A Study to Assess the Efficacy and Safety of Enzalutamide in Subjects With Advanced Hepatocellular Carcinoma

Study Overview
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Brief Summary
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The purpose of the study was to evaluate the efficacy of enzalutamide in participants with advanced hepatocellular carcinoma (HCC) as measured by overall survival (OS). This study also evaluated the safety of enzalutamide; pharmacokinetics of enzalutamide and the active metabolite N-desmethyl and Progression Free Survival (PFS) of enzalutamide as compared to placebo in participants with advanced HCC.

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Enzalutamide in Subjects With Advanced Hepatocellular Carcinoma

Conditions
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Advanced Hepatocellular Carcinoma

Intervention / Treatment
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* Drug: Enzalutamide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is ≥ 18 years of age or is considered an adult according to local regulation at the time of signing informed consent. Subject has a documented diagnosis of advanced HCC of any etiology. Subject has BCLC stage B or C. Subject's lesions are not amenable to local therapies which may be beneficial, such as transarterial chemoembolization (TACE), radiofrequency ablation, radiotherapy, etc., and the subject is not a candidate for any curative treatments such as resection or liver transplant. Subject has hepatic function status of Child Pugh Class A at Screening. Subject received prior systemic treatment for HCC with sorafenib or other anti-VEGF therapy and had confirmed disease progression or discontinued treatment due to a drug-related toxicity. Subject may have received 1 line of systemic therapy before or after sorafenib/anti-VEGF treatment. Subject has adequately recovered from toxicities due to prior HCC therapy to ≤ grade 1. Subject has an ECOG performance status ≤ 1 at Screening and on Day 1. Subject has available formalin-fixed, paraffin-embedded tumor specimen with adequate viable tumor cells in a tissue block or unstained serial slides accompanied by an associated pathology report prior to enrollment. Archival or fresh biopsy tissue is required. Subject has an estimated life expectancy of at least 3 months on Day 1, in the opinion of the investigator. Female subject is either: Not of childbearing potential: postmenopausal (defined as no spontaneous menses for at least 12 consecutive months prior to Screening with follicle-stimulating hormone [FSH] > 40 IU/L for women < 55 years of age at Screening), or documented to be surgically sterile or status posthysterectomy (at least 1 month prior to Screening). Or, if of childbearing potential: must have a negative urine pregnancy test at Screening and on Day 1 before the first dose of study drug is administered, and must use 2 acceptable methods of birth control* if sexually active from Screening through 3 months after the last dose of study drug. Sexually active male subject and his female partner who is of childbearing potential must use 2 acceptable methods of birth control from Screening through 3 months after the last dose of study drug. * Two acceptable methods of birth control are as follows: Condom (barrier method of contraception); AND One of the following is required: Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female subject or female partner of a male subject; Additional barrier method: contraceptive sponge or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female subject or female partner of a male subject. For male subject or male partner of female subject, vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy) performed at least 6 months before Screening. Tubal ligation in the female partner of a male subject performed at least 6 months before Screening. Established and ongoing use of oral, injected, or implanted hormonal contraceptive by female partner of a male subject. Female subject must not be breastfeeding at Screening or during the study period and for 3 months after final study drug administration. Subject must agree not to donate sperm or ova from first dose of study drug through 3 months after the last dose of study drug. Throughout the study, male subject must use a condom if having sex with a pregnant woman. Subject must be able to swallow study drug and comply with study requirements. Subject agrees not to participate in another interventional study while on treatment. Received double-blind enzalutamide study treatment during the main study. Exclusion Criteria: Subject has a severe concurrent disease, infection or comorbidity that, in the judgment of the investigator, would make the subject inappropriate for enrollment. Subject has fibrolamellar variant of HCC. Subject has status of Child-Pugh Class B or C at Screening. Subject has a history of organ allograft including liver transplant. Subject has uncontrolled symptomatic ascites. Subject has known or suspected brain metastasis or active leptomeningeal disease. Subject has a history of a non-HCC malignancy with the following exceptions: The subject with a previous history of a noninvasive carcinoma is eligible if in the opinion of the investigator he/she has had successful curative treatment any time prior to Screening and requires no further therapy for the malignancy. For all other malignancies, the subject is eligible if he/she has undergone potentially curative therapy and has been considered disease free for at least 3 years prior to Screening. Subject has inadequate marrow, hepatic, and/or renal function at the Screening Visit defined as: Absolute neutrophil count < 1.5 x109/L (< 1500 cells/mm3) Platelet count < 50 x109/L (< 50,000 cells/mm3) Hemoglobin < 8.5 g/dL (< 5.3 mmol/L) International normalized ratio > 1.7 Albumin < 2.8 g/dL (< 28 g/L) Total bilirubin (TBL) > 2 x ULN AST or ALT > 5 x ULN Creatinine > 1.5 x ULN Note: Transfusions/infusions to meet eligibility criteria are not allowed but if in the opinion of the Principal Investigator, it is beneficial, the patient may be rescreened after receiving one of these procedures. Subject has a history of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma, encephalopathy within 3 months of Day 1). Subject has a history of bleeding esophageal varices within 3 months before the Day 1 visit. Subject has a history of loss of consciousness or transient ischemic attack within 12 months before the Day 1 visit. Subject has clinically significant cardiovascular disease including: Myocardial infarction within 6 months before the Day 1 visit. Uncontrolled angina within 6 months before the Day 1 visit. Congestive heart failure New York Heart Association (NYHA) Class III or IV or history of congestive heart failure NYHA Class III or IV in the past, unless a Screening echocardiogram or multi-gated acquisition scan performed within 3 months before the Day 1 visit reveals a left ventricular ejection fraction that is ≥ 45%. History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, Torsade de Pointes). History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place. Hypotension as indicated by systolic blood pressure < 86 mmHg on 2 consecutive measurements at the Screening visit. Bradycardia (in the presence of known cardiovascular disease) as indicated by a heart rate of < 50 beats per minute on the Screening electrocardiogram (ECG) recording. Uncontrolled hypertension as indicated by systolic blood pressure > 170 mmHg or diastolic blood pressure > 105 mmHg on 2 consecutive measurements at the Screening visit. Subject has a gastrointestinal disorder affecting absorption. Subject had previous local therapy (e.g., surgery, radiation therapy, hepatic arterial therapy, chemoembolization, radiofrequency ablation, percutaneous ethanol injection or cryoablation) within 14 days prior to Day 1, has not recovered from toxicities from prior local therapy or may require major surgical procedure during the course of the study. Subject has received chemotherapy, immunotherapy or any other systemic anticancer therapy (including sorafenib) or any other investigational drug within 14 days prior to the Day 1 visit. Subject has received an agent that either blocks androgen synthesis or targets the AR (e.g., abiraterone acetate, bicalutamide, enzalutamide, ARN-509 or other investigational AR signaling inhibitors). The exception of spironolactone is allowed after Medical Monitor consultation. Subject has used any of the following within 28 days before the Day 1 visit: 5-α reductase inhibitors Systemic androgens and estrogens (vaginal estrogen creams are allowed) Herbal therapies, with an antitumor effect. Subject has a known history of positive test for Human Immunodeficiency Virus. Subject has shown a hypersensitivity reaction to the active pharmaceutical ingredient or any of the enzalutamide capsule components, including caprylocaproyl polyoxylglycerides (Labrasol), butylated hydroxyanisole and butylated hydroxytoluene. Subject has addictive/substance abuse problems. Subject has any other condition or reason that, in the opinion of the investigator, interferes with the ability of the subject to participate in the trial, places the subject at undue risk or complicates the interpretation of safety data. Received double-blind placebo during the main study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzalutamide 160 mg<br>Participants received enzalutamide 160 milligrams (mg) capsules, orally QD during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Eligible participants received enzalutamide 160 mg capsules, orally QD during open label period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days. | Drug: Enzalutamide<br>* Oral capsule<br>* Other names: Xtandi;|
| Placebo Comparator: Placebo<br>Participants received enzalutamide matching placebo orally, once daily (QD) during double blind treatment period until disease progression, unacceptable toxicity, or any other discontinuation criterion was met. Median treatment duration was 64 days. | Drug: Placebo<br>* Oral capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was defined as the time from the date of randomization until the documented date of death from any cause. Participants who were still alive at the time of the data cut-off date was censored on the last date known to be alive or at the data cutoff date, whichever occurs first. Results based on Kaplan-Meier estimates. | From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc.) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug or initiation of new treatment, whichever comes first. AEs were considered as serious if resulted in in death, was life-threatening resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly or birth defect, required inpatient hospitalization or led to prolongation of hospitalization and other medically important events. | From first dose of study drug up to 30 days after last dose of study drug median (minimum, maximum) treatment duration was 64.0 (6, 1736) days for enzalutamide and 64.0 (12, 490) for placebo | 
| Plasma Trough Concentrations of Enzalutamide | Blood samples were collected for analysis. | Predose at weeks 5, 9 and 13 | 
| Plasma Trough Concentrations N-desmethyl Enzalutamide (M2 Metabolite) | Blood samples were collected for analysis. | Predose at weeks 5, 9 and 13 | 
| Plasma Trough Concentrations of MDPC0001 (M1 Metabolite) | Blood samples were collected for analysis. | Predose at weeks 5, 9 and 13 | 
| Progression Free Survival (PFS) | PFS was defined as the time from the date of randomization until the date of documented radiographic disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator or death from any cause on study, whichever occurred first. The earliest of the censoring times was used: Participants with (1) no evaluable postbaseline imaging assessments or did not die were censored at the randomization date; (2) no radiographical progression or did not die before analysis cutoff date were censored at the last radiological assessment date before analysis cutoff date; (3) with no radiographical progression or did not die before new HCC treatment was censored at the last radiological assessment date before start of new HCC treatment. Based on Kaplan-Meier. | From date of randomization up to data cut-off date 02 Oct 2017 (approximately 22 months); median follow-up time was 14.65 months for enzalutamide and 13.83 for placebo. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDV3100, advanced hepatocellular carcinoma, enzalutamide, Xtandi, ASP9785