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

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

Official Title
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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.

Conditions
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Carcinoma, Hepatocellular

Intervention / Treatment
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* Drug: Sorafenib
* Drug: BIBF 1120


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nintedanib (BIBF 1120)<br>Phase I dose escalation and phase II using dose determined in phase I | Drug: BIBF 1120<br>* Twice daily<br>|
| Active Comparator: Sorafenib<br>Twice daily dosing in phase II | Drug: Sorafenib<br>* 400 mg twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 4 weeks | 
| 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. | From randomization until data cut-off (28 Sep 2012); Up to 77 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From randomization until disease progression or data cut-off (16 Jul 2014); Up to 171 weeks | 
| 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). | AEs with an onset during therapy with study treatment or within 28 days after discontinuation of study treatment (up to 1066 days) | 
| Incidence of Dose Limiting Toxicity in Phase I | Number of patients with dose limiting toxicity are presented | 4 weeks | 
| 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. | From randomization until data cut-off (16 July 2014); Up to 171 weeks | 
| 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. | From randomization until data cut-off (16 July 2014); Up to 171 weeks | 
| Overall Survival | Overall survival was defined as the duration from date of randomisation to the date of death. | From randomization until data cut-off (16 July 2014); Up to 171 weeks | 
| 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. | Day1, Day15 and Day 16 | 
| 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. | Day1, Day15 and Day 16 | 
| 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. | Day1, Day15 and Day 16 | 
| 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. | Day1, Day15 and Day 16 | 
| 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. | Day1, Day15 and Day 16 | 
| 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. | Day1, Day15 and Day 16 | 
| 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. | 0 to 4 hours (h), 4 to 12 h, and 12 to 24 h after nintedanib |