Phase I/II Comparison of Efficacy and Safety of BIBF 1120 and Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Study Overview
=================
Brief Summary
-----------------
The study aim is to determine maximally tolerated dose (MTD) of BIBF 1120 in HCC (hepatocellular cancer) and compare efficacy of BIBF 1120 to Sorafenib in HCC patients

Official Title
-----------------
A Multicenter, Open Label, Phase I /Randomised Phase II Study to Evaluate Safety, Pharmacokinetics and Efficacy of BIBF 1120 in Comparison With Oral Sorafenib for Advanced Hepatocellular Carcinoma Patients.

Conditions
-----------------
Carcinoma, Hepatocellular

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


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: Histologically or cytologically confirmed diagnosis of hepatocellular carcinoma (HCC) not amenable to curative surgery or loco-regional therapy (RFA, percutaneous ethanol injection (PEI), TACE) Age 18 years or older Eastern Cooperative Oncology Group performance score of 2 or less Child-Pugh score A (score 5-6) At least one measurable lesion according to RECIST 1.0 (this criterion is limited to phase II only) In case a measurable lesion was previously treated by loco-regional therapy (RFA, PEI, TACE or RT) , this lesion must have to be documented as progression according to RECIST 1.0 by CT or MRI (this criterion is limited to phase II only). Time interval from last local therapy (e.g. radiofrequency ablation, percutaneous ethanol injection, radiotherapy, transarterial chemoembolization) more than 4 weeks prior to start of study treatment Written informed consent consistent with International Conference on Harmonisation/ Good Clinical Practice (ICH-GCP) and local legislation Exclusion criteria: Prior systemic therapy for HCC Fibrolamellar hepatocellular carcinoma (HCC) Bilirubin greater than 1.5 times ULN AST or ALT greater than 2 times ULN Uncontrolled or refractory ascites to adequate medical therapy Hepatic encephalopathy more than grade 1 according to Child-Pugh criteria Prothrombin time international normalized ratio greater than 2.3, or prothrombin time more than 6 seconds prolonged than control Absolute neutrophil count less than 1000 /µL Platelet count less than 60000 /µL Hemoglobin less than 9 g/dL Serum creatinine greater than 1.5 times Upper Limit of Normal (ULN) Proteinuria of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or greater Variceal bleeding within last 6 months prior to start of study treatment History of major thrombotic (except portal vein thrombosis) or clinically relevant major bleeding event in the past 6 months Known inherited predisposition to bleeding or thrombosis Significant cardiovascular diseases (i.e. hypertension not controlled by medical therapy, blood pressure > 150/90 mmHg), unstable angina, history of myocardial infarction within the past 6 months, congestive heart failure > class II according to New York Heart Association (NYHA), serious cardiac arrhythmia, pericardial effusion) Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid =< 325mg per day) Major surgery within 4 weeks prior to start of study treatment Treatment with other investigational drugs or participation in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial (except for present trial drug) Known serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least twelve months after end of active therapy Current alcohol abuse or drug abuse that would limit pt ability to comply with protocol Symptomatic central nervous system (CNS) metastasis Life expectancy less than 12 weeks Patient unable to take oral medication

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBF 1120<br>Phase I dose escalation and phase II using dose determined in phase I ( 200 mg BID) | Drug: BIBF 1120<br>* Dose escalated in phase I until MTD or adjusted by investigator, dose in phase II part based on phase I data<br>|
| Active Comparator: Sorafenib<br> | Drug: Sorafenib<br> <br> |

What is the study measuring?
-----------------
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 dose limiting toxicities (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 (15 July 2014); Up to 1031 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 (15 July 2014); Up to 1031 days | 
| 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 (15 July 2014); Up to 1031 days | 
| Overall Survival | Overall survival was defined as the duration from date of randomisation to the date of death. | From randomization until data cut-off (15 July 2014); Up to 1031 days |