Dose Escalation Study of Nintedanib (BIBF 1120) in Japanese Patients With Hepatocellular Carcinoma

Study Overview
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Brief Summary
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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

Official Title
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An Open Label, Dose Escalation Phase I Study to Evaluate the Safety and Tolerability of Continuous Twice-daily Oral Treatment of Nintedanib in Japanese Patients With Hepatocellular Carcinoma.

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Nintedanib high dose
* Drug: Nintedanib low dose
* Drug: Nintedanib medium dose
* Drug: Nintedanib medium dose
* Drug: Nintedanib high dose


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Histologically/cytologically confirmed hepatocellular carcinoma not amenable to curative surgery or loco-regional therapy Age 20 years or older Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1 Child-Pugh score of 7 or less Life expectancy more than 3 months Time interval from last loco-regional therapy more than 4 weeks Written informed consent in accordance with good clinical practice (GCP) Exclusion criteria: More than one line of prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (HCC) Fibrolamellar HCC Uncontrolled or refractory ascites Inadequate organ function Variceal bleeding within 6 months or the presence of inappropriate varices History of major thrombotic (except portal vein thrombosis) or clinically relevant major bleeding event in the past 6 months Major surgery within 4 weeks Known inherited predisposition to bleeding or thrombosis Significant cardiovascular diseases

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group I<br>patients with mild liver dysfunction according to their AST/ALT values and Child-Pugh score | Drug: Nintedanib high dose<br>* twice daily oral dosing<br>Drug: Nintedanib medium dose<br>* twice daily oral dosing<br>|
| Experimental: Group II<br>patients with moderate liver dysfunction according to their AST/ALT values and Child-Pugh score | Drug: Nintedanib low dose<br>* twice daily oral dosing<br>Drug: Nintedanib medium dose<br>* twice daily oral dosing<br>Drug: Nintedanib high dose<br>* twice daily oral dosing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | up to 28 months | 
| 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. | up to 28 months | 
| 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. | up to 28 months | 
| 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. | up to 28 months |