Phase Ib/II Study of INC280 + PDR001 or PDR001 Single Agent in Advanced HCC

Phase 1

Completed

Conditions: Advanced Hepatocellular Carcinoma

Interventions: Drug: Spartalizumab
Drug: Capmatinib

Registration Number: NCT02795429

Lead Sponsor: Novartis Pharmaceuticals

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 89

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W	Spartalizumab	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
Phase Ib: Capmatinib 200 mg BID + Spartalizumab 300 mg Q3W	Capmatinib	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
Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W	Capmatinib	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
Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W	Capmatinib	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
Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W	Capmatinib	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
Phase Ib: Capmatinib 300 mg BID + Spartalizumab 300 mg Q3W	Spartalizumab	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
Phase Ib: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W	Spartalizumab	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
Phase II: Spartalizumab 300 mg Q3W	Spartalizumab	Spartalizumab 300 mg administered intravenously once every 3 weeks (Q3W) in Phase II
Phase II: Capmatinib 400 mg BID + Spartalizumab 300 mg Q3W	Spartalizumab	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

Primary Outcome Measures

Name	Time	Method
Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab	From first dose of study medication up to last dose, with a maximum duration of 3.2 years	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: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period	From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.3 years	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	42 days	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 II: Overall Response Rate (ORR) Per RECIST v1.1	From start of treatment until end of treatment, assessed up to 2.2 years	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.
Phase Ib: Dose Intensity of Capmatinib	From first dose of study medication up to last dose, with a maximum duration of 3.2 years	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	From first dose of study medication up to last dose, with a maximum duration of 3.2 years	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).

Secondary Outcome Measures

Name	Time	Method
Phase Ib and Phase II: Time to Response (TTR) Per irRC	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	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: Overall Survival (OS)	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	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	From first dose of study medication up to 30 days after last dose, with a maximum duration of 2.3 years	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 and Phase II: Best Overall Response (BOR) Per irRC	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	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	From start of treatment until end of treatment, assessed up to 3.2 years	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 II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab	From first dose of study medication up to last dose, with a maximum duration of 2.2 years	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 and Phase II: Best Overall Response (BOR) Per RECIST v1.1	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	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: Overall Response Rate (ORR) Per irRC	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	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	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	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: Time to Response (TTR) Per RECIST v1.1	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	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 Progression (TTP) Per RECIST v1.1	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	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: Duration of Response (DOR) Per irRC	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	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: Progression-Free Survival (PFS) Per RECIST v1.1	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	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	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	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 irRC	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	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 II: Dose Intensity of Capmatinib	From first dose of study medication up to last dose, with a maximum duration of 2.2 years	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	From first dose of study medication up to last dose, with a maximum duration of 2.2 years	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	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.	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	Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).	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	Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).	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.