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

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.

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00987935

Enrollment

134

Registered

2009-10-01

Start date

2009-10-31

Completion date

2016-01-31

Last updated

2016-03-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Carcinoma, Hepatocellular

Brief summary

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

Interventions

DRUGSorafenib

400 mg twice daily

DRUGBIBF 1120

Twice daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

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

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 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 (28 Sep 2012); Up to 77 weeks	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 (16 July 2014); Up to 171 weeks	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 (16 July 2014); Up to 171 weeks	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 (16 July 2014); Up to 171 weeks	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	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 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 to Progression (TTP) in Phase II (Follow-up Analyses)	From randomization until disease progression or data cut-off (16 Jul 2014); Up to 171 weeks	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.
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)	Day1, Day15 and Day 16	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)	Day1, Day15 and Day 16	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)	Day1, Day15 and Day 16	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)	Day1, Day15 and Day 16	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	0 to 4 hours (h), 4 to 12 h, and 12 to 24 h after 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.
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)	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). 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.
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.	AEs with an onset during therapy with study treatment or within 28 days after discontinuation of study treatment (up to 1066 days)	Incidence and worst intensity (severity) of Adverse Events with grading according to the Common Terminology Criteria for Adverse Events (CTCAE version 3.0).

Countries

South Korea, Taiwan

Participant flow

Recruitment details

The trial consisted of 2 Phases. Patients were stratified into 1 of 2 groups according to their aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and Child-Pugh score at baseline.

Pre-assignment details

Group 1 patients had a baseline Child-Pugh score of 5 or 6, and AST (aspartate aminotransferase ) and ALT (alanine transaminase) ≤2 times the upper limit of normal (ULN). Group 2 patients had a baseline Child-Pugh score of 7, or AST or ALT \>2 to ≤5 times ULN

Participants by arm

Arm	Count
Phase I Group I, 100 mg 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) and pharmacokinetics (PK) of nintedanib.	4
Phase I Group 1, 150 mg 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 and pharmacokinetics (PK) of nintedanib.	3
Phase I Group 1, 200 mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	3
Phase I Group 2, 50 mg 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 and pharmacokinetics (PK) of nintedanib.	3
Phase I Group 2, 100 mg 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 and pharmacokinetics (PK) of nintedanib.	7
Phase I Group 2, 150 mg 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 and pharmacokinetics (PK) of nintedanib.	3
Phase I Group 2, 200 mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase I: A standard 3+3 dose escalation part to determine the MTD and pharmacokinetics (PK) of nintedanib.	16
Phase II, 200 mg Nintedanib Bid Oral administration of Nintedanib (BIBF 1120) 200 mg soft gelatine capsules twice daily (bid). Phase II: Patients were randomly assigned to open-label treatment with nintedanib or sorafenib. Patients were stratified for macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	63
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 macro-vascular invasion (MVI) and/or extra-hepatic spread (EHS).	32
Total	134

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005	FG006	FG007	FG008
Overall Study	Adverse Event	0	1	0	1	1	0	2	10	6
Overall Study	Progressive disease	3	2	3	2	5	3	9	48	23
Overall Study	Reason other than those specified above	0	0	0	0	0	0	0	0	1
Overall Study	Refused to continue taking trial med.	1	0	0	0	1	0	4	4	2

Baseline characteristics

Characteristic	Phase I Group I, 100 mg Nintedanib Bid	Phase I Group 1, 150 mg Nintedanib Bid	Phase I Group 1, 200 mg Nintedanib Bid	Phase I Group 2, 50 mg Nintedanib Bid	Phase I Group 2, 100 mg Nintedanib Bid	Phase I Group 2, 150 mg Nintedanib Bid	Phase I Group 2, 200 mg Nintedanib Bid	Phase II, 200 mg Nintedanib Bid	Phase II, 400 mg Sorafenib Bid	Total
Age, Continuous	44.5 years STANDARD_DEVIATION 14.5	55.7 years STANDARD_DEVIATION 4.2	47.7 years STANDARD_DEVIATION 6.8	64.3 years STANDARD_DEVIATION 15.3	62.3 years STANDARD_DEVIATION 11.1	68.7 years STANDARD_DEVIATION 10.1	56.1 years STANDARD_DEVIATION 11.7	58.2 years STANDARD_DEVIATION 12.6	61.2 years STANDARD_DEVIATION 11.5	58.6 years STANDARD_DEVIATION 12.3
Sex: Female, Male Female	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants	3 Participants	6 Participants	6 Participants	16 Participants
Sex: Female, Male Male	4 Participants	3 Participants	3 Participants	3 Participants	7 Participants	2 Participants	13 Participants	57 Participants	26 Participants	118 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	4 / 4	3 / 3	3 / 3	3 / 3	7 / 7	3 / 3	16 / 16	61 / 63	32 / 32
serious Total, serious adverse events	2 / 4	1 / 3	0 / 3	3 / 3	4 / 7	1 / 3	10 / 16	29 / 63	18 / 32

Outcome results

Primary

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 frame: 4 weeks

Population: Treated set (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
Group 2	Maximum Tolerated Dose in Phase I	200 mg

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 (28 Sep 2012); Up to 77 weeks

Population: Treated set, only phase II participants.

Arm	Measure	Value (MEDIAN)
Group 1	Time to Progression (TTP) in Phase II	2.73 months
Group 2	Time to Progression (TTP) in Phase II	3.71 months

95% CI: [0.802, 2.296]

Secondary

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.