A Dose-Finding and Exploratory Study of RO5323441 in Combination With Sorafenib in Patients With Hepatocellular Carcinoma

• Part I : Safety/dose-limiting toxicity: Incidence of adverse events [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
• Part I: Determination of recommended Part II dose [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
• Part II: Safety/tolerability: Incidence of adverse events [ Time Frame: up to 28 months ] [ Designated as safety issue: No ]

• Pharmacokinetics of RO5323441 in combination with sorafenib [ Time Frame: up to 40 months ] [ Designated as safety issue: No ]
• Pharmacokinetics of sorafenib in combination with RO5323441 [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
• Pharmacodynamic biomarkers (DCE-Magnetic Resonance Imaging evaluations, Placental Growth Factor, Vascular Endothelial Growth Factor Receptors) [ Time Frame: up to 40 months ] [ Designated as safety issue: No ]
• Efficacy: tumor assessments by Magnetic Resonance Imaging or Computed Tomography according to RECIST criteria [ Time Frame: up to 40 months ] [ Designated as safety issue: No ]
• Impact on wound healing (skin biopsies) [ Time Frame: up to 40 months ] [ Designated as safety issue: No ]
• Safety: additional anti-drug antibodies sampling after termination of study drug treatment [ Time Frame: 2 and 4 months after last dose of study drug ] [ Designated as safety issue: No ]

This open-label study will assess the safety, efficacy and pharmacokinetics of RO5323441 in combination with sorafenib in patients with advanced or metastatic hepatocellular carcinoma previously untreated with systemic therapy. In the dose-finding Part I, cohorts of patients will receive escalating doses of RO5323441 intravenously (iv) every 2 weeks in combination with sorafenib 400 mg orally twice daily. In the exploratory Part II, patients will be randomized to receive either the previously established dose of RO5323441 iv every 2 weeks plus continuous oral sorafenib or sorafenib alone. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs. For patients in the sorafenib arm with disease progression crossover to combination treatment with RO5323441 will be allowed.

• Drug: RO5323441
  escalating doses iv
• Drug: RO5323441
  iv every 2 weeks
• Drug: sorafenib
  400 mg orally twice daily to once every other day

• Experimental: Part I
  Interventions:

  • Drug: RO5323441
  • Drug: sorafenib
• Experimental: Part II (A)
  Interventions:

  • Drug: RO5323441
  • Drug: sorafenib
• Active Comparator: Part II (B)
  Intervention: Drug: sorafenib

Inclusion Criteria:

• Adult patients >/= 21 years of age
• Advanced or metastatic and/or unresectable hepatocellular carcinoma
• At least 1 measurable lesion according to RECIST criteria
• Primary tumor in situ (Expansion Cohort Part I, Part II)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Adequate bone marrow, liver and renal function

Exclusion Criteria:

• Prior systemic treatment for metastatic hepatocellular carcinoma or patients who had tumor removed (Expansion Cohort Part I, Part II)
• Major surgery within previous 4 weeks or planned major surgical procedure during course of study
• Radiation therapy within 28 days prior to start of study treatment
• Serious non-healing wound, ulcer ore bone fracture
• History of uncontrolled seizures or encephalopathy within the last 6 months
• Current central nervous system (CNS) metastases or spinal cord compression
• History of gastrointestinal perforation or esophageal/gastric bleeding within 6 months prior to study enrollment
• History of another primary malignancy and off treatment for </= 3 years, except for non-melanoma skin cancer and carcinoma in situ of the cervix
• Patients with prior liver transplant
• Inadequately controlled hypertension or prior history of hypertensive crisis or hypertensive encephalopathy
• Active bleeding diathesis