Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
Investigate the effect of multiple oral doses of nintedanib on the single dose kinetics of a combination of ethinylestradiol and levonorgestrel (Microgynon®)
Detailed description
Purpose:
Interventions
DRUGMicrogynon
DRUGNintedanib
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Female patients 18 years or older at screening * Female patient is postmenopausal or surgically sterilised * Patient with locally advanced, metastatic or locally recurrent non-small cell lung cancer with histology of adenocarcinoma * Nintedanib (Vargatef®) is planned to be prescribed in accordance with the marketing authorisation (SmPC) * Signed and dated written informed consent in accordance with Good Clinical Practice (GCP) and local legislation prior to admission to the trial
Exclusion criteria
* Any contraindication to nintedanib (Vargatef®), ethinylestradiol or levonorgestrel (Microgynon®), as specified in the respective labels * Use of hormone containing contraceptives (including vaginal and intrauterine devices and including hormone replacement therapy) within 30 days prior to first administration of Microgynon® * Systemic use of drugs known to induce (e.g. rifampicin, St. John's Wort, carbamazepine) or to inhibit (e.g. azole antimycotics, macrolides) CYP3A4 within 7 days prior to first trial drug administration until last pharmacokinetic(PK)-sampling in the trial. Exception: allowed is the intake of corticosteroids as docetaxel (pre)medication * History of major thrombotic or clinically relevant major bleeding event in the past 6 months * Persistence of clinically relevant therapy related toxicities (i.e. \> Common Terminology Criteria for Adverse Events \[CTCAE\] grade 2) from previous chemotherapy and/or radiotherapy * Treatment with other investigational drugs or treatment in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial * Gastrointestinal disorders or abnormalities that would interfere with absorption of the trial drugs * Major surgery (major according to the investigator's assessment) performed within 4 weeks prior to first treatment within the trial and without complete wound healing * Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial * Patients unable to comply with the protocol * Previous enrolment in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Please refer to description section for the details about the actual sampling time points | Area under the concentration-time curve in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC 0-tz) for ethinylestradiol and levonorgestrel after a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®. |
| Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel | Please refer to description section for the details about the actual sampling time points | Maximum blood concentrations (Cmax) for ethinylestradiol and levonorgestrel after a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). | Please refer to description section for the details about the actual sampling time points | Area under curve from zero to infinity (AUC0-∞) for ethinylestradiol and for levonorgestrel after intake of a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®. |
Countries
Germany
Participant flow
Recruitment details
Phase I study to investigate the effect of multiple oral doses of nintedanib on the single dose kinetics of a combination of ethinylestradiol and levonorgestrel (Microgynon®) in patients with non-small cell lung cancer.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites to ensure that all subjects met all inclusion/exclusion criteria. Patients were not to be entered to trial treatment if any one of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| All Patients Patients were orally administered one tablet of Microgynon® (combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel per tablet) after a standardised breakfast in Period 1.
Patients were orally administered one tablet of Microgynon® after continuous 2x2 nintedanib soft gelatine capsule containing 100 mg per day (with dose reduction to 2x1 capsule containing 150 mg, if required) for at least 7 consecutive days in Period 2.
Nintedanib was to be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they had taken nintedanib for at least 7 consecutive days before intake of Microgynon®. Same subjects were continued to Period 2, hence baseline characteristics are presented by Period 1. | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | All Patients |
|---|---|
| Age, Continuous | 67.0 years STANDARD_DEVIATION 11.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 1 / 2 | 1 / 2 | 1 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 |
Outcome results
Primary
Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve in plasma over the time interval from 0 to the time of the last quantifiable data point (AUC 0-tz) for ethinylestradiol and levonorgestrel after a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®.
Time frame: Please refer to description section for the details about the actual sampling time points
Population: Pharmacokinetic Set (PKS): This analysis set includes all patients in the Treated Set (TS) who contributes only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon® | Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Ethinylestradiol | 410 picogram*hour/mililiter | Geometric Coefficient of Variation 6.61 |
| Microgynon® | Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Levonorgestrel | 41500 picogram*hour/mililiter | Geometric Coefficient of Variation 11 |
| Microgynon® With Nintedanib | Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Ethinylestradiol | 348 picogram*hour/mililiter | — |
| Microgynon® With Nintedanib | Area Under the Concentration-time Curve of the the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Levonorgestrel | 43600 picogram*hour/mililiter | — |
Primary
Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel
Maximum blood concentrations (Cmax) for ethinylestradiol and levonorgestrel after a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®.
Time frame: Please refer to description section for the details about the actual sampling time points
Population: Pharmacokinetic Set (PKS): This analysis set includes all patients in the TS who contributes only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon® | Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel | Ethinylestradiol | 32.6 picogram/milliliter[pg/mL] | Geometric Coefficient of Variation 3.04 |
| Microgynon® | Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel | Levonorgestrel | 2680 picogram/milliliter[pg/mL] | Geometric Coefficient of Variation 23.2 |
| Microgynon® With Nintedanib | Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel | Ethinylestradiol | 36.9 picogram/milliliter[pg/mL] | — |
| Microgynon® With Nintedanib | Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel | Levonorgestrel | 1630 picogram/milliliter[pg/mL] | — |
Secondary
Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity).
Area under curve from zero to infinity (AUC0-∞) for ethinylestradiol and for levonorgestrel after intake of a single dose of the combination of ethinylestradiol and levonorgestrel. In Period 1, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after drug administration of Microgynon®. Nintedanib in Period 2 was started at least 7 days before Microgynon® administration. In Period 2, blood samples were collected at pre-dose at 0.35 hour (h) and at 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 11.55h, 23.55h, 47.55h and 71.55h after drug administration of Microgynon®.
Time frame: Please refer to description section for the details about the actual sampling time points
Population: Pharmacokinetic Set (PKS): This analysis set includes all patients in the TS who contributes only one PK parameter value for one period to the statistical assessment.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Microgynon® | Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). | Ethinylestradiol | 503 pg*h/mL | Geometric Coefficient of Variation 0.394 |
| Microgynon® | Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). | Levonorgestrel | 54500 pg*h/mL | Geometric Coefficient of Variation 9.52 |
| Microgynon® With Nintedanib | Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). | Ethinylestradiol | 580 pg*h/mL | — |
| Microgynon® With Nintedanib | Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity). | Levonorgestrel | 57600 pg*h/mL | — |