Study of Enzalutamide With and Without Sorafenib in Advanced Hepatocellular Carcinoma Patients

This is a multicenter, open label, phase I/II study of enzalutamide with or without sorafenib
to define the safety, MTD, and pharmacokinetic parameters of each regimen in advanced HCC
patients.

The study will have 4 parts as indicated in the Study Schema, an enzalutamide dose escalation
(Part 1A), a sorafenib and enzalutamide dose escalation (Part 1B), and dose expansion cohorts
for the Part 1A and Part 1B MTDs (Part 2). Dose escalation will occur using a standard 3 + 3
design and is described in Section 4.2.1. For Part 2, the enzalutamide expansion cohort (Part
2A), will enroll 10 patients and is exploratory in nature; however, it will allow for
acquisition of additional PK sampling at the MTD, for determination of safety and efficacy.
The MTD sorafenib and enzalutamide combination expansion (Part 2B) will be designed using a
Simon minimax design to formally evaluate the 4-month PFS.

Inclusion Criteria:

- Histologic proof of HCC reviewed and confirmed at per the local standard of care.

- Advanced unresectable or metastatic disease

- Measurable disease as defined by RECIST version 1.1

- Tissue available for the evaluation of AR by IHC on pretreatment HCC samples. If
tissue is not available, a pretreatment biopsy will not be necessary for eligibility

- Age ≥ 18 years-old

- ECOG performance status ≤ 2

- Child-Pugh category A

- Adequate hepatic function defined by:

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5.0 x upper
limit of normal (ULN)

- Total Bilirubin ≤ 1.5 x ULN

- Adequate hematologic function defined by:

- Absolute neutrophil count (ANC) ≥ 1200/mm3 (≥ 1.2 x 10^9/L)

- Platelets ≥ 75,000/mm3 (≥ 75 x 10^9/L)

- Hemoglobin ≥ 8 g/dL (≥ 80 g/L)

- Adequate renal function defined by:

- Serum creatinine ≤ 1.5 × ULN or calculated creatinine clearance ≥ 40 mL/min
(using the Cockcroft-Gault equation)

- Patients must be on antiviral therapy per the local standard of care if active or
occult hepatitis B (HBV) infection.

- Patients with active hepatitis C (HCV) may not be antiviral therapy.

- Patients with a history of hypertension should be well controlled (BP ≤ 140/90) on a
regimen of antihypertensive therapy.

- Gastrointestinal disorders in the opinion of the treating physician that would impair
absorption.

- Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (e.g., male or female condom) during the course of the study.
All subjects of reproductive potential must agree to use both a barrier method and a
second method of birth control during the course of the study.

- Patients with history of liver transplantation may be eligible for the dose expansion
cohorts (Parts 2A and 2B) of this study provided all eligibility criteria are met and
provided the subject has not had any episodes of acute rejection or serious
opportunistic infection within 3 months from enrollment.

- Female subjects of childbearing potential must not be pregnant or lactating at
screening.

- Participants must be capable of understanding and complying with the protocol
requirements and signing informed consent.

- Certain immunosuppressive agents such as tacrolimus and sirolimus are prohibited
due to drug interaction risk thus liver transplant patients who require these
medications for immunosuppression are not eligible.

- Patients receiving everolimus at immunosuppressive dosages are eligible since the
everolimus doses used are lower than standard anti-neoplastic dosages and this
agent does not demonstrate anti-cancer activity in HCC. Everolimus does not
interact adversely like other immunosuppressive agents.

Exclusion Criteria:

- Fibrolamellar carcinoma or mixed hepatocellular cholangiocarcinoma

- For patients who will receive enzalutamide monotherapy, failure or intolerance of
prior sorafenib is required for enrollment. For patients who will receive combination
therapy, prior sorafenib is excluded.

- Patients may not have received cytotoxic, biologic or small molecule kinase inhibitor
systemic therapy f or at least 3 weeks prior to the first dose of study treatment.

- Patients must not have received prior regional therapy such as ablation, embolization,
or radiation therapy for at least 2 weeks prior to the first dose of study treatment.
Patients who receive such therapy should have evidence of radiologic progression at
this site or other progressing measurable disease.

- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months
before study enrollment. Eligible subjects must be without corticosteroid treatment at
the time of study enrollment.

- History of seizure including febrile seizure or any condition that may predispose to
seizure (e.g., prior stroke, brain arteriovenous malformation, head trauma with loss
of consciousness requiring hospitalization). Also, current or prior treatment with
antiepileptic medications for the treatment of seizures or history of loss of
consciousness or transient ischemic attack within 12 months of enrollment.

- Clinically significant cardiovascular disease including:

- Myocardial infarction within six months prior to Screening;

- Uncontrolled angina within three months prior to Screening;

- Congestive heart failure NYHA class 3 or 4, or subjects with history of
congestive heart

- failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or MUGA
scan

- performed within 3 months results in a left ventricular ejection fraction that is
≥ 45%;

- History of clinically significant ventricular arrhythmias (e.g., ventricular
tachycardia, ventricular fibrillation, torsades de pointes);

- History of Mobitz II second degree or third degree heart block without a
permanent pacemaker in place;

- Anticoagulation with warfarin

- Inability to swallow tablets

- Subjects with history of another primary cancer, with the exception of:

- curatively resected non-melanoma skin cancer;

- curatively treated cervical carcinoma in situ;

- other primary solid tumor with no known active disease present in the opinion of
the investigator will not affect patient outcome in the setting of current HCC.

- Patients who are on strong inhibitors of CYP2C8, strong or moderate inducers of CY3A4
and CYP2C8 should discontinue these medications 2 weeks prior to the start of
treatment