Study Efficacy and Safety of INC280 in Patients With Advanced Hepatocellular Carcinoma.

A Phase II, Open Label, Single Arm, Multicenter Study of INC280 Administered Orally in Adults With Advanced Hepatocellular Carcinoma

This study is to find out if INC280 is safe and has beneficial effects in patients with advanced hepatocellular carcinoma known to have dysregulation of c-MET pathway.

This study was designed as a Phase II, single arm, open-label, multicenter study to evaluate the safety and efficacy of INC280 as first-line treatment in patients with advanced hepatocellular carcinoma (HCC) who were not eligible for or had disease progression after surgical or locoregional therapies, with c-MET dysregulation.

The study included a Dose-Determining Part and a Dose Expansion Part. Pharmacokinetic and safety profiles of INC280 in the setting of liver dysfunction were determined in the Dose-Determining Part. The Dose Expansion Part started when the appropriate dose for patients with liver dysfunction was determined based on pharmacokinetics (PK) and safety data from the Dose-Determining Part and other INC280 clinical studies. The initial dose of INC280 assessed during the dose expansion part was 600 mg twice daily (BID) administered as capsules of 50 mg. Later during the dose expansion part, a tablet with higher dosage strengths (50 mg, 150 mg, and 200 mg) was developed and introduced to improve the convenience of study drug administration for patients. PK data on INC280 tablet at 400 mg BID from other studies (NCT01324479, NCT01546428 and NCT01610336) showed that systemic exposure to INC280 was in the range of that achieved with the capsule at 600 mg BID.

During the Dose Expansion part of the study, Novartis halted the enrollment in Dec-2016 due to difficulty in identifying patients who met the definition of c-MET high as defined in the inclusion criteria. Patients who were already enrolled and signed the informed consent were allowed to continue in the study according to the protocol. The enrollment halt was not a consequence of any safety concerns.

Inclusion Criteria:

• Confirmed c-MET pathway dysregulation.
• Advanced hepatocellular carcinoma which could not be suitable for treatment with locoregional therapies or has progressed following locoregional therapy.
• Measurable disease as determined by RECIST version 1.1.
• Current cirrhotic status of Child-Pugh class A with no encephalopathy.
• Eastern Cooperative Oncology Group (ECOG) performance status < or = 2.

Exclusion Criteria:

• Received any prior systemic chemotherapy or molecular-targeted therapy for hepatocellular carcinoma such as sorafenib.
• Previous treatment with c-MET inhibitor or hepatocyte growth factor targeting therapy.
• Previous local therapy completed less than 4 weeks prior to dosing and, if present, any acute toxicity > grade 1.
• Known active bleeding (e.g. bleeding from gastro-intestinal ulcers or esophageal varices) within 2 months prior to screening or with history or evidence of inherited bleeding diathesis or coagulopathy.
• Clinically significant venous or arterial thrombotic disease within past 6 months.
• History of acute or chronic pancreatitis, surgery of pancreas or any risk factors that may increase risk of pancreatitis.