Trial Outcomes & Findings for BIBF 1120 + Carboplatin/Pegylated Liposomal Doxorubicin (PLD) in Patients With Advanced Ovarian Cancer, Fallopian Tube Carcinoma or Primary Peritoneal Cancer (NCT NCT01314105)

Last Updated: 2025-02-13

Results Overview

Maximum Tolerated Dose (MTD) of nintedanib in combination with carboplatin and pegylated liposomal doxorubicin based on the occurrence of dose limiting toxicities (DLTs) during treatment course 1. MTD will be determined among the first 6 evaluable patients in each dose level. MTD is the highest dose at which the incidence of DLT is less than 2/6.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

19 participants

Primary outcome timeframe

First 28-day treatment cycle

Results posted on

2025-02-13

Participant Flow

Abbreviations Used: CTCAE: Common Terminology Criteria for Adverse Events ALT: Alanine Amino Transferase AST: Aspartate Aminotransferase ULN: Upper Limit of Normal

Participant milestones

Participant milestones
Measure	Nintedanib 150mg Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Overall Study STARTED	7	12
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	7	12

Reasons for withdrawal

Reasons for withdrawal
Measure	Nintedanib 150mg Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Overall Study Progressive Disease	6	10
Overall Study Refused to continue taking medication	0	1
Overall Study Other Adverse Event	1	1

Baseline Characteristics

BIBF 1120 + Carboplatin/Pegylated Liposomal Doxorubicin (PLD) in Patients With Advanced Ovarian Cancer, Fallopian Tube Carcinoma or Primary Peritoneal Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Nintedanib 150mg n=7 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Total n=19 Participants Total of all reporting groups
Age, Continuous	58.0 years STANDARD_DEVIATION 12.7 • n=5 Participants	53.1 years STANDARD_DEVIATION 6.4 • n=7 Participants	54.9 years STANDARD_DEVIATION 9.2 • n=5 Participants
Sex: Female, Male Female	7 Participants n=5 Participants	12 Participants n=7 Participants	19 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: First 28-day treatment cycle

Population: MTD set which included patients in the dose escalation part of the trial who started treatment course 2 and/or took 1 dose of carboplatin and PLD, started nintedanib (nin) and did not miss more than 13 doses of nin and/or took 1 dose of carboplatin and PLD, started nin and discontinued treatment due to a dose limiting toxicity during the MTD period

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=6 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=6 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Maximum Tolerated Dose of Nintedanib Based on the Occurrence of DLTs During Treatment Course 1	NA mg MTD was not determined for this dose group	200 mg

PRIMARY outcome

Timeframe: First 28-day treatment cycle

Number of patients with dose limiting toxicity (DLT) occurring during treatment course 1 The following AEs were to be reported as DLT events if their occurrence was considered to be drug-related: Haematological toxicity: * Any CTCAE grade 4 haematological toxicity * CTCAE grade 4 neutropenia that was not associated with fever ≥38.5°C, if persisting for \>7 days despite adequate supportive treatment * CTCAE grade ≥3 neutropenia of any duration if associated with fever ≥38.5°C * Any CTCAE grade 4 thrombocytopenia * CTCAE grade ≥3 thrombocytopenia if associated with bleeding of CTCAE grade ≥2 Non-haematological toxicity: * CTCAE grade ≥3 diarrhoea despite optimal medical management * CTCAE grade 2 diarrhoea persisting for more than 7 days despite optimal medical management * CTCAE grade ≥2 vomiting despite optimal medical management * ALT and/or AST elevation of CTCAE grade ≥3 * ALT and/or AST elevation of \>3x ULN in conjunction with bilirubin increase \>2x ULN

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=6 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=6 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Dose Limiting Toxicities During Treatment Course 1	1 participants	1 participants

SECONDARY outcome

Timeframe: 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration

Population: Pharmacokinetic (PK) set: All patients in the treated set who were documented to have received at least one dose of nintedanib and who had at least one valid pharmacokinetic parameter concentration available

Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of nintedanib during course 1 and course 2

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=7 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib Treatment Course 1 (150mg: N=5; 200mg: N=10)	335 nanogramhour/millilitre (ngh/mL) Geometric Coefficient of Variation 88.5	482 nanogramhour/millilitre (ngh/mL) Geometric Coefficient of Variation 38.8
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib Treatment Course 2 (150mg: N=7)	482 nanogramhour/millilitre (ngh/mL) Geometric Coefficient of Variation 76.1	NA nanogramhour/millilitre (ngh/mL) Geometric Coefficient of Variation NA Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the gMean and gCV is not calculated according to internal rules.

SECONDARY outcome

Timeframe: 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration

Population: PK set

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of nintedanib during course 1 and course 2.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=7 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Nintedanib Treatment Course 1 (150mg: N=6; 200mg: N=11)	283 ng*h/mL Geometric Coefficient of Variation 70.2	422 ng*h/mL Geometric Coefficient of Variation 36.9
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Nintedanib Treatment Course 2 (150mg: N=8; 200mg: N=7)	406 ng*h/mL Geometric Coefficient of Variation 59.0	476 ng*h/mL Geometric Coefficient of Variation 37.6

SECONDARY outcome

Timeframe: 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration

Population: PK set

Maximum measured plasma concentration (Cmax) of nintedanib during course 1 and course 2

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=7 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Maximum Measured Plasma Concentration (Cmax) of Nintedanib Treatment Course 1 (150mg: N=6; 200mg: N=11)	38.8 ng/mL Geometric Coefficient of Variation 40.3	69.0 ng/mL Geometric Coefficient of Variation 27.9
Maximum Measured Plasma Concentration (Cmax) of Nintedanib Treatment Course 2 (150mg: N=8; 200mg: N=7)	65.8 ng/mL Geometric Coefficient of Variation 51.6	82.2 ng/mL Geometric Coefficient of Variation 43.0

SECONDARY outcome

Timeframe: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 26h, 28h, 32h, 48h, 168h, 336h and 480h after drug administration

Population: PK set.Goal is to find MTD for nintedanib,two doses of nintedanib separately displayed.However carboplatin,PLD are given as background,therefore only measured to know exposure.As result displaying all subjects is sufficient.Further we decided to make separate table for MTD dose(200mg nintedanib).Separate table for 150mg nintedanib doesnt add value.

Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of carboplatin (determined as total platinum) during treatment course 1 and course 2.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=12 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carboplatin (Determined as Total Platinum) Treatment Course 1 (200mg:N=10; All Patients:N=16)	271000 ng/mL Geometric Coefficient of Variation 15.1	267000 ng/mL Geometric Coefficient of Variation 15.1
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carboplatin (Determined as Total Platinum) Treatment Course 2 (200mg:N=7; All Patients:N=16)	325000 ng/mL Geometric Coefficient of Variation 15.4	324000 ng/mL Geometric Coefficient of Variation 14.7

SECONDARY outcome

Timeframe: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 23h 55min, 25h, 26h, 27h, 28h, 30h, 32h, and 34h after drug administration

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC 0-inf) of carboplatin during treatment course 1 and course 2 (determined as ultrafilterable platinum). Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 2 as 2/3 of patients had quantifiable values.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=9 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of Carboplatin During Treatment Course 1 and Course 2 (Determined as Ultrafilterable Platinum) Treatment Course 1 (200mg:N=9; All Patients:N=16)	71000 ng*h/mL Geometric Coefficient of Variation 69.3	70700 ng*h/mL Geometric Coefficient of Variation 107
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of Carboplatin During Treatment Course 1 and Course 2 (Determined as Ultrafilterable Platinum) Treatment Course 2 (200mg:N=NA; All Patients:N=NA)	NA ng*h/mL Geometric Coefficient of Variation NA Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the gMean and gCV is not calculated according to internal rules.	NA ng*h/mL Geometric Coefficient of Variation NA Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the gMean and gCV is not calculated according to internal rules.

SECONDARY outcome

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of carboplatin during course 1 and course 2 (determined as total platinum).

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=12 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Carboplatin (Determined as Total Platinum) Treatment Course 1 (200mg:N=10; All Patients:N=16)	223000 ng*h/mL Geometric Coefficient of Variation 18.4	220000 ng*h/mL Geometric Coefficient of Variation 17.1
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Carboplatin (Determined as Total Platinum) Treatment Course 2 (200mg:N=7; All Patients:N=16)	258000 ng*h/mL Geometric Coefficient of Variation 15.8	260000 ng*h/mL Geometric Coefficient of Variation 14.7

SECONDARY outcome

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=12 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Carboplatin (Determined as Ultrafilterable Platinum) Treatment Course 1 (200mg:N=9; All Patients:N=16)	58500 ng*h/mL Geometric Coefficient of Variation 26.0	53800 ng*h/mL Geometric Coefficient of Variation 26.7
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Carboplatin (Determined as Ultrafilterable Platinum) Treatment Course 2 (200mg:N=6; All Patients:N=15)	56200 ng*h/mL Geometric Coefficient of Variation 26.5	55700 ng*h/mL Geometric Coefficient of Variation 29.8

SECONDARY outcome

Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as total platinum).

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=12 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum) Treatment Course 1 (200mg:N=10; All Patients:N=16)	24600 ng/mL Geometric Coefficient of Variation 49.1	24000 ng/mL Geometric Coefficient of Variation 37.7
Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum) Treatment Course 2 (200mg:N=7; All Patients:N=16)	27100 ng/mL Geometric Coefficient of Variation 22.7	23900 ng/mL Geometric Coefficient of Variation 25.2

SECONDARY outcome

Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as ultrafilterable platinum).

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=12 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Maximum Measured Plasma Concentration (Cmax) of Carboplatin During Course 1 and Course 2 (Determined as Ultrafilterable Platinum) Treatment Course 1 (200mg:N=9; All Patients:N=16)	26000 ng/mL Geometric Coefficient of Variation 48.4	24600 ng/mL Geometric Coefficient of Variation 38.0
Maximum Measured Plasma Concentration (Cmax) of Carboplatin During Course 1 and Course 2 (Determined as Ultrafilterable Platinum) Treatment Course 2 (200mg:N=6; All Patients:N=15)	27000 ng/mL Geometric Coefficient of Variation 26.6	24400 ng/mL Geometric Coefficient of Variation 23.0

SECONDARY outcome

Timeframe: 5 minutes (min) before drug administration and 30 min,59 min, 1 hour (h) 15 min, 1h 29min, 1h 45min, 2h 15min, 2h 45min, 4h, 6h, 7h 30min, 9h, 25h, 27h, 30h, 34h, 48h, 168h, 336h and 480h after drug administration

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC 0-inf) of pegylated liposomal doxorubicin (PLD) (determined as total plasma doxorubicin) during treatment course 1 and course 2. Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 1 as for only 2 patients evaluable concentrations were available.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=3 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 Treatment Course 1 (200mg:N=NA; All Patients:N=8)	NA µg*h/mL Geometric Coefficient of Variation NA Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the gMean and gCV is not calculated according to internal rules.	2280 µg*h/mL Geometric Coefficient of Variation 20.1
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 Treatment Course 2 (200mg:N=3; All Patients:N=10)	2120 µg*h/mL Geometric Coefficient of Variation 38.4	2300 µg*h/mL Geometric Coefficient of Variation 25.5

SECONDARY outcome

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of pegylated liposomal doxorubicin (PLD) (determined as total plasma doxorubicin) during treatment course 1 and course 2. Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 1 as for only 2 patients evaluable concentrations were available.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=3 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 Treatment Course 1 (200mg:N=NA; All Patients:N=8)	NA µg*h/mL Geometric Coefficient of Variation NA Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the gMean and gCV is not calculated according to internal rules.	2230 µg*h/mL Geometric Coefficient of Variation 19.3
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 Treatment Course 2 (200mg:N=3; All Patients:N=10)	2060 µg*h/mL Geometric Coefficient of Variation 35.2	2210 µg*h/mL Geometric Coefficient of Variation 24.8

SECONDARY outcome

The maximum measured plasma concentration (Cmax) of pegylated liposomal doxorubicin (PLD) (determined as total plasma doxorubicin) during treatment course 1 and course 2. Geometric mean (gMean) and Geometric coefficient of Variation (gCV) were not calculable for treatment course 1 as for only 2 patients evaluable concentrations were available.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=3 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=19 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 Treatment Course 1 (200mg:N=NA; All Patients:N=8)	NA µg/mL Geometric Coefficient of Variation NA Not calculated as reliable estimation can only be performed when at least 2/3 of the data are available and thus the gMean and gCV is not calculated according to internal rules.	18.9 µg/mL Geometric Coefficient of Variation 14.5
Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 Treatment Course 2 (200mg:N=3; All Patients:N=8)	19.0 µg/mL Geometric Coefficient of Variation 13.5	19.0 µg/mL Geometric Coefficient of Variation 18.0

SECONDARY outcome

Area under the plasma concentration-time curve over the time interval from zero extrapolated to infinity (AUC 0-inf) of pegylated liposomal doxorubicin (PLD) (determined as plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Area under the plasma concentration-time curve from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of pegylated liposomal doxorubicin (PLD) (determined as plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

The maximum measured plasma concentration (Cmax) of pegylated liposomal doxorubicin (PLD) (determined as plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the first drug administration until 28 days after the last drug administration, up to 31 months

Population: Treated Set

Safety of nintedanib as indicated by intensity and incidence of adverse events, graded according to Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. The CTCAE grades are the worst grade per patient. The CTCAE grades are Grade 1 as mild AE, Grade 2 as moderate AE, Grade 3 as severe AE, Grade 4 as lifethreatening or disabling AE, and Grade 5 as death related to AE.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=7 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Incidence and Intensity of Adverse Events Grade 1	0 participants	0 participants
Incidence and Intensity of Adverse Events Grade 2	2 participants	0 participants
Incidence and Intensity of Adverse Events Grade 3	3 participants	9 participants
Incidence and Intensity of Adverse Events Grade 4	2 participants	3 participants
Incidence and Intensity of Adverse Events Grade 5	0 participants	0 participants

SECONDARY outcome

Timeframe: From the first drug administration until 28 days after the last drug administration, up to 31 months

Population: Treated Set

Change from baseline in safety laboratory parameters.

Outcome measures

Outcome measures
Measure	Nintedanib 150mg n=7 Participants Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 Participants Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Change From Baseline in Safety Laboratory Parameters Alanine aminotransferase increased	57.1 percentage of participants	91.7 percentage of participants
Change From Baseline in Safety Laboratory Parameters Aspartate aminotransferase increased	71.4 percentage of participants	91.7 percentage of participants
Change From Baseline in Safety Laboratory Parameters Gamma-glutamyltransferase increased	42.9 percentage of participants	66.7 percentage of participants
Change From Baseline in Safety Laboratory Parameters Platelet count decreased	28.6 percentage of participants	58.3 percentage of participants
Change From Baseline in Safety Laboratory Parameters Blood alkaline phosphatase	28.6 percentage of participants	0 percentage of participants
Change From Baseline in Safety Laboratory Parameters Blood lactate dehydrogenase increased	28.6 percentage of participants	16.7 percentage of participants
Change From Baseline in Safety Laboratory Parameters Blood alkaline phosphatase increased	14.3 percentage of participants	25.0 percentage of participants
Change From Baseline in Safety Laboratory Parameters Haemoglobin decreased	0 percentage of participants	16.7 percentage of participants
Change From Baseline in Safety Laboratory Parameters Neutrophil count decreased	0 percentage of participants	16.7 percentage of participants
Change From Baseline in Safety Laboratory Parameters Blood bilirubin increased	14.3 percentage of participants	8.3 percentage of participants
Change From Baseline in Safety Laboratory Parameters Blood creatinine decreased	14.3 percentage of participants	0 percentage of participants
Change From Baseline in Safety Laboratory Parameters Gamma-glutamyltransferase	14.3 percentage of participants	0 percentage of participants
Change From Baseline in Safety Laboratory Parameters Haemoglobin	14.3 percentage of participants	0 percentage of participants
Change From Baseline in Safety Laboratory Parameters Neutrophil count	14.3 percentage of participants	0 percentage of participants
Change From Baseline in Safety Laboratory Parameters White blood cell count decreased	14.3 percentage of participants	0 percentage of participants
Change From Baseline in Safety Laboratory Parameters Amylase increased	0 percentage of participants	8.3 percentage of participants
Change From Baseline in Safety Laboratory Parameters Blood creatinine increased	0 percentage of participants	8.3 percentage of participants
Change From Baseline in Safety Laboratory Parameters Platelet count increased	0 percentage of participants	8.3 percentage of participants

Adverse Events

Nintedanib 150mg

Serious events: 3 serious events

Other events: 6 other events

Deaths: 0 deaths

Nintedanib 200mg

Serious events: 4 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Nintedanib 150mg n=7 participants at risk Nintedanib (150 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.	Nintedanib 200mg n=12 participants at risk Nintedanib (200 mg twice daily (BID), except the day of chemotherapy infusion) administered orally plus standard therapy of carboplatin (Area Under the Curve (AUC) 5 mg/mL\*min) and PLD (30 mg/m2) which were administered by intravenous infusion once every 28 days.
Gastrointestinal disorders Ileus	0.00% 0/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	8.3% 1/12 • From the first drug administration until 28 days after the last drug administration, up to 31months
Gastrointestinal disorders Intestinal obstruction	0.00% 0/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	8.3% 1/12 • From the first drug administration until 28 days after the last drug administration, up to 31months
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	8.3% 1/12 • From the first drug administration until 28 days after the last drug administration, up to 31months
Immune system disorders Hypersensitivity	14.3% 1/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	0.00% 0/12 • From the first drug administration until 28 days after the last drug administration, up to 31months
Investigations Alanine aminotransferase increased	14.3% 1/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	0.00% 0/12 • From the first drug administration until 28 days after the last drug administration, up to 31months
Investigations Platelet count decreased	14.3% 1/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	0.00% 0/12 • From the first drug administration until 28 days after the last drug administration, up to 31months
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/7 • From the first drug administration until 28 days after the last drug administration, up to 31months	8.3% 1/12 • From the first drug administration until 28 days after the last drug administration, up to 31months

Other adverse events

Additional Information

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Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
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