A Study to Assess the Efficacy and Safety of Enzalutamide in Subjects With Advanced Hepatocellular Carcinoma
Condition: Advanced Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Intervention: Enzalutamide; Placebo
Intervention description: Oral capsule; Oral capsule
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 165.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MDV3100; advanced hepatocellular carcinoma; enzalutamide; Xtandi; ASP9785

Summary:

      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.
    

Eligibility criteria:

        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.