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

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).

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)