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

Study Overview
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Brief Summary
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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.

Official Title
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Exploratory Open Label Dose-escalation Phase Ib Study to Evaluate Safety, Pharmacokinetics and Therapeutic Activity of RO5323441, Administered Intravenously, in Combination With Sorafenib (Nexavar®), in Patients With Advanced or Metastatic and/or Unresectable Hepatocellular Carcinoma

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: RO5323441
* Drug: RO5323441
* Drug: sorafenib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part I<br> | Drug: RO5323441<br>* escalating doses iv<br>Drug: sorafenib<br>* 400 mg orally twice daily to once every other day<br>|
| Experimental: Part II (A)<br> | Drug: RO5323441<br>* iv every 2 weeks<br>Drug: sorafenib<br>* 400 mg orally twice daily to once every other day<br>|
| Active Comparator: Part II (B)<br> | Drug: sorafenib<br>* 400 mg orally twice daily to once every other day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part I : Safety/dose-limiting toxicity: Incidence of adverse events |  | up to 12 months | 
| Part I: Determination of recommended Part II dose |  | up to 12 months | 
| Part II: Safety/tolerability: Incidence of adverse events |  | up to 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of RO5323441 in combination with sorafenib |  | up to 40 months | 
| Pharmacokinetics of sorafenib in combination with RO5323441 |  | up to 12 months | 
| Pharmacodynamic biomarkers (DCE-Magnetic Resonance Imaging evaluations, Placental Growth Factor, Vascular Endothelial Growth Factor Receptors) |  | up to 40 months | 
| Efficacy: tumor assessments by Magnetic Resonance Imaging or Computed Tomography according to RECIST criteria |  | up to 40 months | 
| Impact on wound healing (skin biopsies) |  | up to 40 months | 
| Safety: additional anti-drug antibodies sampling after termination of study drug treatment |  | 2 and 4 months after last dose of study drug |