Dose Escalation Study for Japanese Patients With Hepatocellular Carcinoma

• Predose (trough) and maximum measured concentration in plasma at steady state [ Time Frame: up to 2 months ] [ Designated as safety issue: No ]
• Terminal rate constant in plasma at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Time from last dosing to the maximum concentration in plasma at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Mean residence time in the body at steady state after administration [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Apparent clearance in plasma at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Apparent volume of distribution during the terminal phase at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Amount of drug eliminated in urine at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Terminal half-life in plasma at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Incidence and intensity of adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 [ Time Frame: up to 12 months ] [ Designated as safety issue: Yes ]
• Area under the concentration-time curve in plasma at steady state [ Time Frame: up to 1 month ] [ Designated as safety issue: No ]
• Changes of safety laboratory values from baseline [ Time Frame: up to 12 months ] [ Designated as safety issue: Yes ]
• Incidence of hepatitis B virus (HBV) reactivation [ Time Frame: up to 12 months ] [ Designated as safety issue: Yes ]
• Objective tumour response according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
• Progression free survival (PFS) [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
• Time to progression (TTP) [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]
• Response by alpha fetoprotein (AFP) [ Time Frame: up to 12 months ] [ Designated as safety issue: No ]

The aim of the study is to investigate the safety, tolerability, efficacy and pharmacokinetics (PK) for Japanese hepatocellular carcinoma which are not amenable to curative surgery or loco regional therapy

• Drug: Nintedanib high dose
  twice daily oral dosing
• Drug: Nintedanib low dose
  twice daily oral dosing
• Drug: Nintedanib medium dose
  twice daily oral dosing

• Experimental: Group I
  patients with mild liver dysfunction according to their AST/ALT values and Child-Pugh score
  Interventions:

  • Drug: Nintedanib high dose
  • Drug: Nintedanib medium dose
• Experimental: Group II
  patients with moderate liver dysfunction according to their AST/ALT values and Child-Pugh score
  Interventions:

  • Drug: Nintedanib low dose
  • Drug: Nintedanib medium dose
  • Drug: Nintedanib high dose

Inclusion criteria:

1. Histologically/cytologically confirmed hepatocellular carcinoma not amenable to curative surgery or loco-regional therapy
2. Age 20 years or older
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1
4. Child-Pugh score of 7 or less
5. Life expectancy more than 3 months
6. Time interval from last loco-regional therapy more than 4 weeks
7. Written informed consent in accordance with good clinical practice (GCP)

Exclusion criteria:

1. More than one line of prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (HCC)
2. Fibrolamellar HCC
3. Uncontrolled or refractory ascites
4. Inadequate organ function
5. Variceal bleeding within 6 months or the presence of inappropriate varices
6. History of major thrombotic (except portal vein thrombosis) or clinically relevant major bleeding event in the past 6 months
7. Major surgery within 4 weeks
8. Known inherited predisposition to bleeding or thrombosis
9. Significant cardiovascular diseases