Clinical trial NCT01737827: Study Efficacy and Safety of INC280 in Patients With Advanced Hepatocellular Carcinoma.
Official title: A Phase II, Open Label, Single Arm, Multicenter Study of INC280 Administered Orally in Adults With Advanced Hepatocellular Carcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Advanced Hepatocellular Carcinoma With c-MET Dysregulation
Keywords: INC280
capmatinib
advanced hepatocellular carcinoma
c-MET pathway dysregulation
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2012-11-30
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to Progression (TTP) by Investigator Assessment Per RECIST v1.1
timeFrame: Up to approximately 8 years and 2 months
Secondary outcomes:
measure: Overall Response Rate (ORR) by Investigator Assessment Per RECIST 1.1
timeFrame: Up to approximately 8 years and 2 months
measure: Disease Control Rate (DCR) by Investigator Assessment Per RECIST 1.1
timeFrame: Up to approximately 8 years and 2 months
measure: Progression-Free Survival (PFS) by Investigator Assessment Per RECIST 1.1
timeFrame: Up to approximately 8 years and 2 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 8 years and 2 months
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug to 30 days after last dose, up to approximately 8 years and 2 months
measure: Number of Participants With Dose Reductions and Dose Interruptions of CINC280
timeFrame: From first dose of study drug to last dose, up to approximately 8 years and 1 month
measure: Dose Intensity of INC280
timeFrame: From first dose of study drug to last dose, up to approximately 8 years and 1 month
measure: Maximum Observed Plasma Concentration (Cmax) of INC280 in the Dose-Determining Part
timeFrame: 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.
measure: Time to Reach Maximum Plasma Concentration (Tmax) of INC280 in the Dose-Determining Part
timeFrame: 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.
measure: Area Under the Plasma Concentration-time Curve From Time Zero to 12 Hours (AUC0-12h) of INC280 in the Dose-Determining Part
timeFrame: 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.
measure: Apparent Plasma Clearance (CL/F) of INC280 in the Dose-Determining Part
timeFrame: 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.
measure: Terminal Elimination Half-life (T1/2) of INC280 in the Dose-Determining Part
timeFrame: 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.
measure: Accumulation Ratio (Racc) of INC280 in the Dose-Determining Part
timeFrame: 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.
Other outcomes:
Locations:
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Xi'an
country: China
facility: Novartis Investigative Site
state: Shanxi
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Khon Kaen
country: Thailand
facility: Novartis Investigative Site
state: THA
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.