Ovarian Neoplasms, Peritoneal Neoplasms
Conditions
Brief summary
This phase I, open label dose escalation study will investigate the addition of BIBF 1120 to treatment with the combination of carboplatin and Pegylated Liposomal Doxorubicin (PLD) in patients with advanced, platinum sensitive relapsed ovarian cancer, fallopian tube carcinoma or primary peritoneal cancer.
Interventions
DRUGBIBF 1120 + PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min
BIBF1120 twice daily along with standard therapy of PLD + carboplatin
DRUGBIBF 1120+ PLD 30 mg/m2 + CBDCA AUC5 mg/mL*min
BIBF1120 twice daily along with standard therapy of PLD + carboplatin
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Female patients, age 18 years or older, with a first, second or third relapse of histologically (on initial diagnosis) confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal cancer 2. Up to three lines of prior chemo (chemotherapy before and after interval surgery to be counted as one line therapy), with treatment free interval of \> 6 months (= time between last administration of prior anti-cancer treatment, including chemotherapy, hormonal therapy, or radiation therapy, and diagnosis of progressive disease) 3. Platinum based chemo in immediately preceding line 4. Eligibility for treatment with i.v. chemotherapy regimen of carboplatin AUC 5 and PLD 30 mg/m2 every 4 weeks 5. Life expectancy of at least 3 months 6. Written informed consent that is consistent with International Conference of Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines 7. Eastern Cooperative Oncology Group (ECOG) performance score 0 or1 8. Prior treatment with angiogenesis inhibitor (bevacizumab, TKI inhibiting VEGFR-2) is allowed provided treatment with bevacizumab has been discontinued = 28 days prior to start of therapy and treatment with the TKI has been discontinued = 3 months prior to start of therapy, provided anti-angiogenic therapy was added to only one of the preceding lines of therapy
Exclusion criteria
1. Prior chemotherapy with doxorubicin (any formulation, liposomal or non-liposomal doxorubicin). 2. Any contraindications for therapy with PLD or carboplatin, e.g. a history of hypersensitivity reactions to platinum-containing compounds and their excipients. 3. Hypersensitivity to active substance or to any of the excipients of BIBF 1120. 4. Treatment with other investigational drugs or participation in another clinical trial testing a drug within the past four weeks before start of therapy or concomitantly with this trial (exception: for previous treatment with angiogenesis inhibitors, cf. inclusion criterion #8). 5. Laboratory values indicating an increased risk for adverse events. 6. Major surgery within 4 weeks prior to start of study treatment. 7. Patients for whom surgery is planned, e.g. interval debulking surgery. 8. Clinically relevant non-healing wound, ulcer (intestinal tract, skin) or bone fracture. 9. Clinical symptoms or signs of gastrointestinal obstruction that require parenteral nutrition or hydration. 10. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug. 11. History of clinical symptoms of brain metastases. 12. Prior thrombosis or thromboembolic event in the presence of an inherited coagulopathy. 13. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months. 14. Known inherited or acquired bleeding disorder. 15. Significant cardiovascular diseases. 16. Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy. 17. Other malignancy diagnosed within the past 5 years. 18. Known serious illness or concomitant non-oncological disease. 19. Patients unable to comply with the protocol. 20. Patients with preserved reproductive capacity who are sexually active and unwilling to use a medically acceptable method of contraception. 21. Pregnancy or breast feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Nintedanib Based on the Occurrence of DLTs During Treatment Course 1 | First 28-day treatment cycle | 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. |
| Dose Limiting Toxicities During Treatment Course 1 | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Measured Plasma Concentration (Cmax) of Nintedanib | 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration | Maximum measured plasma concentration (Cmax) of nintedanib during course 1 and course 2 |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carboplatin (Determined as Total Platinum) | 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 | 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. |
| 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) | 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. |
| 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) | 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 | 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). |
| 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) | 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 from time zero to the time of the last quantifiable drug concentration (AUC0-tz) of carboplatin during course 1 and course 2 (determined as ultrafilterable platinum). |
| Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum) | 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 | Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as total platinum). |
| Maximum Measured Plasma Concentration (Cmax) of Carboplatin During Course 1 and Course 2 (Determined as Ultrafilterable Platinum) | 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 | Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as ultrafilterable platinum). |
| Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib | 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration | Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of nintedanib during course 1 and course 2 |
| 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 | 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 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. |
| Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2 | 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 | 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. |
| Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of PLD (Determined as Plasma Doxorubicinol) | 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 plasma doxorubicinol). Due to interference from doxorubicin, doxorubicinol concentrations could not be determined and doxorubicinol PK parameters could not be evaluated. |
| 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 Plasma Doxorubicinol) | 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 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. |
| Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Plasma Doxorubicinol) | 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 | 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. |
| Incidence and Intensity of Adverse Events | From the first drug administration until 28 days after the last drug administration, up to 31 months | 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. |
| Change From Baseline in Safety Laboratory Parameters | From the first drug administration until 28 days after the last drug administration, up to 31 months | Change from baseline in safety laboratory parameters. |
| 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 | 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. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Nintedanib | 5 minutes (min) before drug administration and 1 hour (h) 2h, 3h, 4h, 6h, 8h, 10h, 24h, 144h, 312h and 456h after drug administration | 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. |
Countries
Spain
Participant flow
Pre-assignment details
Abbreviations Used: CTCAE: Common Terminology Criteria for Adverse Events ALT: Alanine Amino Transferase AST: Aspartate Aminotransferase ULN: Upper Limit of Normal
Participants by arm
| Arm | Count |
|---|---|
| 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. | 7 |
| 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. | 12 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other Adverse Event | 1 | 1 |
| Overall Study | Progressive Disease | 6 | 10 |
| Overall Study | Refused to continue taking medication | 0 | 1 |
Baseline characteristics
| Characteristic | Nintedanib 150mg | Nintedanib 200mg | Total |
|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 12.7 | 53.1 years STANDARD_DEVIATION 6.4 | 54.9 years STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 7 Participants | 12 Participants | 19 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 7 | 12 / 12 |
| serious Total, serious adverse events | 3 / 7 | 4 / 12 |
Outcome results
Primary
Dose Limiting Toxicities During Treatment Course 1
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
Time frame: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib 150mg | Dose Limiting Toxicities During Treatment Course 1 | 1 participants |
| Nintedanib 200mg | Dose Limiting Toxicities During Treatment Course 1 | 1 participants |
Primary
Maximum Tolerated Dose of Nintedanib Based on the Occurrence of DLTs During Treatment Course 1
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.
Time frame: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nintedanib 150mg | Maximum Tolerated Dose of Nintedanib Based on the Occurrence of DLTs During Treatment Course 1 | NA mg |
| Nintedanib 200mg | Maximum Tolerated Dose of Nintedanib Based on the Occurrence of DLTs During Treatment Course 1 | 200 mg |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carboplatin (Determined as Total Platinum)
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 267000 ng/mL | Geometric Coefficient of Variation 15.1 |
| Nintedanib 200mg | 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) | 324000 ng/mL | Geometric Coefficient of Variation 14.7 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib
Area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC0-inf) of nintedanib during course 1 and course 2
Time frame: 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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 nanogram*hour/millilitre (ng*h/mL) | Geometric Coefficient of Variation 88.5 |
| Nintedanib 150mg | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib | Treatment Course 2 (150mg: N=7) | 482 nanogram*hour/millilitre (ng*h/mL) | Geometric Coefficient of Variation 76.1 |
| Nintedanib 200mg | 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) | 482 nanogram*hour/millilitre (ng*h/mL) | Geometric Coefficient of Variation 38.8 |
| Nintedanib 200mg | Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Nintedanib | Treatment Course 2 (150mg: N=7) | NA nanogram*hour/millilitre (ng*h/mL) | — |
Secondary
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)
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).
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 220000 ng*h/mL | Geometric Coefficient of Variation 17.1 |
| Nintedanib 200mg | 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) | 260000 ng*h/mL | Geometric Coefficient of Variation 14.7 |
Secondary
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)
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 ultrafilterable platinum).
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 53800 ng*h/mL | Geometric Coefficient of Variation 26.7 |
| Nintedanib 200mg | 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) | 55700 ng*h/mL | Geometric Coefficient of Variation 29.8 |
Secondary
Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Drug Concentration (AUC0-tz) of Nintedanib
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.
Time frame: 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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 422 ng*h/mL | Geometric Coefficient of Variation 36.9 |
| Nintedanib 200mg | 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) | 476 ng*h/mL | Geometric Coefficient of Variation 37.6 |
Secondary
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 Plasma Doxorubicinol)
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.
Time frame: 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
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.
Secondary
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
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.
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 | — |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 2230 µg*h/mL | Geometric Coefficient of Variation 19.3 |
| Nintedanib 200mg | 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) | 2210 µg*h/mL | Geometric Coefficient of Variation 24.8 |
Secondary
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)
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.
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 | — |
| Nintedanib 200mg | 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) | 70700 ng*h/mL | Geometric Coefficient of Variation 107 |
| Nintedanib 200mg | 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 | — |
Secondary
Area Under the Plasma Concentration-time Curve Over the Time Interval From Zero Extrapolated to Infinity (AUC 0-inf) of PLD (Determined as Plasma Doxorubicinol)
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.
Time frame: 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
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.
Secondary
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
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.
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 | — |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 2280 µg*h/mL | Geometric Coefficient of Variation 20.1 |
| Nintedanib 200mg | 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) | 2300 µg*h/mL | Geometric Coefficient of Variation 25.5 |
Secondary
Change From Baseline in Safety Laboratory Parameters
Change from baseline in safety laboratory parameters.
Time frame: From the first drug administration until 28 days after the last drug administration, up to 31 months
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Alanine aminotransferase increased | 57.1 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Aspartate aminotransferase increased | 71.4 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Gamma-glutamyltransferase increased | 42.9 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Platelet count decreased | 28.6 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Blood alkaline phosphatase | 28.6 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Blood lactate dehydrogenase increased | 28.6 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Blood alkaline phosphatase increased | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Haemoglobin decreased | 0 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Neutrophil count decreased | 0 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Blood bilirubin increased | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Blood creatinine decreased | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Gamma-glutamyltransferase | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Haemoglobin | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Neutrophil count | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | White blood cell count decreased | 14.3 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Amylase increased | 0 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Blood creatinine increased | 0 percentage of participants |
| Nintedanib 150mg | Change From Baseline in Safety Laboratory Parameters | Platelet count increased | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Neutrophil count | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Alanine aminotransferase increased | 91.7 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Blood bilirubin increased | 8.3 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Aspartate aminotransferase increased | 91.7 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Platelet count increased | 8.3 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Gamma-glutamyltransferase increased | 66.7 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Blood creatinine decreased | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Platelet count decreased | 58.3 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | White blood cell count decreased | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Blood alkaline phosphatase | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Gamma-glutamyltransferase | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Blood lactate dehydrogenase increased | 16.7 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Blood creatinine increased | 8.3 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Blood alkaline phosphatase increased | 25.0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Haemoglobin | 0 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Haemoglobin decreased | 16.7 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Amylase increased | 8.3 percentage of participants |
| Nintedanib 200mg | Change From Baseline in Safety Laboratory Parameters | Neutrophil count decreased | 16.7 percentage of participants |
Secondary
Incidence and Intensity of Adverse Events
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.
Time frame: From the first drug administration until 28 days after the last drug administration, up to 31 months
Population: Treated Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib 150mg | Incidence and Intensity of Adverse Events | Grade 2 | 2 participants |
| Nintedanib 150mg | Incidence and Intensity of Adverse Events | Grade 4 | 2 participants |
| Nintedanib 150mg | Incidence and Intensity of Adverse Events | Grade 3 | 3 participants |
| Nintedanib 150mg | Incidence and Intensity of Adverse Events | Grade 5 | 0 participants |
| Nintedanib 150mg | Incidence and Intensity of Adverse Events | Grade 1 | 0 participants |
| Nintedanib 200mg | Incidence and Intensity of Adverse Events | Grade 5 | 0 participants |
| Nintedanib 200mg | Incidence and Intensity of Adverse Events | Grade 1 | 0 participants |
| Nintedanib 200mg | Incidence and Intensity of Adverse Events | Grade 2 | 0 participants |
| Nintedanib 200mg | Incidence and Intensity of Adverse Events | Grade 3 | 9 participants |
| Nintedanib 200mg | Incidence and Intensity of Adverse Events | Grade 4 | 3 participants |
Secondary
Maximum Measured Plasma Concentration (Cmax) of Carboplatin During Course 1 and Course 2 (Determined as Ultrafilterable Platinum)
Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as ultrafilterable platinum).
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 24600 ng/mL | Geometric Coefficient of Variation 38 |
| Nintedanib 200mg | 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) | 24400 ng/mL | Geometric Coefficient of Variation 23 |
Secondary
Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum)
Maximum measured plasma concentration (Cmax) of carboplatin during course 1 and course 2 (determined as total platinum).
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum) | Treatment Course 1 (200mg:N=10; All Patients:N=16) | 24000 ng/mL | Geometric Coefficient of Variation 37.7 |
| Nintedanib 200mg | Maximum Measured Plasma Concentration (Cmax) of Carboplatin (Total Platinum) | Treatment Course 2 (200mg:N=7; All Patients:N=16) | 23900 ng/mL | Geometric Coefficient of Variation 25.2 |
Secondary
Maximum Measured Plasma Concentration (Cmax) of Nintedanib
Maximum measured plasma concentration (Cmax) of nintedanib during course 1 and course 2
Time frame: 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
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | Maximum Measured Plasma Concentration (Cmax) of Nintedanib | Treatment Course 1 (150mg: N=6; 200mg: N=11) | 69.0 ng/mL | Geometric Coefficient of Variation 27.9 |
| Nintedanib 200mg | Maximum Measured Plasma Concentration (Cmax) of Nintedanib | Treatment Course 2 (150mg: N=8; 200mg: N=7) | 82.2 ng/mL | Geometric Coefficient of Variation 43 |
Secondary
Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Plasma Doxorubicinol)
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.
Time frame: 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
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.
Secondary
Maximum Measured Plasma Concentration (Cmax) of PLD (Determined as Total Plasma Doxorubicin) During Treatment Course 1 and Course 2
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.
Time frame: 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
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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib 150mg | 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 | — |
| Nintedanib 150mg | 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 |
| Nintedanib 200mg | 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) | 18.9 µg/mL | Geometric Coefficient of Variation 14.5 |
| Nintedanib 200mg | 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 18 |