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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
38
INC280 was administered orally on a continuous twice a day (BID) dosing schedule, from Day 1 until Day 21 of each 21-day cycle. INC280 was initially supplied as hard gelatin capsules and subsequently also as film-coated tablets.
Novartis Investigative Site
Nanjing, Jiangsu, China
Novartis Investigative Site
Xi’an, Shanxi, China
Novartis Investigative Site
Hangzhou, Zhejiang, China
Novartis Investigative Site
Hong Kong, Hong Kong
Time to Progression (TTP) by Investigator Assessment Per RECIST v1.1
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.
Time frame: Up to approximately 8 years and 2 months
Overall Response Rate (ORR) by Investigator Assessment Per RECIST 1.1
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.
Time frame: Up to approximately 8 years and 2 months
Disease Control Rate (DCR) by Investigator Assessment Per RECIST 1.1
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).
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Novartis Investigative Site
Singapore, Singapore
Novartis Investigative Site
Khon Kaen, THA, Thailand
Novartis Investigative Site
Bangkok, Thailand
Novartis Investigative Site
Bangkok, Thailand
Time frame: Up to approximately 8 years and 2 months
Progression-Free Survival (PFS) by Investigator Assessment Per RECIST 1.1
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.
Time frame: Up to approximately 8 years and 2 months
Overall Survival (OS)
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.
Time frame: Up to approximately 8 years and 2 months
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
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.
Time frame: From first dose of study drug to 30 days after last dose, up to approximately 8 years and 2 months
Number of Participants With Dose Reductions and Dose Interruptions of CINC280
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.
Time frame: From first dose of study drug to last dose, up to approximately 8 years and 1 month
Dose Intensity of INC280
Dose intensity of INC280 was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Time frame: From first dose of study drug to last dose, up to approximately 8 years and 1 month
Maximum Observed Plasma Concentration (Cmax) of INC280 in the Dose-Determining Part
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 frame: 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.
Time to Reach Maximum Plasma Concentration (Tmax) of INC280 in the Dose-Determining Part
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.
Time frame: 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.
Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of INC280 in the Dose-Determining Part
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.
Time frame: 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.
Apparent Plasma Clearance (CL/F) of INC280 in the Dose-Determining Part
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.
Time frame: 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.
Terminal Elimination Half-life (T1/2) of INC280 in the Dose-Determining Part
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.
Time frame: 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.
Accumulation Ratio (Racc) of INC280 in the Dose-Determining Part
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.
Time frame: 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.