Carcinoma, Hepatocellular
Conditions
Brief summary
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
Interventions
DRUGNintedanib high dose
twice daily oral dosing
DRUGNintedanib low dose
twice daily oral dosing
DRUGNintedanib medium dose
twice daily oral dosing
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib | up to 28 days | The MTD is based on the incidence of Dose Limiting Toxicities (DLTs). A drug-related AE was considered as a DLT if one of the following met: CTCAE grade 4 thrombocytopenia of any duration, CTCAE grade 4 neutropenia lasting for ≥8 days, CTCAE grade 4 febrile neutropenia of any duration, CTCAE grade 3 or 4 non-haematologic toxicity (with the following exception: Alopecia, Vomiting, nausea, or diarrhoea with no adequate supportive care, Transient electrolyte abnormality, which resolves spontaneously or can be corrected with appropriate treatment within 3 days, Liver toxicity), Liver enzyme toxicity of AST, ALT, alkaline phosphatase \[ALP\] elevation \>5x ULN, or total bilirubin \>3x ULN if baseline liver enzymes are within the normal range, or AST, ALT or ALP \> baseline value + 4x ULN if the baseline value is elevated. The MTD was determined to be 200mg bid. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | up to 28 months | Objective response (Complete response (CR) + Partial response (PR), regardless of confirmation) is derived from a patient's best objective response by RECIST. Best objective response is calculated based on the overall visit response from each assessment. Best objective response represents the best response a patient has had during their time in the study up until progression, last evaluable assessment in the absence of progression or the start of subsequent anti-cancer therapy. For patients whose progression event is death, best objective response will be calculated based on data up until the last evaluable RECIST assessment prior to death. |
| Progression Free Survival (PFS) | up to 28 months | PFS is defined as the duration from start date of the study treatment to PD according to RECIST 1.0, or any death whichever occurs earlier. |
| Time to Progression (TTP) | up to 28 months | TTP is defined as the duration from the start date of the study treatment to PD according to RECIST 1.0. |
| Number of Participants With Response by Alpha Fetoprotein (AFP) | up to 28 months | Response by AFP is defined as 20% or more decline in AFP between the baseline value and the AFP value after three courses (12 weeks) of therapy. If patients only receive two courses of therapy the AFP value after two courses (8 weeks) will be used for the analysis. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group I: Nintedanib 150mg Bid Patients with mild liver dysfunction according to their aspartate amino transferase (AST)/ alanine amino transferase (ALT) values (\<=2 x upper limit of normal (ULN)) and Child-Pugh A treated with Nintedanib 150mg twice daily | 4 |
| Group I: Nintedanib 200mg Bid Patients with mild liver dysfunction according to their aspartate amino transferase (AST)/ alanine amino transferase (ALT) values (\<=2 x upper limit of normal (ULN)) and Child-Pugh A treated with Nintedanib 200mg twice daily | 12 |
| Group II: Nintedanib 100mg Bid Patients with moderate liver dysfunction according to their aspartate amino transferase (AST)/ alanine amino transferase (ALT) values (\>2 to \<=5 x upper limit of normal (ULN)) and Child-Pugh B (score 7) treated with Nintedanib 100mg twice daily | 3 |
| Group II: Nintedanib 150mg Bid Patients with moderate liver dysfunction according to their aspartate amino transferase (AST)/ alanine amino transferase (ALT) values (\>2 x to \<=5 upper limit of normal (ULN)) and Child-Pugh B (score 7) treated with Nintedanib 150mg twice daily | 4 |
| Group II: Nintedanib 200mg Bid Patients with moderate liver dysfunction according to their aspartate amino transferase (AST)/ alanine amino transferase (ALT) values (\>2 to \<=5 x upper limit of normal (ULN)) and Child-Pugh B (score 7) treated with Nintedanib 200mg twice daily | 7 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Progressive Disease | 3 | 12 | 3 | 3 | 7 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Group I: Nintedanib 150mg Bid | Group I: Nintedanib 200mg Bid | Group II: Nintedanib 100mg Bid | Group II: Nintedanib 150mg Bid | Group II: Nintedanib 200mg Bid | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 67.0 years STANDARD_DEVIATION 14.72 | 63.1 years STANDARD_DEVIATION 9.84 | 73.3 years STANDARD_DEVIATION 2.31 | 66.5 years STANDARD_DEVIATION 6.56 | 67.4 years STANDARD_DEVIATION 4.35 | 66.1 years STANDARD_DEVIATION 8.81 |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants | 2 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 11 Participants | 0 Participants | 2 Participants | 6 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 12 / 12 | 3 / 3 | 4 / 4 | 7 / 7 |
| serious Total, serious adverse events | 0 / 4 | 4 / 12 | 1 / 3 | 2 / 4 | 3 / 7 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib
The MTD is based on the incidence of Dose Limiting Toxicities (DLTs). A drug-related AE was considered as a DLT if one of the following met: CTCAE grade 4 thrombocytopenia of any duration, CTCAE grade 4 neutropenia lasting for ≥8 days, CTCAE grade 4 febrile neutropenia of any duration, CTCAE grade 3 or 4 non-haematologic toxicity (with the following exception: Alopecia, Vomiting, nausea, or diarrhoea with no adequate supportive care, Transient electrolyte abnormality, which resolves spontaneously or can be corrected with appropriate treatment within 3 days, Liver toxicity), Liver enzyme toxicity of AST, ALT, alkaline phosphatase \[ALP\] elevation \>5x ULN, or total bilirubin \>3x ULN if baseline liver enzymes are within the normal range, or AST, ALT or ALP \> baseline value + 4x ULN if the baseline value is elevated. The MTD was determined to be 200mg bid.
Time frame: up to 28 days
Population: Patients from the MTD set: The MTD set contains only treated patients from the dose escalation that were not replaced for MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Nintedanib 150mg Bid | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib | 0 participants |
| Group I: Nintedanib 200mg Bid | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib | 0 participants |
| Group II: Nintedanib 100mg Bid | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib | 0 participants |
| Group II: Nintedanib 150mg Bid | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib | 0 participants |
| Group II: Nintedanib 200mg Bid | Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib | 0 participants |
Secondary
Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0
Objective response (Complete response (CR) + Partial response (PR), regardless of confirmation) is derived from a patient's best objective response by RECIST. Best objective response is calculated based on the overall visit response from each assessment. Best objective response represents the best response a patient has had during their time in the study up until progression, last evaluable assessment in the absence of progression or the start of subsequent anti-cancer therapy. For patients whose progression event is death, best objective response will be calculated based on data up until the last evaluable RECIST assessment prior to death.
Time frame: up to 28 months
Population: Treated Set (TS): The treated set includes all patients who were administered at least one dose of any study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Nintedanib 150mg Bid | Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | 0 participants |
| Group I: Nintedanib 200mg Bid | Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | 0 participants |
| Group II: Nintedanib 100mg Bid | Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | 0 participants |
| Group II: Nintedanib 150mg Bid | Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | 0 participants |
| Group II: Nintedanib 200mg Bid | Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 | 0 participants |
Secondary
Number of Participants With Response by Alpha Fetoprotein (AFP)
Response by AFP is defined as 20% or more decline in AFP between the baseline value and the AFP value after three courses (12 weeks) of therapy. If patients only receive two courses of therapy the AFP value after two courses (8 weeks) will be used for the analysis.
Time frame: up to 28 months
Population: Patients from TS and AFP evaluation (\>20μg/L) at baseline and post-baseline AFP assessment after two or three courses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I: Nintedanib 150mg Bid | Number of Participants With Response by Alpha Fetoprotein (AFP) | 2 participants |
| Group I: Nintedanib 200mg Bid | Number of Participants With Response by Alpha Fetoprotein (AFP) | 1 participants |
| Group II: Nintedanib 100mg Bid | Number of Participants With Response by Alpha Fetoprotein (AFP) | 1 participants |
| Group II: Nintedanib 150mg Bid | Number of Participants With Response by Alpha Fetoprotein (AFP) | 1 participants |
| Group II: Nintedanib 200mg Bid | Number of Participants With Response by Alpha Fetoprotein (AFP) | 1 participants |
Secondary
Progression Free Survival (PFS)
PFS is defined as the duration from start date of the study treatment to PD according to RECIST 1.0, or any death whichever occurs earlier.
Time frame: up to 28 months
Population: Patients from TS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Nintedanib 150mg Bid | Progression Free Survival (PFS) | 6.05 months |
| Group I: Nintedanib 200mg Bid | Progression Free Survival (PFS) | 2.76 months |
| Group II: Nintedanib 100mg Bid | Progression Free Survival (PFS) | 7.26 months |
| Group II: Nintedanib 150mg Bid | Progression Free Survival (PFS) | 2.40 months |
| Group II: Nintedanib 200mg Bid | Progression Free Survival (PFS) | 2.76 months |
Secondary
Time to Progression (TTP)
TTP is defined as the duration from the start date of the study treatment to PD according to RECIST 1.0.
Time frame: up to 28 months
Population: Patients from TS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group I: Nintedanib 150mg Bid | Time to Progression (TTP) | 6.05 months |
| Group I: Nintedanib 200mg Bid | Time to Progression (TTP) | 2.76 months |
| Group II: Nintedanib 100mg Bid | Time to Progression (TTP) | 7.26 months |
| Group II: Nintedanib 150mg Bid | Time to Progression (TTP) | 2.40 months |
| Group II: Nintedanib 200mg Bid | Time to Progression (TTP) | 2.76 months |