Carcinoma, Hepatocellular
Conditions
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
Interventions
DRUGSorafenib
DRUGBIBF 1120
Dose escalated in phase I until MTD or adjusted by investigator, dose in phase II part based on phase I data
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose in Phase I | 4 weeks | 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. |
| Time to Progression (TTP) in Phase II | From randomization until data cut-off (15 July 2014); Up to 1031 days | 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Dose Limiting Toxicity in Phase I | 4 weeks | Number of patients with dose limiting toxicity are presented |
| Objective Tumour Response by RECIST | From randomization until data cut-off (15 July 2014); Up to 1031 days | 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) | From randomization until data cut-off (15 July 2014); Up to 1031 days | 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 | From randomization until data cut-off (15 July 2014); Up to 1031 days | Overall survival was defined as the duration from date of randomisation to the date of death. |
Countries
Austria, France, Germany, Hungary, Netherlands, Poland, Romania, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Group 1, 100mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the maximal tolerated dose (MTD). Group 1 patients had a baseline Child-Pugh score of 5 or 6, and aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤2 times the upper limit of normal (ULN). | 6 |
| Phase I Group 1, 150mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 1 patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN). | 3 |
| Phase I Group 1, 200mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 1 patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN). | 4 |
| Phase I Group 2, 50mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 50 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT \>2 to ≤5 times ULN. | 3 |
| Phase I Group 2, 100mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 100 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT \>2 to ≤5 times ULN. | 4 |
| Phase I Group 2, 150mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 150 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT \>2 to ≤5 times ULN. | 4 |
| Phase I Group 2, 200mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD. Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT \>2 to ≤5 times ULN. | 8 |
| Phase II, 200 mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules (two capsules of 100mg) twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macrovascular invasion (MVI) and/or extra-hepatic spread (EHS). Patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN). | 62 |
| Phase II, 400 mg Sorafenib Bid Oral administration of Sorafenib 400 mg film coated tablets twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macrovascular invasion (MVI) and/or extra-hepatic spread (EHS). Patients had a baseline Child-Pugh score of 5 or 6, and AST and ALT ≤2 times the upper limit of normal (ULN). | 31 |
| Total | 125 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 2 | 3 | 3 | 2 | 2 | 7 | 21 | 6 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 2 | 1 | 1 | 0 | 2 | 1 | 1 | 39 | 22 |
| Overall Study | Refused to continue taking trial med. | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase 1 Group 1, 100mg Nintedanib Bid | Phase I Group 1, 150mg Nintedanib Bid | Phase I Group 1, 200mg Nintedanib Bid | Phase I Group 2, 50mg Nintedanib Bid | Phase I Group 2, 100mg Nintedanib Bid | Phase I Group 2, 150mg Nintedanib Bid | Phase I Group 2, 200mg Nintedanib Bid | Phase II, 200 mg Nintedanib Bid | Phase II, 400 mg Sorafenib Bid | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 69.7 Years STANDARD_DEVIATION 6.8 | 65.0 Years STANDARD_DEVIATION 7.8 | 66.5 Years STANDARD_DEVIATION 4 | 72.3 Years STANDARD_DEVIATION 11.7 | 56.3 Years STANDARD_DEVIATION 6.4 | 59.3 Years STANDARD_DEVIATION 13.9 | 57.0 Years STANDARD_DEVIATION 11 | 65.4 Years STANDARD_DEVIATION 10 | 63.1 Years STANDARD_DEVIATION 11.8 | 64.2 Years STANDARD_DEVIATION 10.5 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 2 Participants | 14 Participants | 5 Participants | 24 Participants |
| Sex: Female, Male Male | 5 Participants | 2 Participants | 4 Participants | 3 Participants | 4 Participants | 3 Participants | 6 Participants | 48 Participants | 26 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 4 / 4 | 3 / 3 | 4 / 4 | 4 / 4 | 7 / 8 | 61 / 62 | 31 / 31 |
| serious Total, serious adverse events | 3 / 6 | 1 / 3 | 4 / 4 | 3 / 3 | 2 / 4 | 3 / 4 | 4 / 8 | 34 / 62 | 14 / 31 |
Outcome results
Primary
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.
Time frame: 4 weeks
Population: Treated set which included all patients who received at least one single dose of trial medication, including phase I patients from the dose escalation part that were not replaced for MTD determination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Maximum Tolerated Dose in Phase I | 200 mg bid |
| Group 2 | Maximum Tolerated Dose in Phase I | 200 mg bid |
Primary
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.
Time frame: From randomization until data cut-off (15 July 2014); Up to 1031 days
Population: Treated set, only phase II participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 | Time to Progression (TTP) in Phase II | 5.45 months |
| Group 2 | Time to Progression (TTP) in Phase II | 4.63 months |
95% CI: [0.805, 2.565]
Secondary
Incidence of Dose Limiting Toxicity in Phase I
Number of patients with dose limiting toxicity are presented
Time frame: 4 weeks
Population: Treated set (Phase I patients from the dose escalation part that were not replaced for MTD determination).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
| Group 2 | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
| Phase I Group 1, 200 mg Nintedanib Bid | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
| Phase I Group 2, 50 mg Nintedanib Bid | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
| Phase I Group 2, 100 mg Nintedanib Bid | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
| Phase I Group 2, 150 mg Nintedanib Bid | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
| Phase I Group 2, 200 mg Nintedanib Bid | Incidence of Dose Limiting Toxicity in Phase I | 0 participants |
Secondary
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.
Time frame: From randomization until data cut-off (15 July 2014); Up to 1031 days
Population: Treated set, phase II participants only
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 | Objective Tumour Response by RECIST | 1.6 percentage of participants |
| Group 2 | Objective Tumour Response by RECIST | 6.5 percentage of participants |
Secondary
Overall Survival
Overall survival was defined as the duration from date of randomisation to the date of death.
Time frame: From randomization until data cut-off (15 July 2014); Up to 1031 days
Population: Treated set, only phase II participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 | Overall Survival | 11.86 months |
| Group 2 | Overall Survival | 11.40 months |
95% CI: [0.522, 1.473]
Secondary
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.
Time frame: From randomization until data cut-off (15 July 2014); Up to 1031 days
Population: Treated set, only phase II participants
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group 1 | Progression Free Survival (PFS) | 5.32 months |
| Group 2 | Progression Free Survival (PFS) | 3.94 months |
95% CI: [0.779, 2.343]