Carcinoma, Non-Small-Cell Lung
Conditions
Brief summary
To determine the appropriateness of the dose of nintedanib 200 mg b.i.d. plus docetaxel 75 mg/m2 as starting dose by evaluating the safety in Japanese patients with body surface area (BSA) \<1.5 m2 and locally advanced or metastatic adenocarcinoma subtype non-small cell lung cancer (NSCLC) after failure of first line platinum- based chemotherapy
Interventions
DRUGNintedanib
Nintedanib
DRUGDocetaxel
Docetaxel
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients aged 20 years or older at the date of informed consent 2. Patients with body surface area (BSA)\<1.5 m2 at screening 3. Patients with histologically/cytologically confirmed locally advanced or metastatic adenocarcinoma subtype non-small cell lung cancer (NSCLC) after failure of first line platinum-based chemotherapy (patients with non-target lesion only are eligible) First line chemotherapy may include continuation or switch maintenance therapy. One prior adjuvant and/or neoadjuvant chemotherapy is accepted. 4. Patients who have life expectancy of at least 3 months 5. Patients who are Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at screening 6. Patients obtained written informed consent in accordance with International Conference on Harmonisation-Good Clinical Practice (ICH-GCP)and Japanese GCP
Exclusion criteria
1. Patients who have received more than one prior line of chemotherapy (i.e., second or third line chemotherapy) for advanced or metastatic NSCLC (Prior monotherapies with an epidermal growth factor receptor tyrosine kinase inhibitors \[EGFR-TKI\]) or anaplastic lymphoma kinase (ALK) inhibitor can be allowed) 2. Patients who have received previous therapy with other vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) inhibitors (other than bevacizumab) for the treatment of NSCLC at any time 3. Patients who have received following treatments within 4 weeks prior to start of study therapy 1) Other investigational drugs 2) Chemo-, hormone-, immunotherapy, or monoclonal antibody. 4. Patients who have received molecular target therapy including EGFR TKIs and ALK inhibitors within 2 weeks prior to start of study therapy 5. Patents who have received radiotherapy within the past 3 months (in the case of limited -field \[e.g. brain or bone metastasis\] radiotherapy with palliative intent), within 2 weeks) prior to start of study therapy 6. Patients who not recovered clinically relevant therapy related toxicities from previous chemotherapy and/or radiotherapy (=CTCAE grade 2 Adverse Event from previous treatment) at screening further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Cycle 1, from first administration of study medication up to 21 days thereafter. | DLT was defined as any of the following study drug related adverse events (AEs): * Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 non-haematological toxicity except transient electrolyte abnormality and isolated increase of gamma-glutamyltransferase (GGT); gastrointestinal toxicity, despite adequate supportive care * CTCAE grade 4 haematological toxicity; Neutrophil count decreased or white blood cell count (not associated with fever) for \>7 days despite adequate supportive treatment * CTCAE grade 4 febrile neutropenia with fever ≥38.5 degrees * CTCAE grade ≥2 alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) increase in conjunction with CTCAE grade ≥2 total bilirubin increase * Inability to resume nintedanib dosing within 14 days after stopping Investigators judged clinically as DLT after dose reduction and severity medically notable (CTCAE, version 3). Sponsor with safety review committee was allowed to confirm the adequacy of this judgment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Docetaxel | just before administration of docetaxel administration -0:05 hours (h), at the end of infusion (1:00), and at timepoints after the first dose of docetaxel 1:30 h, 2, 3, 4, 7, 23:55, 47:55 h in cycle 1 and 2 (if administered) | This outcome measure presents the Cmax of docetaxel in plasma in cycles 1 and 2. |
| Area Under the Concentration-time Curve of Nintedanib Over the Time Interval From 0 to Time of the Last Quantifiable Concentration (AUC0-tz) | At 23:55 hours (h) after the first dose of docetaxel (which is 5 minutes prior to first dose of nintedanib) and at 25, 26, 27, 28, 30, 31, 34 and 47:55 after first drug administration of docetaxel in cycle 1. | This outcome measure presents the area under the concentration-time curve of nintedanib over the time interval from 0 to time of the last quantifiable concentration in plasma (AUC0-tz) in cycle 1. |
| Maximum Measured Concentration (Cmax) of Nintedanib | At 23:55 hours (h) after the first dose of docetaxel (which is 5 minutes prior to first dose of nintedanib) and at 25, 26, 27, 28, 30, 31, 34 and 47:55 h after first drug administration of docetaxel in cycle 1. | This outcome measure presents the maximum measured concentration (Cmax) of nintedanib in plasma in cycle 1. |
| Area Under the Concentration-time Curve of Nintedanib Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) | at 23:55 hours (h) after the first dose of docetaxel (which is 5 minutes prior to first dose of nintedanib) and at 25, 26, 27, 28, 30, 31, 34 and 47:55 h after first drug administration of docetaxel in cycle 1. | This outcome measure presents the Area under the concentration-time curve of nintedanib over the time interval from 0 extrapolated to infinity in plasma (AUC0-infinity) in cycle 1. |
| AUC0-infinity of Docetaxel | just before administration of docetaxel administration -0:05 hours (h), at the end of infusion (1:00), and at timepoints after the first dose of docetaxel 1:30 h, 2, 3, 4, 7, 23:55, 47:55 h in cycle 1 and 2 (if administered) | This outcome measure presents the AUC0-infinity of docetaxel in plasma in cycles 1 and 2. |
| AUC0-tz of Docetaxel | just before administration of docetaxel administration -0:05 hours (h), at the end of infusion (1:00), and at timepoints after the first dose of docetaxel 1:30 h, 2, 3, 4, 7, 23:55, 47:55 h in cycle 1 and 2 (if administered) | This outcome measure presents AUC0-tz of docetaxel in plasma in cycles 1 and 2. |
Countries
Japan
Participant flow
Recruitment details
This is a single arm study but it was allowed to discontinue the docetaxel treatment and continue the nintedanib treatment.
Pre-assignment details
All patients were screened for eligibility to participate in the trial. Patients attended specialist sites which would then ensure that they (the patient) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomised to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib Plus Docetaxel The patient received 200 mg of nintedanib b.i.d. (orally) and once every 21 days 75 mg/m² of docetaxel was administered intravenous. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Disposition for Docetaxel | other adverse event | 0 | 4 |
| Disposition for Docetaxel | Progressive disease | 0 | 6 |
| Disposition for Nintedanib | Progressive disease | 10 | 0 |
Baseline characteristics
| Characteristic | Nintedanib Plus Docetaxel |
|---|---|
| Age, Continuous | 67.30 Years STANDARD_DEVIATION 6.98 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 10 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 | 0 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 6 / 10 |
Outcome results
Primary
Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1
DLT was defined as any of the following study drug related adverse events (AEs): * Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 non-haematological toxicity except transient electrolyte abnormality and isolated increase of gamma-glutamyltransferase (GGT); gastrointestinal toxicity, despite adequate supportive care * CTCAE grade 4 haematological toxicity; Neutrophil count decreased or white blood cell count (not associated with fever) for \>7 days despite adequate supportive treatment * CTCAE grade 4 febrile neutropenia with fever ≥38.5 degrees * CTCAE grade ≥2 alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) increase in conjunction with CTCAE grade ≥2 total bilirubin increase * Inability to resume nintedanib dosing within 14 days after stopping Investigators judged clinically as DLT after dose reduction and severity medically notable (CTCAE, version 3). Sponsor with safety review committee was allowed to confirm the adequacy of this judgment.
Time frame: Cycle 1, from first administration of study medication up to 21 days thereafter.
Population: Treated set 2 included all patients who were dispensed study medication and were documented to have taken at least one dose of study treatment, except replaced patients according to the trial clinical protocol.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - AST increased - grades 3/4/5 | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Total with DLTs - all grades | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Total with DLTs - grade 1/2 | 0 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Total with DLTs - grade 3/4/5 | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Hepatobiliary disorders (hep. dis.) - all grades | 1 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Hep. dis. - grade 1/2 | 1 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Hep. dis. - grade 3/4/5 | 0 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Hep. dis. - hyperbilirubinaemia - all grades | 1 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Hep. dis. - hyperbilirubinaemia - grade 1/2 | 1 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Hep. dis. - hyperbilirubinaemia - grades 3/4/5 | 0 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Investigations (inv.) - all grades | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - grade 1/2 | 0 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - grade 3/4/5 | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - ALT increased - all grades | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - ALT increased - grades 1/2 | 0 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - ALT increased - grades 3/4/5 | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - AST increased - all grades | 2 Participants |
| Nintedanib Plus Docetaxel | Number of Patients Experiencing Dose Limiting Toxicity (DLT) in Cycle 1 | Inv. - AST increased - grades 1/2 | 0 Participants |
Secondary
Area Under the Concentration-time Curve of Nintedanib Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity)
This outcome measure presents the Area under the concentration-time curve of nintedanib over the time interval from 0 extrapolated to infinity in plasma (AUC0-infinity) in cycle 1.
Time frame: at 23:55 hours (h) after the first dose of docetaxel (which is 5 minutes prior to first dose of nintedanib) and at 25, 26, 27, 28, 30, 31, 34 and 47:55 h after first drug administration of docetaxel in cycle 1.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Area Under the Concentration-time Curve of Nintedanib Over the Time Interval From 0 Extrapolated to Infinity (AUC0-infinity) | 381 ng*h/mL | Geometric Coefficient of Variation 62.7 |
Secondary
Area Under the Concentration-time Curve of Nintedanib Over the Time Interval From 0 to Time of the Last Quantifiable Concentration (AUC0-tz)
This outcome measure presents the area under the concentration-time curve of nintedanib over the time interval from 0 to time of the last quantifiable concentration in plasma (AUC0-tz) in cycle 1.
Time frame: At 23:55 hours (h) after the first dose of docetaxel (which is 5 minutes prior to first dose of nintedanib) and at 25, 26, 27, 28, 30, 31, 34 and 47:55 after first drug administration of docetaxel in cycle 1.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Area Under the Concentration-time Curve of Nintedanib Over the Time Interval From 0 to Time of the Last Quantifiable Concentration (AUC0-tz) | 342 ng*h/mL | Geometric Coefficient of Variation 59.8 |
Secondary
AUC0-infinity of Docetaxel
This outcome measure presents the AUC0-infinity of docetaxel in plasma in cycles 1 and 2.
Time frame: just before administration of docetaxel administration -0:05 hours (h), at the end of infusion (1:00), and at timepoints after the first dose of docetaxel 1:30 h, 2, 3, 4, 7, 23:55, 47:55 h in cycle 1 and 2 (if administered)
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib Plus Docetaxel | AUC0-infinity of Docetaxel | Cycle 1 | 3320 ng*h/mL | Geometric Coefficient of Variation 26.2 |
| Nintedanib Plus Docetaxel | AUC0-infinity of Docetaxel | Cycle 2 | 3590 ng*h/mL | Geometric Coefficient of Variation 26.6 |
Secondary
AUC0-tz of Docetaxel
This outcome measure presents AUC0-tz of docetaxel in plasma in cycles 1 and 2.
Time frame: just before administration of docetaxel administration -0:05 hours (h), at the end of infusion (1:00), and at timepoints after the first dose of docetaxel 1:30 h, 2, 3, 4, 7, 23:55, 47:55 h in cycle 1 and 2 (if administered)
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib Plus Docetaxel | AUC0-tz of Docetaxel | Cycle 1 | 3080 ng*h/mL | Geometric Coefficient of Variation 27.4 |
| Nintedanib Plus Docetaxel | AUC0-tz of Docetaxel | Cycle 2 | 3320 ng*h/mL | Geometric Coefficient of Variation 29.8 |
Secondary
Cmax of Docetaxel
This outcome measure presents the Cmax of docetaxel in plasma in cycles 1 and 2.
Time frame: just before administration of docetaxel administration -0:05 hours (h), at the end of infusion (1:00), and at timepoints after the first dose of docetaxel 1:30 h, 2, 3, 4, 7, 23:55, 47:55 h in cycle 1 and 2 (if administered)
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Nintedanib Plus Docetaxel | Cmax of Docetaxel | Cycle 1 | 2710 nanogram (ng)/ millilitre (mL) | Geometric Coefficient of Variation 37.6 |
| Nintedanib Plus Docetaxel | Cmax of Docetaxel | Cycle 2 | 2680 nanogram (ng)/ millilitre (mL) | Geometric Coefficient of Variation 49.6 |
Secondary
Maximum Measured Concentration (Cmax) of Nintedanib
This outcome measure presents the maximum measured concentration (Cmax) of nintedanib in plasma in cycle 1.
Time frame: At 23:55 hours (h) after the first dose of docetaxel (which is 5 minutes prior to first dose of nintedanib) and at 25, 26, 27, 28, 30, 31, 34 and 47:55 h after first drug administration of docetaxel in cycle 1.
Population: Pharmacokinetic set (PKS) included all patients in treated set who had at least one valid drug plasma concentration available. This patient set was used for the analysis of pharmacokinetics.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib Plus Docetaxel | Maximum Measured Concentration (Cmax) of Nintedanib | 65.1 nanogram (ng)/ millilitre (mL) | Geometric Coefficient of Variation 86.6 |