Safety and Efficacy Study of CC-122 Combined With Sorafenib for Primary Liver Cancer

The primary objective of the study is to determine the safety and tolerability of CC-122
administered orally in combination with sorafenib, and to define the non-tolerated dose
(NTD), the maximum tolerated dose (MTD), and the recommended phase 2 dose (RP2D).

The secondary objective of the study is to determine the preliminary efficacy of CC-122 in
combination with sorafenib, based on response Evaluation Criteria in Solid Tumors (RECIST
1.1)

Inclusion Criteria:

1. Subject understands and voluntarily signs an informed consent document prior to
conducting any study related assessments/procedures

2. Subject is 18 years of age or more at the time of signing the Informed Consent Form

3. Subject has a confirmed pathologic diagnosis of Hepatocellular carcinoma according to
the American Association for the Study of Liver Diseases Guidelines.A biopsy
performed at screening may serve as a diagnostic biopsy for subjects with
radiographic diagnosis.

4. Subject has unresectable stage B (intermediate), or C (advanced) Hepatocellular
carcinoma according to the Barcelona Clinic Liver Cancer staging.Stage B subjects
must have progressed after, or are not eligible for curative resection,
transplantation, embolic, or ablative therapies

5. Subject has at least one measurable lesion according to Response Evaluation Criteria
in Solid Tumors version 1.1. Evaluable target lesions may not have been treated with
local therapy; previously treated lesions may only be evaluated as target lesions if
they are the only lesions available and have shown objective definite progression
after prior treatment. Local therapy must have been completed at least four weeks
prior to baseline tumor evaluation

6. Satisfactory archival tumor biopsy tissue is retrieved, or new tumor biopsy is
performed, prior to starting Cycle 1

7. Subject has life expectancy of more than 12 weeks

8. Subject has Eastern Cooperative Oncology Group Performance Status of 0 or 1

9. Subject has Child-Pugh score of less than 7 (ie, class A or better) with neither
encephalopathy nor clinically significant ascites (ascites requiring paracentesis
within 3 months of signing the ICF is excluded). Child-Pugh status is calculated
based on clinical findings and laboratory results during the screening period.

10. Subject has the following laboratory parameters at screening:

Adequate hematologic function including:

1. Absolute Neutrophil Count of at least 1.5 x 109/L

2. Platelets of at least 75,000 x 106/L

3. Hemoglobin of at least 9 g/dL

4. International Normalized Ratio of at least 1.7

Adequate hepatic function including:

a. Serum aspartate aminotransferase and alanine amino-transferase of at least 5 times
the upper limit of normal b. Serum total bilirubin of at least 3 mg/dL c. Serum
albumin of at least 2.8 g/dL Note: Laboratories in combination must still be Child
Pugh score less than 7

Other laboratory parameters:

1. Serum creatinine of at least 1.5 times the upper limit of normal

2. Potassium within normal range or corrected with supplements

11. For subjects with known or suspected cirrhosis, esophagogastroduodenoscopy ) within
12 months of signing the informed consent form, showing no evidence of untreated
varices or stigmata of active bleeding (such as active ulcer, visible vessel, or
blood) is required.

Subjects with history of upper GI bleeding must have an EGD of 3 months or less prior
to signing the consent form confirming adequate prior endoscopic therapy (eg, no
evidence of any untreated varices, recent or active bleeding, stigmata suggesting
high risk for bleeding, active ulcer). Subjects with history/suspected esophageal
varices must be on optimal medical management (eg, proton pump inhibitor and
non-selective beta-blocker) per local institutional policy.

12. Subject is able to adhere to the study visit schedule and other protocol requirements

13. Pregnancy Prevention Risk Management Plan

1. Females of childbearing potential must undergo pregnancy testing based on the
frequency outlined in Pregnancy Prevention Risk Minimization Plan and pregnancy
results must be negative.

2. Unless practicing complete abstinence from heterosexual intercourse, sexually
active FCBP must agree to use adequate contraceptive methods as specified in
Pregnancy Prevention Risk Minimization Plan.

- Complete abstinence is only acceptable in cases where this is the preferred
and usual lifestyle of the subject.

- Periodic abstinence (calendar ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable.

3. Males (including those who have had a vasectomy) must use barrier contraception
(condoms) when engaging in sexual activity with Female of Childbearing Potential
as specified in Pregnancy Prevention Risk Minimization Plan.

4. Males must agree not to donate semen or sperm for 3 months after last dose of
CC-122.

5. All subjects must:

- Understand that CC-122 could have a potential teratogenic risk.

- Agree to abstain from donating blood while taking CC-122 or sorafenib and
following discontinuation of their use.

- Agree not to share either study drug with another person.

6. Other than the subject, Female of Childbearing Potential and males able to
father a child should not handle CC-122 or touch the capsules, unless gloves are
worn.

7. Be counseled about pregnancy precautions and risks of fetal exposure

Exclusion Criteria:

- 1. Subject has received previous systemic therapy for Hepatocellular carcinoma
including sorafenib, chemotherapy and investigational agents 2. Subject has received
any local anticancer therapy within the last 4 weeks prior to signing the Informed
Consent Form 3. Subject has undergone major surgery within the last 4 weeks or minor
surgery within the last 2 weeks prior to signing the Informed Consent Form or who
have not recovered from surgery 4. Subject has received an investigational drug or
therapy for disease other than Hepatocellular carcinoma within the last 4 weeks or 5
half-lives, whichever is shorter, prior to signing the Informed Consent Form 5.
Subject has completed any radiation treatment less than 2 weeks prior to signing the
Informed Consent Form 6. Subject has received the last dose of α-interferon,
ribavirin, sofobuvir and/or other antiviral therapies for Hepatitis C Virus (HCV)
less than 4 weeks prior to signing the Informed Consent Form 7. Subject has any
clinically significant bleeding, including bleeding from esophageal/gastric varices
within ≤ 3 months of signing the informed consent form, which required transfusion,
surgical procedure or hospitalization. Esophageal varices should be treated according
to local standard practice (eg, ligation or banding and procedure completed ≤ 3
months prior to signing the informed consent form). See Inclusion Criterion 10 8.
Subjects requiring therapeutic anticoagulation with either warfarin or low molecular
weight heparin. Low dose low molecular weight heparin for catheter maintenance are
permitted 9. Subject has tumor invasion of stomach or duodenum 10. Subject has
histologic proof of fibrolamellar carcinoma 11. Subjects with known symptomatic brain
metastasis 12. Subject has persistent diarrhea due to a malabsorptive syndrome (such
as celiac sprue or inflammatory bowel disease) malabsorption ≥ National Cancer
Institute Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03) Grade
2, despite medical management, or any other significant GI disorder that could affect
the absorption of either study drug 13. Subject has history of concurrent second
cancers requiring active, ongoing systemic treatment. 14. Subject has a known history
of human immunodeficiency virus (HIV) seropositivity (HIV testing is not mandatory)
15. Subject has peripheral neuropathy of at least NCI CTCAE Grade 2 16. Subject has a
history of persistent skin rash of at least NCI CTCAE Grade 2 17. Subject has
impaired cardiac function or clinically significant cardiac disease including any of
the following:

1. LVEF (left ventricular ejection fraction) of 45% or less as determined by MUGA
(multi-gated acquisition) or ECHO (Echocardiogram)

2. Complete left bundle branch or bifascicular block

3. Congenital long QT syndrome

4. Persistent or clinically meaningful ventricular arrhythmias

5. QTcF greater than 460 msec on Screening ECG (mean of triplicate recordings)

6. Unstable angina pectoris or myocardial infarction less than 6 months prior to
starting either study drug

7. Uncontrolled hypertension (blood pressure greater than 140/90 mmHg on at least 2
measurements on sequential visits, despite blood pressure medication)

- Subjects with baseline blood pressure 140/90 mmHg are eligible but must have optimal
medication for blood pressure management h. Troponin-T value more than the upper
limit of normal or BNP greater than 100 pg/mL 18. Subject has acute or chronic active
infectious disorders or uncontrolled nonmalignant illnesses whose control, in the
opinion of the investigator, may be jeopardized by complications of this study
therapy. Chronic hepatitis B and C virus are excepted (ie, eligible for study).

19. Subject has undergone liver transplantation or other solid organ transplantation
requiring immunosuppression 20. Subject is receiving chronic treatment with systemic
corticosteroids or other potentially immunosuppressive agent. Intermittent topical or
local injection of corticosteroids and oral/IV aldosterone or other
mineralocorticoids is allowed 21. Subjects with history of non-healing wounds or
ulcers, or bone fractures less than 3 months of a prior fracture 22. Subject is being
treated with concomitant strong CYP3A4 inducers such as St. John's Wort,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital. The use
of concomitant strong CYP3A4 inducers may decrease sorafenib plasma concentrations
and must be avoided.

23. Subject is a female who is pregnant or is breast feeding 24. Subject is unwilling
or unable to comply with the protocol, in the opinion of the investigator 25. Subject
has any significant medical condition, laboratory abnormality, or psychiatric illness
that would prevent the subject from participating in the study 26. Subject has any
condition that confounds the ability to interpret data from the study