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

Primary Purpose

Carcinoma, Hepatocellular

Status
Completed
Phase
Phase 1
Locations
Japan
Study Type
Interventional
Intervention
Nintedanib high dose
Nintedanib low dose
Nintedanib medium dose
Nintedanib medium dose
Nintedanib high dose
Sponsored by
Boehringer Ingelheim
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Carcinoma, Hepatocellular

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • 1199.120.001 Boehringer Ingelheim Investigational Site
  • 1199.120.005 Boehringer Ingelheim Investigational Site
  • 1199.120.002 Boehringer Ingelheim Investigational Site
  • 1199.120.003 Boehringer Ingelheim Investigational Site
  • 1199.120.004 Boehringer Ingelheim Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group I

Group II

Arm Description

patients with mild liver dysfunction according to their AST/ALT values and Child-Pugh score

patients with moderate liver dysfunction according to their AST/ALT values and Child-Pugh score

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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 to Progression (TTP)
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)
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.

Full Information

First Posted
May 2, 2012
Last Updated
January 11, 2016
Sponsor
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT01594125
Brief Title
Dose Escalation Study of Nintedanib (BIBF 1120) in Japanese Patients With Hepatocellular Carcinoma
Official Title
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.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2016
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
November 2014 (Actual)
Study Completion Date
January 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Boehringer Ingelheim

4. Oversight

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carcinoma, Hepatocellular

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group I
Arm Type
Experimental
Arm Description
patients with mild liver dysfunction according to their AST/ALT values and Child-Pugh score
Arm Title
Group II
Arm Type
Experimental
Arm Description
patients with moderate liver dysfunction according to their AST/ALT values and Child-Pugh score
Intervention Type
Drug
Intervention Name(s)
Nintedanib high dose
Intervention Description
twice daily oral dosing
Intervention Type
Drug
Intervention Name(s)
Nintedanib low dose
Intervention Description
twice daily oral dosing
Intervention Type
Drug
Intervention Name(s)
Nintedanib medium dose
Intervention Description
twice daily oral dosing
Intervention Type
Drug
Intervention Name(s)
Nintedanib medium dose
Intervention Description
twice daily oral dosing
Intervention Type
Drug
Intervention Name(s)
Nintedanib high dose
Intervention Description
twice daily oral dosing
Primary Outcome Measure Information:
Title
Number of Participants With Dose Limiting Toxicities to Determine Maximum Tolerated Dose (MTD) of Nintedanib
Description
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
Secondary Outcome Measure Information:
Title
Number of Participants With Objective Tumour Response According to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0
Description
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
Title
Progression Free Survival (PFS)
Description
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
Title
Time to Progression (TTP)
Description
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
Title
Number of Participants With Response by Alpha Fetoprotein (AFP)
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
20 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boehringer Ingelheim
Organizational Affiliation
Boehringer Ingelheim
Official's Role
Study Chair
Facility Information:
Facility Name
1199.120.001 Boehringer Ingelheim Investigational Site
City
Chuo-ku, Tokyo
Country
Japan
Facility Name
1199.120.005 Boehringer Ingelheim Investigational Site
City
Fukuoka, Fukuoka
Country
Japan
Facility Name
1199.120.002 Boehringer Ingelheim Investigational Site
City
Kashiwa, Chiba
Country
Japan
Facility Name
1199.120.003 Boehringer Ingelheim Investigational Site
City
Nagoya, Aichi
Country
Japan
Facility Name
1199.120.004 Boehringer Ingelheim Investigational Site
City
Saga, Saga
Country
Japan

12. IPD Sharing Statement

Citations:
PubMed Identifier
27627050
Citation
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.
Results Reference
derived
Links:
URL
http://trials.boehringer-ingelheim.com
Description
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Dose Escalation Study of Nintedanib (BIBF 1120) in Japanese Patients With Hepatocellular Carcinoma

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