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.

Study Overview

• Status: Terminated
• Conditions: Advanced Hepatocellular Carcinoma With c-MET Dysregulation
• Intervention / Treatment: Drug: INC280

Detailed Description

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
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210002
      • Novartis Investigative Site
  • Shanxi
    • Xi'an, Shanxi, China, 710032
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310016
      • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
• Singapore
  • Singapore, Singapore, 168583
    • Novartis Investigative Site
• Thailand
  • Bangkok, Thailand, 10330
    • Novartis Investigative Site
  • Bangkok, Thailand, 10700
    • Novartis Investigative Site
  • THA
    • Khon Kaen, THA, Thailand, 40002
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: INC280; 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.; Other Names: capmatinib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to approximately 8 years and 2 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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).	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Qin S, Chan SL, Sukeepaisarnjaroen W, Han G, Choo SP, Sriuranpong V, Pan H, Yau T, Guo Y, Chen M, Ren Z, Xu J, Yen CJ, Lin ZZ, Manenti L, Gu Y, Sun Y, Tiedt R, Hao L, Song W, Tanwandee T. A phase II study of the efficacy and safety of the MET inhibitor capmatinib (INC280) in patients with advanced hepatocellular carcinoma. Ther Adv Med Oncol. 2019 Dec 11;11:1758835919889001. doi: 10.1177/1758835919889001. eCollection 2019. Erratum In: Ther Adv Med Oncol. 2020 Mar 12;12:1758835920913426. doi: 10.1177/1758835920913426.

Study record dates

Study Major Dates

• Study Start (Actual): March 25, 2013
• Primary Completion (Actual): April 24, 2023
• Study Completion (Actual): May 24, 2023

Study Registration Dates

• First Submitted: November 12, 2012
• First Submitted That Met QC Criteria: November 29, 2012
• First Posted (Estimated): November 30, 2012

Study Record Updates

• Last Update Posted (Actual): September 24, 2024
• Last Update Submitted That Met QC Criteria: September 18, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: INC280; capmatinib; advanced hepatocellular carcinoma; c-MET pathway dysregulation
• 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
• Other Study ID Numbers: CINC280X2201; 2012-003758-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No