Investigation of the Effect of Nintedanib on the Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Patients With Non-small Cell Lung Cancer

• Sponsor: Boehringer Ingelheim (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02751385
• Collaborator: (none)
• Enrollment: 2
• Location: 1
• Arm: 1
• Actual Duration (Months): 18.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Investigate the effect of multiple oral doses of nintedanib on the single dose kinetics of a combination of ethinylestradiol and levonorgestrel (Microgynon®)

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small-Cell Lung	Drug: Microgynon; Drug: Nintedanib	Phase 1

Detailed Description

Purpose:

Study Design

• Study Type: Interventional
• Actual Enrollment: 2 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Phase I Trial to Investigate the Effect of Nintedanib on the Pharmacokinetics of a Combination of Ethinylestradiol and Levonorgestrel in Patients With Non-small Cell Lung Cancer
• Actual Study Start Date: May 20, 2016
• Actual Primary Completion Date: Nov 28, 2017
• Actual Study Completion Date: Nov 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: All Patients Microgynon alone in Period 1 then with Nintedanib in Period 2	Drug: Microgynon; Drug: Nintedanib

Outcome Measures

Primary Outcome Measures

1. 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®.

2. 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 Outcome Measures

1. 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®.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Klinikum Chemnitz gGmbH	Chemnitz		Germany	09116

Sponsors and Collaborators

• Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

• Study Protocol - Mar 9, 2017
• Statistical Analysis Plan - Jan 29, 2018

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT02751385
• Other Study ID Numbers: 1199.238; 2015-005664-41
• First Posted: Apr 26, 2016
• Last Update Posted: Mar 14, 2019
• Last Verified: Nov 1, 2018

• Additional relevant MeSH terms: Carcinoma, Non-Small-Cell Lung; Nintedanib; Ethinyl estradiol, levonorgestrel drug combination; Ethinyl Estradiol-Norgestrel Combination

Study Results

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 Detail	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.

Arm/Group Title	Microgynon®	Microgynon® With Nintedanib
Arm/Group Description	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®.
Period Title: Period 1
STARTED	2	0
COMPLETED	2	0
NOT COMPLETED	0	0
Period Title: Period 1
STARTED	0	2
COMPLETED	0	2
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	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.
Overall Participants	2
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.0 (11.3)
Sex: Female, Male (Count of Participants)
Female	2 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	2 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	2 100%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	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)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Microgynon®	Microgynon® With Nintedanib
Arm/Group Description	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®.
Measure Participants	2	2
Ethinylestradiol	410 (6.61)	348 (NA)
Levonorgestrel	41500 (11.0)	43600 (NA)

2. Primary Outcome

Title	Maximum Measured Concentration (Cmax) of Ethinylestradiol and Levonorgestrel
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Microgynon®	Microgynon® With Nintedanib
Arm/Group Description	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®.
Measure Participants	2	2
Ethinylestradiol	32.6 (3.04)	36.9 (NA)
Levonorgestrel	2680 (23.2)	1630 (NA)

3. Secondary Outcome

Title	Area Under the Concentration-time Curve of the Ethinylestradiol and Levonorgestrel in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity).
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Microgynon®	Microgynon® With Nintedanib
Arm/Group Description	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®.
Measure Participants	2	1
Ethinylestradiol	503 (0.394)	580 (NA)
Levonorgestrel	54500 (9.52)	57600 (NA)

Adverse Events

Time Frame	From first drug administration until 3 days after the last drug administration. Up to 13 days for Microgynon. From first drug administration until 30 days after the last drug administration. Up to 34 days for nintedanib.
Arm/Group Title	Microgynon®		Loading Nintedanib		Nintedanib+Microgynon®		Nintedanib
Arm/Group Description	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 on nintedanib loading phase		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 in Period 2. In case of a temporary interruption of nintedanib intake, patients could receive Microgynon® in Period 2 only if they have taken nintedanib for at least 7 consecutive days before intake of Microgynon®.		Patients administered with nintedanib
All Cause Mortality
	Microgynon®		Loading Nintedanib		Nintedanib+Microgynon®		Nintedanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Serious Adverse Events
	Microgynon®		Loading Nintedanib		Nintedanib+Microgynon®		Nintedanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/2 (0%)		0/2 (0%)		0/2 (0%)
Other (Not Including Serious) Adverse Events
	Microgynon®		Loading Nintedanib		Nintedanib+Microgynon®		Nintedanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/2 (50%)		1/2 (50%)		1/2 (50%)		0/2 (0%)
Gastrointestinal disorders
Diarrhoea	0/2 (0%)		1/2 (50%)		0/2 (0%)		0/2 (0%)
Investigations
Hepatic enzyme increased	0/2 (0%)		0/2 (0%)		1/2 (50%)		0/2 (0%)
Musculoskeletal and connective tissue disorders
Pain in extremity	1/2 (50%)		0/2 (0%)		0/2 (0%)		0/2 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Other - 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.