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A Phase I / II Trial of Nintedanib in Asian Hepatocellular Carcinoma Patients

Primary Purpose

Carcinoma, Hepatocellular

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Sorafenib
BIBF 1120
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

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

Inclusion criteria:

  1. Hepatocellular carcinoma, either histologically/cytologically confirmed or clinically diagnosed, which is not amenable to curative surgery or loco-regional therapy
  2. Age 18 years or older
  3. Eastern Cooperative Group performance score of 2 or less
  4. Child-Pugh score of 7 or less
  5. Written informed consent in accordance with International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) and local legislation

Exclusion criteria:

  1. Prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (for phase II)
  2. More than one line of prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (for phase I)
  3. Uncontrolled or refractory ascites to adequate medical therapy
  4. Bilirubin greater than 1.5 times upper limit of normal
  5. Aspartate amino transferase or alanine amino transferase greater than 5 times upper limit of normal
  6. Absolute neutrophil count less than 1500/microliter
  7. Platelet count less than 75000/microliter
  8. Hemoglobin less than 9 g/dL
  9. Serum creatinine greater than 1.5 times upper limit of normal

Sites / Locations

  • 1199.39.82001 Boehringer Ingelheim Investigational Site
  • 1199.39.82002 Boehringer Ingelheim Investigational Site
  • 1199.39.82003 Boehringer Ingelheim Investigational Site
  • 1199.39.82004 Boehringer Ingelheim Investigational Site
  • 1199.39.82005 Boehringer Ingelheim Investigational Site
  • 1199.39.82006 Boehringer Ingelheim Investigational Site
  • 1199.39.88606 Boehringer Ingelheim Investigational Site
  • 1199.39.88609 Boehringer Ingelheim Investigational Site
  • 1199.39.88610 Boehringer Ingelheim Investigational Site
  • 1199.39.88605 Boehringer Ingelheim Investigational Site
  • 1199.39.88608 Boehringer Ingelheim Investigational Site
  • 1199.39.88602 Boehringer Ingelheim Investigational Site
  • 1199.39.88601 Boehringer Ingelheim Investigational Site
  • 1199.39.88603 Boehringer Ingelheim Investigational Site
  • 1199.39.88604 Boehringer Ingelheim Investigational Site
  • 1199.39.88607 Boehringer Ingelheim Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Nintedanib (BIBF 1120)

Sorafenib

Arm Description

Phase I dose escalation and phase II using dose determined in phase I

Twice daily dosing in phase II

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose in Phase I
The MTD was defined as the highest dose studied for which the incidence of DLTs was 0/3 or less than 2/6 patients during the first treatment course.
Time to Progression (TTP) in Phase II
TTP according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 criteria based on central independent review. TTP RECIST 1.0 was defined as the time from randomisation to disease progression according to RECIST 1.0.

Secondary Outcome Measures

Time to Progression (TTP) in Phase II (Follow-up Analyses)
TTP according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 criteria based on central independent review. TTP RECIST 1.0 was defined as the time from randomisation to disease progression according to RECIST 1.0.
Incidence and Intensity of Adverse Events (AEs) Reported as the Number of Patients With AEs According to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Throughout the Treatment Period.
Incidence and worst intensity (severity) of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Incidence of Dose Limiting Toxicity in Phase I
Number of patients with dose limiting toxicity are presented
Objective Tumour Response by RECIST
Objective RECIST 1.0 tumour response was defined as Complete Response (CR) or Partial Response (PR) and was derived from the patient's best objective RECIST 1.0 response based on central independent review. 95% Confidence Interval presented below are computed by Clopper and Pearson method.
Progression Free Survival (PFS)
PFS by RECIST 1.0 was defined as the duration from date of randomisation to date of progression or death, whichever occurred earlier, based on central independent review.
Overall Survival
Overall survival was defined as the duration from date of randomisation to the date of death.
AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of Nintedanib
AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of Nintedanib Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 (Metabolite of Nintedanib)
AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of BIBF 1202 (metabolite of Nintedanib). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 Glucuronide (Metabolite of Nintedanib)
AUC0-12,ss,norm of BIBF 1202 glucuronide (Metabolite of Nintedanib): Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Cmax,ss,Norm (Maximum Concentration of the Nintedanib in Plasma at Steady State, Normalised Values)
Cmax,ss,norm (maximum concentration of the Nintedanib in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 in Plasma at Steady State, Normalised Values)
Cmax,ss,norm (maximum concentration of the BIBF 1202 in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 Glucuronide in Plasma at Steady State, Normalised Values)
Cmax,ss,norm (maximum concentration of the BIBF 1202 glucuronide in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
fe0-12,ss (Fraction Excreted in Urine Between 0 and 12 Hours at Steady State) for Nintedanib
fe0-12,ss (fraction excreted in urine between 0 and 12 hours at steady state) for Nintedanib. The reported value corresponds to the percentage of administered dose.

Full Information

First Posted
September 30, 2009
Last Updated
February 9, 2016
Sponsor
Boehringer Ingelheim
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1. Study Identification

Unique Protocol Identification Number
NCT00987935
Brief Title
A Phase I / II Trial of Nintedanib in Asian Hepatocellular Carcinoma Patients
Official Title
A Multicenter, Open Label, Phase I/Randomized II Study to Evaluate Safety, Pharmacokinetics and Efficacy of BIBF 1120 in Comparison With Sorafenib for Advanced Hepatocellular Carcinoma Patients in Asia.
Study Type
Interventional

2. Study Status

Record Verification Date
February 2016
Overall Recruitment Status
Completed
Study Start Date
October 2009 (undefined)
Primary Completion Date
July 2014 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

5. Study Description

Brief Summary
This study is to evaluate the safety, appropriate dose, and efficacy of BIBF 1120 in liver cancer patients

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 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
134 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Nintedanib (BIBF 1120)
Arm Type
Experimental
Arm Description
Phase I dose escalation and phase II using dose determined in phase I
Arm Title
Sorafenib
Arm Type
Active Comparator
Arm Description
Twice daily dosing in phase II
Intervention Type
Drug
Intervention Name(s)
Sorafenib
Intervention Description
400 mg twice daily
Intervention Type
Drug
Intervention Name(s)
BIBF 1120
Intervention Description
Twice daily
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose in Phase I
Description
The MTD was defined as the highest dose studied for which the incidence of DLTs was 0/3 or less than 2/6 patients during the first treatment course.
Time Frame
4 weeks
Title
Time to Progression (TTP) in Phase II
Description
TTP according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 criteria based on central independent review. TTP RECIST 1.0 was defined as the time from randomisation to disease progression according to RECIST 1.0.
Time Frame
From randomization until data cut-off (28 Sep 2012); Up to 77 weeks
Secondary Outcome Measure Information:
Title
Time to Progression (TTP) in Phase II (Follow-up Analyses)
Description
TTP according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.0 criteria based on central independent review. TTP RECIST 1.0 was defined as the time from randomisation to disease progression according to RECIST 1.0.
Time Frame
From randomization until disease progression or data cut-off (16 Jul 2014); Up to 171 weeks
Title
Incidence and Intensity of Adverse Events (AEs) Reported as the Number of Patients With AEs According to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 Throughout the Treatment Period.
Description
Incidence and worst intensity (severity) of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).
Time Frame
AEs with an onset during therapy with study treatment or within 28 days after discontinuation of study treatment (up to 1066 days)
Title
Incidence of Dose Limiting Toxicity in Phase I
Description
Number of patients with dose limiting toxicity are presented
Time Frame
4 weeks
Title
Objective Tumour Response by RECIST
Description
Objective RECIST 1.0 tumour response was defined as Complete Response (CR) or Partial Response (PR) and was derived from the patient's best objective RECIST 1.0 response based on central independent review. 95% Confidence Interval presented below are computed by Clopper and Pearson method.
Time Frame
From randomization until data cut-off (16 July 2014); Up to 171 weeks
Title
Progression Free Survival (PFS)
Description
PFS by RECIST 1.0 was defined as the duration from date of randomisation to date of progression or death, whichever occurred earlier, based on central independent review.
Time Frame
From randomization until data cut-off (16 July 2014); Up to 171 weeks
Title
Overall Survival
Description
Overall survival was defined as the duration from date of randomisation to the date of death.
Time Frame
From randomization until data cut-off (16 July 2014); Up to 171 weeks
Title
AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of Nintedanib
Description
AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of Nintedanib Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame
Day1, Day15 and Day 16
Title
AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 (Metabolite of Nintedanib)
Description
AUC0-12,ss,norm (area under the plasma concentration-time curve between 0 and 12 hours at steady state, normalised values) of BIBF 1202 (metabolite of Nintedanib). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame
Day1, Day15 and Day 16
Title
AUC0-12,ss,Norm (Area Under the Plasma Concentration-time Curve Between 0 and 12 Hours at Steady State, Normalised Values) of BIBF 1202 Glucuronide (Metabolite of Nintedanib)
Description
AUC0-12,ss,norm of BIBF 1202 glucuronide (Metabolite of Nintedanib): Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame
Day1, Day15 and Day 16
Title
Cmax,ss,Norm (Maximum Concentration of the Nintedanib in Plasma at Steady State, Normalised Values)
Description
Cmax,ss,norm (maximum concentration of the Nintedanib in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame
Day1, Day15 and Day 16
Title
Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 in Plasma at Steady State, Normalised Values)
Description
Cmax,ss,norm (maximum concentration of the BIBF 1202 in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame
Day1, Day15 and Day 16
Title
Cmax,ss,Norm (Maximum Concentration of the BIBF 1202 Glucuronide in Plasma at Steady State, Normalised Values)
Description
Cmax,ss,norm (maximum concentration of the BIBF 1202 glucuronide in plasma at steady state, normalised values). Detailed time points of sampling are: Phase I and selected phase II patients in the Nintedanib arm: Cycle 1, Day 15 to 16: Immediately prior to swallowing the dose of nintedanib (predose) and 1 hour (h), 2 h, 3 h, 4 h, 5 h, 7 h, 10 h, 12 h and 24 h after drug administration on Day 15; Cycle 2, Day 1: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 1; Cycle 2, Day 15: Immediately prior to swallowing the dose of nintedanib (predose) and 2 h after drug administration on Day 15.
Time Frame
Day1, Day15 and Day 16
Title
fe0-12,ss (Fraction Excreted in Urine Between 0 and 12 Hours at Steady State) for Nintedanib
Description
fe0-12,ss (fraction excreted in urine between 0 and 12 hours at steady state) for Nintedanib. The reported value corresponds to the percentage of administered dose.
Time Frame
0 to 4 hours (h), 4 to 12 h, and 12 to 24 h after nintedanib

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Hepatocellular carcinoma, either histologically/cytologically confirmed or clinically diagnosed, which is not amenable to curative surgery or loco-regional therapy Age 18 years or older Eastern Cooperative Group performance score of 2 or less Child-Pugh score of 7 or less Written informed consent in accordance with International Conference on Harmonisation (ICH) and Good Clinical Practice (GCP) and local legislation Exclusion criteria: Prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (for phase II) More than one line of prior systemic therapy for metastatic/unresectable hepatocellular carcinoma (for phase I) Uncontrolled or refractory ascites to adequate medical therapy Bilirubin greater than 1.5 times upper limit of normal Aspartate amino transferase or alanine amino transferase greater than 5 times upper limit of normal Absolute neutrophil count less than 1500/microliter Platelet count less than 75000/microliter Hemoglobin less than 9 g/dL Serum creatinine greater than 1.5 times upper limit of normal
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
1199.39.82001 Boehringer Ingelheim Investigational Site
City
Seoul
Country
Korea, Republic of
Facility Name
1199.39.82002 Boehringer Ingelheim Investigational Site
City
Seoul
Country
Korea, Republic of
Facility Name
1199.39.82003 Boehringer Ingelheim Investigational Site
City
Seoul
Country
Korea, Republic of
Facility Name
1199.39.82004 Boehringer Ingelheim Investigational Site
City
Seoul
Country
Korea, Republic of
Facility Name
1199.39.82005 Boehringer Ingelheim Investigational Site
City
Seoul
Country
Korea, Republic of
Facility Name
1199.39.82006 Boehringer Ingelheim Investigational Site
City
Seoul
Country
Korea, Republic of
Facility Name
1199.39.88606 Boehringer Ingelheim Investigational Site
City
Changhua
Country
Taiwan
Facility Name
1199.39.88609 Boehringer Ingelheim Investigational Site
City
Kaohsiung
Country
Taiwan
Facility Name
1199.39.88610 Boehringer Ingelheim Investigational Site
City
Kaohsiung
Country
Taiwan
Facility Name
1199.39.88605 Boehringer Ingelheim Investigational Site
City
Taichung
Country
Taiwan
Facility Name
1199.39.88608 Boehringer Ingelheim Investigational Site
City
Tainan City
Country
Taiwan
Facility Name
1199.39.88602 Boehringer Ingelheim Investigational Site
City
Tainan
Country
Taiwan
Facility Name
1199.39.88601 Boehringer Ingelheim Investigational Site
City
Taipei
Country
Taiwan
Facility Name
1199.39.88603 Boehringer Ingelheim Investigational Site
City
Taipei
Country
Taiwan
Facility Name
1199.39.88604 Boehringer Ingelheim Investigational Site
City
Taoyuan County
Country
Taiwan
Facility Name
1199.39.88607 Boehringer Ingelheim Investigational Site
City
Yunlin County
Country
Taiwan

12. IPD Sharing Statement

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A Phase I / II Trial of Nintedanib in Asian Hepatocellular Carcinoma Patients

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