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The study recruitment was ended due to difficulties in identifying subjects who meet the eligibility criteria and therefore the study never reached its planned sample size per protocol. The study termination was not due to any safety concerns.
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| INC280 | Experimental | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| INC280 | Drug | 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. |
| 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 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Nanjing | Jiangsu | 210002 | China | ||
| Novartis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 31853265 | Derived | 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. |
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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.
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Evidence of c-MET pathway dysregulation had to be available to be eligible to participate in this study.
After the molecular pre-screening, screening assessments had to be done within 14 days prior to the first dose of INC280.
The study included a Dose-Determining Part designed to identify an appropriate dose for patients with hepatocellular carcinoma (HCC) and a Dose Expansion part designed to estimate the efficacy in patients with HCC with different levels of c-MET expression.
Participants took part in 9 investigative sites in 4 countries.
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| ID | Title | Description |
|---|---|---|
| FG000 | CINC280 300 mg BID Capsule | INC280 300 mg orally twice daily (BID) as capsule |
| FG001 | CINC280 600 mg BID Capsule | INC280 600 mg orally twice daily (BID) as capsule |
| FG002 | CINC280 400 mg BID Tablet | INC280 400 mg orally twice daily (BID) as tablet |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | CINC280 300 mg BID Capsule | INC280 300 mg orally twice daily (BID) as capsule |
| BG001 | CINC280 600 mg BID Capsule | INC280 600 mg orally twice daily (BID) as capsule |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the study protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the primary objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing. | Posted | Median | 90% Confidence Interval | months | Up to approximately 8 years and 2 months |
Adverse events and deaths in the on-treatment period were collected from first dose of study treatment to 30 days after last dose, up to approximately 8 years and 2 months. Deaths were collected in the survival follow-up from day 31 after last dose of study treatment until the end of the study, up to approximately 8 years and 2 months. These are not considered AEs.
Patients were analyzed according to the treatment they actually received (Safety Set).
Deaths in the survival follow-up are not considered Adverse Events.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CINC280 300 mg BID Capsule - On-treatment | AEs collected during on-treatment period (up to 30 days after last dose). |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (24.1) | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (24.1) | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study Director | Novartis Pharmaceuticals | 862-778-8300 | Novartis.email@novartis.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 16, 2022 | Mar 25, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Nov 28, 2022 | Mar 25, 2024 | SAP_001.pdf |
| ID | Term |
|---|---|
| C000613976 | capmatinib |
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|
| 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. |
| Xi’an |
| Shanxi |
| 710032 |
| China |
| Novartis Investigative Site | Hangzhou | Zhejiang | 310016 | China |
| Novartis Investigative Site | Hong Kong | Hong Kong |
| Novartis Investigative Site | Singapore | 168583 | Singapore |
| Novartis Investigative Site | Khon Kaen | THA | 40002 | Thailand |
| Novartis Investigative Site | Bangkok | 10330 | Thailand |
| Novartis Investigative Site | Bangkok | 10700 | Thailand |
| Physician Decision |
|
| Progressive Disease |
|
| Study Terminated by Sponsor |
|
| Subject/Guardian Decision |
|
| BG002 | CINC280 400 mg BID Tablet | INC280 400 mg orally twice daily (BID) as tablet |
| BG003 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| c-MET (MET proto-oncogene) status | c-MET status was determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. cMET staining by IHC is scored from 0 (no staining) to 3+ (staining with strong intensity). As introduced in Protocol Amendment 2, c-MET positivity (c-MET High) was defined as IHC intensity score 3+ in >=50% of tumor cells or c-MET IHC intensity score 2+ in >=50% of tumor cells only if they have in addition MET gene copy number >=5 as detected by FISH or MET gene copy number >=5 by FISH and unknown c-MET IHC results. c-MET Low was defined as not fulfilling c-MET high criteria. | Count of Participants | Participants |
|
|
|
|
| Secondary | 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. | All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing. | Posted | Number | 95% Confidence Interval | Percentage of participants | Up to approximately 8 years and 2 months |
|
|
|
| Secondary | 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). | All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing. | Posted | Number | 95% Confidence Interval | Percentage of participants | Up to approximately 8 years and 2 months |
|
|
|
| Secondary | 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. | All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing. | Posted | Median | 95% Confidence Interval | months | Up to approximately 8 years and 2 months |
|
|
|
| Secondary | 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. | All patients who received at least one dose of INC280. Patients were analyzed according to the treatment group defined in the protocol to which they were assigned at baseline: Dose-Determining part and Dose Expansion part. In alignment with the secondary efficacy objective of the study, efficacy was analyzed in the dose expansion part based on the level of c-MET expression, independently of the formulation received, the capsule or the tablet that was introduced later to facilitate the dosing. | Posted | Median | 95% Confidence Interval | months | Up to approximately 8 years and 2 months |
|
|
|
| Secondary | 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. | Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received. | Posted | Count of Participants | Participants | From first dose of study drug to 30 days after last dose, up to approximately 8 years and 2 months |
|
|
|
| Secondary | 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. | Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received. | Posted | Count of Participants | Participants | From first dose of study drug to last dose, up to approximately 8 years and 1 month |
|
|
|
| Secondary | Dose Intensity of INC280 | Dose intensity of INC280 was calculated as actual cumulative dose in milligrams divided by duration of exposure in days. | Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received. | Posted | Median | Full Range | mg/day | From first dose of study drug to last dose, up to approximately 8 years and 1 month |
|
|
|
| Secondary | 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. | Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 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. |
|
|
|
| Secondary | 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. | Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part | Posted | Median | Full Range | hours | 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. |
|
|
|
| Secondary | 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. | Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part | Posted | Geometric Mean | Geometric Coefficient of Variation | hr*ng/mL | 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. |
|
|
|
| Secondary | 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. | Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part | Posted | Mean | Standard Deviation | mL/hr | 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. |
|
|
|
| Secondary | 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. | Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part | Posted | Mean | Standard Deviation | hours | 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. |
|
|
|
| Secondary | 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. | Patients in the pharmacokinetic analysis set (PAS) with an available value for the outcome measure. PAS consists of all patients who provided an evaluable PK profile. A profile is considered evaluable if all the following conditions are satisfied: patient received at least one dose of the planned treatments, patient provided at least one primary PK parameter and patient did not vomit within 4 hours after the dosing of INC280. Full PK blood samples were not collected in the Dose-Expansion Part | Posted | Mean | Standard Deviation | ratio | 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. |
|
|
|
| Post-Hoc | All-Collected Deaths | On-treatment deaths were collected from start of treatment to 30 days after last dose. Survival follow-up deaths were collected from day 31 after last dose of study treatment until end of study. All deaths refer to the sum of on-treatment deaths plus survival follow-up deaths. | Safety Set: All patients who received at least one dose of INC280. Patients were analyzed according to the treatment they actually received. | Posted | Number | participants | On-treatment: Up to approximately 8 years and 2 months. Survival follow-up: Up to approximately 8 years and 2 months. |
|
|
|
| 1 |
| 9 |
| 6 |
| 9 |
| 9 |
| 9 |
| EG001 | CINC280 600 mg BID Capsule - On-treatment | AEs collected during on-treatment period (up to 30 days after last dose). | 5 | 27 | 13 | 27 | 27 | 27 |
| EG002 | CINC280 400 mg BID Tablet - On-treatment | AEs collected during on-treatment period (up to 30 days after last dose). | 1 | 2 | 1 | 2 | 2 | 2 |
| EG003 | CINC280 300 mg BID Capsule - Survival Follow-up | Deaths collected in the survival follow-up period (starting from day 31 after last dose). No AEs were collected during this period. | 8 | 8 | 0 | 0 | 0 | 0 |
| EG004 | CINC280 600 mg BID Capsule - Survival Follow-up | Deaths collected in the survival follow-up period (starting from day 31 after last dose). No AEs were collected during this period. | 17 | 22 | 0 | 0 | 0 | 0 |
| EG005 | CINC280 400 mg BID Tablet - Survival Follow-up | Deaths collected in the survival follow-up period (starting from day 31 after last dose). No AEs were collected during this period. | 1 | 1 | 0 | 0 | 0 | 0 |
| Abdominal pain | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Gastric haemorrhage | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Varices oesophageal | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| General physical health deterioration | General disorders | MedDRA (24.1) | Systematic Assessment |
|
| Bile duct stenosis | Hepatobiliary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hepatic failure | Hepatobiliary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hepatic haemorrhage | Hepatobiliary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hepatic mass | Hepatobiliary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Biliary tract infection | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Septic shock | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Tumour pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (24.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Spinal cord compression | Nervous system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hydronephrosis | Renal and urinary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypovolaemic shock | Vascular disorders | MedDRA (24.1) | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Visual field defect | Eye disorders | MedDRA (24.1) | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Haematochezia | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Lip dry | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Lower gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Mouth ulceration | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Peptic ulcer | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA (24.1) | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA (24.1) | Systematic Assessment |
|
| Peripheral swelling | General disorders | MedDRA (24.1) | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Bronchitis | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA (24.1) | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Amylase increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Bilirubin conjugated increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Blood albumin decreased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Blood bilirubin increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Blood cholesterol increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Blood creatinine increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Hepatitis B DNA increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Lipase increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Platelet count decreased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Weight increased | Investigations | MedDRA (24.1) | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypocalcaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypoglycaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Hypoproteinaemia | Metabolism and nutrition disorders | MedDRA (24.1) | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA (24.1) | Systematic Assessment |
|
| Tumour pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (24.1) | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Syncope | Nervous system disorders | MedDRA (24.1) | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA (24.1) | Systematic Assessment |
|
| Acute kidney injury | Renal and urinary disorders | MedDRA (24.1) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA (24.1) | Systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA (24.1) | Systematic Assessment |
|
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (24.1) | Systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA (24.1) | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
| Title | Measurements |
|---|---|
|
| SAEs |
|
| Treatment-related SAEs |
|
| Fatal SAEs |
|
|
| At least one dose interruption |
|
|
|
|
|
| Survival follow-up deaths |
|
|
| All deaths |
|
|