Study Efficacy and Safety of INC280 in Patients With Advanced Hepatocellular Carcinoma.
- Conditions
- Advanced Hepatocellular Carcinoma With c-MET Dysregulation
- Interventions
- Drug: INC280
- Registration Number
- NCT01737827
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 38
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description INC280 INC280 The protocol consisted of two independent parts (Dose-Determining Part and Dose Expansion Part). Patients were treated with INC280 300 mg twice a day in the Dose-Determining Part. The dose for the Expansion Part could be lower, equal or higher than in the Dose-Determining Part and was determined after the Dose Determining Part at the dose decision analysis.
- Primary Outcome Measures
Name Time Method Time to Progression (TTP) by Investigator Assessment Per RECIST v1.1 Up to approximately 8 years and 2 months TTP is defined as the time from the date of treatment start to the date of the first documented radiological confirmation of disease progression or death due to underlying cancer. Tumor response was based on investigator assessment per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. For RECIST v1.1, Progressive disease (PD) = At least a 20% increase in the sum of diameters of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition, the sum must also demonstrate an absolute increase of at least 5 mm. If a patient had not had the event at the date of analysis cut-off or when he/she received any further anti-neoplastic therapy, TTP was censored at the time of the last adequate assessment. TTP was estimated using the Kaplan-Meier method.
- Secondary Outcome Measures
Name Time Method Overall Response Rate (ORR) by Investigator Assessment Per RECIST 1.1 Up to approximately 8 years and 2 months Tumor response was based on local investigator assessment per RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response (BOR) of Complete Response (CR) or Partial Response (PR).
For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.Disease Control Rate (DCR) by Investigator Assessment Per RECIST 1.1 Up to approximately 8 years and 2 months Tumor response was based on local investigator assessment per RECIST v1.1. DCR is defined as the percentage of participants with a BOR of Complete Response (CR), Partial Response (PR) and Stable Disease (SD).
For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to \< 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).Progression-Free Survival (PFS) by Investigator Assessment Per RECIST 1.1 Up to approximately 8 years and 2 months PFS 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 did not have an event, PFS was censored at the date of the last adequate tumor assessment.
PFS was analyzed using Kaplan-Meier estimates.Overall Survival (OS) Up to approximately 8 years and 2 months OS is defined as the time from date of first study treatment intake to date of death due to any cause. If a patient was not known to have died, survival was censored at the date of last contact.
OS was analyzed using the Kaplan-Meier method.Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) From first dose of study drug to 30 days after last dose, up to approximately 8 years and 2 months Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
Number of Participants With Dose Reductions and Dose Interruptions of CINC280 From first dose of study drug to last dose, up to approximately 8 years and 1 month For patients who did not tolerate the protocol-specified dosing scheme, dose adjustments and interruptions were permitted.
Number of participants with dose reductions and dose interruptions of CINC280 is reported in this table.Dose Intensity of INC280 From first dose of study drug to last dose, up to approximately 8 years and 1 month Dose intensity of INC280 was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Maximum Observed Plasma Concentration (Cmax) of INC280 in the Dose-Determining Part pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days. Pharmacokinetic (PK) parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
Time to Reach Maximum Plasma Concentration (Tmax) of INC280 in the Dose-Determining Part pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days. PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations.
Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of INC280 in the Dose-Determining Part pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days. PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12h calculation. A dosing interval was 12 hours for twice daily dosing.
Apparent Plasma Clearance (CL/F) of INC280 in the Dose-Determining Part pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days. PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Apparent drug clearance from the plasma was calculated as dose/AUCinf.
Terminal Elimination Half-life (T1/2) of INC280 in the Dose-Determining Part pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days. PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Elimination half-life (T1/2) values were calculated as natural logarithm (ln) 2/terminal elimination rate constant.
Accumulation Ratio (Racc) of INC280 in the Dose-Determining Part pre-dose, 30 minutes and 1, 2, 4, 6 and 8 hours after morning dose and 12 hours after evening dose on Cycle 1 Day 1 and Cycle 1 Day 15. The duration of one cycle was 21 days. PK parameters were calculated based on INC280 plasma concentrations by using non-compartmental methods. Accumulation ratio of drug exposure was calculated as AUC0-12h on Cycle 1 Day 15 divided by AUC0-12h on Cycle 1 Day 1.
Trial Locations
- Locations (1)
Novartis Investigative Site
🇹🇭Bangkok, Thailand