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

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

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.

Study Overview

• Status: Completed
• Conditions: Advanced Hepatocellular Carcinoma
• Intervention / Treatment: Drug: Placebo; Drug: Enzalutamide

• Study Type: Interventional
• Enrollment (Actual): 165
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Montreal, Canada, H4A 3J1
    • Site CA15003
  • Ontario
    • Toronto, Ontario, Canada, M5G2C4
      • Site CA15001
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Site CA15002
• Hong Kong
  • Kowloon, Hong Kong, 999077
    • Site HK85202
  • Shatin, Hong Kong, 999077
    • Site HK85204
• Italy
  • Benevento, Italy
    • Site IT39005
  • Milan, Italy, 20132
    • Site IT39002
  • Milano, Italy, 20122
    • Site IT39006
  • Padova, Italy, 35128
    • Site IT39011
  • Pavia, Italy, 27100
    • Site IT39004
  • Milan
    • Rozzano, Milan, Italy, 20089
      • Site IT39008
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Site KR82006
  • Seoul, Korea, Republic of, 03722
    • Site KR82007
  • Seoul, Korea, Republic of, 05505
    • Site KR82004
  • Seoul, Korea, Republic of, 06591
    • Site KR82001
  • Gyeonggi-do
    • Seongnam-Si, Gyeonggi-do, Korea, Republic of, 013620
      • Site KR82002
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 135-710
      • Site KR82005
• Puerto Rico
  • San Juan, Puerto Rico, 00927
    • Site US10001
• Spain
  • Barcelona, Spain, 08035
    • Site ES34003
  • Cordoba, Spain, 14004
    • Site ES34006
  • Madrid, Spain, 28222
    • Site ES34004
• Taiwan
  • Douliu, Taiwan, 640
    • Site TW88603
  • Tainan, Taiwan, 704
    • Site TW88606
  • Tainan, Taiwan, 710
    • Site TW88605
  • Taipei City, Taiwan, 10048
    • Site TW88604
• United Kingdom
  • Birmingham, United Kingdom, B15 2WB
    • Site GB44007
  • London, United Kingdom, SE5 9RS
    • Site GB44004
  • London, United Kingdom, W12 OHS
    • Site GB44008
  • Manchester, United Kingdom, M20 4BX
    • Site GB44005
  • Wirral, United Kingdom, CH63 4JY
    • Site GB44002
• United States
  • California
    • San Francisco, California, United States, 94115
      • Site US10003
  • Illinois
    • Skokie, Illinois, United States, 60077
      • Site US10009
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455-0362
      • Site US10017
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756-1000
      • Site US10021
  • Oregon
    • Portland, Oregon, United States, 97239
      • Site US10008
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Site US10014
    • Philadelphia, Pennsylvania, United States, 19104
      • Site US10019
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3522
      • Site US10016

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enzalutamide 160 mg; 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; Oral capsule; Other Names: Xtandi; MDV3100
Placebo Comparator: Placebo; 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; Oral capsule

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Astellas Pharma Global Development, Inc.
• Collaborators: Pfizer
• Investigators: Study Director: Executive Medical Director, Astellas Pharma Global Development, Inc.

Publications and helpful links

General Publications

• Ryoo BY, Palmer DH, Park SR, Rimassa L, Debashis Sarker, Daniele B, Steinberg J, Lopez B, Lim HY. Efficacy and Safety Results from a Phase 2, Randomized, Double-Blind Study of Enzalutamide Versus Placebo in Advanced Hepatocellular Carcinoma. Clin Drug Investig. 2021 Sep;41(9):795-808. doi: 10.1007/s40261-021-01063-0. Epub 2021 Aug 5. Erratum In: Clin Drug Investig. 2022 Mar;42(3):283. doi: 10.1007/s40261-022-01132-y.

Helpful Links

• Link to results and other applicable study documents on the Astellas Clinical Trials website.
• Link to plain language summary of the study on the Trial Results Summaries website.

Study record dates

Study Major Dates

• Study Start (Actual): November 9, 2015
• Primary Completion (Actual): October 2, 2017
• Study Completion (Actual): February 9, 2021

Study Registration Dates

• First Submitted: August 18, 2015
• First Submitted That Met QC Criteria: August 18, 2015
• First Posted (Estimated): August 19, 2015

Study Record Updates

• Last Update Posted (Actual): December 6, 2024
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Xtandi; MDV3100; enzalutamide; advanced hepatocellular carcinoma; ASP9785
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular
• Other Study ID Numbers: 9785-CL-3021; 2014-004283-37 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Access to anonymized individual participant level data will not be provided for this trial. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.
• IPD Sharing Time Frame: Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.
• IPD Sharing Access Criteria: Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No