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

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.

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

Study Overview

• Status: Completed
• Conditions: Carcinoma, Hepatocellular
• Intervention / Treatment: Drug: Nintedanib high dose; Drug: Nintedanib medium dose; Drug: Nintedanib low dose

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Chuo-ku, Tokyo, Japan
    • 1199.120.001 Boehringer Ingelheim Investigational Site
  • Fukuoka, Fukuoka, Japan
    • 1199.120.005 Boehringer Ingelheim Investigational Site
  • Kashiwa, Chiba, Japan
    • 1199.120.002 Boehringer Ingelheim Investigational Site
  • Nagoya, Aichi, Japan
    • 1199.120.003 Boehringer Ingelheim Investigational Site
  • Saga, Saga, Japan
    • 1199.120.004 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Okusaka T, Otsuka T, Ueno H, Mitsunaga S, Sugimoto R, Muro K, Saito I, Tadayasu Y, Inoue K, Loembe AB, Ikeda M. Phase I study of nintedanib in Japanese patients with advanced hepatocellular carcinoma and liver impairment. Cancer Sci. 2016 Dec;107(12):1791-1799. doi: 10.1111/cas.13077. Epub 2016 Dec 12.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): January 1, 2015

Study Registration Dates

• First Submitted: May 2, 2012
• First Submitted That Met QC Criteria: May 7, 2012
• First Posted (Estimate): May 8, 2012

Study Record Updates

• Last Update Posted (Estimate): February 12, 2016
• Last Update Submitted That Met QC Criteria: January 11, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Nintedanib
• Other Study ID Numbers: 1199.120