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

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

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.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Drug: RO5323441; Drug: RO5323441; Drug: sorafenib

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 119228
  • Singapore, Singapore, 169610

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Hoffmann-La Roche

Study record dates

Study Major Dates

• Study Start: March 1, 2011
• Primary Completion (Actual): January 1, 2012
• Study Completion (Actual): January 1, 2012

Study Registration Dates

• First Submitted: March 2, 2011
• First Submitted That Met QC Criteria: March 2, 2011
• First Posted (Estimate): March 4, 2011

Study Record Updates

• Last Update Posted (Estimate): November 2, 2016
• Last Update Submitted That Met QC Criteria: November 1, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Protein Kinase Inhibitors; Sorafenib; Antibodies, Monoclonal
• Other Study ID Numbers: BP25497