6)

The safety analysis set (SAF) consisted of all patients who took at least 1 dose of study drug during this study.

The full analysis set (FAS) consisted of all registered patients (including 8 patients from the Canadian Special Access Programme who subsequently registered in this expanded access program).

One enrolled patient had previously received enzalutamide as they had participated in the CRPC2 (AFFIRM) study, but discontinued for needed surgery with no evidence of disease progression.

†For every patient only the primary reason for discontinuation was collected.

‡For the purposes of this protocol, a completed patient is one who was on study drug at the time the study drug became commercially available in the study site country, and the sponsor halted enrollment in the study for the study site country. The completed patient may not have had an end of study visit.

§Fifteen of the 30 patients who withdrew from study treatment continued to be followed and assessed for clinical outcome.




Table 2 Summary of Patient Demographics and Baseline Characteristics– Full Analysis Set

Parameter Category/Statistic

Enzalutamide160 mg qd(n = 508)

n (%)

Age (Years)Mean (SD) 70.5 (8.65)Min – Max 43 – 97

Median 71.0

Age group (Years)< 65 131 (25.8)

65 - < 75 200 (39.4)≥ 75 177 (34.8)

Race

White 448 (88.2)Black or African American 34 (6.7)

Asian 12 (2.4)Other 14 (2.8)

EthnicityNot Hispanic or Latino 493 (97.0)

Hispanic or Latino 15 (3.0)

Weight (kg)Mean (SD) 84.5 (16.6)Min – Max 49.3 – 177

Median 82.6

ECOG status†

0 141 (27.8)1 285 (56.1)2 81 (15.9)

Missing 1 (0.2)


ECOG: Eastern Cooperative Oncology Group

†Eastern Cooperative Group Performance Status: 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 = Ambulatory and capable of all self-care but unable to carry out any work activities; Missing = Was randomized but never received study drug.




Table 3 Summary of Patient Baseline Disease Status/History – Full Analysis Set

Parameter Category/Statistic


n (%)

Duration of disease (months)

n 476Mean (SD) 103.2 (64.39)Min – Max 9.5 – 301.8

Median 88.9

Prior unique anti-neoplastic therapies per patient

n 507Mean (SD) 5.5 (2.24)Min – Max 1.0 – 18.0

Median 5.0

Prior unique chemotherapy therapies per patient†

n 507Mean (SD) 1.7 (1.07)Min – Max 0 – 10.0

Median 1.0Patients with prior abiraterone exposure

Abiraterone 386 (76.0)Abiraterone and cabazitaxel 126 (24.8)

Prior docetaxel exposure by total number of cycles per patient

n 362‡Mean (SD) 9.3 (7.02)Min – Max 1.0 – 76.0

Median 8.0

Total Gleason Score at initial diagnosis

Low (2 – 4) 6 (1.2)Medium (5 – 7) 201 (39.6)High (8 – 10) 269 (53.0)

Missing 32 (6.3)Patients with prior radiation therapy for prostate cancer 406 (79.9)Patients with prior surgery/procedures for prostate cancer 267 (52.6)


†One patient who received prior docetaxel in combination with an experimental agent/placebo was coded as OTHER THERAPEUTIC PRODUCT was not identified as receiving a unique prior chemotherapy.

‡ All patients with non-missing docetaxel/taxotere cycles.

Source: 9785-CL-0401 CSR, End-of-Text Tables 12.1.2.2, 12.1.3.1 and 12.1.3.2



Table 4 Summary of Past Medical History (≥ 20% of Patients) – Safety Analysis Set

Parameter


n (%)Patient past medical history (≥ 20% of patients)

Hypertension 287 (56.6)Fatigue 258 (50.9)Back pain 180 (35.5)Constipation 169 (33.3)Anaemia 162 (32.0)Insomnia 149 (29.4)Bone pain 128 (25.2)Depression 114 (22.5)Arthralgia 109 (21.5)Hot flush 108 (21.3)Nausea 103 (20.3)Peripheral oedema 102 (20.1)


Note: Includes patients who initiated enzalutamide treatment via the Special Access Program in Canada (n = 8) and 1 patient who was previously enrolled and randomized in CRPC2 (AFFIRM) to receive enzalutamide but discontinued for needed surgery with no evidence of progression.

Source: End-of-Text Table 12.1.3.4



Table 5 Summary of Study Drug Exposure – Safety Analysis Set

Characteristic Category/Statistic


Duration of Exposure (months)‡

nMean (SD)Min – Max

Median

502†2.90 (1.66)0.03 – 9.07

2.60

Duration of Exposure< 1 month (%)

≥ 1 to < 3 months (%)≥ 3 months (%)

50 (9.9)286 (56.4)166 (32.7)

Number and Percent of Patients with Dose Reductions§ 35 (6.9)Number and Percent of Patients with Dose Interruptions¶ 59 (11.6)


†For 5 patients the date of last dose was not captured.

‡Duration of exposure is defined as [date of last dose – date of first dose + 1]/30.4375.

§The number and percent of patients with dose reductions is calculated by the number of patients with at least one dosing record where total daily dose is < 160 mg.

¶The number and percent of patients with dose interruptions is calculated by the number of patients with a gap > 1 day in their sorted dosing log entries.

Source: 9785-CL-0401 CSR, End-of-Text Table 12.2.1



Table 6 Overview of Treatment-Emergent Adverse Events – Safety Analysis Set

Description


n (%)Patients Experiencing Adverse Events 447 (88.2)Patients Experiencing Drug Related† Adverse Events 280 (55.2)Patients Experiencing AE Resulting in Death‡ 50 (9.9)Patients Experiencing Serious Adverse Events§ 143 (28.2)Patients Experiencing Drug Related† Serious Adverse Events 20 (3.9)Patients Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug

71 (14.0)

Patients Experiencing Drug Related† Adverse Events Leading to Permanent Discontinuation of Study Drug

19 (3.7)

Patients Experiencing AEs leading to Dose Reduction 17 (3.4)Patients Experiencing Drug Related† AEs Leading to Dose Reduction

17 (3.4)

Patients Experiencing AEs Leading to Dose Interruption 60 (11.8)Patients Experiencing Drug Related† AEs leading to Dose Interruption

25 (4.9)

Patients Experiencing AE Grade 3 or Higher 217 (42.8)Patients Experiencing Drug Related† AE Grade 3 or Higher 72 (14.2)


†Possible or Probable, as assessed by the investigator, or records where relationship is missing.

‡TEAEs include 2 patients who died outside of the 30 day window of last dose though the onset date of adverse event leading to death was within 30 day window.

§Includes SAEs upgraded by the sponsor based on review of the sponsor's list of always serious terms, if any upgrade was done.

AE: adverse event; SAE: serious adverse event; TEAE: treatment-emergent adverse event

Source: 9785-CL-0401 CSR, End-of-Text Table 12.6.1.1



Table 7 Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients – Safety Analysis Set

MedDRA (v12.0) System Organ ClassPreferred Term†


n (%)Overall 447 (88.2)General disorders and administration site conditions 274 (54.0)

Fatigue 198 (39.1)Oedema peripheral 58 (11.4)Asthenia 43 (8.5)Pain 22 (4.3)Pyrexia 17 (3.4)

Gastrointestinal disorders 217 (42.8)Nausea 115 (22.7)Vomiting 52 (10.3)Diarrhoea 50 (9.9)Constipation 47 (9.3)Abdominal pain 13 (2.6)

Musculoskeletal and connective tissue disorders 200 (39.4)Back pain 52 (10.3)Arthralgia 51 (10.1)Pain in extremity 41 (8.1)Bone pain 34 (6.7)Muscular weakness 23 (4.5)Myalgia 21 (4.1)Musculoskeletal pain 15 (3.0)Musculoskeletal chest pain 17 (3.4)Neck pain 11 (2.2)

Nervous system disorders 157 (31.0)Headache 36 (7.1)Dizziness 36 (7.1)Dysgeusia 14 (2.8)Hypoaesthesia 12 (2.4)Paraesthesia 12 (2.4)Somnolence 12 (2.4)

Metabolism and nutrition disorders 138 (27.2)Anorexia 75 (14.8)Dehydration 22 (4.3)Decreased appetite 20 (3.9)Hypokalaemia 17 (3.4)

Respiratory, thoracic and mediastinal disorders 105 (20.7)Dyspnoea 43 (8.5)Cough 27 (5.3)Epistaxis 10 (2.0)

Psychiatric disorders 99 (19.5)Insomnia 40 (7.9)Depression 24 (4.7)Confusional state 21 (4.1)Anxiety 19 (3.7)

Infections and infestations 95 (18.7)Urinary tract infection 16 (3.2)Pneumonia 15 (3.0)

Table continued on next page





n (%)Renal and urinary disorders 70 (13.8)

Haematuria 23 (4.5)Pollakiuria 12 (2.4)

Renal and urinary disorders (continued) 70 (13.8)Urinary retention 12 (2.4)

Vascular disorders 68 (13.4)Hot flush 44 (8.7)Hypertension 12 (2.4)

Blood and lymphatic system disorders 67 (13.2)Anaemia 60 (11.8)

Skin and subcutaneous tissue disorders 66 (13.0)Dry skin 14 (2.8)Rash 13 (2.6)

Investigations 56 (11.0)Weight decreased 24 (4.7)

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

51 (10.1)

Malignant neoplasm progression 40 (7.9)Cardiac disorders 31 (6.1)Injury, poisoning and procedural complications 29 (5.7)

Fall 12 (2.4)Eye disorders 21 (4.1)Reproductive system and breast disorders 17 (3.4)Ear and labyrinth disorders 14 (2.8)


†Sorting order: Descending percentage of system organ class, and within system organ class descending percentage of preferred term.




Table 8 Drug-Related Treatment-Emergent Adverse Events Occurring in ≥ 2% of Patients –Safety Analysis Set



n (%)Overall 280 (55.2)General disorders and administration site conditions 162 (32.0)

Fatigue 146 (28.8)Asthenia 17 (3.4)Oedema peripheral 11 (2.2)

Gastrointestinal disorders 98 (19.3)Nausea 64 (12.6)Diarrhoea 23 (4.5)Vomiting 19 (3.7)

Nervous system disorders 64 (12.6)Headache 16 (3.2)Dizziness 17 (3.4)Dysgeusia 11 (2.2)

Metabolism and nutrition disorders 42 (8.3)Anorexia 30 (5.9)Decreased appetite 10 (2.0)

Musculoskeletal and connective tissue disorders 39 (7.7)Arthralgia 12 (2.4)Myalgia 10 (2.0)

Vascular disorders 38 (7.5)Hot flush 30 (5.9)

Psychiatric disorders 31 (6.1)Insomnia 16 (3.2)

Skin and subcutaneous tissue disorders 30 (5.9)Respiratory, thoracic and mediastinal disorders 19 (3.7)Blood and lymphatic system disorders 14 (2.8)Investigations 11 (2.2)






Table 9 Treatment-Emergent Adverse Events of Grade 3 or Higher Occurring in ≥ 2% of Patients – Safety Analysis Set

MedDRA (v12.0) Preferred Term


n (%)Grade 3 Grade 4 Grade 5 Total

Fatigue 50 (9.9) 0 0 50 (9.9)Malignant neoplasm progression 0 0 39 (7.7) 39 (7.7)Anaemia 30 (5.9) 2 (0.4) 1 (0.2) 33 (6.5)Asthenia 16 (3.2) 2 (0.4) 0 18 (3.6)Back pain 14 (2.8) 0 0 14 (2.8)Bone pain 12 (2.4) 0 0 12 (2.4)Nausea 12 (2.4) 0 0 12 (2.4)Pneumonia 9 (1.8) 1 (0.2) 0 10 (2.0)


The number of patients shows the maximum grade.

Source: 9785-CL-0401 CSR, End-of-Text Table 12.6.1.2.2.1.

Table 10 Drug-Related Treatment-Emergent Adverse Events of Grade 3 or Higher Occurring in ≥ 0.5% of Patients – Safety Analysis Set



n (%)Grade 3 Grade 4 Grade 5 Total

Fatigue 30 (5.9) 0 0 30 (5.9)Asthenia 7 (1.4) 0 0 7 (1.4)Nausea 7 (1.4) 0 0 7 (1.4)Anaemia 5 (1.0) 0 0 5 (1.0)Hot flush 4 (0.8) 0 0 4 (0.8)Anorexia 3 (0.6) 0 0 3 (0.6)Convulsion 2 (0.4) 1 (0.2) 0 3 (0.6)Headache 3 (0.6) 0 0 3 (0.6)Vomiting 3 (0.6) 0 0 3 (0.6)


The number of patients shows the maximum grade.

Source: 9785-CL-0401 CSR, End-of-Text Table 12.6.1.3.2.1



Table 11 Treatment-Emergent Grade 5 Adverse Events (Deaths) – Safety Analysis Set



n (%)Overall 50 (9.9)Malignant neoplasm progression 39 (7.7)Death 2 (0.4)Acute myocardial infarction 1 (0.2)Anemia 1 (0.2)Cardiac arrest 1 (0.2)Cardiac failure congestive 1 (0.2)Cerebrovascular accident 1 (0.2)Embolic stroke 1 (0.2)Gastrointestinal perforation 1 (0.2)Hepatic failure 1 (0.2)Lower gastrointestinal haemorrhage 1 (0.2)Metastases to central nervous system 1 (0.2)Myocardial infarction 1 (0.2)Wound sepsis 1 (0.2)


The number of patients shows the maximum grade. Patients may have had more than 1 treatment-emergent Grade 5 event.

Source: 9785-CL-0401 CSR, End-of-Text Tables 12.6.1.2.1 and 12.6.1.7.



Table 12 Serious Treatment-Emergent Adverse Events that Occurred in ≥ 0.5% of Patients –Safety Analysis Set



n (%)Overall 143 (28.2)Neoplasms benign, malignant and unspecified (incl cysts and polyps)

44 (8.7)

Malignant neoplasm progression 40 (7.9)Infections and infestations 26 (5.1)

Pneumonia 10 (2.0)Nervous system disorders 24 (4.7)

Spinal cord compression 5 (1.0)Convulsion 4 (0.8)Cerebrovascular accident 3 (0.6)

General disorders and administration site conditions 21 (4.1)Asthenia 9 (1.8)Pyrexia 4 (0.8)Fatigue 3 (0.6)Non-cardiac chest pain 3 (0.6)

Gastrointestinal disorders 20 (3.9)Abdominal pain 5 (1.0)Vomiting 5 (1.0)Nausea 4 (0.8)

Musculoskeletal and connective tissue disorders 18 (3.6)Back pain 7 (1.4)Bone pain 5 (1.0)Pathological fracture 3 (0.6)

Respiratory, thoracic and mediastinal disorders 12 (2.4)Pleural effusion 5 (1.0)Dyspnoea 4 (0.8)Pulmonary embolism 4 (0.8)

Blood and lymphatic system disorders 11 (2.2)Anemia 8 (1.6)

Renal and urinary disorders 11 (2.2)Haematuria 4 (0.8)

Cardiac disorders 10 (2.0)Metabolism and nutrition disorders 8 (1.6)

Dehydration 4 (0.8)Injury, poisoning and procedural complications 6 (1.2)Vascular disorders 5 (1.0)

Deep vein thrombosis 3 (0.6)Hepatobiliary disorders 4 (0.8)Psychiatric disorders 4 (0.8)

Confusional state 3 (0.6)Investigations 3 (0.6)






Table 13 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation Occurring in ≥ 0.5% of Patients – Safety Analysis Set



n (%)Overall 71 (14.0)Malignant neoplasm progression 13 (2.6%)Fatigue 5 (1.0%)Asthenia 4 (0.8%)Dyspnoea 4 (0.8%)Spinal cord compression 4 (0.8%)Convulsion 3 (0.6%)


Source: 9785-CL-0401 CSR, End-of-Text Table 12.6.1.4.1



Table 14 Targeted Medical Events – Safety Analysis Set

Targeted Medical Event MedDRA (v12.0)Preferred Term†


n (%)Overall 79 (15.6)Cognitive/Memory Impairment 39 (7.7)

Confusional state 21 (4.1)Amnesia 8 (1.6)Memory impairment 8 (1.6)Disturbance in attention 6 (1.2)Cognitive disorder 5 (1.0)

Falls 12 (2.4)Fall 12 (2.4)

Hypertension 12 (2.4)Hypertension 12 (2.4)

Hallucinations 8 (1.6)Hallucination 5 (1.0)Hallucination, visual 2 (0.4)Hallucination, auditory 1 (0.2)

Neutrophil Count Decrease 7 (1.4)Neutropenia 3 (0.6)Neutrophil count decreased 3 (0.6)Leukopenia 1 (0.2)

Non-pathological Fractures 7 (1.4)Foot fracture 2 (0.4)Spinal compression fracture 2 (0.4)Hip fracture 1 (0.2)Rib fracture 1 (0.2)Scapula fracture 1 (0.2)

Loss of Consciousness 5 (1.0)Syncope 3 (0.6)Loss of consciousness 1 (0.2)Presyncope 1 (0.2)

Seizures 4 (0.8)Convulsion 4 (0.8)


Targeted medical events were derived using preferred terms (PT), high level terms (HLT), and standard MedDRA queries (SMQs) as specified in Section 9.1 Appendix 2 of the SAP [Appendix 13.1.9]. For the targeted medical events of falls, only AEs coded into the PT of “falls” are presented.

†Sorting order: Descending percentage of targeted medical event, and within targeted medical event descending percentage of preferred term.


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