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

Study Overview
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Brief Summary
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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.

Detailed Description
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This study is 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 are not eligible for or had disease progression after surgical or locoregional therapies, with c- MET dysregulation. The study includes a Dose-Determining Part and a Dose Expansion Part. Pharmacokinetic and safety profiles of INC280 in the setting of liver dysfunction will be determined in the Dose-Determining Part. The Dose Expansion Part will start when the appropriate dose for patients with liver dysfunction is determined based on pharmacokinetics (PK) and safety data from the Dose-Determining Part and other INC280 ongoing clinical studies.

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

Conditions
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Advanced Hepatocellular Carcinoma With c-MET Dysregulation

Intervention / Treatment
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* Drug: INC280


Participation Criteria
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Eligibility Criteria
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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. Other protocol-defined inclusion criteria may apply. 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. Other protocol-defined exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INC280<br>The protocol consists of two independent parts (Dose-Determining Part and Dose Expansion Part). Approximately 6 patients will be treated with INC280 300 mg twice a day in the Dose-Determining Part. Approximately 50 patients will be treated with INC280 in the Dose Expansion Part. The dose for the Expansion Part can be lower, equal or higher than in the Dose-Determining Part will be determined after the Dose Determining Part at the dose decision analysis. | Drug: INC280<br>* INC280 will be administered orally and continuously on a twice a day dosing schedule.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to progression using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 | Time to progression is the time from the date of baseline evaluation to the date of the first documented radiological confirmation of disease progression or death due to underlying cancer. | Average of 6 weeks, up to 8 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall Response Rate is defined as the proportion of patients with a best overall response of complete response or partial response at any time on study per RECIST version 1.1. | Average of 6 weeks, up to 8 years | 
| Progression free survival | Progression free survival is defined as the time from date of first study treatment intake to the date of the first radiologically documented progression or death due to any cause or initiation of new antineoplastic therapy. if a patient has not had an event, progression free survival is censored at the date of last adequate tumor assessment. | Average of 6 weeks, up to 8 years | 
| Overall survival | Overall survival is defined as the time from date of first study treatment intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. | Average of 6 weeks, up to 8 years | 
| Disease Control Rate | Disease control rate is defined as the proportion of patients with a best overall response of complete response, partial response or stable disease at any time on study per RECIST version 1.1 | Average of 6 weeks, up to 8 years | 
| Safety: adverse events, serious adverse events | Frequency and severity of adverse events. | Average of 6 weeks, up to 8 years | 
| Number of participants with dose interruptions and dose reductions | Number of participants with at least one dose interruption of INC280 and number of participants with at least one dose reduction of INC280. | Average of 6 weeks, up to 8 years | 
| Dose intensity | Dose intensity is defined as the ratio of actual cumulative dose received and actual duration of exposure. | Average of 6 weeks, up to 8 years | 
| Plasma pharmacokinetic parameter: AUC0-t | Plasma concentration of INC280 versus time profiles. AUC=Area Under the Curve | Days 1, 2, 15 and 16 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 | 
| Plasma pharmacokinetic parameter: CL/F | Plasma concentration of INC280 versus time profiles | Days 1, 2, 15 and 16 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 | 
| Plasma pharmacokinetic parameter: Cmax | Plasma concentration of INC280 versus time profiles. Cmax = Maximum concentration | Days 1, 2, 15 and 16 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 | 
| Plasma pharmacokinetic parameter: Tmax | Plasma concentration of INC280 versus time profiles. Tmax =Time to reach maximum concentration | Days 1, 2, 15 and 16 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 | 
| Plasma pharmacokinetic parameter: T1/2 | Plasma concentration of INC280 versus time profiles | Days 1, 2, 15 and 16 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 | 
| Plasma pharmacokinetic parameter: Racc | Plasma concentration of INC280 versus time profiles | Days 1, 2, 15 and 16 of Cycle 1, Day 1 of Cycle 2 and Cycle 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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INC280, advanced hepatocellular carcinoma, c-MET pathway dysregulation