E7050 in Combination With Sorafenib Versus Sorafenib Alone as First Line Therapy in Patients With Hepatocellular Carcinoma

This open-label, multicenter, randomized study will consist of a Phase Ib: a safety run-in
period with 3 ascending doses of E7050 in combination with sorafenib; and a Phase II
portion: a randomized 2-arm period. Approximately 95 patients with hepatocellular carcinoma
will be enrolled in the study (10-15 patients in the Phase Ib portion and 80 patients in the
Phase II portion). Patients will only participate in either the Phase Ib or the Phase II
portion of the study. In both Phase Ib and phase II, Patients will receive study treatment
(E7050 plus sorafenib or sorafenib alone) until the occurrence of progressive disease
(PD)for approximately six 28-day cycles (24 weeks). After 6 cycles. ath the discretion of
the Investigator and in consultation with the Medical Monitor, patients who are experiencing
clinical benefit may continue E7050, with or without sorafenib (Arm 1), or may continue
sorafenib alone (Arm 2), depending on the original randomization treatment arm, for as long
as clinical benefit is sustained and the treatment is well tolerated. Patients will be
followed until death following completion of therapy.

Inclusion Criteria

- Unresectable locally advanced or metastatic HCC;

- Histologic confirmation not required if other diagnostic criteria are met;

- No previous systemic anti-cancer therapy permitted (2 prior systemic anti-cancer
regimen are allowed in Phase Ib). Previous chemoembolization, radioembolization,
radiofrequency ablation, or other local ablative therapies are permitted if greater
than 6 weeks of first day of study-defined treatment;

- ECOG PS 0 or 1; Child-Pugh Cirrhotic Status A or B with a score of 7;

- Blood pressure must be well-controlled (less than or equal to 140/90 mmHg at
screening) with or without antihypertensive medication. Patients must have no history
of hypertensive crisis or hypertensive encephalopathy;

Exclusion Criteria

- Previously received E7050 anti-cmet, or anti-angiogenic therapy (prior
anti-angiogenic therapy is permitted in Phase Ib only);

- Presence of brain metastases, unless the patient has received adequate treatment at
least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids
for at least 4 weeks prior to randomization;

- Palliative radiotherapy is not permitted throughout the study period;

- Active hemoptysis

- Serious non-healing wound, ulcer, or active bone fracture;

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days
prior to commencing study treatment, or anticipation of need for a major surgical
procedure during the course of the study;

- Clinically significant gastrointestinal bleeding (bleeding requiring procedural
intervention, eg. variceal banding, transjugular intrahepatic portosystemic shunt
(TIPS) procedure, arterial embolization, topical coagulation therapy) within 6 months
prior to first dose.