E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histologically or cytologically confirmed hepatocellular carcinoma not amenable to local therapy with adequate renal, hematological and liver paramenters with Child-Pugh score 7 or less, in 1st line systemic therapy.
Note for phase II only liver function group I patients with Child Pugh A will be enrolled |
|
E.1.1.1 | Medical condition in easily understood language |
Hepatocellular carcinoma not amenable to curative or locoregional treatment |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10049010 |
E.1.2 | Term | Carcinoma hepatocellular |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase I part of study:
To identify the maximum tolerated dose (MTD) of BIBF 1120 in terms of drug-related adverse events in HCC patients.
Phase II of study:
To evaluate the efficacy of BIBF 1120 in HCC patients without prior systemic treatment as compared to Sorafenib.
|
|
E.2.2 | Secondary objectives of the trial |
To explore the relationship between pharmacokinetics of BIBF 1120 and liver function assessed by AST, ALT, and bilirubin values as well as by Child-Pugh classification at the study baseline. |
|
E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
No individual trial protocols will be used for substudies. The following investigations are integrated in the protocol of the main study:
PK analysis in phase II part:
Patients in phase II at selected sites (sites that are participating in phase I) will have extended PK sampling for BIBF 1120 (same schedule as the PK sampling in phase I). Purpose is to evaluate BIBF 1120 PK at hepatically impaired population. Specific informed consent will be prepared for relevant sites to cover this additional PK sampling.
Pharmacogenetic analysis:
All Patients with be evaluated for pharmacogenetics of UGT enzymes. This genetic analysis will be carried out in an explorative approach and should help to interpret the pharmacokinetic data of BIBF 1120, BIBF 1202 and especially of BIBF 1202 glucuronide as well as the therapeutic outcome for these patients.
The patients will be informed that pharmacogenetic testing for genes involved in drug metabolism, and tumour response will take place and that no polymorphisms of genes which might predispose for different diseases will be analysed. Only frequent functional polymorphisms will be analyzed. The patients will be informed about the pharmacogenetic analysis and the possibility to review the results of their individual analysis if desired. Moreover, they will be informed, that the results will not have any influence on their actual therapy due to the exploratory nature of the pharmacogenetic analysis.
|
|
E.3 | Principal inclusion criteria |
1. HCC, either histologically/cytologically confirmed diagnosis or clinically diagnosis by
AASLD criteria, which is not amenable to local therapy (RFA, PEI, RT, TACE)
2. Age 18 years or older
3. ECOG performance score of 2 or less
4. Child-Pugh score A (score 5-6)
5. At least one measurable lesion according to RECIST 1.0 (this criterion is limited to
phase II only)
6. 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)
7. Time interval from last local therapy more than 4 weeks prior to start of study
treatment
8. Written informed consent consistent with ICH-GCP and local legislation
|
|
E.4 | Principal exclusion criteria |
1. Prior systemic therapy for metastatic/unresectable HCC (for phase II)
2. More then one line of prior systemic therapy for metastatic/unresectable HCC (for
phase I)
3. Fibrolamellar HCC
4. Uncontrolled or refractory ascites by adequate medical therapy
5. Bilirubin greater than 1.5 times ULN
6. AST or ALT greater than 2 times ULN
7. Hepatic encephalopathy more than grade 1 according to Child-Pugh criteria
8. Prothrombin time international normalized ratio greater than 2.3, or prothrombin
time more than 6 seconds prolonged than control
9. Absolute neutrophil count less than 1000/μL
10. Platelet count less than 60000/μL
11. Hemoglobin less than 9 g/dL
12. Serum creatinine greater than 1.5 times ULN
13. Proteinuria of CTCAE grade 2 or greater
14. Variceal bleeding within 6 months prior to start of study treatment
15. History of major thrombotic (except portal vein thrombosis) or clinically relevant
major bleeding event in the past 6 months
16. Known inherited predisposition to bleeding or thrombosis
17. 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 > NYHA II, serious
cardiac arrhythmia, pericardial effusion)
18. 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)
19. Last administration of systemic treatment for HCC within 4 weeks prior to start
of study treatment or no recovery from any treatment related toxicity
20. Major surgery within 4 weeks prior to start of study treatment
21. Treatment with other investigational drugs concomitantly with this trial (except
for present trial drug)
22. 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
23. 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, condomes for participating males) during the trial and for
at least twelve months after end of active therapy
24. Current alcohol abuse or drug abuse that would limit patient ability to comply
with protocol
25. Symptomatic CNS metastasis
26. Life expectancy less than 12 weeks
27. Patient unable to take oral medication
28. Gastrointestinal disorders or abnormalities that would interfere with absorption
of the study drug
29. Pregnancy or breast feeding
30. Patient unable to comply with the protocol
31. Other malignancy within the past three years other than basal cell skin cancer,
or carcinoma in situ of the cervix
32. Hypersensitivity to active substance or to any of the excipients of both BIBF
1120 or sorafenib
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the phase I part is the MTD of BIBF 1120 for HCC patients.
The primary endpoint of the phase II part is time-to-progression defined as the time from randomization to disease progression according to RECIST
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
-Incidence of DLTs
-Objective RECIST 1.0 tumour response
-Progression free survival by RECIST 1.0
-Overall survival |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Drug metabolism in hepatically impaired patient |
|
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.1.7.1 | Other trial design description |
Open labeled phase I followed by open labeled randomised parallel group design |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.3.1 | Comparator description |
|
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
This is an oncology study with overall survival (OS) as secondary endpoint. Patients will be followed until death.
Interim database lock is expected 6 months after last patient is enrolled. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |