A Study of BBI608 in Combination With Sorafenib, or BBI503 in Combination With Sorafenib in Adult Patients With Hepatocellular Carcinoma

This is an open label, three-arm, phase 1 dose escalation study and phase 2 study of BBI608
in combination with sorafenib, or BBI503 in combination with sorafenib. The study population
is adult patients with advanced hepatocellular carcinoma (HCC) who have not received systemic
chemotherapy.

The phase 1 portion will involve dose-escalation of BBI608 administered in combination with a
fixed starting dose of sorafenib (Arm 1), and dose escalation of BBI503 administered in
combination with a fixed starting dose of sorafenib (Arm 2). The fixed starting dose-level of
sorafenib for both arms will be 400 mg twice daily (800 mg total daily dose). Eligible
patients will be randomized to either Arm 1 or Arm 2.

The phase 2 portion will be an open-label, 3-arm, randomized trial of patients with advanced
HCC who have not received prior systemic treatment. Patients will be randomized to receive
either, Arm 1: sorafenib administered in combination with BBI608 (at the RP2D determined for
BBI608 plus sorafenib during the phase 1 portion); Arm 2: sorafenib in combination with
BBI503 (at the RP2D determined for BBI503 plus sorafenib during the phase 1 portion), or Arm
3: sorafenib alone at a starting dose of 400 mg twice daily. The starting dose for sorafenib
is the same for all study arms.

Inclusion Criteria

1. Signed written informed consent must be obtained and documented according to
International Conference on Harmonisation (ICH) and local regulatory requirements

2. Histologically or cytologically confirmed hepatocellular carcinoma that is metastatic,
unresectable, or recurrent.

1. Patients must not be candidates for curative resection

2. Patients who have recurrent disease after having had one or more prior resections
may be eligible, provided that they are not candidates for further curative
resection.

3. Patients who have recurrent hepatocellular carcinoma following hepatic
transplantation are excluded unless the following criteria are met:

i. Transplantation was performed at least 6 months prior to the relapse of HCC. ii.
Patients are on stable immune suppressive therapy with no clinical evidence of
rejection.

iii. Are receiving ≤ 2.5 mg everolimus daily. d. Patients with known HIV infection are
excluded. e. Patients with Hepatitis B are eligible provided there is no active viral
replication. Patients with Hepatitis C who are not on interferon are eligible.

3. Patients who have a diagnosis of hepatocellular carcinoma made through radiologic
imaging may be eligible, provided they meet the criteria according to the American
Association for the Study of Liver Disease, AASLD (Bruix and Sherman, 2005; Bruix and
Sherman, 2011)

4. Patients must be candidates for sorafenib

5. Must have had no previous systemic anti-cancer treatment, though previous
loco-regional therapy is allowed:

a. Prior treatment with any of the following is allowed: trans-arterial embolization,
trans-arterial chemo-embolization, percutaneous ethanol injection, radio-embolization,
radio-frequency ablation, or other ablation techniques.

6. Must be Child-Pugh class A

a. Patients with uncontrolled massive ascites or presence of hepatic encephalopathy
are excluded

7. Must have total serum bilirubin ≤ 3 mg/dl

8. ≥ 18 years of age

9. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
1.1

10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

11. Male or female patients of child-producing potential must agree to use contraception
or avoidance of pregnancy measures during the study and for 30 days after the last
BBI608 or BBI503 dose

12. Females of childbearing potential must have a negative serum pregnancy test

13. Aspartate Aminotransferase (AST) and Alanine transaminase (ALT) < 5.0x the upper limit
of normal (ULN)

14. Glomerular filtration rate (GFR) > 45 mL/min/1.73m^2 according to the Cockcroft-Gault
estimation.

13. Hemoglobin ≥ 8.5 mg/dl 14. Absolute neutrophil count ≥ 1.5 x 10^9/L 15. Platelets ≥ 75
x 10^9/L 16. Life expectancy ≥ 3 months

Exclusion Criteria

1. Previous treatment with sorafenib

2. Patients with known hypersensitivity to sorafenib or any other component of sorafenib.

3. Previous systemic anti-vascular endothelial growth factor (VEGF) or any prior systemic
anti-cancer therapy, including prior treatment with systemic agents such as
regorafenib, ramucirumab, pazopanib, or experimental agents such as brivanib.

4. Have had a surgical procedure requiring general anesthesia or inpatient
hospitalization for recovery less than 4 weeks prior to beginning protocol therapy.

5. Have had a loco-regional procedure for the treatment of hepatocellular carcinoma (such
as a percutaneous, trans-arterial, or radio-ablative procedure) less than 4 weeks
prior to beginning protocol therapy. Protocol therapy may begin a minimum of 4 weeks
after such a procedure provided the following criteria are met:

1. There is progression of disease documented by RECIST 1.1

2. All adverse events from the procedure have resolved or have been deemed
irreversible and the patient meets inclusion criteria.

6. Any known symptomatic or untreated brain metastases requiring increase of steroid dose
within 2 weeks prior to starting on study. Patients with treated brain metastases must
be stable for 4 weeks after completion of that treatment. Patients must have no
clinical symptoms from brain metastases and must be either off steroids or on a stable
dose of steroids for at least 2 weeks prior to protocol enrollment. Patients with
known leptomeningeal metastases are excluded, even if treated.

7. Pregnant or breastfeeding

8. Significant gastrointestinal disorder(s), (e.g., Crohn's disease, ulcerative colitis,
extensive gastric and small intestine resection) such that, in the opinion of the
treating investigator, absorption of oral medications may be impaired.

9. Unable or unwilling to swallow BBI608, BBI503, or sorafenib capsules or tablets

10. Uncontrolled inter-current illness including, but not limited to: ongoing or active
infection, clinically significant non-healing or healing wounds, symptomatic
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant
pulmonary disease (shortness of breath at rest or mild exertion), or uncontrolled
infection or psychiatric illness/social situations that would limit compliance with
study requirements (e.g. no reliable transportation).

11. Subjects with a history of another primary cancer, with the exception of: a)
curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma
in situ; or c) other primary solid tumor with no known active disease present that, in
the opinion of the investigator, will not affect patient outcome in the setting of
current hepatocellular carcinoma diagnosis.

12. Abnormal ECGs which are clinically significant such as QT prolongation (QTc > 480
msec), clinically significant cardiac enlargement or hypertrophy, new bundle branch
block, or signs of active ischemia. Patients with evidence of prior infarction who are
New York Heart Association (NYHA) functional classes II, III, or IV are excluded, as
are patients with marked arrhythmias such as Wolff Parkinson White pattern or complete
atrioventricular (AV) dissociation.