Clinical trial NCT02795429: 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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Advanced Hepatocellular Carcinoma
Keywords: Phase Ib/II
INC280
PDR001
capmatinib
spartalizumab
checkpoint inhibitor
PD-1
Liver cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-06-10
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. 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).
2. 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),.
3. ECOG Performance Status ≤ 1.
4. Willing and able to swallow and retain oral medication.

Exclusion Criteria:

1. Use of any live vaccines within 4 weeks of initiation of study treatment.
2. History of severe hypersensitivity reactions to other monoclonal antibodies (mAbs).
3. Clinically significant pleural effusion that either required pleurocentesis or is associated with shortness of breath.
4. Active autoimmune disease or a documented history of autoimmune disease.
5. Clinically significant, uncontrolled heart diseases.
6. 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)

Primary outcomes:
measure: Phase Ib: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 3.3 years
measure: Phase Ib: Number of Participants With Dose-Limiting Toxicities (DLTs) During the First 2 Cycles of Treatment
timeFrame: 42 days
measure: Phase Ib: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
measure: Phase Ib: Dose Intensity of Capmatinib
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
measure: Phase Ib: Dose Intensity of Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 3.2 years
measure: Phase II: Overall Response Rate (ORR) Per RECIST v1.1
timeFrame: From start of treatment until end of treatment, assessed up to 2.2 years
Secondary outcomes:
measure: Phase Ib and Phase II: Best Overall Response (BOR) Per RECIST v1.1
timeFrame: 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
measure: Phase Ib and Phase II: Best Overall Response (BOR) Per irRC
timeFrame: 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
measure: Phase Ib: Overall Response Rate (ORR) Per RECIST v1.1
timeFrame: From start of treatment until end of treatment, assessed up to 3.2 years
measure: Phase Ib and Phase II: Overall Response Rate (ORR) Per irRC
timeFrame: 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
measure: Phase Ib and Phase II: Duration of Response (DOR) Per RECIST v1.1
timeFrame: 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
measure: Phase Ib and Phase II: Duration of Response (DOR) Per irRC
timeFrame: 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
measure: Phase Ib and Phase II: Time to Response (TTR) Per RECIST v1.1
timeFrame: 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
measure: Phase Ib and Phase II: Time to Response (TTR) Per irRC
timeFrame: 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
measure: Phase Ib and Phase II: Progression-Free Survival (PFS) Per RECIST v1.1
timeFrame: 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
measure: Phase Ib and Phase II: Progression-Free Survival (PFS) Per irRC
timeFrame: 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
measure: Phase Ib and Phase II: Time to Progression (TTP) Per RECIST v1.1
timeFrame: 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
measure: Phase Ib and Phase II: Time to Progression (TTP) Per irRC
timeFrame: 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
measure: Phase Ib and Phase II: Overall Survival (OS)
timeFrame: 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
measure: Phase II: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) During the On-treatment Period
timeFrame: From first dose of study medication up to 30 days after last dose, with a maximum duration of 2.3 years
measure: Phase II: Number of Participants With Dose Reductions and Dose Interruptions of Capmatinib and Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.2 years
measure: Phase II: Dose Intensity of Capmatinib
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.2 years
measure: Phase II: Dose Intensity of Spartalizumab
timeFrame: From first dose of study medication up to last dose, with a maximum duration of 2.2 years
measure: Phase Ib: Maximum Observed Plasma Concentration (Cmax) of Capmatinib
timeFrame: 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.
measure: Phase Ib: Time to Reach Maximum Plasma Concentration (Tmax) of Capmatinib
timeFrame: 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.
measure: Phase Ib: Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Capmatinib
timeFrame: 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.
measure: Phase II: Pre-dose Plasma Concentration of Capmatinib
timeFrame: 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.
measure: Phase Ib and Phase II: Maximum Observed Serum Concentration (Cmax) of Spartalizumab
timeFrame: 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.
measure: Phase Ib and Phase II: Time to Reach Maximum Serum Concentration (Tmax) of Spartalizumab
timeFrame: 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.
measure: 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
timeFrame: 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.
measure: Phase Ib and Phase II: Percent Marker Area for CD8 Expression in Tumor Samples
timeFrame: Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
measure: Phase Ib and Phase II: PD-L1 Percent Positive Tumor
timeFrame: Baseline (screening) and post-baseline (assessed throughout the treatment up to maximum 115 days).
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: Montpellier cedex 5
country: France
facility: Novartis Investigative Site
state: Herault
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Wuerzburg
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Tainan
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
References: