Back to resultsPhase Ib/II Study of INC280 + PDR001 or PDR001 Single Agent in Advanced HCC
Primary Purpose
Advanced Hepatocellular Carcinoma
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Spartalizumab
Capmatinib
Sponsored by
About this trial
This is an interventional treatment trial for Advanced Hepatocellular Carcinoma focused on measuring Phase Ib/II, INC280, PDR001, capmatinib, spartalizumab, checkpoint inhibitor, PD-1, Liver cancer
Eligibility Criteria
Inclusion Criteria:
- Histologically or cytologically documented locally advanced recurrent or metastatic HCC or for patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the study of the liver (APASL) criteria. Current cirrhotic status of Child Pugh Class A (5-6 points), with no encephalopathy and/or clinically significant ascites (defined as requiring the use of diuretics or paracentesis treatment).
- Patients must have received prior systemic sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment (for France only: patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib discontinuation),.
- ECOG Performance Status ≤ 1.
- Willing and able to swallow and retain oral medication. Other protocol defined Inclusion criteria may apply.
Exclusion Criteria:
- Use of any live vaccines within 4 weeks of initiation of study treatment.
- History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
- Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
- Active autoimmune disease or a documented history of autoimmune disease.
- Clinically significant, uncontrolled heart diseases.
Patient having out of range laboratory values defined as:
- Total bilirubin > 2 mg/dL, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
- Alanine aminotransferase (ALT) > 5 x ULN
- Aspartate aminotransferase (AST) > 5 x ULN
- Coagulation: Prothrombin Time (PT) > 4 seconds more than the ULN or International Normalized Ratio (INR) > 1.7
- Absolute neutrophil count (ANC) < 1.5 x 109/L
- Platelet count < 75 x 109/L
- Hemoglobin < 9 g/dL
- Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 45 mL/min
- Asymptomatic serum amylase grade > 2 (1.5-2.0 x ULN). Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
- Serum lipase > ULN
- Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) outside of normal limits (patients may be enrolled if corrected to within normal limits with supplements during screening)
Other protocol-defined Exclusion criteria may apply.
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Phase II: Spartalizumab 300 mg Q3W
Arm Description
Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
Outcomes
Primary Outcome Measures
Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 2 cycles of treatment with capmatinib in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 21 days.
Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.
No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Phase Ib: Dose Intensity of Capmatinib
Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Phase Ib: Dose Intensity of Spartalizumab
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
Phase II: Overall Response Rate (ORR) Per RECIST v1.1
Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response 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.
Secondary Outcome Measures
Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1.
For RECIST v1.1, R=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 diameters of all target lesions, taking as reference the baseline sum of diameters; 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; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).
The number of participants in each response category is reported in the table.
Phase Ib and Phase II: Best Overall Response (BOR) Per irRC
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per Immune-related Response Criteria (irRC).
For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters; irPD= At least a 20% increase in the sum of diameters of all measured target lesions including new measurable 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; irSD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for irPD).
Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1
Tumor response was based on local investigator assessment as per RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response 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.
Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC
Tumor response was based on local investigator assessment as per irRC. ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR).
For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters.
Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1
DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any.
According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.
Phase Ib and Phase II: Duration of Response (DOR) Per irRC
DOR only applies to patients for whom best overall response is immune-related complete response (irCR) or immune-related partial response (irPR) based on local investigator assessment of overall lesion response according to irRC. DOR is defined as the time from the date of first documented response (confirmed irCR or confirmed irPR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any.
According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm.
Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1
TTR is defined as the time from the date of start of treatment to the date of first documented response (CR or PR, which must be confirmed subsequently) for patients who achieved a confirmed CR or PR. Tumor response was based on local investigator assessment per RECIST v1.1.
Patients who did not achieve a confirmed CR or PR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise.
According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.
Phase Ib and Phase II: Time to Response (TTR) Per irRC
TTR is defined as the time from the date of start of treatment to the date of first documented response (irCR or irPR, which must be confirmed subsequently) for patients who achieved a confirmed irCR or irPR. Tumor response was based on local investigator assessment per irRC.
Patients who did not achieve a confirmed irCR or irPR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise.
According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm.
Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1
PFS is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1.
PFS was estimated using the Kaplan-Meier Method.
Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC
PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC.
PFS was estimated using the Kaplan-Meier Method.
Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1
TTP is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1.
TTP was estimated using the Kaplan-Meier Method.
Phase Ib and Phase II: Time to Progression (TTP) Per irRC
TTP is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC.
Phase Ib and Phase II: Overall Survival (OS)
OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, OS time was censored at the date of last contact.
OS was estimated using the Kaplan-Meier Method.
Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.
No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Phase II: Dose Intensity of Capmatinib
Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Phase II: Dose Intensity of Spartalizumab
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib
Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib
Pharmacokinetic (PK) parameters were calculated based on capmatinib 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.
Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib
Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Phase II: Pre-dose Plasma Concentration of Capmatinib
Capmatinib plasma concentration was assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration.
Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples
The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.
Phase Ib and Phase II: PD-L1 Percent Positive Tumor
The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02795429
Brief Title
Phase Ib/II Study of INC280 + PDR001 or PDR001 Single Agent in Advanced HCC
Official Title
A Phase Ib/II, Open-label, Multi-center Study of INC280 in Combination With PDR001 or PDR001 Single Agent in Advanced Hepatocellular Carcinoma.
Study Type
Interventional
2. Study Status
Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
June 15, 2016 (Actual)
Primary Completion Date
June 1, 2021 (Actual)
Study Completion Date
June 24, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study of capmatinib (INC280) and spartalizumab (PDR001) was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of spartalizumab administered intravenously (i.v.) as a single agent or in combination with capmatinib administered orally in adult patients with advanced hepatocellular carcinoma (HCC).
Detailed Description
This was a Phase Ib/II, open label, multicenter study starting with a Phase Ib dose escalation part followed by a randomized Phase II part in patients with advanced hepatocellular carcinoma. Capmatinib was administered orally twice daily (BID) and spartalizumab was administered i.v. every 3 weeks (Q3W) until the occurrence of unacceptable toxicity, progressive disease as per irRC and/or treatment was discontinued at the discretion of the Investigator or the participant. A complete cycle of treatment was defined as 21 days.
During the Phase Ib dose escalation part of the study, participants were treated with capmatinib in combination with a fixed dose of spartalizumab until the maximum tolerated dose (MTD) was reached or the recommended phase 2 dose (RP2D) was established. The capmatinib dose was increased and the spartalizumab dose remained constant.
Once the MTD and/or RP2D were declared for capmatinib in combination with spartalizumab, additional participants were enrolled in the Phase II part in order to assess the anti-tumor activity of capmatinib in combination with spartalizumab and spartalizumab single agent. Participants were randomly assigned, in a 1:1 ratio, to treatment with either capmatinib in combination with spartalizumab or spartalizumab single agent.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Hepatocellular Carcinoma
Keywords
Phase Ib/II, INC280, PDR001, capmatinib, spartalizumab, checkpoint inhibitor, PD-1, Liver cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
89 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W
Arm Type
Experimental
Arm Description
Capmatinib 200 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
Arm Title
Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W
Arm Type
Experimental
Arm Description
Capmatinib 300 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
Arm Title
Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Arm Type
Experimental
Arm Description
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase Ib
Arm Title
Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W
Arm Type
Experimental
Arm Description
Capmatinib 400 mg administered orally on a continuous twice daily (BID) dosing schedule in combination with spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
Arm Title
Phase II: Spartalizumab 300 mg Q3W
Arm Type
Experimental
Arm Description
Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
Intervention Type
Drug
Intervention Name(s)
Spartalizumab
Other Intervention Name(s)
PDR001
Intervention Description
Spartalizumab administered via intravenous (i.v.) infusion once every 3 weeks (Q3W)
Intervention Type
Drug
Intervention Name(s)
Capmatinib
Other Intervention Name(s)
INC280
Intervention Description
Capmatinib administered orally as a tablet on a continuous twice daily (BID) dosing schedule
Primary Outcome Measure Information:
Title
Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Description
Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Time Frame
From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.3 years
Title
Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment
Description
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications that occurs within the first 2 cycles of treatment with capmatinib in combination with spartalizumab during the dose escalation part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher. The duration of one treatment cycle is 21 days.
Time Frame
42 days
Title
Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
Description
Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.
No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Time Frame
From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Title
Phase Ib: Dose Intensity of Capmatinib
Description
Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Time Frame
From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Title
Phase Ib: Dose Intensity of Spartalizumab
Description
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
Time Frame
From first dose of study medication up to last dose, with a maximum duration of 3.2 years
Title
Phase II: Overall Response Rate (ORR) Per RECIST v1.1
Description
Tumor response was based on local investigator assessment as per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response 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
From start of treatment until end of treatment, assessed up to 2.2 years
Secondary Outcome Measure Information:
Title
Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1
Description
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per RECIST v1.1.
For RECIST v1.1, R=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 diameters of all target lesions, taking as reference the baseline sum of diameters; 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; SD= Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progression).
The number of participants in each response category is reported in the table.
Time Frame
From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Best Overall Response (BOR) Per irRC
Description
BOR is defined as the best response recorded from the start of the study treatment until disease progression/recurrence, based on local investigator assessment per Immune-related Response Criteria (irRC).
For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters; irPD= At least a 20% increase in the sum of diameters of all measured target lesions including new measurable 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; irSD= Neither sufficient shrinkage to qualify for irPR or irCR nor an increase in lesions which would qualify for irPD).
Time Frame
From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1
Description
Tumor response was based on local investigator assessment as per RECIST v1.1. ORR per RECIST v1.1 is defined as the percentage of participants with a best overall response 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
From start of treatment until end of treatment, assessed up to 3.2 years
Title
Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC
Description
Tumor response was based on local investigator assessment as per irRC. ORR per irRC is defined as the percentage of participants with a best overall response of immune related Complete Response (irCR) or immune related Partial Response (irPR).
For irRC, irCR=Disappearance of all non-nodal target lesions and non-target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; irPR= At least a 30% decrease in the sum of diameters of all target lesions including new measurable lesions, taking as reference the baseline sum of diameters.
Time Frame
From start of treatment until end of treatment, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1
Description
DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment of overall lesion response according to RECIST v1.1. DOR is defined as the time from the date of first documented response (confirmed CR or confirmed PR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any.
According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.
Time Frame
From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Duration of Response (DOR) Per irRC
Description
DOR only applies to patients for whom best overall response is immune-related complete response (irCR) or immune-related partial response (irPR) based on local investigator assessment of overall lesion response according to irRC. DOR is defined as the time from the date of first documented response (confirmed irCR or confirmed irPR) to the date of first documented disease progression or death due to any cause. If a patient not had an event, duration was censored at the date of last adequate tumor assessment before the start of a new anticancer therapy, if any.
According to the statistical analysis plan (SAP), summary estimates of DOR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm.
Time Frame
From first documented response to first documented disease progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1
Description
TTR is defined as the time from the date of start of treatment to the date of first documented response (CR or PR, which must be confirmed subsequently) for patients who achieved a confirmed CR or PR. Tumor response was based on local investigator assessment per RECIST v1.1.
Patients who did not achieve a confirmed CR or PR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise.
According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed CR or PR in each treatment group/arm.
Time Frame
From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Time to Response (TTR) Per irRC
Description
TTR is defined as the time from the date of start of treatment to the date of first documented response (irCR or irPR, which must be confirmed subsequently) for patients who achieved a confirmed irCR or irPR. Tumor response was based on local investigator assessment per irRC.
Patients who did not achieve a confirmed irCR or irPR were censored at the maximum follow-up time for patients who had a Progression-Free Survival (PFS) event (i.e. either progressed or died due to any cause), or at the date of last adequate tumor assessment before the start of a new anticancer therapy (if any) otherwise.
According to the statistical analysis plan (SAP), summary estimates of TTR using the Kaplan-Meier method were planned to be reported if there were at least 10 patients achieving a confirmed irCR or irPR in each treatment group/arm.
Time Frame
From start of treatment until first documented response, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1
Description
PFS is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1.
PFS was estimated using the Kaplan-Meier Method.
Time Frame
From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC
Description
PFS is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to any cause. If a patient did not experience an event or started a new anticancer therapy, PFS was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC.
PFS was estimated using the Kaplan-Meier Method.
Time Frame
From start of treatment until first documented progression or death due to any cause, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1
Description
TTP is defined as the time from the date of start of treatment to the date of the first documented progression per RECIST v1.1 or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per RECIST v1.1.
TTP was estimated using the Kaplan-Meier Method.
Time Frame
From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Time to Progression (TTP) Per irRC
Description
TTP is defined as the time from the date of start of treatment to the date of the first documented and confirmed progression per irRC or death due to underlying cancer. If a patient did not experience an event or started a new anticancer therapy, TTP was censored at the date of the last adequate tumor evaluation before the start of a new anticancer therapy, if any. Tumor response was based on local investigator assessment per irRC.
Time Frame
From start of treatment until first documented progression or death due to underlying cancer, assessed up to 3.2 years in Phase Ib and up to 2.2 years in Phase II
Title
Phase Ib and Phase II: Overall Survival (OS)
Description
OS is defined as the time from date of start of treatment to date of death due to any cause. If a patient was not known to have died, OS time was censored at the date of last contact.
OS was estimated using the Kaplan-Meier Method.
Time Frame
From start of treatment until death due to any cause, assessed up to 3.6 years in Phase Ib and up to 2.9 years in Phase II
Title
Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
Description
Number of participants with AEs and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs.
AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. For CTCAE v4.03, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE.
The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.
Time Frame
From first dose of study medication up to 30 days after last dose, with a maximum duration of 2.3 years
Title
Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
Description
Number of participants with at least one dose reduction of capmatinib and spartalizumab and number of participants with at least one dose interruption of capmatinib and spartalizumab.
No dose modifications (i.e. dose reduction) were allowed for spartalizumab.
Time Frame
From first dose of study medication up to last dose, with a maximum duration of 2.2 years
Title
Phase II: Dose Intensity of Capmatinib
Description
Dose intensity of capmatinib was calculated as actual cumulative dose in milligrams divided by duration of exposure in days.
Time Frame
From first dose of study medication up to last dose, with a maximum duration of 2.2 years
Title
Phase II: Dose Intensity of Spartalizumab
Description
Dose intensity of spartalizumab was calculated as actual cumulative dose in milligrams divided by duration of exposure in weeks and then multiplied by 3 weeks (3W).
Time Frame
From first dose of study medication up to last dose, with a maximum duration of 2.2 years
Title
Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib
Description
Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose.
Time Frame
pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
Title
Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib
Description
Pharmacokinetic (PK) parameters were calculated based on capmatinib 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, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
Title
Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib
Description
Pharmacokinetic (PK) parameters were calculated based on capmatinib plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time Frame
pre-dose, 0.5, 1, 2, 4 and 8 hours post capmatinib dose on Cycle 2 Day 1 (C2D1). The duration of one cycle was 21 days.
Title
Phase II: Pre-dose Plasma Concentration of Capmatinib
Description
Capmatinib plasma concentration was assessed in samples taken at pre-dose. Pre-dose samples were collected before the next dose administration.
Time Frame
Pre-dose of capmatinib on Cycle 2 Day 1, Cycle 3 Day 1, Cycle 4 Day 1, Cycle 5 Day 1 and Cycle 6 Day 1. The duration of one cycle was 21 days.
Title
Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab
Description
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose.
Time Frame
pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
Title
Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab
Description
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.
Time Frame
pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
Title
Phase Ib and Phase II: Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Spartalizumab
Description
Pharmacokinetic (PK) parameters were calculated based on spartalizumab serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUClast calculation.
Time Frame
pre-dose, 1, 24, 48, 72, 168, 240, 336 and 504 hours after completion of spartalizumab infusion on Cycle 1 and Cycle 3. The duration of one cycle was 21 days.
Title
Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples
Description
The expression of CD8 was measured in tumor samples by immunohistochemical methods. This record summarizes the percent marker area for CD8 expression in tumor samples.
Time Frame
Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
Title
Phase Ib and Phase II: PD-L1 Percent Positive Tumor
Description
The expression of programmed cell death-ligand 1 (PD-L1) was measured in tumor samples by immunohistochemical methods. This record summarizes the PD-L1 positivity percentage in tumor samples.
Time Frame
Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Histologically or cytologically documented locally advanced recurrent or metastatic HCC or for patients with cirrhosis according to the American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the study of the liver (APASL) criteria. Current cirrhotic status of Child Pugh Class A (5-6 points), with no encephalopathy and/or clinically significant ascites (defined as requiring the use of diuretics or paracentesis treatment).
Patients must have received prior systemic sorafenib treatment for HCC with documented progression during or after discontinuation of sorafenib treatment (for France only: patients must have received at least 8 weeks of prior sorafenib treatment), or are intolerant to sorafenib (defined as documented Grade 3 or 4 adverse events that led to sorafenib discontinuation),.
ECOG Performance Status ≤ 1.
Willing and able to swallow and retain oral medication.
Exclusion Criteria:
Use of any live vaccines within 4 weeks of initiation of study treatment.
History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
Active autoimmune disease or a documented history of autoimmune disease.
Clinically significant, uncontrolled heart diseases.
Patient having out of range laboratory values defined as:
Total bilirubin > 2 mg/dL, except for patients with Gilbert's syndrome who are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN
Alanine aminotransferase (ALT) > 5 x ULN
Aspartate aminotransferase (AST) > 5 x ULN
Coagulation: Prothrombin Time (PT) > 4 seconds more than the ULN or International Normalized Ratio (INR) > 1.7
Absolute neutrophil count (ANC) < 1.5 x 109/L
Platelet count < 75 x 109/L
Hemoglobin < 9 g/dL
Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 45 mL/min
Asymptomatic serum amylase grade > 2 (1.5-2.0 x ULN). Patients with grade 1 or grade 2 serum amylase at the beginning of the study must be confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury (e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc.)
Serum lipase > ULN
Potassium, Magnesium, Phosphorus, total Calcium (corrected for serum albumin) outside of normal limits (patients may be enrolled if corrected to within normal limits with supplements during screening)
Facility Information:
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2M9
Country
Canada
Facility Name
Novartis Investigative Site
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1E2
Country
Canada
Facility Name
Novartis Investigative Site
City
Guangzhou
State/Province
Guangdong
ZIP/Postal Code
510515
Country
China
Facility Name
Novartis Investigative Site
City
Shanghai
State/Province
Shanghai
ZIP/Postal Code
200032
Country
China
Facility Name
Novartis Investigative Site
City
Montpellier cedex 5
State/Province
Herault
ZIP/Postal Code
34059
Country
France
Facility Name
Novartis Investigative Site
City
Lille Cedex
ZIP/Postal Code
59037
Country
France
Facility Name
Novartis Investigative Site
City
Toulouse
ZIP/Postal Code
31059
Country
France
Facility Name
Novartis Investigative Site
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
Novartis Investigative Site
City
Wuerzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
Novartis Investigative Site
City
Hong Kong
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20132
Country
Italy
Facility Name
Novartis Investigative Site
City
Rozzano
State/Province
MI
ZIP/Postal Code
20089
Country
Italy
Facility Name
Novartis Investigative Site
City
Modena
State/Province
MO
ZIP/Postal Code
41124
Country
Italy
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03080
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
ZIP/Postal Code
03722
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Tainan
ZIP/Postal Code
70403
Country
Taiwan
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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
Learn more about this trial
Phase Ib/II Study of INC280 + PDR001 or PDR001 Single Agent in Advanced HCC
We'll reach out to this number within 24 hrs